autopsy & case reports

Electronic Journal of the Hospital Universitário – Universidade de São Paulo, São Paulo/SP – Brazil

President of the University of São Paulo

Professor Marco Antonio Zago

Superintendent of the University Hospital

Professor Waldir Antônio Jorge

Editorial committee

Editor in chief

Professor Maria Claudia Nogueira Zerbini

Scientific Editors

Dr. Aloisio Felipe-Silva

Dr. Amaro Nunes Duarte-Neto

Dr. Fernando Peixoto Ferraz de Campos

Publishing House

Sponsors

Hospital Universitário – Universidade de São Paulo

Research Center of the Hospital Universitário

Programa de apoio à publicações científicas periódicas da USP

Indexing

Portal de Revistas da USP

PKP

IBICT

Latindex

Diadorin

Sumarios.org

Directory of Open Access Journals DOAJ

ISSN 2236-1960

March 2015, volume 5 number 1

Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2014. This is an Open Access article distributed of terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided article is properly cited.

a Department of Immunology, Institute of Biomedical Sciences; Discipline of Molecular Medicine, Department of Internal Medicine, Universidade de São Paulo, São Paulo/SP, Brazil.

Hemophagocytic lymphohistiocytosis: a rare diagnosis, an even rarer opportunity to appraise our understanding of the immune system

José Alexandre Marzagão Barbutoa

Barbuto JAM. Hemophagocytic lymphohistiocytosis: a rare diagnosis, an even rarer opportunity to appraise our understanding of the immune system. Autopsy Case Rep [Editorial]. 2015; 5(1):1-5. http://dx.doi.org/10.4322/acr.2014.042

The syndrome identified as hemophagocytic lymphohistiocytosis (HLH) poses a rather difficult challenge to the physician. HLH was initially described as a familial disorder,1 which was later associated with various genetic defects that affect the cytotoxic machinery of CD8+ T and NK cells,2 but it also occurs sporadically, usually prompted by infections, rheumatic disorders, or neoplasia.3 Although its diagnostic criteria are established, its clinical presentation overlaps with many different conditions, requiring an enhanced awareness of the attending physician in order to reach the diagnosis and to initiate treatment early enough.4

While the diagnostic criteria include either the presence of a known genetic disorder or five of a list of eight signs and symptoms,3 regardless of its presentation, the predominant pathophysiological feature of HLH is an overactive immune system. This can be inferred by the name-giving feature of the syndrome: hemophagocytosis, reflecting a hyperactive mononuclear phagocytic system, as a result of what can be classifi ed as a cytokine storm.5 Thus, one could be satisfi ed by a general view that this syndrome is another one of those where the immune system becomes rogue and turns against the body. Nonetheless, it is worth looking deeper into the known HLH immunopathological features and checking the

believed pathway of its development against our models and assumptions about the physiology of the immune system.

In a sense, all data seem to point to an immune dysfunction that fi ts perfectly with what one expects. The genetic disorders associated with the familial forms of HLH are those that affect the cytotoxic machinery of NK and T lymphocytes, compromising the cytotoxic granule contents themselves or the molecules involved in granule exocytosis, so that in any case, the cytotoxic function of these cells is faulty. Furthermore, even in sporadic cases, the frequent precipitation of this syndrome by viral infections or its association with NK and T-cell lymphomas indicates that there, too, defective cell cytotoxicity may be the culprit.

Actually, after the role of perforin defi ciency was described in familial cases of HLH,6 an experimental model that reproduces the human syndrome was developed.7 Perforin-defi cient mice, when challenged with the lymphocytic choriomeningitis virus (LCMV), develop a progressive disease that leads rapidly to death if not treated. The mice present a disease that includes the major clinical, laboratory, histopathological, and immune features of the human HLH.7 Adding to the resemblance between the human disease, both in its familial and sporadic forms, and the

Editorial

Autopsy and Case Reports 2015; 5(1):1-5


2

experimental mouse disease, is the fact that both are viral infection-triggered and rapidly progressive. From these data, an initial hypothesis about the pathophysiology of HLH is that it is a disease caused by an uncontrolled viral infection, which, maintaining a chronic stimulation of the immune system, would precipitate its derailing and, hence, the disease. This view is further supported by the observation that, in another model, mice lacking the orthologue gene of the human Munc13-4 (a gene involved in the cytotoxic granule exocytosis in NK and CD8+ cytotoxic T cells) develop a very similar disease, when infected by LCMV.8 In humans, it is relevant to note that the Epstein–Barr virus (EBV) infection is frequently the trigger of HLH, both in familial and sporadic cases9 and, likewise, is a disease where cytotoxic CD8+ T cells have a defi nite role (already noticeable by their identifi cation in blood smears as the characteristic “atypical lymphocytes”). So, experimental models data confi rm that what could be inferred from clinical observation: defective cell cytotoxicity indeed plays a very signifi cant role in HLH.

However, a simple explanation—lack of or defective cell cytotoxicity, allowing an unchecked viral expansion—does not explain all observations. It is true that in the perforin-deficiency model, an LCMV infection triggers the HLH-like syndrome and is associated with a very high viral load. However, this insuffi cient clearance of viruses is not enough to cause the disease. First, in the Munc13-4 orthologue gene defi ciency, although the animals have poor cell cytotoxicity and are especially susceptible to the murine cytomegalovirus infection (MCMV), this latter disease does not trigger the HLH-like disease; only the LCMV infection does.8 Second, in the perforin defi cient mice, treating the mice with antibodies against CD8, and thus causing the complete depletion of CD8+ T cells, protects the animals from the HLH-like syndrome,7 but not from a very high viremia. Indeed, when the kinetics of the disease in these mice was investigated, it became clear that it was not the viral load that prompted the immunological imbalance, but rather the excessive activation of the system.10

Moreover, pointing to a possible explanation for the phenomenon, in the same perforin-defi cient animal model, the use of blocking antibodies against IFN-gamma also protects the animals from the HLH-like disease.7 Thus, the initial hypothesis should be modified: defective CD8+ T cells unable to

perform their cytotoxic function effectively, allow the virus to overstimulate CD8+ T cells, which display a deregulated interferon-gamma secretion, thus driving the disease. This modifi ed pathophysiological view is further supported by data showing that, in mice, the continuous injection of IFN-gamma through an osmotic pump is enough to cause acute cytopenias and hemophagocytosis,11 two distinctive features of HLH. In addition, both LCMV in mice and EBV in humans are infections that cause a vigorous IFN-gamma response, while MCMV infection induces hyporesponsiveness to IFN-gamma in macrophages,12 providing a possible explanation for the “virus-specifi city” triggering of HLH-like disease in immunodefi cient mice.8

Complementing the hypothesis, data from the perforin-defi cient animal model show that, in these mice, the absence of the adaptor molecule, MyD88, protects the animals from the HLH-like disease.13 The MyD88 molecule is central to the transduction of signals from most of the Toll-like receptors and from the IL-1 receptor;14 thus, it is clearly involved in the infl ammatory process and, more signifi cantly, in the detection of homeostatic disequilibria within tissues. However, it is noteworthy that here the role of this molecule does not seem to be in the initial detection of the disequilibrium, but rather, in the response to an already established immune response; that is, the secretion of IFN-gamma by CD8+ T cells.

With these experimental observations, it is possible to elaborate a more detailed pathophysiological view of the HLH. This disease would be the consequence of an immune dysfunction, where the immune system, confronted by certain IFN-gamma-inducing challenges, fails to control its secretion due to a defective machinery of cytotoxic cells, namely NK and CD8+ T cells. The excessive IFN-gamma secretion, through a MyD88-dependent pathway, would cause macrophages to go rogue and further disrupt an already shaken physiologic balance in the host, prompting the HLH.

However well this proposed model explains the experimental data, one has to ask, does it fi t the actual human disease? Initially, at the origin of the model, there is a good correlation between the genetic defects of mice and those found in patients with familial HLH. Furthermore, the explanations for the triggering of the disease in mice and humans coincide. But, when the model gets down to identifying the specifi c cytokine

Autopsy and Case Reports 2015; 5(1): 1-5

Barbuto JAM

3

responsible for the generation of the disease, the model starts to fail: in humans, an elevated serum IFN-gamma, although sometimes found, is not typical of HLH.15 Furthermore, in a study where the peripheral blood cells’ gene expression profile from healthy controls and from familial HLH patients was studied, IFN-gamma and IFN-gamma-regulated genes did not show up as differentially expressed.16 One could still argue that cytokine profi les, whether they are established by cytokine serum levels, by intracellular staining, or by gene expression profi les of circulating cells, are still quite distant from the in vivo reality; therefore, one could suggest that the deregulated levels of IFN-gamma, although they do not show up in the studies performed in humans, might still exist within the microenvironment where the disease is initiated.

Then again, one would be missing a real opportunity: to check and even challenge our understanding of the immune system. The immune system is very complex; it was selected to deal specifi cally with molecularly unknown challenges—the antigens—and it performs its function with exceptional effi cacy. Our knowledge of the circuits that control this system is growing rapidly and is becoming so detailed that the whole picture starts to escape from many. In this context, the complexity of the circuits and their interaction requires the construction of (animal) models, where genes can be manipulated at will and hypotheses can be tested with precision. However, diving too quickly into the models may obscure the initial reason for their construction—the understanding of the immune system and how it interacts internally and with its many challenges in nature—and, for the physician, it may also unravel strategies to interfere when the immune system fails and disease ensues due to that failure. Then, reminding us that models are models and diseases are diseases, a syndrome like HLH is invaluable—as are autopsies and case reports—for in these instances, models are often insuffi cient and our relative ignorance shows up, driving us to challenge the models and deepen our understanding.

Specifi cally here, it is not the relative role of one or other cytokine that should cause the impact, but rather the role we ascribe to CD8+ T cells. These cells are identifi ed as antigen-specifi c, HLA-restricted, cytotoxic cells that perform an essential role in viral infections and in tumor immunity. Evidence from

this function comes from both in vitro observation that these cells are, indeed, able to kill specific targets—and this was central to unravel the role of the major histocompatibility antigens in restricting T-cell recognition of antigens,17 but also from animal models, where their absence allows the uncontrolled progression of viral infections, as happens in the perforin-defi cient mouse, which was discussed before.

However, the role of T-cell cytotoxicity in the control of virus infections in humans is not so clear-cut. Since children with immunodeficiencies characterized by the absence of CD8+ T cells are not more susceptible to viral infections than healthy children,18 one must accept that either cytotoxicity in humans is irrelevant against viruses, or that it is not the CD8+ T cell but other cytotoxic cell that performs this function in these immunodefi cient children. Actually, cell cytotoxicity is not an exclusive characteristic of CD8+ T cells—other cells can do it—but CD8+ T cells have the ability to specifi cally recognize antigens in the context of class I HLA molecules, therefore on the surface of any nucleated cell, and this seems to be unique to these cells. This feature leaves CD8+ T cells equipped to recognize and respond to the presence of a virus or of mutated proteins in “any” cell in the body—a function that would be required, in fact, in cells involved in the control of virus infections and cancer. The relevance of this function could be further stressed by the observation that many viruses hinder the expression of HLA molecules by the infected cells, clearly suggesting the role of these molecules in their control.19-21 But if cell cytotoxicity is not the pathway through which CD8+ T cells perform their function once they recognize their targets, what would it be? And the answer seems to be in their cytokine secretion. In animal models of cancer,22 viral infections,23 and human diseases,24,25 cytokine secretion by these cells appears to be the decisive, if not the main, effective factor. Thus, after challenging the model of HLH, where IFN-gamma secretion by CD8+ T cells would be the triggering factor, we are back to this hypothesis. Definitely, IFN-gamma (or cytokines) secretion is characteristic of CD8+ T cells and, if exaggerated, could prompt the derailing of the immune system.

But the question remains: how would a cytotoxic defect prompt a deregulated cytokine secretion? We have seen that the viral load, per se, a simple and direct possibility, does not solve this issue; hence, the



4

answer must be elsewhere. This brings to light another possible role of CD8+ T cells: immunoregulation. In the 1970s and early 1980s, T cells were classifi ed as either helper T cells or suppressor/cytotoxic T cells. The latter population included cells clearly cytotoxic—those that are identifi ed today as CD8+ T cells—and others that were indistinguishable from the cytotoxic cells by the surface markers then available, but whose function seemed to be the specific suppression of immune responses. This putative T-cell population did not resist deeper investigations, and later on, many immune regulatory circuits were described, including the “opposing” T helper subsets and the regulatory T cells, which could explain much of the earlier observations of specifi c immunosupression. Nevertheless, a “revival” of the regulatory role for the “cytotoxic” T cells seems to offer a solution in the case of HLH.

Thus, the pathophysiology of HLH could be described as an initial challenge to the immune system that drives the activation of CD8+ T cells. Due to a genetic defect (in the familial cases), or to local and/or transient conditions (in sporadic cases), these cells fail to perform an essential (and relatively ignored) role: the control of their own activation. With uncontrolled stimulation, CD8+ T cells cause other cells down the pathway of the immune response, like macrophages, to become further active, to secrete other cytokines, and, thus, trigger the disease. Therefore, in the end, it could seem that the pathophysiology of HLH is solved. Yet, this is not true. It could be enough to remember that it remains to be determined how the cytotoxic machinery of cytotoxic T cells affects immune activation and if it does truly occur in patients with HLH. But the uncertainties go further. The main characteristics of HLH are in the name of the syndrome itself: hemophagocytosis, lymphocytosis, and histiocytosis of tissues. Though a possible explanation for hemophagocytosis can be found on the action of cytokines (IFN-gamma in the model), the tissue infi ltration by immune cells is not clearly explained. What drives their movement towards tissues? What keeps them active therein? And if we keep looking at case reports and autopsies of patients that presented HLH, new questions and new challenges will appear—and, hopefully, will drive our investigations towards a more comprehensive view of its pathophysiology and a more effective way to diagnose and treat it.

REFERENCES

1. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27(136):519-25. http://dx.doi.org/10.1136/adc.27.136.519. PMid:13008468

2. Sieni E, Cetica V, Hackmann Y, et al. Familial hemophagocytic lymphohistiocytosis: when rare diseases shed light on immune system functioning. Front Immunol. 2014;5:167. http://dx.doi.org/10.3389/fimmu.2014.00167. PMid:24795715

3. Usmani GN, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol. 2013;161(5):609-22. http://dx.doi.org/10.1111/bjh.12293. PMid:23577835

4. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-52. http://dx.doi.org/10.1182/blood-2011-03-278127. PMid:21828139

5. Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin North Am. 2012;59(2):329-44. http://dx.doi.org/10.1016/j.pcl.2012.03.002. PMid:22560573

6. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957-9. http://dx.doi.org/10.1126/science.286.5446.1957. PMid:10583959

7. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104(3):735-43. http://dx.doi.org/10.1182/blood-2003-10-3413. PMid:15069016

8. Crozat K, Hoebe K, Ugolini S, et al. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J Exp Med. 2007;204(4):853-63. http: / /dx.doi .org/10.1084/ jem.20062447. PMid:17420270

9. Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12(2):435-44. http://dx.doi.org/10.1016/S0889-8588(05)70521-9. PMid:9561911

10. Lykens JE, Terrell CE, Zoller EE, Risma K, Jordan MB. Perforin is a critical physiologic regulator of T-cell activation. Blood. 2011;118(3):618-26. http://dx.doi.org/10.1182/blood-2010-12-324533. PMid:21606480

11. Zoller EE, Lykens JE, Terrell CE, et al. Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med. 2011;208(6):1203-14. http://dx.doi.org/10.1084/jem.20102538. PMid:21624938


Barbuto JAM

5

12. Heise MT, Connick M, Virgin HW 4th. Murine cytomegalovirus inhibits interferon gamma-induced antigen presentation to CD4 T cells by macrophages via regulation of expression of major histocompatibility complex class I I-associated genes. J Exp Med. 1998;187(7):1037-46. http://dx.doi.org/10.1084/jem.187.7.1037. PMid:9529320

13. Krebs P, Crozat K, Popkin D, Oldstone MB, Beutler B. Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. Blood. 2011;117(24):6582-8. http://dx.doi.org/10.1182/blood-2011-01-329607. PMid:21551232

14. Deguine J, Barton GM. MyD88: a central player in innate immune signaling. F1000Prime Rep. 2014;6:97. http://dx.doi.org/10.12703/P6-97. PMid:25580251

15. Henter JI, Horne A, Aricó M, et al. HLH-2004: D iagnos t i c and the rapeut i c gu ide l i ne s fo r hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31. http://dx.doi.org/10.1002/pbc.21039. PMid:16937360

16. Sumegi J, Barnes MG, Nestheide SV, et al. Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis. Blood. 2011;117(15):e151-60. http://dx.doi.org/10.1182/blood-2010-08-300046. PMid:21325597

17. Zinkernagel RM, Doherty PC. The discovery of MHC restriction. Immunol Today. 1997;18(1):14-7. http://dx.doi.org/10.1016/S0167-5699(97)80008-4. PMid:9018968

18. Carneiro-Sampaio M, Coutinho A. Immunity to microbes: lessons from primary immunodeficiencies. Infect Immun. 2007;75(4):1545-55. http://dx.doi.org/10.1128/IAI.00787-06. PMid:17283094

19. Mirandola P, Sponzilli I, Solenghi E, et al. Down-regulation of human leukocyte antigen class I and II and beta 2-microglobulin expression in human herpesvirus-7-infected cells. J Infect Dis. 2006;193(7):917-26. http://dx.doi.org/10.1086/500561. PMid:16518752

20. Lin A, Xu H, Yan W. Modulation of HLA expression in human cytomegalovirus immune evasion. Cell Mol Immunol. 2007;4(2):91-8. PMid:17484802.

21. van Esch EM, Tummers B, Baartmans V, et al. Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV-induced usual vulvar intraepithelial neoplasia and implications for immunotherapy. Int J Cancer. 2014;135(4):830-42. http://dx.doi.org/10.1002/ijc.28713. PMid:24415578

22. Barth RJ Jr, Mulé JJ, Spiess PJ, Rosenberg SA. Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes. J Exp Med. 1991;173(3):647-58. http://dx.doi.org/10.1084/jem.173.3.647. PMid:1900079

23. Goulding J, Abboud G, Tahiliani V, Desai P, Hutchinson TE, Salek-Ardakani S. CD8 T cells use IFN-� to protect against the lethal effects of a respiratory poxvirus infection. J Immunol. 2014;192(11):5415-25. http://dx.doi.org/10.4049/jimmunol.1400256. PMid:24748494

24. Chisari FV. Cytotoxic T cells and viral hepatitis. J Clin Invest. 1997;99(7):1472-7. http://dx.doi.org/10.1172/JCI119308. PMid:9119989

25. Rehermann B. Intrahepatic T cells in hepatitis B: viral control versus liver cell injury. J Exp Med. 2000;191(8):1263-8. PMid:10770794.

CorrespondenceEdifício Biomédicas IV – Departamento de ImunologiaAv. Professor Lineu Prestes, 1730 – Cidade Universitária – São Paulo/SP – BrazilCEP: 05508-000Phone: +55 (11) 3091-7375E-mail: [email protected]


a Department of Pathology and Laboratory Medicine - David Geffen School of Medicine - University of California, Los Angeles/CA - USA.b Department of Pathology and Laboratory Medicine - Weill Cornell Medical College, New York/NY - USA. c Internal Medicine Division - Hospital Universitário - University of São Paulo, São Paulo/SP - Brazil.

Hereditary hemochromatosis

Stephen A. Gellera,b, Fernando P. F. de Camposc

Geller SA, Campos FPF. Hereditary hemochromatosis. Autopsy Case Rep [Internet]. 2015; 5(1):7-10. http://dx.doi.org/10.4322/acr.2014.043

Hereditary hemochromatosis (HH) is the most commonly identified autosomal recessive genetic disorder in the white population, characterized by increased intestinal iron absorption and secondary abnormal accumulation in parenchymal organs, not infrequently accompanied by functional impairment.1 This entity is associated with mutations of the HFE gene (located on the short arm of chromosome 6 at location 6p22.2; closely linked to the HLA-A3 locus), which encodes the HFE protein, a membrane protein thought to regulate iron absorption by affecting the interaction between transferrin receptor and transferrin. One of

these mutations results in a substitution of tyrosine for cysteine at the amino acid 282 position (C282Y).2,3 Subsequently two additional mutations have been noted, aspartate for histidine (H63D), and cysteine for serine (S65C), however the most common form of HFE-related HH is associated with the C282Y homozygous mutation.4 The presence of this mutation varies between 69% to 100% in series from USA, France, Italy, Australia, Germany.5-9 Other HFE defects in addition to homozygosity for C282Y, are found: homozygosity for the H63D mutation, heterozygosity for the C282Y or H63D mutation, or compound

Image in focus Imagem em foco

Dr. Stephen A Geller personal archive



8

heterozygosity.10 Less commonly, the hemojuvelin, hepcidin, ferroportin, or ceruloplasmin encoding genes may also be associated with HH.

There is a substantial controversy on the likelihood of homozygous patients for C282Y developing clinically apparent diseased. In a USA screening study involving 41,000 adults , 152 individuals were positive for C282Y homozygosity, but only one fi t the criteria for the diagnosis of HH (penetrance < 1%).11 In contrast, the Australian series of 31,192 subjects of northern European ancestry found 203 C282Y homozygous. These individuals were followed for 12 years, with 28% of men and 1,2% or women presenting with clinical HH.12

Once thought to be a rare disease, HH was initially considered when the patient presented an unusual manifestation such as “bronze diabetes”. Indeed the first case description by Armand Trousseau, in 1865, was of a diabetic patient with hepatic cirrhosis and bronzed skin. The name hemochromatosis was applied in subsequent 1890 report by Daniel von Recklinghausen. Recklinghausen suggested the association between tissue iron storage and the resultant condition. The image above shows well the brown discoloration of the liver and also the pancreas, the body of which is almost mahogany. The inherited nature of the disease was first explained by J.H. Sheldon in his textbook Haemochromatosis. He also suggested an abnormality of iron metabolism as the basis for the disease.

With genetic studies, families have been accurately studied showing that transferrin saturation values greater than 60% in men and greater than 50% in women (in the absence of hepatopathy of any etiology) indicates the presence of abnormality in iron metabolism with 95% accuracy. In the USA and Europe the frequency of HFE mutations among Caucasian is 10% for heterozygous and 5 per 1000 (0.5%) for homozygous.13

Body iron stores inversely correlate with the normal intestinal absorption of heme and non-heme iron. In HH this regulation is lost and iron overload ensues since there is no mechanism for excess excretion. Clinical symptoms appear when greater than 20g of iron is accumulated in the body, typically occurring after the age of 40 in men and, when menstruation occurs, 50 in women. Differing from acquired (secondary)

hemosiderosis, HH iron is initially stored in parenchymal cells and later in the reticuloendothelial system cells.

The clinical picture refl ects the involvement of liver, skin, pancreas, joints, and heart, with impotence in males.14 Liver function abnormalities, weakness and fatigue, and skin hyperpigmentation were present in more than 70% of cases in the series by Niederau et al14.

Liver involvement manifests as hepatomegaly, increasing fi brosis and eventual cirrhosis, potentially reversible in early stages. Although infection with hepatitis-C virus may potentiate fi brosis, the major risk co-factor for the development of liver disease is excess alcohol intake. The deposition of iron alone in hepatocytes is not infl ammatory and hepatic fi brosis may ensue with low or normal serum aminotransferase determinations.15,16 However in almost 50% of patients with HH, another cause of liver disease is present that is more likely responsible for hepatic liver enzyme elevations. Hepatocellular carcinoma is the most serious complication of the hepatic iron overload. The magnitude of the risk varies between 20- to 200-fold.17,18

Pancreatic deposition of iron occurs in beta cells and diabetes is clinically demonstrable in 50% of symptomatic patients. Although insulin and C-peptide secretion are reduced, the alpha cell function remains intact, and glucagon values are similar to those in type-1 diabetes.19

HH can lead to dilated cardiomyopathy, heart failure and conduction disturbances, such as sick sinus syndrome.20,21

Arthritis associated with HH clinically resembles rheumatoid arthritis with predominant involvement of metacarpophalangeal joints. The iron deposition within the joints triggers an infl ammatory process that is often complicated by calcium pyrophosphate deposition (“pseudogout”) and subsequent chondrocalcinosis and chronic arthropathy.22-24

Secondary hypogonadism, responsible for impotence and decreased libido in men, is the result of iron deposition in the anterior pituitary, which results in low levels of trophic hormones (e.g., follicle stimulating hormone) and therefore testosterone. Amenorrhea rarely occurs in women and is much less common than hypogonadism in men.25,26

The d iagnos t i c workup o f HH inc ludes determination of iron overload (increased body


Geller SA, Campos FPF

9

iron burden), family history of this disorder and genetic studies. In addition to serum iron assay, liver biopsy and magnetic resonance imaging studies are usually employed. However liver biopsy is often not performed for patients with HH when the diagnosis is clearly established based upon genetic testing, including findings of C282Y/C282Y, heterozygous C282Y, and C282Y/H63D genotypes. The findings of H63D homozygosity or heterozygosity is of uncertain signifi cance since most will not present iron overload.27,28

Keywords: hemochromatosis, Iron Overload, Liver Diseases, Pancreatic Disease.

REFERENCES

1. Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol. 2002;64(1):663-80. http://dx.doi.org/10.1146/annurev.physiol.64.081501.155838. PMid:11826284

2. NCBI. Entrez Gene. HFE hemochromatosis. Available from: http://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3077

3. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399-408. http://dx.doi.org/10.1038/ng0896-399. PMid:8696333

4. European Association for the Study of the Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3-22. http://dx.doi.org/10.1016/j.jhep.2010.03.001. PMid:20471131

5. Jouanol le AM, Gandon G, Jézéquel P, et a l . Haemochromatos i s and HLA-H. Nat Genet . 1996;14(3):251-2. http://dx.doi.org/10.1038/ng1196-251. PMid:8896550

6. Jazwinska EC, Cullen LM, Busfield F, et al. Haemochromatosis and HLA-H. Nat Genet. 1996;14(3):249-51. http://dx.doi.org/10.1038/ng1196-249. PMid:8896549

7. Beutler E, Gelbart T, West C, et al. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis. 1996;22(2):187-94. http://dx.doi.org/10.1006/bcmd.1996.0027. PMid:8931958

8. Carella M, D’Ambrosio L, Totaro A, et al. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet. 1997;60(4):828-32. PMid:9106528.

9. Nielsen P, Carpinteiro S, Fischer R, Cabeda JM, Porto G, Gabbe EE. Prevalence of the C282Y and H63D mutations in the HFE gene in patients with hereditary haemochromatosis and in control subjects from Northern Germany. Br J Haematol. 1998;103(3):842-5.

http://dx.doi.org/10.1046/j.1365-2141.1998.01037.x. PMid:9858243

10. Sham RL, Raubertas RF, Braggins C, Cappuccio J, Gallagher M, Phatak PD. Asymptomatic hemochromatosis subjects: genotypic and phenotypic profiles. Blood. 2000;96(12):3707-11. PMid:11090050.

11. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G—> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002;359(9302):211-8. http://dx.doi.org/10.1016/S0140-6736(02)07447-0. PMid:11812557

12. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358(3):221-30. http://dx.doi.org/10.1056/NEJMoa073286. PMid:18199861

13. Edwards CQ, Kushner JP. Screening for hemochromatosis. N Engl J Med. 1993;328(22):1616-20. http://dx.doi.org/10.1056/NEJM199306033282208. PMid:8110209

14. Niederau C, Strohmeyer G, Stremmel W. Epidemiology, clinical spectrum and prognosis of hemochromatosis. Adv Exp Med Biol. 1994;356:293-302. http://dx.doi.org/10.1007/978-1-4615-2554-7_31. PMid:7887234

15. Adams PC, Barton JC. A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation. J Hepatol. 2011;55(2):453-8. http://dx.doi.org/10.1016/j.jhep.2011.02.010. PMid:21354228

16. Adams PC, Speechley M, Barton JC, McLaren CE, McLaren GD, Eckfeldt JH. Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the hemochromatosis and iron overload screening study. Hepatology. 2012;55(6):1722-6. http://dx.doi.org/10.1002/hep.25538. PMid:22183642

17. Yang Q, McDonnell SM, Khoury MJ, Cono J, Parrish RG. Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of Multiple-Cause Mortality Data. Ann Intern Med. 1998;129(11):946-53. http://dx.doi.org/10.7326/0003-4819-129-11_Part_2-199812011-00005. PMid:9867747

18. Bradbear RA, Bain C, Siskind V, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J Natl Cancer Inst. 1985;75(1):81-4. PMid:2989605.

19. Nelson RL, Baldus WP, Rubenstein AH, Go VL, Service FJ. Pancreatic alpha-cell function in diabetic hemochromatotic subjects. J Clin Endocrinol Metab. 1979;49(3):412-6. http://dx.doi.org/10.1210/jcem-49-3-412. PMid:381322

20. Olson LJ, Edwards WD, McCall JT, Ilstrup DM, Gersh BJ. Cardiac iron deposition in idiopathic hemochromatosis: histologic and analytic assessment of 14 hearts from autopsy. J Am Coll Cardiol. 1987;10(6):1239-43. http://dx.doi.org/10.1016/S0735-1097(87)80124-9. PMid:3680791



10

21. Cabot RC, Scully RE, Mark EJ, et al. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 31-1994. A 25-year-old man with the recent onset of diabetes mellitus and congestive heart failure. N Engl J Med. 1994;331(7):460-6. http://dx.doi.org/10.1056/NEJM199408183310708. PMid:8035843

22. Schumacher HR. Articular cartilage in the degenerative arthropathy of hemochromatosis. Arthritis Rheum. 1982;25(12):1460-8. http://dx.doi.org/10.1002/art.1780251212. PMid:7150378

23. Dymock IW, Hamilton EB, Laws JW, Williams R. Arthropathy of haemochromatosis. Clinical and radiological analysis of 63 patients with iron overload. Ann Rheum Dis. 1970;29(5):469-76. http://dx.doi.org/10.1136/ard.29.5.469. PMid:5476674

24. Hamilton EB, Bomford AB, Laws JW, Williams R. The natural history of arthritis in idiopathic haemochromatosis: progression of the clinical and radiological features over ten years. Q J Med. 1981;50(199):321-9. PMid:7330169.

25. Walton C, Kelly WF, Laing I, Bu’lock DE. Endocrine abnormalities in idiopathic haemochromatosis. Q J Med. 1983;52(205):99-110. PMid:6683854.

26. Kelly TM, Edwards CQ, Meikle AW, Kushner JP. Hypogonadism in hemochromatosis: reversal with iron depletion. Ann Intern Med. 1984;101(5):629-32. http://dx.doi.org/10.7326/0003-4819-101-5-629. PMid:6435491

27. Moirand R, Jouanolle AM, Brissot P, Le Gall JY, David V, Deugnier Y. Phenotypic expression of HFE mutations: a French study of 1110 unrelated iron-overloaded patients and relatives. Gastroenterology. 1999;116(2):372-7. http://dx.doi.org/10.1016/S0016-5085(99)70134-4. PMid:9922318

28. Leão GD, Freire JM, Cunha Fernandes AL, et al. Analysis of HFE genes C282Y, H63D, and S65D in patients with hyperferritinemia from northeastern Brazil. J Clin Lab Anal. 2014;28(3):178-85. http://dx.doi.org/10.1002/jcla.21663. PMid:24395214

CorrespondenceStephen A. GellerDepartment of Pathology and Laboratory MedicineDavid Geffen School of Medicine, UCLALos Angeles/CA - USAE-mail: [email protected]

Fernando P. F. de CamposInternal Medicine DivisionHospital UniversitárioUniversity of São PauloSão Paulo/SP – BrazilE-mail: [email protected]


a Pediatrics Department - Hospital das Clínicas - Universidade de São Paulo, São Paulo/SP - Brazil.b Pediatrics Division - Intensive Care Unit - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil.c Anatomy Pathology Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil.

Hemophagocytic syndrome: a dilemma chasing the intensivists

Adriana Façanha Queiroza, Gabriel Nuncio Benevidesa, Iracema de Cassia Oliveira Ferreira Fernandesb, Patricia de Freitas Goesb, Albert Boussob, Cristiane Rubia Ferreirac

Queiroz AF, Benevides GN, Fernandes ICOF, Goes PF, Bousso A, Ferreira CR. Hemophagocytic syndrome: a dilemma chasing the intensivists. Autopsy Case Rep [Internet]. 2015; 5(1):11-19. http://dx.doi.org/10.4322/acr.2014.044

ABSTRACT

Hemophagocytic lymphohistiocytosis or hemophagocytic syndrome is represented by an uncontrolled infl ammatory response characterized by marked histiocyte activation and a cytokine storm. The entity may present a primary or genetic type, and the secondary type is usually triggered by infectious diseases of any kind, autoimmune disease, or neoplasia. This entity, although well described and with defi nite diagnostic criteria, still remains misdiagnosed because of the overlap presentation with other infl ammatory processes. The authors present the case of a 13-year-old girl who was submitted to an appendicectomy complicated with a pericolic abscess, which required a second operation in order to be drained surgically. During the postoperative period of this second surgical procedure, the patient remained febrile, developing cytopenias, and multiple organ failure. Unfortunately, she died despite the efforts of the intensive care. The autopsy fi ndings were characteristic of hemophagocytic syndrome. The authors report the case to call attention to this diagnosis whenever unexpected outcomes of infections are experienced.

KeywordsHemophagocytic Syndrome; Hemophagocytic Lymphohistiocytosis; Appendicectomy; Autopsy

CASE REPORT

A 13-year-old girl was brought to medical

attention complaining of fever and loss of appetite

for 3 days, soon after she had been discharged after

an appendectomy. On physical examination she

was dehydrated, presenting tachycardia, tachypnea,

and fever (axillary temperature was 38.8 ° C). Blood

pressure was 120/70 mmHg. Cardiac and pulmonary

examination was normal, but the abdomen was

diffusely tender; the rebound test was painful; intestinal

sounds were present and normal. The surgical scar was

hyperemic. The abdominal ultrasound examination

showed a pericolic image consistent with abscess,

which was surgically drained. The abdominal secretion

culture was positive for multisensitive E. coli and group

G, -hemolytic Streptococcus sp. Ceftriaxone and

metronidazole were prescribed.

On the third post-operative day, the patient still

referred abdominal pain, and the fever relapsed.

Antibiotics were changed to vancomycin, ceftazidime

and amikacin, but fever remained intermittently

Article / Autopsy Case Report Artigo / Relato de Caso de Autópsia



12

present. Abdominal computed tomography (CT) ruled out any surgical complication and the patient remained on a broad-spectrum antibiotic regimen, to which fl uconazole was added. On the twelfth post-operative day (from the second surgery) the patient became hypotensive and tachycardic, and her temperature rose to 39.4 °C, reason why she was referred to the ICU. Vasoactive drugs were required for hemodynamic stabilization. The laboratory work-up is shown in Table 1. Blood and urine cultures were negative, and the transthoracic echo Doppler cardiogram was normal. The patient outcome worsened with progressive respiratory failure.

Another abdominal CT was done, which ruled out the presence of abscesses. Serologies are shown in Table 2.

A thorough microbiological examination was repeated. The blood, urine, catheter, and abdominal fl uid cultures were negative. At the twentieth post-operative day, the blood cell count showed thrombocytopenia, hyperbilirubinemia, enlarged prothrombin time, and altered liver enzymes. On the twenty-second post-

operative day, the patient underwent an exploratory

laparotomy in the pursuit of an abscess not evidenced

by CT, which could explain the septic shock. On this

third surgical procedure, loose peritoneal adhesions

were present, but neither purulent secretion, nor

intestinal perforation or bowel necrosis was found.

The patient’s outcome was worse and troublesome

with multiple organ failure, requiring hemodialysis

and frequent blood transfusions. Despite all efforts,

she died on the twenty-fourth post-operative day. An

autopsy was performed.

AUTOPSY FINDINGS

The corpse ectoscopy showed a Bogota bag

closing the peritoneotomy. At the cavity overture,

mild serohemorrhagic effusion was drained and non-

dehiscent surgical sutures were revealed joining the

distal ileum with the ascending colon. Neither signs

of peritonitis nor intra-abdominal purulent collection

were found.

Table 1. Laboratory work-up

Exam Result RV Exam Result RV

Hemoglobin 8.9 12.3–15.3 g/dL ALT 16556 9–36 IU/L

Hematocrit 24.6 36.0–45.0% AST 6126 10–31 IU/L

Leukocytes 7.2 4.4–11.3 × 103/mm3 AP 926 10–100 IU/L

Bands 14 1–5% GT 202 2–30 IU/L

Segmented 64 45–70% TB 7.6 0.3 –1.2 mg/dL

Eosinophil 0 1–4% INR 4.66 1

Basophil 0 0–2.5% Fibrinogen 98 175–400 mg/dL

Lymphocyte 8 18–40% Triglycerides 105 < 150 mg/dL

Monocytes 1 2–9% Ferritin 1287 22–322 ng/mL

Platelets 26.9 150–400 × 103/mm3

ALT = alanine aminotransferase; AP = alkaline phosphatase; AST= aspartate aminotransferase; GT = gamma-glutamyl-transferase; INR = international normalized ratio; RV = reference value; TB = total bilirubin.

Table 2. Serologic investigation

Exam Result Exam Result

Anti-HIV Negative Hepatitis B Anti HBs+/HBsAg−/HBC−

Anti-CMV IgG+/IgM- Anti-HCV Negative

Anti-EBV IgG+/IgM- Rubella IgG+/IgM−

Hepatitis A IgG+/IgM- Aslo < 80 UI/mLCMV = cytomegalovirus; EBV = Epstein-Barr virus; HCV = hepatitis C virus; HIV = human immunodefi ciency virus; IgG = immunoglobulin G; IgM = immunoglobulin M.


Queiroz AF, Benevides GN, Fernandes ICOF, Goes PF, Bousso A, Ferreira CR

13

The liver was enlarged and weighed 1280 g (mean reference value [mRV]: 1275 g); the capsular surface exhibited winy-colored areas. At the cut surface, extensive poorly defi ned yellowish parenchyma areas were evident intermingled with winy-colored areas consistent with infarction. At microscopy, extensive ischemic lobular necrosis was present as well as macro and microvesicular steatosis (Figure 1).

The spleen was enlarged and weighed 271 g (reference value [RV]: 112 g). The cut surface was winy, friable, and consistent with a reactive pattern. At microscopy, the white pulp was depleted and the red pulp was congested, and both were intermingled with ischemic infarction areas. Numerous histiocytes, phagocytizing red blood cells, and lymphocytes were present (Figure 2).

Figure 1. Gross view of the liver cutting surface showing a wide yellowish-brown area of ischemic infarction intermingled by winy-colored areas; B - Photomicrography of the liver showing extensive ischemic infarction of the hepatic lobule, zone 1 macro and microvesicular steatosis and preserved portal triad (HE, 100X).

Figure 2. A - Gross view of the cutting surface of the spleen showing a reactive winy-colored parenchyma intermingled by ill-defi ned brown and friable areas. Photomicrography of the spleen in B - panoramic view showing areas of ischemic infarction and red pulp congestion (HE, 25X); C - white pulp lymphocytic depletion (HE,100X); D - the presence of macrophage phagocyting an erythrocyte and a lymphocyte in the red pulp(arrow) (HE, 1000X).



14

The pancreas weighed 70 g (mRV: 97.5 g), and presented purplish areas at the cut surface, which microscopy disclosed to be consistent with steatonecrosis and ischemic necrosis (Figure 3A and 3B). Both adrenal glands exhibited extensive cortical ischemic necrosis (Figure 3C and 3D).

At the opening of the thoracic cavity, petechiae were evident on both lung surfaces and pericardium. The heart weighed 191 g (mRV: 221 g) and exhibited myocardial hemorrhagic suffusions mainly on the left ventricle (Figure 4). Recent pericardial and myocardial hemorrhage were found at the necropsy.

Figure 3. Photomicrography of the pancreas, in A - presence of ischemic infarcted areas (HE, 100X); in B - steatonecrosis in the pancreatic parenchyma (HE, 100X). Photomicrography of adrenal glands, in C - extensive cortical ischemic infarction (HE, 100X); D - corticomedullary transition showing a cortical coagulative necrosis (HE, 100X).

Figure 4. Gross view of the heart showing petechiae and hemorrhagic suffusions on the pericardial surface in A and in the myocardium and endocardium in B.



15

Both lungs presented increased volume; the cut surface was winy-colored, and the parenchyma was not friable, which was consistent with shock lung. At microscopy, the alveolar spaces were filled by numerous macrophages, fi brin, and red blood cells; no hemophagocytosis was found at this site (Figure 5).

Numerous mediastinal and intra-abdominal lymph nodes were detected showing a sinusal histiocytosis lymphadenitis pattern with associated lymphocytic depletion and histiocytes with erythrocytes phagocytosis (intracytoplasmic erythrocytes). The histiocytes were phenotypically CD68-positive, S100-negative (Figure 6).

The bone marrow showed evident hypercellularity, predominantly represented by the granulocytic series elements associated with the presence of numerous histiocytes with hemophagocytosis (Figure 7).

Hypoxic-ischemic encephalopathy and acute tubular necrosis were evident and were attributed to the long-lasting hemodynamic shock.

The autopsy f indings are consistent with hemophagocytic syndrome, which was probably triggered by acute appendicitis.

DISCUSSION

The hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH) is a rare and severe entity. In 1939, Scott and Robb-Smith1 first described what they called histiocytic medullary reticulosis, a condition characterized by histiocytic proliferation with erythrophagocytosis throughout the lymphoreticular tissue. Similar cases were published by Anderson in 19442 and Asher in 19463, but only in 1952 two Scottish pediatricians published the case of two 9-week-old twins with “hemophagocytic reticulosis.”4 Since then, numerous cases have been reported widening the clinical presentation and proposing a diagnostic approach.5,6

Initially, HLH was believed to be a syndrome of childhood, as most of the patients presenting this

Figure 5. A and B - Gross view of the right lung with petechiae on the pleural surface in A and left lung in B, showing winy-colored fi rm parenchyma, without friable areas; photomicrography of the lung showing in C - alveolar spaces fi lled by macrophages, erythrocytes and fi brin deposits (HE, 100X); D - alveolar hemorrhage (HE, 100X).



16

Figure 6. Photomicrography of the lymph node showing in A - marked lymphocytic depletion and subcapsular sinus congestion and the presence of numerous histiocytes (HE, 40X); B - dilated medullary sinus histiocytosis (HE-100X); C - (HE-1000X) detail of the histiocyte phagocyting numerous erythrocytes (hemophagocytosis) (HE, 1000X); D - presence of numerous histiocytes with hemophagocytosis, positive immunophenotype for CD68 in the medullary sinus (immunohistochemistry, 400X).

Figure 7. Photomicrography of the bone marrow showing in A - hypo cellularity for the age with the presence of interstitial histiocytes (HE, 100X); B - Detail of the histiocytes with numerous intracytoplasmic erythrocytes (arrow) (HE, 400X); C - delayed granulocytic maturation (HE, 200X); D - numerous interstitial histiocytes immunophenotypically positive for CD68 (immunohistochemistry, 400X).



17

disease were younger than 2 years; however, numerous cases in teenagers and adults have been reported. The incidence varies widely between geographic regions and different populations. In Turkey, an incidence of 7.5 cases in 10,000 live births has been reported, and three Texas (USA) academic centers reported 1 case in 100,000 live births.5,7-10

HLH is classifi ed in two types: primary or genetic, and secondary or acquired. Primary HLH is an autosomal recessive disease and may exhibit a familial form (FHL), which is rare and fatal without treatment. Other genetic forms include Chédiak-Higashi, Griscelli syndrome, and chromosome-X-linked lymphoproliferative disease, which present distinct phenotypic characteristics and may present the HLH syndrome in their clinical course.11,12

HLH can be faced as a clinical condition caused by hypercytokinemia in a scenario where the immune system is over activated but ineffective. In a broad sense, HLH is currently understood as an immune system’s lack of ability to deal with trigger events, which, in the majority of the cases, are infectious. The last decade has focused on the determination of HLH etiopathogenesis, especially the genetic and molecular bases of this entity.12

The mutations of perforin (PFR-1), hMunc13.4, and syntaxin-11 were implicated in the familial HLH. These genes are related to the NK-cells and T-cells cytotoxic granules exocytosis. The -interferon hypersecretion in conjunction with macrophage activation, the NK cells, and CD8 T-lymphocytes have a central role in the HLH physiopathology. The familial form is based on the mutation of the perforin-encoding gene, a key protein of cytotoxic granules. A recent study with a perforin-defi cient murine model infected by lymphocytic choriomeningitis virus, produced the development of HLH.12-17

The secondary or acquired HLH form, in contrast to the familial form, is not associated with known mutations and is frequent among children and adults. Infectious, autoimmune diseases and neoplasm may represent the trigger events responsible for the uncontrolled immune system and infl ammatory responses. Viral infections like Epstein-Barr virus (EBV), cytomegalovirus (CMV), type 8 herpes virus, HIV, influenza virus, parvovirus and hepatitis A, B, and C virus, as well as Gram-negative bacteria, yeast,

and parasitic infections are frequently associated with the HLH etiology. HLH may also be associated to malignancy mainly those of hematologic lineage, either as the initial presentation or during the course of chemotherapy.18 NK or T-cell lymphomas are the most common HLH-associated malignancies.7

HLH clinically presents as a febrile illness associated with multiple organ involvement. The commonest clinical fi nding is hepatomegaly, which has presented in 95% of the patients, followed by lymphadenopathy, edema, jaundice, rash, and neurological symptoms. Unfortunately, the initial presentation of HLH may often be misdiagnosed and interpreted with hyper infl ammatory diseases, like severe sepsis or diseases that require surgical treatment, challenging and delaying the diagnosis. Siminas et al.19 reported four pediatric cases of HLH that presented by masquerading as surgical diseases (neonatal abdominal distension, ileostomy closure, and Hirschsprung’s disease; iatrogenic sigmoid perforation and Crohn’s disease, and streptococcal toxic shock syndrome with primary peritonitis). HLH was suspected after several days of unexplained fever (average of 23 days), hepatomegaly, and pancytopenia. In 2014, Kassel et al.20 reported the fi rst case of HLH that clinically and radiologically mimicked acute appendicitis. Interestingly, during the laparoscopy, fi ndings of diffuse plaque-like lesions in the small intestine required attention and were biopsied, showing HLH histological patterns.5,16,20-21

Cytopenia is the commonest laboratory fi nding in HLH, particularly, thrombocytopenia, which presented in 97% of the patients. Other laboratory abnormalities are elevated ferritin determination, hypofibrinogenemia, hypertriglyceridemia, liver dysfunction (elevated lactate dehydrogenase, serum transaminases, and bilirubin), impaired or absent NK cells, and T cell cytotoxicity (characteristic of FHL).5-7,21 Thrombocytopenia is a common fi nding in Pediatrics; in the intensive care setting it is quite often associated with severe diseases and poor prognosis. In children, immune thrombocytopenia is common, but the presence of thrombocytopenia should raise the suspicion of hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), sepsis accompanied or not by disseminated intravascular coagulation (DIC) and drug-induced thrombocytopenia (like heparin adverse event).22-27



18

The diagnosis of HLH can be made following the diagnostic criteria proposed by the Histiocyte Society, which was revised in 2007.6 A molecular diagnosis consistent with HLH is enough to make the diagnosis of the familial form with known genetic abnormalities. In other cases, fi ve out of eight positive criteria is required: fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, evidence of hemophagocytosis, low/absent NK cell activity, hyperferritinemia, and high soluble interleukin 2 receptor levels.6,28

Without treatment, HLH has a dismal prognosis, with less than 5% having long-term survival, and a median survival time of 2 months. With newer chemotherapy regimens (etoposide, dexamethasone, and methotrexate) and protocols (HLH-94), the overall survival rate of 5 years has raised to 54%, clinically relevant disease is still present in 28% of the survivors and 19% have late neurological effects. For patients with the familial form of HLH, after the initial chemotherapy, or with recurrent or refractory disease a hematopoietic stem cell transplant is the defi nitive treatment.5,6,16,21,29

The case reported herein presented sustained fever, cytopenias, hypofi brinogenemia, hyperferritinemia, and the findings of hemophagocytosis, which permitted the diagnosis of HLH (Table 1 and Table 2).

The HLH still remains a poor suspected entity in critical care patients, which invariably detains the proper treatment, and consequently increase the mortality. HLH may not be present at the beginning of an infectious, autoimmune, or neoplastic disease; however, it can be responsible for an unfavorable outcome in some cases. When patients experience unexpected outcomes, despite intensive care and appropriate and optimized antibiotic regimens, intensive care physicians should recall the hypothesis of HLH as a differential diagnosis.

REFERENCES

1. Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet. 1939;234(6047):194-8. http://dx.doi.org/10.1016/S0140-6736(00)61951-7.

2. Anderson RG. Histiocytic medullary reticulosis with transient skin lesion. BMJ. 1944;1(4336):220-1. http://dx.doi.org/10.1136/bmj.1.4336.220-a. PMid:20785276

3. Asher R. Histiocytic medullary reticulosis: a case without lymphadenopathy. Lancet. 1946;1(6401):650. http://dx.doi.org/10.1016/S0140-6736(46)90495-3. PMid:21027953

4. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27(136):519-25. http://dx.doi.org/10.1136/adc.27.136.519. PMid:13008468

5. Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577-84. http://dx.doi.org/10.1182/blood-2011-06-356261. PMid:21900192

6. Henter JI, Horne A, Aricó M, et al. HLH-2004: D iagnos t i c and the rapeut i c gu ide l i ne s fo r hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31. http://dx.doi.org/10.1002/pbc.21039. PMid:16937360

7. Tothova Z, Berliner N. Hemophagocytic syndrome and critical illness: new insights into diagnosis and management. J Intensive Care Med. 2014 Jan 8. http://dx.doi.org/10.1177/0885066613517076. [Epub ahead of print] PMid:24407034

8. Gürgey A, Gö ü� S, Ozyürek E, et al. Primary hemophagocytic lymphohistiocytosis in Turkish children. Pediatr Hematol Oncol. 2003;20(5):367-71. http://dx.doi.org/10.1080/08880010390203891. PMid:12775534

9. Niece JA, Rogers ZR, Ahmad N, Langevin AM, McClain KL. Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer. 2010;54(3):424-8. http://dx.doi.org/10.1002/pbc.22359. PMid:19953651

10. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503-16. http://dx.doi .org/10.1016/S0140-6736(13)61048-X. PMid:24290661

11. Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21(5):245-53. http://dx.doi.org/10.1016/j.blre.2007.05.001. PMid:17590250

12. Janka GE, Lehmberg K. Hemophagocytic syndromes: an update. Blood Rev. 2014;28(4):135-42. http://dx.doi.org/10.1016/j.blre.2014.03.002. PMid:24792320

13. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957-9. http://dx.doi.org/10.1126/science.286.5446.1957. PMid:10583959

14. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 2003;115(4):461-73. http://dx.doi.org/10.1016/S0092-8674(03)00855-9. PMid:14622600



19

15. zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14(6):827-34. http://dx.doi.org/10.1093/hmg/ddi076. PMid:15703195

16. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104(3):735-43. http://dx.doi.org/10.1182/blood-2003-10-3413. PMid:15069016

17. Mahlaoui N, Ouachée-Chardin M, Saint Basile G, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120(3):e622-8. http://dx.doi.org/10.1542/peds.2006-3164. PMid:17698967

18. Paes VR, Lima PP, Siqueira SAC. Hemophagocytic lymphohistiocytosis associated with hepatosplenic T-cell lymphoma: case report. Autops Case Rep. 2014;4(4):19-24. http://dx.doi.org/10.4322/acr.2014.035.

19. Siminas S, Caswell M, Kenny SE. Hemophagocytic lymphohistiocytosis mimicking surgical symptoms and complications: lessons learned from four cases. J Pediatr Surg. 2013;48(7):1514-9. http://dx.doi.org/10.1016/j.jpedsurg.2012.12.024. PMid:23895965

20. Kassel R, Robertson JO, Kung VL, et al. Small intestinal ulcers in hemophagocytic lymphohist iocytosis presenting as acute appendicitis. J Ped Surg Case Reports. 2014;2(6):325-7. http://dx.doi.org/10.1016/j.epsc.2014.05.009.

21. Gholam C, Grigoriadou S, Gilmour KC, Gaspar HB. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. Clin Exp Immunol. 2011;163(3):271-83. http://dx.doi.org/10.1111/j.1365-2249.2010.04302.x. PMid:21303357

22. Recht M. Thrombocytopenia and anemia in infants and children. Emerg Med Clin North Am. 2009;27(3):505-23. http://dx.doi.org/10.1016/j.emc.2009.04.009. PMid:19646651

23. Sakr Y. Heparin-induced thrombocytopenia in the ICU: an overview. Crit Care. 2011;15(2):211. PMid:21457505.

24. Chaari A, Medhioub F, Samet M, et al. Thrombocytopenia in critically ill patients: a review of the literature. Trends in Anaesthesia and Critical Care. 2011;1(4):199-202. http://dx.doi.org/10.1016/j.tacc.2011.05.003.

25. Hui P, Cook DJ, Lim W, Fraser GA, Arnold DM. The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest. 2011;139(2):271-8. http://dx.doi.org/10.1378/chest.10-2243. PMid:21071526

26. Parker RI. Etiology and significance of thrombocytopenia in critically ill patients. Crit Care Clin. 2012;28(3):399-411. http://dx.doi.org/10.1016/j.ccc.2012.04.007. PMid:22713614

27. Krishnan J, Morrison W, Simone S, Ackerman A. Implications of thrombocytopenia and platelet course on pediatric intensive care unit outcomes. Pediatr Crit Care Med. 2008;9(5):502-5. http://dx.doi.org/10.1097/PCC.0b013e3181849af1. PMid:18679144

28. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4):428-35. http://dx.doi.org/10.1111/j.1651-2227.1991.tb11878.x. PMid:2058392

29. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140(3):221-30. http://dx.doi.org/10.1007/BF00443367. PMid:6354720

Conflict of interest: None

Submitted on: January 28, 2015Accepted on: February 21, 2015

CorrespondenceGabriel Nuncio BenevidesDivisão de Clínica Pediátrica – Hospital UniversitárioAvenida Prof. Lineu Prestes, 2565 – São Paulo/SP – BrazilCEP: 05508-000Phone +55 (11) 97484-0708E-mail: [email protected]


1 Department of Pediatrics - Childrens Institute - Hospital das Clínicas - Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil. 2 Department of Pathology - Hospital das Clínicas - Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil.3 Anatomy Pathology Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP, Brazil.4 Department of Neonatology - Hospital Universitário - Universidade de São Paulo, São Paulo/SP, Brazil.

Recurrence of alveolar capillary dysplasia with misalignment of pulmonary veins in two consecutive siblings

Gabriel Nuncio Benevides1, Patricia Picciarelli de Lima2, Aloisio Felipe-Silva3, Silvana Maria Lovisolo3, Ana Maria Andrello Gonçalves Pereira de Melo4

Benevides GN, Lima PP, Felipe-Silva A, Lovisolo SM, Melo AMAGP. Recurrence of alveolar capillary dysplasia with misalignment of pulmonary veins in two consecutive siblings. Autopsy Case Rep [Internet]. 2015; 5(1):21-27. http://dx.doi.org/10.4322/acr.2014.045

ABSTRACT

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, developmental lung disorder, which has been increasingly reported. This entity usually presents as neonatal persistent pulmonary hypertension that is unresponsive to treatment, and is known to be uniformly fatal. Recent discoveries in the genetic fi eld, and intensive treatments, may change the natural course of this disease, permitting easier diagnosis and giving new hope for the dismal prognosis. The authors present two cases of siblings, with two years of difference, from different fathers - one of them was a fi rst-degree and the other a second-degree cousin of the mother. Both patients were full-term babies born apparently without malformations and were sent to the nursery. Both siblings near 35 hours of age presented severe respiratory failure due to pulmonary hypertension. The outcome was fatal in both cases and at autopsy ACD/MPV was diagnosed. The authors call attention to this entity in the differential diagnosis of acute respiratory distress in early life.

KeywordsAlveolar capillary dysplasia; Respiratory Insuffi ciency; Hypertension; Pulmonary; Newborn; Siblings; Autopsy.

CASE REPORTS

First Sibling

The fi rst sibling was a full-term female newborn from fi rst-degree cousins; the mother was 27-year-old, gravida 4, para 1, born by cesarean section due to fetal distress and oligohydramnios. The pregnancy was uneventful. At birth, the Apgar score was 7, 10, 10 at 1, 5, and 10 minutes, respectively. The mother’s obstetric history was remarkable for two prior pregnancy losses. Her family history was negative for any congenital

cardiac or pulmonary disease. The newborn received routine prenatal care and no congenital abnormality was detected.

At 31 hours of age, the newborn developed progressive tachypnea, pallor, and hyperglycemia requiring neonatal intensive care unit (NICU) support. At admission, she promptly required endotracheal intubation and mechanical ventilatory support. Within 1 hour after admission, the hemodynamic parameters



Recurrence of alveolar capillary dysplasia with misaligment of pulmonary veins in two consecutive siblings

22

deteriorated even after the administration of vasoactive drugs. Despite all efforts, the patient presented six episodes of cardiac arrest in a 1-hour period and died soon after.

Second Sibling

The second sibling was a full-term male born two years after the fi rst sibling by cesarean section due to iteractivity. The father was a second-degree cousin of the mother with whom he had previously had a healthy son. The pregnancy was uneventful. At birth, the Apgar score was 9, 9, and 10 at 1, 5, and 10 minutes, respectively. The infant received routine prenatal care and no congenital abnormality was detected on the physical examination.

At 40 hours of age, the newborn developed progressive tachypnea, pal lor, hypotonia and hemodynamic instability, requiring NICU support. On admission, he promptly required endotracheal intubation and mechanical ventilatory support. Despite optimized hemodynamic care with vasoactive drugs (dopamine, dobutamine, milrinone, adrenaline and noradrenaline), hydrocortisone and E-prostacyclin, the hemodynamic parameters deteriorated. The patient presented eight episodes of cardiac arrests in a 12-hour period and died soon after.

AUTOPSIES

First Sibling

The external examination did not show any malformations. The lungs, weighed together 23.4 g (reference value [RV]: 42.6 g +/– 14.9 g), and were reddened and boggy. Histological analyses showed lobular simplifi cation (enlarged, round or elongated, with deficient septation leading to insufficient alveoli within the acinar unit) and immaturity with a somewhat reduced number of alveoli plus widened alveolar septa with areas of a reduced number of capillaries—some of which were located away from the alveolar epithelium. Some areas showed anomalous pulmonary veins accompanying pulmonary arteries and bronchi (misaligned pulmonary veins) together with mild lymphatic dilatation (Figure 1). The medial muscle wall of small pulmonary arteries was thickened, and muscularization of tiny intracinar arterioles was present. Focal thrombi in pulmonary branches were

seen, as well as foci of alveolar damage with hyaline membranes and alveolar hemorrhage (Figure 2).

Other organs and systems showed signs of hypoxic-ischemic damage related to shock; namely, myocardial and encephalic ischemic focal changes, acute tubular necrosis, intense sinusoidal liver and splenic congestion, and generalized visceral congestion.

Second Sibling

Histological analyses of the lungs showed a very similar picture to the fi ndings of the fi rst sibling. Lobular simplifi cation and immaturity, misaligned pulmonary veins (which were more easily found within the adventitia of pulmonary arteries), and muscularization of capillaries located somewhat away from the alveolar septa. A few bronchial arteries were very thickened and foci of alveolar damage with hyaline membranes and alveolar hemorrhage were found as well (Figure 3).

DISCUSSION

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) was thought to be an extremely rare and uniformly fatal neonatal disease.1 However, this condition has been increasingly reported. Up to 200 cases in the English literature2,3 have been reported, and new treatment options have arisen, giving time and opportunity for patients to achieve the lung transplantation.4 Since the first report of “congenital alveolar dysplasia of the lungs” in the 1940s, MacMahon5 addressed that this condition may have already been seen but not always recognized.5,6

ACD/MPV is the most common interstitial lung diseases of the newborn.7,8 In a study undertaken in the UK, the incidence of irreversible lung dysplasia is 1 in 236,947 live births, in which fi ve out of nine patients were diagnosed with ACD/MPV. Moreover, one in six patients, with no obvious cause of severe persistent neonatal pulmonary hypertension, had ACD/MPV. Three out of four newborns who underwent extracorporeal membrane oxygenation (ECMO) due to idiopathic persistent pulmonary hypertension presented ACD/MPV, and 25% of those who died after ECMO, indicated for any reason, were also diagnosed with ACD/MPV.3,9

Over the past last decade, a better understanding of the ACD/MPV genetics has changed the epidemiology,


Benevides GN, Lima PP, Felipe-Silva A, Lovisolo SM, Melo AMAGP

23

Figure 1. Photomicrography of the lungs (fi rst sibling). A - Lobular simplifi cation (H&E, 50X); B - Immaturity (H&E, 100X); C - Dilated subpleural lymphatics (*) (H&E, 100X); D - Thin-walled vein (white arrow) anomalously positioned adjacent to a muscular pulmonary artery (black arrow) close to the airway (bronchioles [arrowhead]) in the bronchovascular bundle (H&E, 400X).

Figure 2. Photomicrography of the lungs (fi rst sibling). A - Thickened alveolar septae with poor capillary bed and a thickened arteriole (H&E, 400X); B - Extension of smooth muscle into intracinar small arteries (arrowheads) (H&E, 400X); C - Small alveoli with a reduced capillary bed (H&E, 400X); D - Focal alveolar damage with hyaline membrane and alveolar hemorrhage (H&E, 400X).



24

the phenotype, and the way the diagnosis has been made. In 2009, Stankiewicz et al.10 demonstrated inactivating mutations in the FOXF1 gene in patients with ACD/MPV.10 The FOXF1 protein is involved in organogenesis, especially in the lung, but is located in all types of cells; therefore, FOXF1 mutations are related to ACD/MPV with the involvement of other organs2. More recently, more mutations and deletions were found in the FOXF1 gene related to ACD/MPV.2,6,11 To date, 40% of all ACD/MPV cases have mutations in the FOXF1 gene1,12, the majority are de novo mutations, but familial inheritance and siblings’ involvement were also reported in some cases.13,14,15,16

ACD/MPV has a constellation of histopathological features, which include immature lobular development, decreased number of pulmonary capillaries located away from the alveolar epithelium, thickened alveolar septae, medial hypertrophy of small pulmonary arteries with muscularization of distal arterioles, and lymphangiectasia (in up to 30%).1 Malposition of pulmonary vein branches adjacent to pulmonary arteries (usually with the same adventitial sheath) is considered pathognomonic, although it is not detected in every case.17

Pathological differential diagnosis includes other diffuse developmental lung disorders or “congenital lung dysplasia”, which is clinically indistinguishable.18 The most relevant are congenital acinar dysplasia and congenital alveolar dysplasia. In acinar dysplasia, there is an almost complete absence of mature alveoli, a large increase in the amount of interstitial connective tissue, and dysplastic bronchial cartilage plates. On the other hand, in congenital alveolar dysplasia there is a very large capillary bed, the alveolar epithelium resembles mature lung, the bronchial epithelium is well developed, and the alveolar walls are very wide and composed of primitive mesenchyme without mature collagen fi bers.19

The natural course of ACD/MPV is not yet fully understood. The majority of the cases occur in full-term neonates, and a slight male predominance has been observed.1,10,15,16,20-27 Up to 80% have extrapulmonary malformations, which include involvement in the gastrointestinal, genitourinary, and cardiovascular systems.1,6,10,15,21,26-31 The newborns are usually asymptomatic at the time of delivery, present normal Apgar scores, and are therefore sent to the baby nursery. The onset of symptoms are subtle and usually occur

Figure 3. Photomicrography of the lungs (second sibling). A - Misalignement of thin-walled veins anomalously positioned within the same adeventitia of the adjacent to a muscular pulmonary artery close to the airway (H&E, 200X); B - Muscularization of intracinar small artery (H&E, 400X); C - Malpositioning of thin-walled veins adjacent to a thickened pulmonary artery (H&E, 400x); D - Focal alveolar damage with hyaline membrane (H&E, 400X).



25

in the fi rst hours or days of life, and are represented by progressive pulmonary hypertension (respiratory distress, cyanosis, and oxygen desaturation). However, late-onset cases, which become symptomatic after weeks or months, have been reported.3,10,15,28,29,32,33

The initial chest radiography may be normal, or present a hazy pattern or pneumothorax . The echocardiography shows moderate-to-severe pulmonary hypertension causing r ight-to-left extrapulmonary shunting.4,10,23,28,32,34 Despite the appropriate treatment in the NICU with pulmonary vasodilators (sildenafil, nitric oxide), prostacyclin, surfactants, bosentan, vasoactive drugs (dopamine, dobutamine, milrinone), ventilatory support (using high-frequency oscillatory ventilation in some cases), and ECMO, the behavior of the disease is still uniformly fatal, and the majority of the patients expire in the fi rst month of life.6,10,15,16,20-31,33-38 In 2014, Hoganson et al.4 used a pumpless paracorporeal lung assist device in a patient of 9 months old, with ACD, as a bridge to lung transplantation. Hoganson reports that the child was doing well 10 months after the transplantation, giving a new hope of a better prognosis for this disease management.

The diagnosis of ACD/MPV requires an experienced pathologist to identify the characteristic pulmonary histologic features.10 Autopsies confi rm 90% of the diagnosis and lung biopsies confirm only 10%.1,39 However, potential diagnoses are missed because probable cases are not submitted to lung biopsies nor to post-mortem examinations.10 Early lung biopsy should be indicated for neonates requiring ECMO support for refractory pulmonary hypertension.21,40,41 Lung biopsies in patients with ECMO were demonstrated to be safe.39,40 In patients with suspected ACD/MPV and extrapulmonary manifestations, testing for FOXF1 mutation could possibly avoid the need for a future biopsy, but more studies in this setting should be undertaken.13

CONCLUSION

We presented a case of ACD/MPV without extrapulmonary manifestations. This patient died despite intensive care, and the diagnosis was made at autopsy. Increasing knowledge on the genetics, pathophysiology, early suspicion, and diagnosis may help to design better management required to alter the gloomy prognosis of this entity.

REFERENCES

1. Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar capillary dysplasia. Am J Respir Crit Care Med. 2011;184(2):172-9. http://dx.doi.org/10.1164/rccm.201010-1697CI. PMid:21471096

2. Sen P, Yang Y, Navarro C, Silva I, Szafranski P, Kolodziejska KE, et al. Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Hum Mutat. 2013;34(6):801-11. http://dx.doi.org/10.1002/humu.22313. PMid:23505205

3. Tibballs J, Chow CW. Incidence of alveolar capillary dysplasia in severe idiopathic persistent pulmonary hypertension of the newborn. J Paediatr Child Health. 2002;38(4):397-400. http://dx.doi.org/10.1046/j.1440-1754.2002.00014.x. PMid:12174004

4. Hoganson DM, Gazit AZ, Boston US, Sweet SC, Grady RM, Huddleston CB, et al. Paracorporeal lung assist devices as a bridge to recovery or lung transplantation in neonates and young children. J Thorac Cardiovasc Surg. 2014;147(1):420-6. http://dx.doi.org/10.1016/j.jtcvs.2013.08.078. PMid:24199759

5. MacMahon HE. Congenital alveolar dysplasia; a developmental anomaly involving pulmonary alveoli. Pediatrics. 1948;2(1):43-57. PMid:18874463.

6. Nguyen L, Riley MM, Sen P, Galambos C. Alveolar capillary dysplasia with misalignment of pulmonary veins with a wide spectrum of extrapulmonary manifestations. Pathol Int. 2013;63(10):519-21. http://dx.doi.org/10.1111/pin.12102. PMid:24147432

7. Dishop MK. Paediatric interstitial lung disease: classification and definitions. Pathol Int. 2013;63(10):519-21. PMid:24147432.

8. Deutsch GH, Young LR, Deterding RR, Fan LL, Dell SD, Bean JA, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176(11):1120-8. http://dx.doi.org/10.1164/rccm.200703-393OC. PMid:17885266

9. Cassidy J, Smith J, Goldman A, Haynes S, Smith E, Wright C, et al. The incidence and characteristics of neonatal irreversible lung dysplasia. J Pediatr. 2002;141(3):426-8. http://dx.doi.org/10.1067/mpd.2002.126602. PMid:12219067

10. Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA, et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009;84(6):780-91. http://dx.doi.org/10.1016/j.ajhg.2009.05.005. PMid:19500772

11. Miranda J, Rocha G, Soares H, Vilan A, Brandão O, Guimarães H. Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV): A



26

Case Series. Case Rep Crit Care. 2013;2013:327250. PMid:24829819.

12. Citti A, Peca D, Petrini S, Cutrera R, Biban P, Haass C, et al. Ultrastructural characterization of genetic diffuse lung diseases in infants and children: a cohort study and review. Ultrastruct Pathol. 2013;37(5):356-65. http://dx.doi.org/10.3109/01913123.2013.811454. PMid:24047351

13. Nogee LM. Genetic basis of children’s interstitial lung disease. Pediatr Allergy Immunol Pulmonol. 2010;23(1) :15-24. http: / /dx.doi .org/10.1089/ped.2009.0024. PMid:22087432

14. Sen P, Gerychova R, Janku P, Jezova M, Valaskova I, Navarro C, et al. A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human. Eur J Hum Genet. 2013;21(4):474-7. http://dx.doi.org/10.1038/ejhg.2012.171. PMid:22990143

15. Alameh J, Bachiri A, Devisme L, Truffert P, Rakza T, Riou Y, et al. Alveolar capillary dysplasia: a cause of persistent pulmonary hypertension of the newborn. Eur J Pediatr. 2002;161(5):262-6. http://dx.doi.org/10.1007/s00431-002-0927-7. PMid:12012221

16. Licht C, Schickendantz S, Sreeram N, Arnold G, Rossi R, Vierzig A, et al. Prolonged survival in alveolar capillary dysplasia syndrome. Eur J Pediatr. 2004;163(3):181-2. http://dx.doi.org/10.1007/s00431-003-1385-6. PMid:14677063

17. Garola RE, Thibeault DW. Alveolar capillary dysplasia, with and without misal ignment of pulmonary veins: an association of congenital anomalies. Am J Perinatol. 1998;15(2):103-7. http://dx.doi.org/10.1055/s-2007-993907. PMid:9514134

18. Don M, Orsaria M, Da Dalt E, Tringali C, Sacher B. Rapidly fatal “congenital lung dysplasia”: a case report and review of the literature. Fetal Pediatr Pathol. 2014;33(2):109-13. http://dx.doi.org/10.3109/15513815.2013.878009. PMid:24467188

19. Langenstroer M, Carlan SJ, Fanaian N, Attia S. Congenital acinar dysplasia: report of a case and review of literature. AJP Rep. 2013;3(1):9-12. http://dx.doi.org/10.1055/s-0032-1329126. PMid:23943701

20. Sen P, Thakur N, Stockton DW, Langston C, Bejjani BA. Expanding the phenotype of alveolar capillary dysplasia (ACD). J Pediatr. 2004;145(5):646-51. http://dx.doi.org/10.1016/j.jpeds.2004.06.081. PMid:15520767

21. Gamillscheg A, Zobel G, Spuller E, Reiterer F, Beitzke A. Aortic coarctation associated with alveolar capillary dysplasia and misalignment of the pulmonary veins. Pediatr Cardiol. 2008;29(1):191-4. http://dx.doi.org/10.1007/s00246-007-9063-5. PMid:17874220

22. Hung SP, Huang SH, Wu CH, Chen WC, Kou KE, Wang NK, et al. Misalignment of lung vessels and alveolar capillary dysplasia: a case report with autopsy. Pediatr

Neonatol. 2011;52(4):232-6. http://dx.doi.org/10.1016/j.pedneo.2011.05.010. PMid:21835371

23. Roy PG, Patel P, Vayalakkad A, Bowker C, Lakhoo K. Alveolar capillary dysplasia presenting as pneumothorax: a case report and review of literature. Pediatr Surg Int. 2007;23(9):915-7. http://dx.doi.org/10.1007/s00383-007-1904-z. PMid:17394004

24. Shimizu T, Fukuda T, Inomata S, Satsumae T, Tanaka M. A novel association of alveolar capillary dysplasia, atypical duodenal atresia, and subglottic stenosis. J Anesth. 2011;25(2):298-300. http://dx.doi.org/10.1007/s00540-010-1080-5. PMid:21194000

25. Sihoe AD, Lee AT, To KF, Thung KH, Lee TW, Yim AP. Alveolar capillary dysplasia with congenital misalignment of pulmonary vessels. Asian Cardiovasc Thorac Ann. 2005;13(1) :82-4. http: / /dx.doi .org/10.1177/021849230501300121. PMid:15793061

26. Taborosi B, Tödt-Pingel I, Kayser G, Dittrich S. A rare case of aortic coarctation and ventricular septal defect combined with alveolar capillary dysplasia. Pediatr Cardiol. 2007;28(4):319-23. http://dx.doi.org/10.1007/s00246-007-0049-0. PMid:17530317

27. Antao B, Samuel M, Kiely E, Spitz L, Malone M. Congenital alveolar capillary dysplasia and associated gastrointestinal anomalies. Fetal Pediatr Pathol. 2006;25(3):137-45. http://dx.doi.org/10.1080/15513810600908230. PMid:17060189

28. Michalsky MP, Arca MJ, Groenman F, Hammond S, Tibboel D, Caniano DA. Alveolar capillary dysplasia: a logical approach to a fatal disease. J Pediatr Surg. 2005;40(7):1100-5. http://dx.doi.org/10.1016/j.jpedsurg.2005.03.067. PMid:16034752

29. Kodama Y, Tao K, Ishida F, Kawakami T, Tsuchiya K, Ishida K, et al. Long survival of congenital alveolar capillary dysplasia patient with NO inhalation and epoprostenol: effect of sildenafil, beraprost and bosentan. Pediatr Int. 2012;54(6):923-6. http://dx.doi.org/10.1111/j.1442-200X.2012.03712.x. PMid:23279022

30. Usui N, Kamiyama M, Kamata S, Yoneda A, Tazuke Y, Fukuzawa M. A novel association of alveolar capillary dysplasia and duodenal atresia with paradoxical dilatation of the duodenum. J Pediatr Surg. 2004;39(12):1808-11. http://dx.doi.org/10.1016/j.jpedsurg.2004.08.026. PMid:15616937

31. Vassal HB, Malone M, Petros AJ, Winter RM. Familial persistent pulmonary hypertension of the newborn resulting from misalignment of the pulmonary vessels (congenital alveolar capillary dysplasia). J Med Genet. 1998;35(1):58-60. http://dx.doi.org/10.1136/jmg.35.1.58. PMid:9475097

32. Morin FC 3rd, Stenmark KR. Persistent pulmonary hypertension of the newborn. Am J Respir Crit Care



27

Med. 1995;151(6):2010-32. http://dx.doi.org/10.1164/ajrccm.151.6.7767553. PMid:7767553

33. Ahmed S, Ackerman V, Faught P, Langston C. Profound hypoxemia and pulmonary hypertension in a 7-month-old infant: late presentation of alveolar capillary dysplasia. Pediatr Crit Care Med. 2008;9(6):e43-6. http://dx.doi.org/10.1097/PCC.0b013e31818e383e. PMid:18997591

34. Singh SA, Ibrahim T, Clark DJ, Taylor RS, George DH. Persistent pulmonary hypertension of newborn due to congenital capillary alveolar dysplasia. Pediatr Pulmonol. 2005;40(4):349-53. http://dx.doi.org/10.1002/ppul.20244. PMid:15957181

35. Hugosson CO, Salama HM, Al-Dayel F, Khoumais N, Kattan AH. Primary alveolar capillary dysplasia (acinar dysplasia) and surfactant protein B deficiency: a clinical, radiological and pathological study. Pediatr Radiol. 2005;35(3):311-6. http://dx.doi.org/10.1007/s00247-004-1349-7. PMid:15490144

36. Janney CG, Askin FB, Kuhn C 3rd. Congenital alveolar capillary dysplasia: an unusual cause of respiratory distress in the newborn. Am J Clin Pathol. 1981;76(5):722-7. PMid:7293984.


Submitted on: November 19, 2014Accepted on: February 13, 2015

CorrespondenceGabriel Nuncio BenevidesDivisão de Clínica Pediátrica - Hospital Universitário Avenida Prof. Lineu Prestes, 2565 – São Paulo/SP – BrazilCEP: 05508-000Phone: +55 (11) 97484-0708E-mail: [email protected]

37. Plat G, Rouquette I, Marcoux MO, Bloom MC, Acar P, Dulac Y. [Alveolar capillary dysplasia and persistent pulmonary hypertension of the newborn]. Arch Mal Coeur Vaiss. 2007;100(5):458-61. PMid:17646774.

38. Shankar V, Haque A, Johnson J, Pietsch J. Late presentation of alveolar capillary dysplasia in an infant. Pediatr Crit Care Med. 2006;7(2):177-9. http://dx.doi.org/10.1097/01.PCC.0000202570.58016.67. PMid:16474258

39. Eulmesekian P, Cutz E, Parvez B, Bohn D, Adatia I. Alveolar capillary dysplasia: a six-year single center experience. J Perinat Med. 2005;33(4):347-52. http://dx.doi.org/10.1515/JPM.2005.067. PMid:16207122

40. Deshmukh H, Lioy J. The use of early lung biopsy in detection of fatal pulmonary disease in the neonate. J Pediatr. 2014;164(4):934-6. http://dx.doi.org/10.1016/j.jpeds.2013.11.035. PMid:24373577

41. Lazar DA, Olutoye OO, Cass DL, Fernandes CJ, Welty SE, Johnson KE, et al. Outcomes of neonates requiring extracorporeal membrane oxygenation for irreversible pulmonary dysplasia: the Extracorporeal Life Support Registry experience. Pediatr Crit Care Med. 2012;13(2):188-90. http://dx.doi.org/10.1097/PCC.0b013e3182231060. PMid:21666536


a Offi ce of the Chief Medical Examiner, Santos/SP - Brazil.

Pulmonary agenesis and respiratory failure in childhood

Paula Vanessa Valverde Dinamarcoa, Cesar Cilento Poncea

Dinamarco PVV, Ponce CC. Pulmonary agenesis and respiratory failure in childhood. Autopsy Case Rep [Internet]. 2015; 5(1):29-32. http://dx.doi.org/10.4322/acr.2014.046

ABSTRACT

Pulmonary agenesis (PA) is a rare congenital anomaly, which may be unilateral or bilateral. Unilateral PA may be associated with nonspecifi c respiratory symptoms. We report the case of 5-month-old infant who presented a normal development until the age of 4 months when a respiratory infection caused an acute respiratory distress syndrome with a fatal outcome. The autopsy fi ndings depicted the right lung agenesis without any other concomitant malformation. Although respiratory symptoms represent frequent complaints in pediatrics, the aim of this study is not only to draw attention to the unilateral pulmonary agenesis as a possible underlying malformation in children who present recurrent and severe respiratory symptoms, but also to report a case diagnosed at autopsy.

KeywordsLung agenesis; Respiratory Insuffi ciency; Autopsy.

INTRODUCTION

Pulmonary agenesis is an extremely rare congenital anomaly defi ned as a complete absence of the lung parenchyma, bronchus, and pulmonary vessels.1 This anomaly was fi rst discovered accidentally by De Pozze (1673) during the autopsy of an adult woman.2,3

The estimated prevalence is 24–34 per 1,000,000 live births, and 1 per 10,000–15,000 autopsies with a slight preponderance of females.4 The etiology remains unknown, but its pathogenesis may be associated with genetic factors, such as the duplication of the distal part of the upper arm of chromosome 2, viral factors, or vitamin A defi cits.5-6

In normal development, the embryonic phase begins during the fourth week of gestation with the formation of the respiratory diverticulum from the ventral wall of the primitive foregut.7 It is possible that

pulmonary agenesis occurs due to the failure of the bronchial analogue to divide equally between the two lung buds. If this balance is not established, one side will develop normally while the other side will fail to develop and will lead to pulmonary agenesis/aplasia or pulmonary hypoplasia.4

Pulmonary agenesis is often associated with anomalies in the cardiovascular, gastrointestinal, genitourinary, or musculoskeletal systems.1,2-4,5 Both lungs are equally affected but right lung agenesis shows worse prognosis.3,5

In the absence of other malformations, unilateral pulmonary agenesis is compatible with normal life, but is often associated with severe respiratory infections during childhood, which is associated with high mortality rates.4,8




30

CASE REPORT

A 5-month-old white female patient was brought to the hospital with severe respiratory distress syndrome. She was born at term and her mother had no remarkable past medical or obstetric history. The patient developed normally until the age of 4 months. At admission, the child presented with cough, fever, and dyspnea. The physical examination revealed tachypnea with subcostal and intercostal retractions. Breath sounds were absent in the right hemithorax on pulmonary auscultation.

A plain chest x-ray showed a homogeneous opacity of the entire right hemithorax with cardiac displacement to the right and left lung hyperinfl ation. The working diagnosis was bacterial pneumonia (Figure 1). The patient was treated with intravenous fl uids, oxygen, and antibiotics. The hospital stay was characterized by progressive worsening of clinical parameters in the following 24 hours and the child died due to irreversible cardiorespiratory arrest.

Permission for autopsy was granted and an autopsy was performed. The thoracic cavity revealed a deviation and of the mediastinal structures to the right hemithorax, and hyperinfl ation of the left lung.

A thorough dissection of the thoracic organs showed the absence of the right lung, right bronchus, and right pulmonary vasculature. The displaced heart showed normal anatomic relationship with the great arteries. No other cardiac or systemic malformations (Figure 2) were found.

A single pulmonary artery was responsible for the left lung perfusion, and an obliterated ductus arteriosus was present (Figure 3).

Histological sections performed of the left lung, stained with hematoxilin and eosin (H&E) and Masson’s trichrome, revealed interstitial infl ammatory infi ltrate composed of lymphocytes and macrophages associated with intense edema and numerous macrophages in the alveolar spaces consistent with interstitial pneumonia, felt to be a contributing factor for the child’s demise (Figure 4).

DISCUSSION

According to the classifi cation, pulmonary agenesis was divided into three groups: Type 1 – Agenesis: complete absence of the lung, bronchus, and vascular supply of the affected side; Type 2 – Aplasia:

rudimentary bronchus with complete absence of the lung; Type 3 – Hypoplasia: a variable amount of the bronchial tree, lung parenchyma, and blood vessels.9 The case reported herein can be classifi ed as Type 1, because of the complete absence of vessels, bronchus, and right lung parenchyma.

In unilateral lung agenesis, the trachea extends directly into the main bronchus of the normally developed lung, and respiratory distress usually occurs due to infl ammation and the retention of bronchial secretions.4

Right lung agenesis is usually associated with the displacement of the heart and mediastinum rightwards accompanied by a distortion of the bronchial and vascular structures, which worsens the prognosis.10

Although the specifi city and sensitivity of fetal ultrasound has substantially improved in the last 20 years,11 diagnosis of isolated pulmonary agenesis is quite often challenging during prenatal routine examination.

The clinical presentation of the disease is quite variable. In some cases, respiratory distress syndrome is present at birth, while, in other cases, the patients remain asymptomatic until adulthood when they are

Figure 1. Chest x-ray showing a right hemithorax opacifi cation and left lung vicariance. Note the rightward deviation of the mediastinal structures.


Dinamarco PVV, Ponce CC

31

Figure 4. Photomicrography of the lung. A - Interstitial infl ammatory infi ltration and alveolar edema (H&E, 400X). B - The presence of numerous macrophages and edema in the alveolar spaces (Masson’s Tr ichrome, 400X).

Figure 3. A - Non-bifurcate trunk of the pulmonary artery. B - Note at the tip of the forceps the obliterated ductus arteriosus.

Figure 2. A - Front view of the thoracic organs. Note a single pulmonary artery perfusing the left lung and lack of the right lung. B - Posterior view characterized by the complete absence of the right main bronchus and lung.



32

incidentally diagnosed.6 More than 50% of children with lung agenesis die within 5 years of birth. Respiratory tract infections are the greatest risk for these individuals.4 In our case, the lung microscopic findings revealed mononuclear cells composed of mature lymphocytes and macrophages in the septa and edema in the alveolar spaces, features of interstitial pneumonitis. Unfortunately, the respiratory failure rapidly progressed to a fatal outcome.

In children with recurrent respiratory infections if no improvement is observed in the plain chest x-ray imaging, contrasted thoracic computed tomography is recommended in order to establish an accurate diagnosis of infection or a possible malformation.

Asymptomatic patients do not require intervention, especially in the absence of associated anomalies.6 However, pulmonary infection or other lung diseases should be treated early.4,6

When signs of respiratory failure are due to the torsion and compression of the trachea by the rotation of the heart, mediastinum, and displacement of the aortic arch, diaphragmatic translocation and aortopexy are indicated.8

Although pulmonary agenesis is a rare congenital anomaly, the pursuit of an accurate diagnosis is fundamental for prenatal counseling and better medical management to reduce mortality and improve prognosis.

REFERENCES

1. Sharma S, Kumar S, Yaduvanshi D, Chauhan D. Isolated unilateral pulmonary agenesis. Indian Pediatr. 2005;42(2):170-2. PMid:15767714.

2. Kisku KH, Panigrahi MK, Sudhakar R, Nagarajan A, Ravikumar R, Daniel JR. Agenesis of lung: a report of two cases. Lung India. 2008;25(1):28-30. http://dx.doi.org/10.4103/0970-2113.44136. PMid:20396661

3. De Pozze S, Brescia MA, Amermon EE, Sharma KK. Agenesis of the Left Lung. Arch Pediatr. 1960;77:485-90.

4. Kumar B, Kandpal DK, Sharma C, Sinha DD. Right lung agenesis. Afr J Paediatr Surg. 2008;5(2):102-4. http://dx.doi.org/10.4103/0189-6725.44189. PMid:19858680

5. Say B, Carpenter NJ, Giacoia G, Jegathesan S. Agenesis of the lung associated with a chromosome abnormality (46,XX,2p+). J Med Genet. 1980;17(6):477-8. http://dx.doi.org/10.1136/jmg.17.6.477. PMid:7205432

6. Malcon MC, Malcon CM, Cavada MN, Caruso PE, Real LF. Unilateral pulmonary agenesis. J Bras Pneumol. 2012;38(4):526-9. http://dx.doi.org/10.1590/S1806-37132012000400016. PMid:22964938

7. Biyyam DR, Chapman T, Ferguson MR, Deutsch G, Dighe MK. Congenital lung abnormalities: embryologic features, prenatal diagnosis, and postnatal radiologic-pathologic correlation. Radiographics. 2010;30(6):1721-38. http://dx.doi.org/10.1148/rg.306105508. PMid:21071385

8. Khurram MS, Rao SP, Vamshipriya A. Pulmonary agenesis: a case report with review of literature. Qatar Med J. 2013;2013(2):38-40. http://dx.doi.org/10.5339/qmj.2013.14. PMid:25003063

9. Bachh AA, Pulluri S, Beigh A, Raju C, Deshpande R. Pulmonary aplasia with unusual associations in a woman. Iran J Med Sci. 2014;39(2):148-51. PMid:24644386.

10. Chou AK, Huang SC, Chen SJ, et al. Unilateral lung agenesis: detrimental roles of surrounding vessels. Pediatr Pulmonol. 2007;42(3):242-8. http://dx.doi.org/10.1002/ppul.20561. PMid:17238192

11. Zhang Y, Fan M, Ren WD, et al. Prenatal diagnosis of fetal unilateral lung agenesis complicated with cardiac malposition. BMC Pregnancy Childbirth. 2013;13(1):79. http://dx.doi.org/10.1186/1471-2393-13-79. PMid:23530545



CorrespondenceCesar Cilento Ponce MD, PhDAv. Vicente de Carvalho, 65, 72 – Santos/SP – BrasilCEP: 11045-501Phone: +55 (13) 3284-0015 / Fax: +55 (13) 3226-0601E-mail: [email protected]


a Faculty of Medicine - Pontifícia Universidade Católica de Campinas, São Paulo/SP, Brazil.b Internal Medicine Department - Pontifícia Universidade Católica de Campinas, São Paulo/SP, Brazil.

Occult esophageal squamous cell carcinoma with metastases to the spine and central nervous system

Ana Lídia Viaroa, Carla Adriane Roballob, Pompeu Tomé Ribeiro de Camposb, Carlos Osvaldo Teixeirab, Maria Aparecida Barone Teixeirab

Viaro AL, Roballo CA, Campos PTR, Teixeira CO, Teixeira MAB. Occult esophageal squamous cell carcinoma with metastases to the spine and central nervous system. Autopsy Case Rep [Internet]. 2015; 5(1):33-37. http://dx.doi.org/10.4322/acr.2014.047

ABSTRACT

Esophageal malignancy encompasses a group of diseases that are mostly represented by the squamous cell carcinoma and the adenocarcinoma. Quite frequently, these neoplasms present aggressive behavior; therefore, the diagnosis is often made when the condition is in advanced stages. Dysphagia is the typical clinical complaint, although it is present only when most of the lumen is obstructed. Therefore, quite often, the metastatic disease is fi rst diagnosed, which contributes to the patient’s poor survival expectancy. The authors report the case of a 58-year-old man who looked for medical care complaining of a long-term history of scapular pain. The diagnostic work-up disclosed a cervical spine lytic lesion surrounded by a tumoral mass shown by computed tomography. The cervical tumor was sampled by fi ne needle aspiration, revealing an undifferentiated carcinoma. The outcome was unfavorable and the patient died. The autopsy fi ndings revealed metastatic disease to the spine and central nervous system, and the primary tumor was found to be an esophageal squamous cell carcinoma, which had progressed without typical dysphagia.

KeywordsCarcinoma; Squamous Cells; Esophageal Neoplasms; Neoplasm Metastasis; Spine; Brain.

CASE REPORT

A 58-year-old Caucasian man, born in a southern

state of Brazil, sought the medical facility complaining

of a 3-month history of continuous right shoulder

burning pain (precisely in the scapular region). This

symptom irradiated from the cervical spine hampering

the movements of his right arm and was alleviated with

the fl exion of the neck to the right position. He referred

8 kg of weight loss during this period, but denied

inappetence, dysphagia, other dyspeptic symptoms or

change in intestinal habits. He was a pottery worker for

25 years, was used to drinking daily 250 g of alcohol for 5 years and smoking 40 packs/year of tobacco.

The cervical spine radiography disclosed a lytic lesion in the vertebral body of C6 characterized as a ghost vertebra, consistent with bone metastasis (Figure 1A). The patient was hospitalized for investigation and pain control. The cervical spine computed tomography (CT) depicted a tumor mass (Figure 1B and 1C), which cytological examination of the fi ne needle aspirate was consistent with an undifferentiated carcinoma (Figure 2).




34

During hospitalization, the patient presented

mental confusion, psychomotor agitation, and

drowsiness, followed by loss of muscular strength

in the right superior limb. The brain CT revealed the

presence of a left parietal nodular lesion (Figure 1D).

Neurological and clinical status worsened; therefore,

palliative care was instituted and the investigation for

malignancy of unknown primary site was discontinued.

Immunohistochemical analysis of the aspirate could

not be performed. The patient died soon after hospitalization and an autopsy was performed.

AUTOPSY FINDINGS

An ulcerated and vegetating lesion, measuring 3.0 × 1.5 cm was found in the distal third of the esophagus (Figure 3A), which, on histology, was represented by an epidermoid carcinoma with

Figure 1. A – Lateral cervical spine radiography showing lytic lesion in C6 (arrow); B – Cervical computed tomography (CT) (bone window) showing vertebral body and left pedicle lytic lesion; C – Cervical CT (soft tissue window) showing the tumoral mass with heterogeneous contrast enhancement; D – Parietal nodular lesion that shows contrast enhancement, consistent with metastasis.


Viaro AL, Roballo CA, Campos PTR, Teixeira CO, Teixeira MAB

35

poorly-differentiated and well-differentiated areas with basaloid transformation (Figure 3B). Metastasis to the left brain hemisphere (Figure 4A and 4B) was found. Thoracic and cervical spine vertebrae were

enlarged by tumoral infi ltration of the bone and soft tissue. Additional fi ndings included liver metastasis and neoplastic cells fi lling the pulmonary vessels.

DISCUSSION

Esophageal carcinoma (EC) is the eighth most common type of cancer. In 2008, 481,000 new cases per year were registered accompanied by 406,000 deaths, worldwide, in the same period representing the sixth cause of death due to neoplasia.1 This neoplasm predominantly affects men (male:female ratio of 5.84:1) with a mean age of 61.6 years; whereas women show a mean age of 72.9 years at the time of diagnosis.2

The diagnosis of EC is frequently challenging since the typical symptom, represented by dysphagia, occurs only when two-thirds of the visceral lumen is involved.3,4 Therefore, the diagnosis is predominantly done in the advanced stages (stages III and IV),3 which

Figure 2. Photomicrography of the fi ne needle aspiration cytology showing the presence of non-differentiated malignancy (H&E, 400X).

Figure 3. A – Gross view of the ulcerovegetating lesion on the esophageal distal third, measuring 3 × 1.5 cm; B – Photomicrography of the ulcerated esophageal lesion showing the presence of epidermoid carcinoma (H&E, 40X).

Figure 4. A – Gross view of the brain showing the presence of a cortical nodular lesion (arrow); B – Photomicrography of the transition between the nervous parenchyma and the neoplastic infi ltration (H&E, 40X).



36

justifies the poor prognosis, represented by the fi ve-year survival rate of less than 10% in Western countries.5

EC is a neoplasia that has a high lethality. The number of deaths per year is very similar to the number of new cases.6 Survival after the diagnosis ranges from 3 to 6 months.7

According to the Brazilian National Institute of Cancer (INCA-Brazil), genetic and environmental factors are involved with the development of EC. Around 80% of EC are related to tobacco smoking, alcoholism, and alimentary habits.1,3,4

Sons and Borchard,2 in their study comprising 171 cases of EC, found 91.8% of cases of epidermoid carcinoma, 6.4% of adenocarcinoma, and 1.8% of other types. Epidermoid carcinoma, derived from the non-keratinized stratifi ed epithelium, occurs mainly after prolonged tobacco exposure, arises in the middle and distal third of the esophagus, and characteristically involves men over 50 years.8,9 Adenocarcinoma frequently involves the distal third of the esophagus, occurs more frequently among obese patients, and is related to gastroesophageal refl ux disease.8,9

EC presents fast growth, which is evidenced by 50% of the new cases showing non-resectable metastases at the time of diagnosis.10 Metastatic dissemination may occur through the lymphatic system, the blood stream, or by contiguity. The main metastatic sites are: abdominal lymph nodes (45%) cervical and supraclavicular lymph nodes (3–37%), liver (23–47%), lungs (22–52%), bones (45–14%), and central nervous system (1–5%).11,12

The case reported herein is in accordance with the literature with respect to the histologic type and the risk factors; namely, age, gender, origin,13 lifestyle, and alimentary habits, besides the history of alcoholism and tobacco smoking.3,14

Dysphagia and odynophagia, or any retrosternal discomfort, are fundamental diagnostic clues.4,15 In our case, the lack of such symptoms was responsible for the misdiagnosis, and was the reason for not performing an upper digestive endoscopy. The lack of esophageal symptoms was explained by the non-stenotic pattern of the lesion.

The right shoulder pain, which presented the patient’s complaint, was due to the cervical spine metastasis. Esophageal epidermoid carcinoma bone

metastases most commonly occur in the lumbar spine followed by the involvement of the thoracic and cervical regions. Compressive symptoms are more frequently found in the thoracic area of the spine, followed by the cervical (10–30%) and sacral/lumbar (20–30%), probably because of the narrow diameter of the spinal canal.16

In 1982, 1984, and 1986, three different researchers reported autopsy studies on esophageal cancer.2,17,18 In these series, which comprised 79, 171, and 231 cases, respectively, no bone metastases were found. However, Siame et al.7 reported three cases of esophageal epidermoid carcinoma with no esophageal symptoms, which presented bone metastases to the femur and vertebrae.

In the case reported herein, the mental status and neurological signs, as well as the tomographic fi ndings, were concordant with the autopsy fi ndings. Liver and pulmonary metastases are also in accordance with the literature.11,12,17

As aforementioned, EC is frequently asymptomatic, which, in this case, was responsible for the lack of clinical investigation. Therefore, once again, the autopsy shows undeniable value for medical assistance and teaching purposes, besides the demonstration of the rare metastatic site of EC.

REFERENCES

1. Almodova EC, Oliveira WK, Machado LF, Grejo JR, Cunha TR, Colaiacovo W, et al. Atrophic gastritis: risk factor for esophageal squamous cell carcinoma in a Latin-American population. World J Gastroenterol. 2013;19(13):2060-4. http://dx.doi.org/10.3748/wjg.v19.i13.2060. PMid:23599625

2. Sons HU, Borchard F. Esophageal cancer. Autopsy findings in 171 cases. Arch Pathol Lab Med. 1984;108(12):983-8. PMid:6548903.

3. Henriques AC, Pezollo S, Faure MG, Luz LT, Godinho CA, Speranzini MB. Tubo gástrico isoperistáltico no tratamento paliativo do carcinoma irressecável do esôfago. Rev Col Bras Cir. 2001;28(6):408-13. http://dx.doi.org/10.1590/S0100-69912001000600005.

4. Thuler FP, Forones NM, Ferrari AP. Neoplasia avançada de esôfago: diagnóstico ainda muito tardio. Arq Gastroenterol. 2006;43(3):206-11.

5. Song Z, Lin B, Shao L, Zhang Y. Brain metastases from esophageal cancer: clinical review of 26 cases.


Viaro AL, Roballo CA, Campos PTR, Teixeira CO, Teixeira MAB

37

World Neurosurg. 2014;81(1):131-5. http://dx.doi.org/10.1016/j.wneu.2013.02.058. PMid:23435161

6. Barros SG, Ghisolfi ES, Luz LP, Barlem GG, Vidal RM, Wolff FH, et al. Mate (chimarrão) é consumido em alta temperatura por população sob risco para o carcinoma epidermóide de esôfago. Arq Gastroenterol. 2000;37(1):25-30. http://dx.doi.org/10.1590/S0004-28032000000100006. PMid:10962624

7. Siame JL, Duquesne B, Cocheteux P. [Atypical metastases disclosing cancer of the esophagus. Apropos of 3 cases]. Sem Hop. 1983;59(15):1191-4. PMid:6306796.

8. Queiroga RC, Pernambuco AP. Câncer de esôfago: epidemiologia, diagnóstico e tratamento. Rev Bras Cancerol. 2006;52:173-8.

9. Justino PB, Carvalho HA, Ferauche D, Ros R. Planejamento tridimensional para radioterapia de tumores de esôfago: comparação de técnicas de tratamento e análise de probabilidade de complicações. Rev Radiologia Brasileira. 2003;36:157-62.

10. Go PH, Klaassen Z, Meadows MC, Chamberlain RS. Gastrointestinal cancer and brain metastasis: a rare and ominous sign. Cancer. 2011;117(16):3630-40. http://dx.doi.org/10.1002/cncr.25940. PMid:21319152

11. Smith RS, Miller RC. Incidence of brain metastasis in patients with esophageal carcinoma. World J Gastroenterol. 2011;17(19):2407-10. http://dx.doi.org/10.3748/wjg.v17.i19.2407. PMid:21633640

12. Ogawa K, Toita T, Sueyama H, Fuwa N, Kakinohana Y, Kamata M, et al. Brain metastases from esophageal

carcinoma: natural history, prognostic factors, and outcome. Cancer. 2002;94(3):759-64. http://dx.doi.org/10.1002/cncr.10271. PMid:11857310

13. Instituto Nacional de Câncer (INCA). Estimativa da Incidência de Câncer para 2008 no Brasil e nas cinco Regiões. Rio de Janeiro. Available from: http://www.inca.gov.br/conteudo_view.asp?id=1793.

14. Altorki N. En-bloc esophagectomy: the three-field dissection. Surg Clin North Am. 2005;85(3):611-9, xi. http://dx.doi.org/10.1016/j.suc.2005.01.005. PMid:15927655

15. Monteiro NML, Araújo DF, Basste-Soares E, Vieira JPFB, Santos MRM, Oliveira PPL Jr, et al. Cancer de esôfago: Perfil das manifestações clínicas, histologia, localização e comportamento metastático em pacientes submetidos a tratamento oncológico em um centro de referência de Minas Gerais. Rev Bras Cancerol. 2009;55:27-32.

16. Joaquim AF, Maturana FAP, Anderle DV, Zambelli HJL, Maldaun MVC. Metástases na coluna vertebral. Rev Neurocienc. 2007;15:240-5.

17. Anderson LL , Lad TE . Autopsy f ind ings in squamous-ce l l carc inoma of the esophagus. Cancer. 1982;50 (8 ) :1587-90. h t tp : / /dx .do i .org/10.1002/1097-0142(19821015)50:8<1587::AID-CNCR2820500820>3.0.CO;2-S. PMid:7116290

18. Chan KW, Chan EY, Chan CW. Carcinoma of the esophagus. An autopsy study of 231 cases. Pathology. 1986;18(4):400-5. http://dx.doi.org/10.3109/00313028609087559. PMid:3822518


Submitted on: November 2, 2014Accepted on: January 5, 2015

CorrespondenceAna Lídia ViaroRua Luís Lopes, 517 – Alcides Mesquita – Ituverava/SP – BrasilCEP: 14500-000Phone: +55 (16) 98177-6390E-mail: [email protected]


a Department of Clinical Oncology - Instituto do Câncer do Estado de São Paulo, São Paulo/SP - Brazil.b Department of Pathology - Hospital das Clínicas da Universidade de São Paulo, São Paulo/SP - Brazil.

Pulmonary nodules: a challenging diagnosis during the follow up of cancer patients

Rafael Caparica Bittona, Ricardo Emanuel Oliveira Ramosa, Sheila Siqueirab, Olavo Fehera

Bitton RC, Ramos REO, Siqueira S, Feher O. Pulmonary nodules: a challenging diagnosis during the follow up of cancer patients. Autopsy Case Rep [Internet]. 2015; 5(1):39-42. http://dx.doi.org/10.4322/acr.2014.048

ABSTRACT

Pulmonary nodules (PN), frequently found on imaging studies, represent a diagnostic challenge during the follow up of cancer patients. However, published data regarding investigation of PNs incidentally found on chest imaging is scarce. The PN may be present at the time of cancer diagnosis, or arise during the treatment or follow-up periods. In the context of the oncologic patient these lesions are quite invariably considered as metastases, what impacts directly on patients´ treatment and prognosis. The present study reports 2 cases of pulmonary nodules found in two patients already diagnosed with cancer. Case 1 referred to a woman with squamous cell carcinoma and two pulmonary nodules, and in case 2 the patient was diagnosed with duodenal adenocarcinoma. Both patients were submitted to pulmonary biopsies before the oncologic treatment. In both cases the nodules were of infectious origin, what changed signifi cantly the neoplasia staging and the oncologic treatment intention. The authors performed a literature review as well as a discussion about the management of PN in cancer patients.

KeywordsMultiple Pulmonary Nodules, Neoplasms, Tuberculosis, Biopsy.

CASE 1

A 68-year-old female patient complaining of

vaginal itching and pain presented a vulvar mass, with

vaginal invasion at gynecological examination. She

denied tobacco smoking. Tumoral biopsy diagnosed

vulvar squamous cell carcinoma. Staging exams

included pelvic MRI, abdominal and thoracic computed

tomography (CT), revealed two spiculated irregular

lung nodules (Figure 1), establishing the diagnosis of

a T3 N0 M1 (lung), stage IV vulvar carcinoma. As the

patient did not present the typical and expected pelvic

and/or inguinal lymph node involvement, we decided

to biopsy the lung nodules, to confi rm the diagnosis of metastasis.

Thus, two nodules were biopsied, revealing the presence of chronic infl ammatory reaction with granulomas (Figure 2A) and the Ziehl-Neelsen staining was positive for mycobacteria, consistent with the diagnosis of pulmonary tuberculosis (Figure 2B). No evidence of neoplasia was found in the biopsied specimen.

After the diagnosis of pulmonary tuberculous nodules, the patient was referred to gynecological

Article / Clinical Case Reports Artigo / Relato de Caso Clínico



40

surgery, with curative intention, as a T3 N0 M0 vulvar cancer, and started the antituberculous standard treatment.

CASE 2

A 73-year-old female patient, previously diagnosed with diabetes mellitus and hypertension, sought medical attention because of jaundice and abdominal pain. Abdominal CT scan revealed a periampular mass measuring 4,7cm at its longest axis and endoscopy confi rmed a necrotic lesion in the duodenal papilla. Biopsy was performed and revealed adenocarcinoma,

consistent with duodenal origin. Staging CTs revealed bilateral pulmonary nodules (1,5cm), raising the suspicion of metastatic disease (Figure 3). Lung biopsies (2 nodules) were performed, revealing chronic infl ammatory granulomatous reaction with caseous necrosis (Figure 4). Ziehl-Neelsen staining was positive for acid fast bacilli, consistent with pulmonary tuberculosis. She started on anti tuberculous treatment, and was referred to surgery with the diagnosis of T4 N0 M0 duodenal adenocarcinoma.

DISCUSSION

The diagnosis of pulmonary nodules in cancer patients, whether metastatic or localized disease, is crucial to determine the best therapeutic approach, ranging from curative intention (non-metastatic) to palliative (metastatic) in most cases. Both cases reported herein presented pulmonary nodules concomitantly with nonpulmonary tumors, what would be presumably interpreted as metastatic disease.

A literature review was performed, using the keywords “tuberculosis and pulmonary nodules”; “tuberculosis and cancer” and “pulmonary nodules and cancer” on the MEDLINE (PUBMED) and TRIP databases. We sought for publications (including case reports and review articles) which described the

Figure 2. Photomicrography of the pulmonary nodule biopsy. A - Presence of granulomas with giant cells (HE, 100X); B - Presence of acid- fast bacilli small arrows, in detail in the inset (Ziehl-Neelsen, 1000X).

Figure 1. Thoracic computed tomography showing subpleural spiculated nodules.


Bitton RC, Ramos REO, Siqueira S, Feher O

41

diagnosis and prevalence of tuberculosis in cancer patients, and we did not defi ne a specifi c period of time for the articles included in the present review.

Pulmonary nodules (PNs) are f requent ly encountered on imaging studies, and represent a diagnostic challenge.1 The range of differentials is wide, including metastases, primary lung cancer, infectious diseases, scar tissue, anthracosis and others. Among patients already diagnosed with cancer, there is scarce data regarding the optimal investigation of PNs. In a series of 800 patients with solitary lung nodules and a previous diagnosis of extra pulmonary cancer, submitted to lung biopsy, resection or autopsy, Cahan et al.2 found approximately 500 primary lung cancers, and 11 benign lesions. In 2006, Khokhar et al.3 published

the evaluation of the records from 151 patients with extrapulmonary cancers and non-calcifi ed pulmonary nodules, finding 42% of malignant nodules, and 58% of benign lesions. In this study, 50% of the patients who were considered to have a malignant nodule had lung cancers (new primary cancer). In a study with 1.104 patients submitted to PN resection, Mery et al.4 observed a 63% percent rate of malignancy in 337 patients with previous cancer history. These results, despite their methodological considerations (retrospective studies), suggest a high incidence of secondary malignancies among patients with extra pulmonary cancers. Albeit, not infrequently, some of the lung nodules may present as non-neoplastic lesions, such as scar tissue, sarcoidosis, or infections, like the cases presented herein.

The decision of performing a pulmonary nodule biopsy in a cancer patient can not be guided by robust evidence due to data scarcity. Although biopsy is the best way to obtain a tissue sample for analysis and to reach an accurate diagnosis, complications associated with the procedure might occur, and this must be taken into account when requesting a diagnostic PN biopsy. Also, we have to consider the costs involved in the procedure, since it requires sophisticated imaging studies, appropriate equipment, a trained radiologist and hospital facilities prepared to deal with procedure´s associated complications. The evaluation on the likelihood of a PN being a metastasis or not should take into account: the primary site of the cancer,

Figure 3. Thoracic computed tomography showing multiple bilateral scattered pulmonary nodules, some of them confl uents and spiculated.

Figure 4. Photomicrography of the lung biopsy showing chronic granulomatous infl ammatory process.



42

previous history of tobacco exposure, the presence of concomitant other sites of metastatic disease, the size of the nodule, it´s evolution over time (nodules which are progressively increasing in size are very suspicious for malignancy), and the aspect on imaging studies (irregular nodules, with a necrotic center and cavitation suggest cancer).1

In the Case 1, for example, patient had no history of tobacco smoking and the presence of lung metastasis would not be expected in a vulvar squamous cell cancer without regional lymph nodes involvement. Given the possibility of a non-metastatic pulmonary disease, we performed the biopsy. In Case 2 we also found odd the presence of a marked pulmonary involvement in the absence of hepatic and other evident regional lymph nodes enlargement. Biopsy results changed our approach from palliative (metastatic disease) to curative (local disease) treatment.

We strongly consider the importance and therefore recommend to raise the suspicion of a non-malignant origin of a PN in a cancer patient. Given the impossibility to accurately estimate the origin of a PN based solely on imaging studies, and the relative safety of the pulmonary

biopsy,2-4 we recognize the lung biopsy as an important tool for therapeutics guidance.

REFER ENCES

1. Ost D, Fein AM, Feinsilver SH. Clinical practice. The solitary pulmonary nodule. N Engl J Med. 2003;348(25):2535-42. http://dx.doi.org/10.1056/NEJMcp012290. PMid:12815140

2. Cahan WG, Shah JP, Castro EB. Benign solitary lung lesions in patients with cancer. Ann Surg. 1978;187(3):241-4. http://dx.doi.org/10.1097/00000658-197803000-00004. PMid:637578

3. Khokhar S, Vickers A, Moore MS, Mironov S, Stover DE, Feinstein MB. Significance of non-calcified pulmonary nodules in patients with extrapulmonary cancers. Thorax. 2006;61(4):331-6. http://dx.doi.org/10.1136/thx.2005.051508. PMid:16467070

4. Mery CM, Pappas AN, Bueno R, et al. Relationship between a history of antecedent cancer and the probability of malignancy for a solitary pulmonary nodule. Chest. 2004;125(6):2175-81. http://dx.doi.org/10.1378/chest.125.6.2175. PMid:15189939


Submitted on: October 30, 2014Accepted on: November 21, 2014

CorrespondenceRafael Caparica BittonClinical OncologyInstituto do Câncer de São Paulo Octavio Frias de Oliveira, ICESPAvenida Doutor Arnaldo, 251 – Sumaré – São Paulo/SP – BrasilCEP: 01255-000Phone: +55 (11) 3893-2000Email: [email protected]


a Department of Neurosurgery - Clínica Multiperfi l, Luanda - Angola.b Department of Physiotherapy - Clínica Multiperfi l, Luanda - Angola.

Huge interparietal posterior fontanel meningohydroencephalocele

Jorge Félix Companioni Rosildoa, Manuel Filipe Dias dos Santosa, Rita de Cassia de Santa Barbarab

Rosildo JFC, Santos MFD, Santa Barbara RC. Huge interparietal posterior fontanel meningohydroencephalocele. Autopsy Case Rep [Internet]. 2015; 5(1):43-48. http://dx.doi.org/10.4322/acr.2014.049

ABSTRACT

Congenital encephalocele is a neural tube defect characterized by a sac-like protrusion of the brain, meninges, and other intracranial structures through the skull, which is caused by an embryonic development abnormality. The most common location is at the occipital bone, and its incidence varies according to different world regions. We report a case of an 1-month and 7-day-old male child with a huge interparietal-posterior fontanel meningohydroencephalocele, a rare occurrence. Physical examination and volumetric computed tomography were diagnostic. The encephalocele was surgically resected. Intradural and extradural approaches were performed; the bone defect was not primarily closed. Two days after surgery, the patient developed hydrocephaly requiring ventriculoperitoneal shunting. The surgical treatment of the meningohydroencephalocele of the interparietal-posterior fontanel may be accompanied by technical challenges and followed by complications due to the presence of large blood vessels under the overlying skin. In these cases, huge sacs herniate through large bone defects including meninges, brain, and blood vessels. The latter present communication with the superior sagittal sinus and ventricular system. A favorable surgical outcome generally follows an accurate strategy taking into account individual features of the lesion.

KeywordsEncephalocele; Brain; Meninges; Physical Examination; Hydrocephalus

CASE REPORT

The fi rst child of his parents, a 37 days old boy,

born through a normal vaginal delivery at term,

was admitted at the Department of Neurosurgery

with the diagnosis of a fi rm interparietal-posterior

fontanel tumor measuring 21 × 7.7 × 7 cm protruding

through a wide circular skull defect, consistent with a

encephalocele. The encephalocele had a sessile base

and also scattered skin ulcerations. The malformation

was cystic on its superior part where trans-illumination

was positive (Figure 1).

The child’s head circumference measured 38 cm; the hairline and ears were normally set. The fontanel had normal tension on both the supine and the vertical positions. The neck and all four limbs had normal confi guration and there were no movement abnormalities. Volumetric computed tomography (VCT) of the head showed a malformation on the midline measuring 22.2 × 8.7 × 8.3 cm protruding through an annular skull defect at the interparietal posterior fontanel region measuring 6.38 × 6.67 cm. The protruded malformation showed two large




44

blood vessels in the midline under the overlying

skin, which extended to the frontal region (Figure 2).

The encephalocele sac was fi lled by cerebral tissue,

meninges, and large blood vessels, which were in

communication with the superior sagittal sinus. The sac

had various partitions, which were in communication

with the ventricular system (Figure 3).

T h e r e f o r e , t h e d i a g n o s i s o f

meningohydroencephalocele was confi rmed. Other

imaging studies such as plain chest x-ray and abdominal

ultrasonography were performed and ruled out

additional defects. Ancillary blood tests were normal.

The patient was operated on in the supine position

with his head tilted to the left. After antisepsis of the

surgical fi eld, a stitch was set at the midline of the

interparietal scalp, 1 cm before the sac neck, in order

to occlude the large scalp blood vessel revealed on

the VCT.

The amount of 255 mL of cerebrospinal fl uid was

drained from the encephalocele cystic portion. An

incision beginning at the puncture site, 1.5 cm laterally

shifted to the right side of midline, was extended,

rounded in shape, until the contralateral paramedian

region. The sac layers were all dissected until the limits

of the bone defect (Figure 4).

The duramater was opened and all the non-

viable and gliotic brain tissue was excised; meticulous

hemostasis observed, preserving as many of the vast

number of veins as possible. The surgical wound was

sutured with absorbable monocryl 2-0 (Figure 5A).

The immediate postoperative was uneventful until the second day when the patient developed hydrocephalus, which required ventriculoperitoneal shunting. The patient was discharged on the fi fth day after the second surgical procedure and was well on the regular follow-up at the neurosurgery outpatient service (Figure 5B). The patient’s mother and the

Figure 1. Interparietal posterior fontanel meningohydroencephalocele (A and B); positive sac transillumination (B).

Figure 2. Brain volumetric CT showing a large epicranial blood vessel extending from the frontal region to the encephalocele.


Rosildo JFC, Santos MFD, Santa Barbara RC

45

clinic’s ethic committee signed their consent for this publication.

DISCUSSION

Congenital encephalocele is a neural tube defect characterized by a sac-like protrusion of the brain, its overlying membranes, and other intracranial structures through a skull defect. It is the neural tube defect of lowest incidence, variable according to different world regions. Occipital encephalocele is the most common type represented by 75–80% of all cases, while the

parietal type represents only 10% .1,2 A large number of encephalocele classifi cations has been proposed according to the (1) origin (congenital or acquired); (2) sac contents (meninges: meningocele, brain: encephalocele; ventricular system, meninges and brain: hydromeningoencephalocele); (3) location (occipital, sincipital, basal, anterior, posterior, supratorcular, infratorcular); (4) intensity of protrusion (grades I, II, and III); and (5) morphological, aesthetical, and functional (internal, external, sincipital, craniofacial malformation). Anterior encephalocele refers to the occurrence anteriorly to the coronal suture; parietal when it is located between the lambdoid and the coronal sutures; and occipital or posterior when it occurs at the lambdoid suture.3,4 Occipital encephaloceles are the most common type, while the interparietal is uncommon. The interparietal encephalocele associated with the posterior fontanel location is rare; our research revealed no publications involving these two locations simultaneously. Other remarkable features of this case include the great sac volume, the large bone defect, and the presence of large blood vessels in the midline under overlying skin and into the sac in communication with the superior sagittal sinus.5

Figure 3. Brain CT scan showing the encephalocele sac content (coronal (A) and sagittal (B) views).

Figure 4. Operating view showing sac dissection.



46

The exact etiology of encephalocele is not entirely defi ned. There are some hypotheses based on experimental studies. The occurrence among brothers and twins points towards a genetic origin of some types. Other authors highlighted environmental factors in the genesis of encephalocele, such as drugs (high doses of vitamin A, valproic acid, cytostatic agents, and folic acid defi ciency); hyperthermia; maternal chronic diseases; and radiation effects.

Congenital encephalocele originates from the lack of separation of the neuroectoderm and the ectodermic surface during neural tube formation, blocking the interposition of the mesoderm between the two germinative layers.

Another hypothesis concerning the secondary protrusion of intracranial structures relates to a primary bone defect due to a failure of cartilage formation during skull ossifi cation. The intracranial hypertension during intrauterine life could be of paramount importance in causing intracranial structure herniation through the bone defect.6,7 The theoretical relation of pressure and force of liquids and solids against surfaces (P = F/S), generates an outwards vectorial force (“protrusion force”) perpendicular to the defi cient bone surface that could enlarge some parts of the brain and other intracranial structures, in case of intracranial pressure elevation during intrauterine life.

Generally, the diagnosis of encephalocele is easy. In these cases, noticeable deformities are present and diagnosis may be made immediately

after birth. Sometimes, the diagnosis is challenging and incidentally discovered during a routine physical examination in asymptomatic patients. Clinical features vary depending on multiple factors, such as the location and volume of the malformation, the grade, sac contents and associated complications. Symptoms include mental retardation, nasal congestion, ocular symptoms, and craniofacial bulging with or without cerebrospinal fl uid leakage.8

Intrauterine diagnosis of encephalocele became feasible by alpha-fetoprotein level determination and by ultrasonography. After birth, the diagnosis is based on physical examination and imaging studies, which evaluate the encephalocele and other possibly associated malformations.

Sac transillumination must be performed whenever possible to detect solid contents within the sac. Cervical spinal x-ray is required to study the anatomy of vertebrae, as well as head CT and magnetic resonance imaging (MRI). The latter is the imaging examination of choice because of its higher specifi city and sensibility to defi ne the sac contents, complemented with angio MRI to better study the malformation’s vascular pattern.9 In this case, MRI was not performed in accordance to the patient’s family decision. The diagnosis was confi rmed by VCT, which showed the presence of blood vessels under the overlying skin from the frontal region of the skull to the malformation. Other encephalocele sac blood vessels were in communication with the sagittal sinus. VCT was also useful to study the skull defect.

Figure 5. Sutured surgical wound (A) and scar incisions 15 days after surgery (B).


Rosildo JFC, Santos MFD, Santa Barbara RC

47

These details were important for surgical planning, preventing complications, and technical challenges.

Surgical treatment of encephaloceles consists of resecting the redundant layers (skin and meninges), repositioning the protruding elements back into the skull, and correcting the deformities. Aspiration of the cerebrospinal fl uid before the incision—in patients with a large encephalocele as in our case—helps the dissection of the sac. The surgical procedure may be performed by endoscopy or by open surgery, as in this case.

Open surgery techniques may access the lesion either intradurally or extradurally, or both. Some surgeons suggest that small bone defects do not necessarily need surgical correction.10,11 In this case report, intradural and extradural approaches were performed. The duramater was opened to permit the evaluation of the inner defect. Brain tissue with gliosis was then excised. The duramater was sutured in watertight fashion followed by multiple-layer suture of the skin. During the surgical procedure, the sac was dissected to its limit with the skull defect, which was not primarily closed until intracranial pressure control and all tissues repair was completed. The surgical wound suture was held with an adequate tension. Every layer was sutured separately to create a strong surface, generating a “contention force” to avoid further protrusion and to permit the reduction of the bone defect as the child’s skull grows with age.

A large number of factors infl uence the outcome of encephalocele surgical treatment; namely, the location, the size, the amount of the herniated brain, the presence of blood vessels into the sac, the presence of hydrocephalus, and additional birth defects.12 Surgeons’ expertise on this type of malformation is also considered a risk factor for surgical results.

Despite the unusual location, the presence of large blood vessels, the size of the sac and skull defect, and the venous drainage to the sagittal sinus, no surgical complications was observed in this case.

CONCLUSIONS

Even in the presence of non-negligible number of complicating factors that may hamper the surgical treatment, a thorough imaging study followed by meticulous surgical planning by an experienced

neurosurgeon allows good outcomes in operative treatment of huge encephalocele.

REFERENCES

1. Volpe JJ. Neurology of the newborn. 3rd ed. Philadelphia: W.B. Saunders; 1995. p. 3-42: Neural tube formation and prosencephalic development.

2. Chávez-Corral DV, López-Serna N, Levario-Carrillo M, Sanín LH. Defectos del tubo neural y de labio y paladar hendido: un estudio morfológico. Int J Morphol. 2013;31(4):1301-8. http://dx.doi.org/10.4067/S0717-95022013000400025. [ Spanish.]

3. Barreto E, Barbosa J, Telles C. [Anatomical classification of anterior encephaloceles]. Arq Neuropsiquiatr. 1993;51(1):107-11. http://dx.doi.org/10.1590/S0004-282X1993000100017. PMid:8215917

4. Vila Morales D. Clasificación de las alteraciones cefa logénicas desde una v i s ión integradora craneomaxilofacial. Rev Cubana Estomatol. 2013;50(1):2-27. Spanish.

5. Rivera Oliva L, Sarmiento Portal Y, Hernández León O, Portal Miranda ME, Martínez Vergara Y. Encefalomenigocele atrésico parietal. Rev Cubana Pediatr. 2011;83(3):296-301. Spanish.

6. Blustajn J, Netchine I, Frédy D, Bakouche P, Piekarski JD, Meder JF. Dysgenesis of the internal carotid artery associated with transsphenoidal encephalocele: a neural crest syndrome? AJNR Am J Neuroradiol. 1999;20(6):1154-7. PMid:10445462.

7. Mylanus EA, Marres HA, Vlietman J, et al. Transalar sphenoidal encephalocele and respiratory distress in a neonate: a case report. Pediatrics. 1999;103(1):E12. http://dx.doi.org/10.1542/peds.103.1.e12. PMid:9917492

8. Berlucchi M, Pedruzzi B, Sessa M, Nicolai P. Diagnostic and therapeutic sinonasal endoscopy in pediatric patients. In: Iancu C, editor. Advances in endoscopic surgery. Rijeka: InTech; 2011 [cited 2014 Oct 31]. Available from: http://www.intechopen.com/books/advances-in-endoscopicsurgery/diagnostic-and-therapeutic-sinonasal-endoscopy-in-pediatric-patients. http://dx.doi.org/10.5772/21886.

9. Sánchez R, Gómez E, Martin M, Burgueño M. Obstrucción nasal neonatal: encefalocele basal. Rev Esp Cir Oral Maxilofac. 2012;34(3):133-5. http://dx.doi.org/10.1016/j.maxilo.2011.08.004.

10. Almirón JF, Arévalo MJA, Bellazzi MV, Fernández NG, Arévalo JC. Encefalocele frontonasal: reporte de un caso clínico. Rev. posgrado VIa. Cátedra Med [Internet]. 2009 [cited 2014 Oct 31];(195):13-6. Available from: http://med.unne.edu.ar/revista/revista195/3_195.pdf



48

11. Diego MC, Gabriel H, Omaira N, Edelmary N, Lenier N, Odalis V. Encefalocele occipital y reparación quirúrgica: presentación de un caso clínico. Rev Mex Neurocienc. 2012 Nov-Dec 13(6):319-23. Spanish.

12. Samaniego Fernández CM, Cancho Candela R, Centeno Malfaz F. Enfermedades graves con diagnóstico prenatal. Cuad Bioet. 2012;23(77):195-214. Spanish. PMid:22548667


Submitted on: October 12, 2014Accepted on: November 10, 2014

CorrespondenceJorge Félix Companioni RosildoDepartment of NeurosurgeryClinica Multiperfi lRua do Futungo de Belas - Morro Bento - Luanda - AngolaPhone: (244) 226434415Email: [email protected]


a Surgery Division - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil.b Surgery Department - Clínica Girassol, Luanda - Angola.

Feeding tube replacement: not always that simple!

Mateus Quitembo Soares da Silvaa,b, Alex Ledermana, Ricardo Frank Coelho da Rochaa, Rodrigo Montenegro Lourençãoa

Silva MQS, Lederman A, Rocha RFC, Lourenção RM. Feeding tube replacement: not always that simple! Autopsy Case Rep [Internet]. 2015; 5(1):49-52. http://dx.doi.org/10.4322/acr.2014.050

ABSTRACT

Although surgical gastrostomy is not a technically troublesome surgery, the procedure may be accompanied by unfavorable outcomes. Most complications occur early in the post-operative period and include feeding tube dislodgment, stomal infection, peritonitis, and pneumonia. The authors report the case of an 83-year-old man who underwent a surgical gastrostomy because of a swallowing disorder after an ischemic stroke. Nine months after the procedure, the feeding tube dislodged and a new tube was inserted with a certain delay and with some diffi culty, causing a false path and consequently an intrabdominal abscess after diet infusion. The outcome was fatal. The authors call attention for meticulous care with the insertion of feeding tubes and advise the performance of imaging control to assure its precise positioning.

KeywordsGastrostomy; Peritonitis; Shock Septic.

INTRODUCTION

Gastrostomy was one of the first abdominal surgeries ever undertaken. In 1837, Egeberg, a Norwegian surgeon, initially conceived the procedure.1,2 In 1849, Sèdilot performed the fi rst gastrostomy, but the patient died due to peritonitis. In the very beginning, this procedure was associated with 100% mortality.3 In 1875, the fi rst successful attempt was attributed to Jones,4 but in 1876, another publication attributed it to Verneuil.1,2 However, the gastrostomy techniques changed over time and the outcomes improved. In 1894, Stamm5 proposed a new technique, which is still being used today. Up until 1979, all gastrostomies were

surgically performed. In 1979, Gauderer and Ponsky6 accomplished the fi rst procedure through endoscopy, and in 1981, Preshaw7 performed a percutaneous procedure with fl uoroscopic guidance.

Although, apparently, the surgical gastrostomy technique seems to be simple, its complications are fairly common. When they occur within the fi rst 15 days of the procedure, re-operation is always mandatory, since the stomach has not yet adhered to the abdominal wall and the tube path has not yet formed. Therefore, when necessary, feeding tube replacement should be postponed for 1 month after the procedure. Prudent




50

surgeons do not recommend replacement of the tube before 3 months to prevent complications.8

CASE REPORT

An 83-year-old man was brought to the emergency facility because of the dislodgment of his gastrostomy feeding tube the day before. He had undergone the gastrostomy 9 months before (Stamm’s technique) because of a swallowing disorder acquired after an acute ischemic stroke. As the stoma was stenotic, it was dilated and a new tube was inserted through the original orifi ce. The patient was discharged afterwards. He experienced abdominal pain and vomiting soon after the diet administration through the replaced tube. He returned to the hospital within 36 hours. Physical examination showed an ill-looking patient, dehydrated, with hypotension, and tachycardia. The abdomen was distended and diffusely tender, predominantly in the left hypochondrium and flank, close to the stoma. The abdominal computed tomography (CT), after the infusion of 40 mL of iodine contrast medium through the gastrostomy tube, showed a cavity formed by peritoneal blockade fi lled by gas and fl uid (Figure 1).

Therefore, the patient was submitted to an exploratory laparotomy. Surgical fi ndings included a signifi cant amount of a lumpy liquid in the peritoneal cavity, and peritoneal adhesions between the loops and

the abdominal wall. At the site of the gastrostomy, a false path was found linking the abdominal orifi ce with a blockade purulent collection, adjacent to the stomach. Another gastrostomy was performed and the stomach was sutured to the abdominal wall. A thorough lavage of the peritoneal cavity with saline was undertaken and the abdomen was drained. The patient was referred to the intensive care unit, but the outcome was accompanied with evisceration requiring re-operation. Multiple organ failure ensued and he died 43 days later.

DISCUSSION

Regardless of the technique used to carry out a gastrostomy, complications occur. At fi rst glance it could be supposed that surgical gastrostomy would always be associated with successful tube placement, but in a meta-analysis this procedure was signifi cantly associated with higher procedure-related mortality and major complications.1,9 In the literature, a 30-day mortality rate after surgical gastrostomy was higher than percutaneous endoscopic gastrostomy, ranging between 21% and 41%. These high percentages are probably due to the severe disability of the patients in the different series.9-11 However, other studies did not find such a difference between the techniques.11-14 Complications after a gastrostomy are divided into minor and major categories. The former include: periostomal

Figure 1. Abdominal CT. A – The extremity of the feeding tube (T) inserted within the abdominal collection (C), which displaced the stomach (S) to the left; B – Contrast medium fi lling the abdominal collection after the injection through the feeding tube.


Silva MQS, Lederman A, Rocha RFC, Lourenção RM

51

infection, stomal leakage, and tube dislodgment. Major complications are represented by severe wound infection, septicemia, dehiscence, aspiration, peritonitis, and gastrointestinal perforation or bleeding. The overall rate of complications after surgical gastrostomy varies between 35% and 60%.12,15-18 In the study by Consentini et al.,12 the rate of major and minor complications were higher among those submitted to the surgical procedure.

Long-term complications of gastrostomy are usually minor and include skin ulceration, dislodgment of the feeding tube, and superfi cial abscesses. Severe long-term complications are rare. Govednnik, Cover and Regner19 reported a severe case of retrograde jejunoduodenogastric intussusception. In the case reported herein, a minor long-term complication occurred represented by the dislodgment of the feeding tube, followed by a major complication, which was the false path during the replacement of a new tube. No imaging control was held before refeeding the patient, and the diet infusion into the peritoneal cavity resulted in peritonitis, septicemia, and death.

We would like to emphasize the care during the replacement of a new feeding tube, because this maneuver is not always that simple. In these cases, a long time after the gastrostomy, one could expect that the stomach should be strongly adhered to the abdominal wall. However, as reinforced with this case report, this impression is seriously in doubt.

We conclude and advise that every feeding tube replacement should be accompanied by an imaging study control.

REFERENCES

1. Wollman B, D’Agostino HB, Walus-Wigle JR, Easter DW, Beale A. Radiologic, endoscopic, and surgical gastrostomy: an institutional evaluation and meta-analysis of the literature. Radiology. 1995;197(3):699-704. http://dx.doi.org/10.1148/radiology.197.3.7480742. PMid:7480742

2. Walker LG Jr. L. L. Staton, M.D., and the first successful gastrostomy in America. Surg Gynecol Obstet. 1984;158(4):387-8. PMid:6369586.

3. Minard G. The history of surgically placed feeding tubes. Nutr Clin Pract. 2006;21(6):626-33. http://dx.doi.org/10.1177/0115426506021006626. PMid:17119170

4. Baehr FH, Frehling S. The spivack gastrostomy. N Engl J Med. 1938;219(9):305-9. http://dx.doi.org/10.1056/NEJM193809012190904.

5. Stamm M. Gastrostomy by a new method. Med Newsl. 1894;65:324-6.

6. Gauderer MWL, Ponsky JL, Izant RJ Jr. Gastrostomy without laparotomy: a percutaneous endoscopic technique. J Pediatr Surg. 1980;15(6):872-5. http://dx.doi.org/10.1016/S0022-3468(80)80296-X. PMid:6780678

7. Preshaw RM. A percutaneous method for inserting a feeding gastrostomy tube. Surg Gynecol Obstet. 1981;152(5):658-60. PMid:6784260.

8. Beres A, Bratu I, Laberge JM. Attention to small details: big deal for gastrostomies. Semin Pediatr Surg. 2009;18(2):87-92. http://dx.doi.org/10.1053/j.sempedsurg.2009.02.005. PMid:19348997

9. Ljungdahl M, Sundbom M. Complication rate lower after percutaneous endoscopic gastrostomy than after surgical gastrostomy: a prospective, randomized trial. Surg Endosc. 2006;20(8):1248-51. http://dx.doi.org/10.1007/s00464-005-0757-6. PMid:16865614

10. Oyogoa S, Schein M, Gardezi S, Wise L. Surgical feeding gastrostomy: are we overdoing it? J Gastrointest Surg. 1999;3(2):152-5. http://dx.doi.org/10.1016/S1091-255X(99)80025-0. PMid:10457338

11. Moller P, Lindberg CG, Zilling T. Gastrostomy by various techniques: evaluation of indications, outcome, and complications. Scan J Gastroenterol. 1999;34:1050-4.

12. Cosentini EP, Sautner T, Gnant M, Winkelbauer F, Teleky B, Jakesz R. Outcomes of surgical, percutaneous endoscopic, and percutaneous radiologic gastrostomies. Arch Surg. 1998;133(10):1076-83. http://dx.doi.org/10.1001/archsurg.133.10.1076. PMid:9790204

13. Stiegmann GV, Goff JS, Silas D, Pearlman N, Sun J, Norton L. Endoscopic versus operative gastrostomy: final results of a prospective randomized trial. Gastrointest Endosc. 1990;36(1):1-5. http://dx.doi.org/10.1016/S0016-5107(90)70911-X. PMid:2107116

14. Rustom IK, Jebreel A, Tayyab M, England RJ, Stafford ND. Percutaneous endoscopic, radiological and surgical gastrostomy tubes: a comparison study in head and neck cancer patients. J Laryngol Otol. 2006;120(6):463-6. http://dx.doi.org/10.1017/S0022215106000661. PMid:16772054

15. Akkersdijk WL, van Bergeijk JD, van Egmond T, et al. Percutaneous endoscopic gastrostomy (PEG): comparison of push and pull methods and evaluation of antibiotic prophylaxis. Endoscopy. 1995;27(4):313-6. http://dx.doi.org/10.1055/s-2007-1005699. PMid:7555937

16. Jarnagin WR, Duh QY, Mulvihi l l SJ, Ridge JA, Schrock TR, Way LW. The efficacy and limitations of percutaneous endoscopic gastrostomy. Arch



52

Surg. 1992;127(3):261-4. http://dx.doi.org/10.1001/

archsurg.1992.01420030023003. PMid:1550470

17. Meguid MM, Williams LF. The use of gastrostomy to correct

malnutrition. Surg Gynecol Obstet. 1979;149(1):27-32.

PMid:451824.

18. Mamel JJ. Percutaneous endoscopic gastrostomy. Am J Gastroenterol. 1989;84(7):703-10. PMid:2500845.

19. Govednik C, Cover J, Regner JL. Preventing retrograde jejunoduodenogastric intussusception as a complication of a long-term indwelling gastrostomy tube. Proc (Bayl Univ Med Cent). 2015;28(1):34-7. PMid:25552793



CorrespondenceMateus Quitembo Soares da SilvaHospital Universitário USPAvenida Professor Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – BrazilCEP: 05508-000E-mail: [email protected]


a Oral and Maxillofacial Surgery Department - University Hospital - University of Sao Paulo, São Paulo/SP, Brazil.

Late treatment of a mandibular gunshot wound

Yuri Slusarenko da Silvaa, Marcia Maria de Gouveiaa, Carlos Augusto Ferreira Alvesa, Rodrigo Chenu Miglioloa

Silva YS, Gouveia MM, Alves CAF, Migliolo RC. Late treatment of a mandibular gunshot wound. Autopsy Case Rep [Internet]. 2015; 5(1):53-59. http://dx.doi.org/10.4322/acr.2014.051

ABSTRACT

Mandibular gunshot injuries are esthetically and functionally devastating, causing comminuted fractures and adjacent tissue destruction depending on the weapon gauge, projectile shape, impact kinetic energy, and density of the injured structures. If the mandibular fracture is not adequate or promptly treated, the broken fragments will fail to heal. In case of a treatment delay, progressive bone loss and fracture contracture will require a customized approach, which includes open reduction, removal of fi brous tissue between the bony stumps, and fi xation of the fracture with a reconstruction plate and autogenous graft. The authors report the case of a 34-year-old man wounded on the mandible 15 years ago. With the aid of computed tomography and a prototype, a surgical plan was designed including open reduction and internal fi xation of the segmental mandibular defect with a reconstruction plate and bone graft harvested from the iliac crest. The postoperative follow-up was uneventful and the 12-month follow up showed a positive aesthetic and functional result.

KeywordsWounds, Gunshot; Mandibular Fractures; Jaw Fixation Techniques; Mandibular Reconstruction.

INTRODUCTION

Several studies demonstrate the high incidence of gunshot injuries to the head and neck among civilians,1-3 which are frequently fatal,3 mainly due to airway involvement and hemodynamic instability4 in accordance with the classic trimodal distribution of trauma deaths.

These injuries are either accidentally caused or due to suicide attempts, homicides, or robberies.1,3 The severity of these injuries varies according to the weapon gauge and its distance to the target,2,4 causing penetration, perforation, or avulsion of the involved tissue.3 Shotguns fi red next to the victim (3 meters distance) are generally devastating or cause death.2,3

Surgeons should be trained to recognize the type of injuries caused by different weapons, and therefore diagnose the extent of the injury,2 since, in these cases, obtaining the patient’s or witnesses’ information is somewhat challenging.4

Theoretically, the establishment of the wound extent depends on the kinetic energy of the projectile and its interaction with the specific tissue.2,3 In this setting, the kinetic energy formula exponent (KE = 1⁄2 MV2, where M = mass and V = velocity) differs from soft to hard tissues, which is 0.5 and 2.5, respectively. In other words, when a hard structure is struck, the final formula will be: KE = 1⁄2 MV.2,5

Article / Clinical Case Report Artigo / Relato de Caso Clínico



54

Therefore, as the mandible is structurally more cortical than cancellous, when it is hit by a projectile, bone will be fragmented3 and soft tissue damaged.

According to the speed, projectile shape, and injured anatomic region of the head and neck, these wounds will be more or less destructive, depending on the dissipated energy. In cases of high-energy dissipation, the impact will create a temporary tissue cavity reaching 11 times the projectile size, and this “ shock wave” will damage distant vessels and nerves.2,3,5

The initial therapeutic approach to all patients is based on the Advance Trauma Life Support (ATLS) to exclude life-threatening lesions.1-4 After respiratory and hemodynamic stabilization, the recommended treatment for the mandibular gunshot injury comprehends the immediate4 copious saline irrigation, necrotic tissue and debris removal,3 open reduction, fracture stabilization, and rigid internal fi xation with a mandibular reconstruction plate.6,7 The choice between the primary or secondary bone graft reconstruction4 should be evaluated depending on the local receptor area conditions, especially regarding the infection risk.3 Autogenous non-vascularized bone grafts, harvested from the anterior or the posterior iliac crest,8 are frequently used, unless the case severity requires a vascularized fi bular graft. In the event that these injuries are not promptly nor adequately treated, the fracture will not heal and progressive bone loss as well as soft tissue contracture will ensue.4,9

The late treatment requires a customized approach, including the open reduction; fi brous tissue removal, and fragments stabilization with a heavy plate reconstruction of the mandibular perimeter.8,9 In order to optimize the results regarding a satisfactory mandibular rehabilitation, the preoperative planning should be based on a prototype10, which will allow a better choice of the fi xation device and graft, as well as to prebend the plate, which will decrease the intraoperative time.6,8

We report the case of a patient with sequalae from a non-treated mandibular gunshot injury.

CASE REPORT

A 32-year-old man arrived at the Oral and Maxillofacial Surgery Department with a history of having been shot 15 years ago. During those years,

the patient could not be treated because of the lack of fi nancial support and social conditions. External examination revealed a depression in the projection of the left mandibular body, shortening of the mandibular length (Figure 1A and B) and mobility of the mandibular body, which was adequately covered by soft tissue (Figure 2).

No spontaneous occlusion was observed due to the lack of some superior and inferior teeth. A craniofacial computed tomography (CT) was performed and prototypes of mandible and face were manipulated, which demonstrated a segmental defect of the left mandibular body. The prototype was manipulated and adjusted following some craniometric points, aligning together the midline of the face and the mandible. The condyles were set in their best fossae position. A 5 cm defect could be determined, which was fi lled with auto-cure resin to maintain the structural positions (Figure 3).

A long and heavy mandibular plate extending from the mandibular ramus to the symphysis was prebent preoperatively and an occlusal guide was fabricated to stabilize the mandible position to the maxilla (Figure 4).

The surgery was undertaken under general anesthesia with nasal intubation, permitting free manipulation of the patient to set an ideal occlusal relationship before fastening the plate, which was step aided by the occlusal guide. A submandibular approach with anterior extension was suffi cient to show the segmental defect. The fragments were repositioned, stabilized, and fixed with the prebent mandibular reconstruction plate that was perfectly adapted without any complementary adjustments. An autogenous corticocancellous free and non-vascularized graft measuring 9 cm was harvested from the left iliac crest, which was adapted to increase the contact surface with the lingual aspect of the proximal stump, improving the graft’s stability and blood supply. The graft was fi xed in an interfragmentary manner with two long screws of 2.4 system and the plate was further fi xed to the mandible. Additional graft stability was gained with a four holes 2.0 system plate fi xed to the graft (Figure 5).

The postoperative period was uneventful, local or systemic infection was not detected during the 6-month follow up was and bone graft maintained viability. The control CT demonstrated adequate bone


Silva YS, Gouveia MM, Alves CAF, Migliolo RC

55

tissue for the further insertion of implants. At the sixth

month, the patient was referred for oral rehabilitation.

Physiotherapy began with the objective of improving

his maximal open mouth until 40 mm was reached

and muscular function was re-established (Figure 6).

Figure 7 shows the long-term postoperative aesthetics

vision and the amplitude of mouth opening.

DISCUSSION

The treatment of mandibular gunshot injuries is challenging from the initial ATLS approach to the bone reconstruction techniques.1

It is necessary to differentiate delayed treatment from late treatment. The former consists of closed treatment with maxillomandibular fixation, or the use of an external pin to stabilize the fragments for 3–6 months,3 while the latter refers to the patient with no prompt care developing mal-union or non-union of bone segments and consequently malocclusion.1,6,8

The conservative treatment of mandibular gunshot wounds was formerly recommended2 based on the bone fragments’ viability assured by the periosteal contact. Another concern was the presence of wound infection. However, recent studies recommend primary reconstruction1,3,4 accompanied by immediate open reduction of fractures and internal rigid fi xation using a titanium reconstruction plate of at least 3 mm thickness and 5 mm width6,7 placed at the inferior border.7 In case a vascularized graft is required, it is cautious to wait until vascular derangements are solved, like thrombosis, swelling, and venous congestion.3 Nevertheless, a temporary reconstruction plate may

Figure 1. A - note the depression in the left mandible body; in B - note the shortening of the anteroposterior mandibular length.

Figure 2. Intraoral aspect. It is possible to note the segmental defect between the wood spatulas.



56

Figure 4. A - A long prebent plate molded to the prototype, from mandibular ramus to symphysis; B - The occlusal guide in position.

Figure 3. A - Frontal view of 3D CT reconstruction demonstrating the initial aspect of the mandibular fracture; B - Frontal view of the prototype, mimicking the CT image shown in A; C - The segmental defect measured 5 cm; D - The acrylic was placed in the defect to re-establish the original anatomy of the mandible.



57

Figure 5. A - An extended submandibular approach was enough to see all defects and adapt the whole plate and graft without excessive tissues traction; B - The plate with at least 4 screws was fi xed to each side of the defect; C - corticocancellous bone graft from the left iliac crest, which size and shape were adequate to reproduce an ideal alveolar ridge; D - The graft was fi xed to the plate, spanning the defect.

Figure 6. Five months CT – 3D reconstruction control; fi nal aspect.

be fi xed as a manner to stabilize the fragments and the three-dimensional mandibular format,7 thus preventing excessive soft-tissue retraction.

The present report demonstrates the feasibility to treat a patient 15 years after the trauma. The concepts aforementioned helped us to design an elective therapeutic plan aiming the re-establishment of stomatognathic system.8,9 Even in the presence of excessive tissue retractions and muscular atrophy, the viability of the non-vascularized graft was assured by the suffi cient remaining soft tissue.7 After a prototype manipulation, a segmental mandibular defect of 5 cm was detected, leading us to use an autogenous corticocancellous bone graft.8 This technique, besides reproducing the mandibular alveolar ridge,3,7 optimizes the osseointegration process through the presence



58

of osteocompetent cells.3,8 The use of a prototype

reduced the operation time signifi cantly, since all plate

adjustments could be undertaken before the surgery.10

The postoperative outcome was uneventful and the

graft maintained viability and capacity to receive

further osseointegrated dental implants.

FINAL CONSIDERATIONS

Despite sc ient if ic and medical advances,

mandibular reconstruction after a gunshot wound

remains challenging. Particularities of each case

prevent a standardized therapeutic approach. CT

imaging and the use of preoperative prototyping

will help the clinician to choose the best graft

characteristics as well as pre bending the plate. Defects

up to 5 cm in length with suffi cient intraoral and extra

oral soft tissue covering are prone to receive a free and

non-vascularized bone graft.

ACKNOWLEDGMENTS

The authors are thankful for the Center

for Information Technology Renato Archer,

Campinas/SP, Brazil, for the prototyping confection.

Figure 7. Aesthetic view and mouth opening amplitude after 12 months of the surgery.

REFERENCES

1. Rana M, Warraich R, Rashad A, et al. Management of comminuted but continuous mandible defects after gunshot injuries. Injury. 2014;45(1):206-11. http://dx.doi.org/10.1016/j.injury.2012.09.021. PMid:23084488

2. Walker RV, Frame JW. Civilian maxillo-facial gunshot injuries. Int J Oral Surg. 1984;13(4):263-77. http://dx.doi.org/10.1016/S0300-9785(84)80033-2. PMid:6434445

3. Cunningham LL, Haug RH, Ford J. Firearm injuries to the maxillofacial region: an overview of current thoughts regarding demographics, pathophysiology, and management. J Oral Maxillofac Surg. 2003;61(8):932-42. http://dx.doi.org/10.1016/S0278-2391(03)00293-3. PMid:12905447

4. Hollier L, Grantcharova EP, Kattash M. Facial gunshot wounds: a 4-year experience. J Oral Maxillofac Surg. 2001;59(3):277-82. http://dx.doi.org/10.1053/joms.2001.20989. PMid:11243609

5. Powers DB, Delo RI. Characteristics of ballistic and blast injuries. Atlas Oral Maxillofac Surg Clin North Am. 2013;21(1):15-24. http://dx.doi.org/10.1016/j.cxom.2012.12.001. PMid:23498328

6. Bak M, Jacobson AS, Buchbinder D, Urken ML. Contemporary reconstruction of the mandible. Oral Oncol. 2010;46(2):71-6. http://dx.doi.org/10.1016/j.oraloncology.2009.11.006. PMid:20036611

7. Goh BT, Lee S, Tideman H, Stoelinga PJ. Mandibular reconstruction in adults: a review. Int J Oral Maxillofac Surg. 2008;37(7):597-605. http://dx.doi.org/10.1016/j.ijom.2008.03.002. PMid:18450424



59

8. Kademani D, Keller E. Iliac crest grafting for mandibular

reconstruction. Atlas Oral Maxillofac Surg Clin North

Am. 2006;14(2):161-70. http://dx.doi.org/10.1016/j.

cxom.2006.05.005. PMid:16959603

9. Coletti DP, Caccamese JF. Diagnosis and management

of mandible fractures. In: Fonseca RJ, editor. Oral and

maxillofacial surgery. Philadelphia: W.B. Saunders Company; 2004. chapter 10; p. 139-61.

10. Primo BT, Presotto AC, de Oliveira HW, et al. Accuracy assessment of prototypes produced using multi-slice and cone-beam computed tomography. Int J Oral Maxillofac Surg. 2012;41(10):1291-5. http://dx.doi.org/10.1016/j.ijom.2012.04.013. PMid:22578568



CorrespondenceYuri Slusarenko da SilvaDivisão de Odontologia Hospital Universitário da Universidade de São PauloAv. Prof. Lineu Prestes, 2565 – Cidade Universitária – São Paulo/SP – BrazilCEP: 05508-000Phone: +55 (11) 3091-9200E-mail: [email protected]

autopsy & case reports

Documents