hodgkin's disease associated with histoplasmosis

HODGKIN 'S DISEASE ASSOCIATED WITH HISTOPLASiMOSIS

NORMAN ENDE, M.D., PHILIP PIZZOLATO, M.D., AND JOSEPH Z I S K I l D , M.D.

IIE i ' uwosE OF THIS PAPER is to present two T additional cases of Hodgkin's disease associated with histoplasmosis. One of these cases Imsented the unique problem of a lymph-node biopsy resembling typical histological tuberculosis superimposed on Hodgkin's disease; however, instead of the cultures producing Koch bacillus a heavy growth of Histoplasma capsu- latzrnz was obtained. Repeated histological examinations of the biopsy tissue failed to reveal any definite bodies compatible with H . capsu- lntum. The fungus was not definitely identified on microscopic sections until autopsy.

Prior to this report, approximately ten cases of lymphoma associated with histoplasmosis have been reported. Hodgson found 138 au- thentic cases of histoplasmosis recorded up to ,January 1, 1950, four of which were associated with Hodgkin's disease, while two of the patients had leukemia. Since then, a case of Hodg- kin's disease corn-lica ted by histoplasmosis, cryptococcosis, an6 tuberculosis has been reported.' I n addition, there have been three recent references in the literature.31 5l 0

CASE REPORTS

Case 1. This patient was a 23-year-old white man who was first admitted to this. hospital in February, 1949, with a complaint of cervical, axillary, and inguinal lymphadenopathy of three months' duration. This was accompanied by a weight loss of approximately 15 lb. Three clays prior to admission, the patient had expe- rienced an onset of fever, cough, sore throat, weakness, and general malaise. Physical exanii- nation at the time of admission revealed an elevated temperature (101 F.), marked generalized lymphadenopathy, splenomegaly, and hepatoniegaly. Agglutination, serology, and liver-function studies and urinalysis were within normal limits at that time. The white blood

From the Clinical Laboratory, Veterans Administra- tion Hospital; and the Department of Pathology, 'I'u- lane University of 1.ouisiana School of Nedicine, New Orleans, Louisiana.

Sponsored by the Veterans Administration and published with the approval of the Chief Medical Director. The statements and conclusions published by the authors are a result of their own study and do not neces- sarily reflect the opinion or policy of the Veterans Administration.

-.____

Received for publication, February 25, 1952.

count was 6250, with 66 per cent neutrophils; the red blood count, 5,020,000, with hemoglobin of 15.5 gin. per 100 cc. T h e total serum protein was recorded as 5.7 gm. per 100 cc.; albuiiiin, 3.9 gin. per 100 cc.; globulin, 1.8 gm. per 100 cc. The patient ran a fever intermit- iently, varying from 101" to 104" F., for the first two weeks, after which time the temperature subsided to normal. A lymph-node biopsy clone shortly a1 ter admission revealed the typical appearance of Hodgkin's disease.

1 lie patient was treated with nitrogen mustard lor a total of 23 mg. over a period of four days. ?'he bone marrow became depressed, the patient became afebrile, and the lymph nodes decreased markedly in size. One month following conipletion of therapy, he complained of tenderness in the left upper quadrant that was associated with a persistent splenomegaly. Koentgen-ray therapy was instituted, and he responded symptomatically. This therapy was followed, however, by a persistent leukopenia. On May 6, 1949, the patient suffered a return of fever and chills and a general recurrence 01 his previous symptoms. An examination on June 1, 1949, showed numerous small discrete nodes palpable in the cervical and supraclavicu- lar areas. Moderately enlarged lymph nodes were present in the left axillary and right fem- oral areas. The liver and spleen were firm, slightly tender, and palpable. Although the patient had a leukopenia, with a white blood count of 3500, it was decided to irradiate the abdomen. However, he showed very little response and continued to be febrile, with a temperature that ranged from 102" to 105" F. Roentgenograms taken on September 14, 1919, revealed widening of the superior mediastinuin with considerable left hilar lymphadenopathy; a mottled appearance in the left upper lung field was also noted.

The patient continued to run a downhill course with a persistent leukopenia. There was no response to the various antibiotics and, despite multiple blood transfusions, the leukopenia was not alleviated. A liver-function test on January 5, 1950, revealed a one-minute bili- rubin of 3.12 mg. per 100 cc. and a total ol 5.25 mg. per 100 cc.; the alkaline pliosphatase was 14.7 Bodansky units. The hemoglobin was 14 gm. per 100 cc. with a red blood count of 1,750,000. The hepatomegaly and s lenomegaly at that time were very marked, an! the patient developed some evidence of ascites. On Janu- ary 18, 1950, he died quietly.

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764 CANCER July 1952

FIG. 1. Lymph node showing both histoplasmosis and Hodgkin’s disease. FIG. 2. Lymph node showing numerous €listoplasi,ia-cap~ulatum bodies. FIG. 3. Adrenal showing granulomatous reaction with Histoplasma capsulutunt. FIG. 4. Original biopsy of case 2, showing Hodgkin’s disease.

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No. 4 HOIXKIN'S DISEASE WITH HISTOPLASMOSIS - Ende et al. 765

A u x w s Y FINDINGS

The lungs revealed subpleural nodules, as well as peribronchial and perivascular infiltra- tions. The liver weighed 2750 gm. and showed numerous gray nodules varying in size from 1 to 3 cm. in diameter. The spleen weighed 900 gin. and showed numerous, irregular, ivory- yellow nodules on the surface and scattered throughout the parenchyma. The terminal ileum and cecum had a few polypoid, gray nodules on the mucosal surface. A linear ulceration was also found in the cecum, measuring 1x0.4 :<0.2 cm. In the transverse colon, submucosal nodules with some evidence of ulceration on the mucosal surface were also found. The right adrenal weighed 15 gm.; the left adrenal, 10 gni. Much of the right adrenal had been replaced by a firm, white, infiltrative type of tissue. A marked generalized lymphadenopathy was noted, particularly of the periaortic nodes and the axillary nodes. There was an enlarge- ment of the nodes in the lesser omentum, porta hepatis, and mediastinum. T h e cut section of the lymph nodes was pale gray and soft. The remaining organs of the body were within normal limits.

Microscopically, the lymph nodes in general revealed a complete replacement of their nor- ma1 architecture by a proliferation of the reticulo-endothelial cells. Considerable pleo- morphism was present, and scattered through- o u t the nodes were seen large cells of the Reed- Sternberg type. In one of the mesenteric lymph nodes and several of the periaortic lymph nodes, well within the lymphomatous tissue, large reticulo-endothelial cells were seen that contained numerous bodies within their cyto- plasni (Fig. 1). These bodies resembled H . capsulatum (Fig. 2). About some areas of necrosis, large reticulo-endothelial cells were seen containing the fungi. Hodgkin's tissue was also lound in the lungs, liver, bone marrow, spleen, and gallbladder.

The adrenal contained large numbers of fungi, but no evidence of lymphoma was found (Fig. 3). Marked erythrophagocytosis was noted in the spleen and bone marrow.

H . rapsulatum was found in the ulcers of the small and large intestine, as well as in the mucosal areas of the colon and ileum in which the iiiucosa was elevated but still intact. No cultures were made at autopsy, and later cultural work was impossibIe because of the fixation of the tissues in formalin.

Case 2. This patient was a 63-year-old white

inan whose history dated back two years prior to his first admission, a t which time he noted general malaise and low-grade fever, particularly in the afternoon. The patient had fre- quent dizziness, tinnitus, blurring of vision, anorexia, and a weight loss of approximately 30 Ib. Six months prior to admission, he developed "hard chills" approximately every other day. A physical examination on May 8, 1951, at another hospital revealed left axillary lymphadenopathy; these lym h nodes appeared hard but were movable an B nontender. A chest roentgenogram was normal. The white blood count was 5650, with 69 per cent neutrophils, 27 per cent lymphocytes, 2 per cent monocytes, and 2 per cent eosinophils. The red blood count was 4,370,000; the hemoglobin, 12.5 gni. per 100 cc. The sedimentation rate (Wester- gren) was 78 mm. per hour. Serology studies and urinalysis were negative. A sputum examination was negative for acid-fast organisms. On hlay 14, 1951, the patient had a biopsy of a lymph node in the left axilla, and a diagnosis of Hodgkin's disease was made (Fig. 4). This lymph node was cultured but was sterile after seventy-two hours. A smear of the lymph node was negative for acid-fast bacilli. A culture of the lymph node for tuberculosis was reported negative after nine weeks. No cultures were made on Sabouraud's dextrose agar. Dur- ing this hospitalization, the patient had a sep- tic type of fever curve, his temperature ranging from 101" to 103" F., chiefly in the afternoon, with a morning temperature varying from 97" to 101" F. The patient was transferred to this hospital on June 30, 1951, for deep roentgen- ray therapy. The slides of the original biopsy were received here, and the diagnosis of Hodg- kin's disease concurred in.

The laboratory findings showed a white blood count of 9050 with 93 per cent neutro-

hils. The red blood count was 5,000,000; the ematocrit, 47 er cent. Serology examination

at this hospita revealed 31 Kahn units. The spinal fluid had a negative com lement fixa-

peated white blood counts varied between 7600 and 8500. T h e total serum protein was 6.8 gni. per 100 cc., with an albumin of 3.9 gm. per 100 cc. Liver-function studies and urinalyses were essentially normal. A chest roentgenogram on July 2, 1951, revealed moderate cardiac en- largement and dense, lymphangitic- type infiltration extending throughout both lung fields and greatest in the hilar regions. This paren- chymal infiltration was not noted in the roentgenogram taken May 9, 1951.

On July 18, 1951, a biopsy of a left supra- clavicular lymph node revealed marked necro- biosis but very few viable cells. Those present were suggestive of a granulomatous reaction, but no definite diagnosis could be made. Acid-

f H tion and a normal colloidal g o d P curve. Ke-

766 CANCER July 1952 VOI. 5

gus was found in one slide of this biopsy, when i t was reviewed after death.

A bone-marrow biopsy on July 20, 1951, was reported as essentially normal, but no cultures were made. Bone-marrow examination on Aug- ust 7, 1951, failed to show any fungus; cultures, however, obtained at this time grew the patho- gen. Tuberculin, coccidioidin, and histoplas- niin skin tests were negative. Later in the patient's course, additional positive cultures were obtained from the bone marrow, blood, and sputum. Following the use of nitrogen mustard, the patient improved clinically, with a decrease in the size ot his axillary lymph nodes but with progression of his chest roentgeno- graphic findings. The patient received 88 mg. of ACTH from July 27, 1951, to July 30, 1951, and a total of 22.3 mg. of nitrogen mustard in divided doses over a ten-day period.

During his course in the hospital, the patient ran an intermittent spiking fever, his temperature going up practically every afternoon to 101 a or 102" F. When the patient was suspected of having tuberculosis, he was taken off ACTH and put on streptomycin. He did not respond to any form of therapy except for a moderate decrease in the size of the axillary nodes. He went progressively downhill and died on Sep- tember 29, 1951.

FIG. 5. Lymph node showing an area of necrosis with Langhans giant cells, resembling tuberculosis.

fast stains on the tissue sections were negative, but no cultures were taken from this lymph node. On July 20, 1951, the patient was given nitrogen-mustard therapy. However, a chest roentgenogram taken on July 25, 1951, showed further increasc in the lyrnphangitic parenchy- mal infiltration throughout both lung fields. On July 26, 1951, another biopsy of the left axillary nodes was done. At this time the diagnosis of Hodgkin's disease was made, and granulomatous areas with necrosis compatible with tuberculosis were seen (Fig. 5). No yeastlike bodies were found in the tissue sections of this biopsy or at later retrospective examinations. Rare acid-fast rods were seen in one tissue section. T h e lymph ilode was cultured on Pet- ragnani medium and on Sabouraud's dextrose agar and blood agar. On the eighth day, a fungus growth was noted in the blood agar and Sabouraud's. On the eleventh day, a few definite tuberculate chlamydospores of H . capsu- lutum were seen (Fig. 6 ) . This fungus was later verified by the Army Medical Service Graduate School. Cultures on Petra nani medium re-

tember 5 , 1951, another biopsy of a left axillary node was carried out. Tissue sections revealed a few bodies that, in the light of the culture, might have re resented H . capsulatum. One

vealed no growth after eig a t weeks. On Sep-

small focus de i nitely identifiable as the fun-

T h e heart weighed 360 gm. T h e initral valve showed moderate thickening, and elevated, grayish-yellow material was found intimately attached to the posterior papillary muscle and chordae tendineae as well as to the endocardium underlying the papillary muscle. A similar nodule, 0.3 cm. in diameter, was noted in the right ventricle, 1 cm. beneath the middle cusp of the puIinonic valve. The combined weight of the lungs was 1000 gm. Both lungs had generally smooth pleura, except for scat-

FIG. 6. Thirty-day culture on Sabouraud's dextrose agar showing tuberculate chlarnydospores.

No. 4 HODCKIN’S DISEASE WITH HISTOPLASMOSIS . Ende et al. 767

tered areas of thickening. On section, the lungs showed considerable emphysema, and a diffuse iiidurative process was present throughout all the lobes, particularly the upper lobes bilaterally. These infiltrated areas were grayish white, and associated with them there appeared to be considerable dark, grayish-black areas of fibrosis. T h e hilar lymph nodes bilaterally were enlarged and grayish white. The liver weighed 1400 gin., and the cut surface revealed no unusual changes. Each kidney weighed 150 gni. and revealed a finely granular surface. Occasional, irregular yellow nodules were encountered on the surface and in the parenchyma. Some of the yellow areas gave the appearance of linear streaks and ran parallel to the cortical and medullary striations. Numer- ous, large, partially necrotic lymph nodes were cncoun tered, particularly around the body of pancreas, some measuring up to 4 cm. in diameter. The right axillary lymph nodes were greatly enlarged and formed a confluent mass measuring 12X6x4 cm. (Fig. 7). Numerous necrotic areas were present. The stomach contained a sinall amount of bloody mucus. A punched-out ulcer crater was encountered 1 cm. below the pylorus, the center of which had a blood vessel projecting into the defect with a small thrombus in its lumen. I’he small and laige intestines contained a large amount of blood. The remainder of the organs appeared essentially normal.

Microscopically, the axillary lymph nodes were replaced by a granulomatous reaction in which numerous reticulum cells and some mul- tinucleated forms were present. Plasma cells, lymphocytes, and fibroblasts were present, and many o f the reticulum cells were filled with yeastlike Hisloplasma bodies. There were small and large areas of necrosis at the periphery of which were seen reticulum cells with H . capsu- Ia t t sm. These lymph nodes were felt to repre- sent the combined picture of histoplasmosis and Hodgkin’s disease. T h e thyroid showed granulomas focally placed, but no evidence of yeastlike bodies was found.

T h e liver had evidence of fatty metamorpho- sis and granulomas composed of epithelioid cells, lymphocytes, and plasma cells. These were located in portal spaces as well as lobules, but no yeastlike bodies could be identified.

T h e lungs showed marked interstitial fibrosis with thickening of arterioles. Large areas of caseation were present, surrounded by epithelioid cells and reticulum cells that contained yeastlike bodies. Numerous smaller

granulomas were present, containing yeastlike bodies associated with lymphocytes and plasma cells. Evidence of H . capsulatuin was found in the pancreas, epididymides, testes, seminal vesicles, aclrenals, and kidneys. T h e spleen contained evidence of erythrophagocytosis. T h e heart showed necrotic material on the chordae tentlineae of the posterior niitral cusp and underlying endocardium, in which macro- phages containing yeastlike bodies werc present. I’he brain sections were essentially normal.

DISCUSSION

Case 1 is similar to some of the cases previously described in the medical literature. T h e original diagnosis in case 1 was Hodgkin’s disease, which was concurred in by the Armed Forces Institute of Pathology. These original biopsy slides were reviewed after autopsy, and even in retrospect no bodies identifiable as H . capsulatuin were found. T h e Schiff stains did not yield additional information in either of the two cases. Whether the fungus could have been cultured in the first case remains a matter of conjecture, since no cultures were made.

The unique features of case 2 are wch as to make i t worthy of further discussion. The first biopsy was considered to be Hodgkin’s disease, and the third biopsy was diagnosed as Hodg- kin’s disease with tuberculosis. The slides were reviewed by two other institutions, one of which was the Armed Forces Institute of Pathology, and all concurred in the combined diagnosis. Numerous sections of the third biopsy, stained with hematoxylin and cosin, Masson, Schiff, and silver, did not yield histological evidence of a fungus. It was not until eight days after the biopsy, when a heavy growth of H . capsu- Zatuin appeared on the culture mediums, that the diagnosis of a fungus infection was considered pathologically. So far as we can deter- mine, this phenomenon of positive cultures without evidence of the fungus on the tissue sections has not occurred in the previously described cases in which histoplasmosis and Hodgkin’s disease occurred simultaneously. ‘The two acid-fast rods found on one section o f the lymph node from case 2 must be considered as contaminants, as no further bac- teria were seen and the cultures for tuberculosis were negative after six weeks. T h e sources oE such bacterial contamination are manifold. We have found H.-capsulatum filaments them- selves to be acid-fast, particularly if the slides are underdecolorized, and according to some

768 CANCER July 1952 1’01. 5

authorities an exceptional case of histoplasmosis has shown the niycelial form of the fungus in tissue.’ Whether this is what occurred in case 2 must be considered only as a possibility. .

Ewing has said that “. . . tuberculosis follows Hodgkin’s disease like a shadow.” Sternberg described tuberculosis in ten out of fifteen cases in which the diagnosis was based on the occur-

rence of acid-fast rods, but in sonic cases he had niade the diagnosis purely on histological appearance. In the light of case 2, one wonders if some of Sternberg’s and other authors’ cases8 could have actually been histoplasmosis and Hodgkin’s disease instead of tuberculosis and Hodgkin’s disease.

T h e possible explanations concerning the

FIG. 7 . A inass of right-axillary lymph nodes, showing enlargeiiient and marked necrosis.

No. 4 HODGKIN’S DISEASE WITH HISTOPLASMOSIS - En& et aI. 769

association of the two diseases have recently been adequately discussed by Murray and Brandt,s and further discussion at present is unnecessary. The postulates are: 1. Coincidence 2. Malignant lymphoma predisposing to fun-

gus infection. 3. Development of a malignant reticulosis as

a result of the fungus 4. A histological reaction to the fungus that

stimulates a malignant lymphoma. Since our experience with case 2, we have

instituted the policy of receiving all lyinph nodes in a sterile condition from the operating room. They are then cultured on Sabouraud’s dextrose agar, Petragnani agar, and blood agar routinely. We kecp all cultures for thirty days, which is perhaps longer than necessary. T h e use of blood agar and Sabouraud’s is of partic- ular importance, since in our cases here the fungus has not grown on Petragnani. It is unfortunate that blood-agar plates are dis- carded at niany institutions at the end of forty- eight to seventy-two hours, for the fungus will not appear usually until about the seventh to tenth day.

With this method of culturing, perhaps addi-

tional unsuspected cases may be rliagriosecl when routine histological sec Lions I d i l , ali t l

lurther correlation of nialignant 1yinphoni;t and histoplasmosis may be established.

SUMMARY

Two cases are presented that had the simul- L;lneous picture of histoplasmosis and of Hotlg- kin’s disease. Both were originally diagnosed as Hodgkin’s disease. The presence of N. capszi- lati ini was first established at autopsy in one case and by cultural work in the other. The latter patient presented a unique feature: the fungus grew on cultures from a lymph-node biopsy that gave no evidence of the yeastlike bodies on tissue sections, despite study of many sections with various types of staining. l ’he tissue slides, however, presented a picture resembling Hodgkin’s disease and tuberculosis. Rare acid-fast rods were found, but cultures were negative for tuberculosis.

A suggestion is offered to receive lymph-node biopsies, particularly in suspected 1yniphoni;i cases, in a sterile condition from the operating room, and to culture them routincly for lungus and other organisms.

KEFEREKCES

I . ( :OSANT. S. F.; M A W I N , I). S.; Sxfrrl l , I). ‘I. .; BAKER, R. I)., a i d CALLAWAY, J. L.: Manual of Clinical Mycol- ogy. Philadelphia. W. H. Saunders Co. 191.5.

2. EWING, J: Neoplastic Diseases; a Treatise on T ~ I - mors, 4th ed. Philadelphia. W. 13. Saunders Co. 1940.

3. FURCOLOW, M. L.: Further observations on histo. plasmosis. Pub. Health R e p . 65: 96994 , 1950.

4. Holx;so~. C. H.; WEED, L. A., and CLAGETT, 0. T.: I’ulinonary histoplasmosis; summary of data on reported cases and a report on two patients treated by lol)ectomy. J . A . M . A . 145: 807-810, 1951.

5. MURRAY, J. F., and BRAHDT, F. A,: Histoplasmosis and malignant lymphoma. Am. 1. Z’alli. 27: 783-799, 19.51.

6. KAFTERY, A.: Subclinical histoplasmosis; gastro- intestinal histoplasmosis of children. I . A . df . A . 145: 216-219, 1951.

7. KODCXR, R. C.; TERRY, L. L., arid BIWOKD, C. 11.: Histoplasmosis, cryptococcosis and tuberculosis compli- cating Hodgkin’s disease. A m . 1. C h i . Pullr. 21: 153-157, 1951.

8. SIMONDS, J . P.: Hodgkin’s disease. Arch. F d h . 1 : 394-430, 1926.

9. STERSBERG, C.: Uber eine eigenartigc untcr clcni Dilde der Pseudoleukaniie verlaufcntle ‘l’ul)erriilosc tlcs lymphatischen Apparatcs. Zeilscltr. f . f f e i /kur ide I!): 21-90, PI. I , 11, 1898.

hodgkin's disease associated with histoplasmosis

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