chapter 4 tumours of the small intestine · global vision of the abdomen, can con-tribute to...

CHAPTER 4

Tumours of the Small Intestine

The small intestine has a remarkably low incidence of primarycarcinomas, especially considering its size. Those that dooccur are often related to genetic syndromes, especially famil-ial adenomatous polyposis.

Lymphomas and endocrine tumours are as frequent as carci-nomas and have important associations with precursor condi-tions such as coeliac sprue, multiple endocrine neoplasia andVon Recklinghausen Syndrome.

The small intestine is the main site for metastatic tumours inthe gastrointestinal tract.

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WHO histological classification of tumours of the small intestine1

70 Tumours of the small intestine

Epithelial tumoursAdenoma 8140/02

Tubular 8211/0Villous 8261/0Tubulovillous 8263/0

Intraepithelial neoplasia2 (dysplasia)associated with chronic inflammatory diseases

Low-grade glandular intraepithelial neoplasiaHigh-grade glandular intraepithelial neoplasia

CarcinomaAdenocarcinoma 8140/3Mucinous adenocarcinoma 8480/3Signet-ring cell carcinoma 8490/3Small cell carcinoma 8041/3Squamous cell carcinoma 8070/3Adenosquamous carcinoma 8560/3Medullary carcinoma 8510/3Undifferentiated carcinoma 8020/3

Carcinoid (well differentiated endocrine neoplasm) 8240/3Gastrin cell tumour, functioning (gastrinoma) 8153/1

or non-functioning Somatostatin cell tumour 8156/1EC-cell, serotonin-producing neoplasm 8241/3L-cell, glucagon-like peptide and PP/PYY producing tumour

Mixed carcinoid-adenocarcinoma 8244/3Gangliocytic paraganglioma 8683/0Others

Non-epithelial tumoursLipoma 8850/0Leiomyoma 8890/0Gastrointestinal stromal tumour 8936/1Leiomyosarcoma 8890/3Angiosarcoma 9120/3Kaposi sarcoma 9140/3Others

Malignant lymphomasImmunoproliferative small intestinal disease 9764/3

(includes α-heavy chain disease)Western type B-cell lymphoma of MALT 9699/3Mantle cell lymphoma 9673/3Diffuse large B-cell lymphoma 9680/3Burkitt lymphoma 9687/3Burkitt-like /atypical Burkitt-lymphoma 9687/3T-cell lymphoma 9702/3

enteropathy associated 9717/3unspecified 9702/3

Others

Secondary tumours

PolypsHyperplastic (metaplastic)Peutz-JeghersJuvenile

_____________1 This classification is modified from the previous WHO histological classification of tumours {845} taking into account changes in our understanding of these lesions. In the case of

endocrine neoplasms, it is based on the recent WHO classification {1784} but has been simplified to be of more practical utility in morphological classification.2 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded

/0 for benign tumours, /3 for malignant tumours, /2 for in situ carcinomas and grade III intraepithelial neoplasia, and /1 for unspecified, borderline or uncertain behaviour. Intraepithelialneoplasia does not have a generic code in ICD-O. ICD-O codes are available only for lesions categorized as glandular intraepithelial neoplasia grade III (8148/2), and adenocarcino-ma in situ (8140/2).

TNM classification1, 2

T – Primary TumourTX Primary tumour cannot be assessedT0 No evidence of primary tumourTis Carcinoma in situ

T1 Tumour invades lamina propria or submucosaT2 Tumour invades muscularis propriaT3 Tumour invades through muscularis propria into subserosa or

into non-peritonealized perimuscular tissue (mesentery orretroperitoneum3) with extension 2 cm or less

T4 Tumour perforates visceral peritoneum or directly invades otherorgans or structures (includes other loops of small intestine,mesentery, or retroperitoneum more than 2 cm and abdominalwall by way of serosa; for duodenum only, invasion of pancreas)

N – Regional Lymph NodesNX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasis

M – Distant MetastasisMX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Stage Grouping

Stage 0 Tis N0 M0Stage I T1 N0 M0

T2 N0 M0Stage II T3 N0 M0

T4 N0 M0Stage III Any T N1 M0Stage IV Any T Any N M1

_____________1 {1, 66}. This classification applies only to carcinomas.2 A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.3 The non-peritonealized perimuscular tissue is, for jejunum and ileum, part of the mesentery and, for duodenum in areas where serosa is lacking, part of the retroperitoneum.

TNM classification of tumours of the small intestine

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71Squamous cell carcinoma

DefinitionA malignant epithelial tumour of the smallintestine. Neoplasms of the periam-pullary region include those of the duo-denal mucosa, ampulla of Vater, commonbile duct and pancreatic ducts.

ICD-O codesAdenocarcinoma 8140/3Mucinous adenocarcinoma 8480/3Signet-ring cell carcinoma 8490/3

EpidemiologyRelative to the length and surface area ofthe small intestine, adenocarcinomas ofthe duodenum, jejunum and ileum areremarkably rare. Data from the UnitedStates SEER program {1928} for 1973 to1987 show an age-adjusted incidencerate for adenocarcinoma of the smallintestine of 0.4 per 100,000 per year.Although some reports suggest anincreasing incidence of adenocarcinomaof the small intestine {1339, 1715}, this isnot reflected in the SEER data base. Themedian age at manifestation is approxi-mately 67 years for non-mucinous ade-nocarcinoma, mucinous carcinoma andcarcinoids.

AetiologyA major factor in the development ofsmall bowel adenocarcinoma is chronicinflammation. In particular, long-standingCrohn’s disease with multiple strictures isassociated with small bowel carcinoma{1016, 1223, 582, 1578}. One studyshowed that individuals with Crohn’s dis-ease have an 86-fold increased risk ofadenocarcinoma of the small intestine{623}. Coeliac disease is another wellrecognized aetiological factor for smallbowel carcinoma {116, 1354, 2141}.There is some epidemiological evidencethat cigarette use and alcohol consump-tion are also risk factors {1339}.Carcinoma can develop in ileostomies inpatients with ulcerative colitis or familialadenomatous polyposis (FAP) subse-quent to colonic metaplasia and intraepi-thelial neoplasia in the ileostomy mucosa{1599, 558}. Carcinoma can also arise in

ileal conduits {1965} and in ileal reser-voirs, both continent abdominal (Kock){347} and pelvic {2013, 1730}. Theoccurrence of adenocarcinomas inMeckel’s diverticulum {985} and in smallbowel duplications {496} has beenreported.

LocalizationThe duodenum is the main site, contain-ing more adenocarcinomas than thejejunum and ileum combined {1928}. Inthe duodenum, carcinomas are mostcommon around the ampulla of Vater{1657, 2123}, possibly due to biliary orpancreatic effluents.

Clinical featuresSymptoms and signsThe symptoms of small bowel adenocar-cinoma are related to the size and loca-tion of the tumour. In the jejunum and ileum, early symp-toms are often non-specific, with vagueperiumbilical abdominal pain and rum-bling. Later, cramp-like pain is present inup to 80% of cases, and this may beaccompanied by nausea, vomiting,weight loss, asthenia, and intermittentobstructive episodes. Massive bleedingis rare (8%), but an important clinicalfinding is chronic bleeding with second-ary iron-deficiency anaemia, which maybe found in the early stages of develop-ment of the tumour. Other clinical signsare bloating of the loops of the bowel,meteorism, and the presence of a palpa-ble mass {20}. Perforation is a possiblecomplication of small intestinal carcino-mas {681}. Duodenal carcinomas present in a differ-ent manner, because of the larger cir-cumference of the duodenum comparedwith the more distal parts of the smallintestine, and because of the relativeaccessibility of the duodenum to endo-scopy {498, 1657}. Unlike jejunal andileal carcinomas, carcinomas of the duo-denum, especially those of the proximalduodenum, do not present with bowelobstruction. Biliary obstruction, frank oroccult blood loss and abdominal pain

are the commonest presentations {2123}.Some tumours are largely asymptomaticand may be discovered by endoscopy{1809}.

ImagingThe radiological methods that have thehighest diagnostic accuracy are spiralCT scan with contrast medium and ente-roclysis; the two methods can be com-plementary. With enteroclysis, a fillingdefect, an irregular and circumscribedthickening of the folds with wall rigidity,slowed motility, eccentric passage of thecontrast medium, or a clear stenosis maybe observed {199}. Small bowel adeno-carcinoma may appear on CT scan as anannular lesion, a discrete nodular mass,or an ulcerative lesion. CT scan, withglobal vision of the abdomen, can con-tribute to staging the tumour {1145}.With push enteroscopy, it is possible tovisualize endoscopically the entirejejunum. Expansion or infiltrative growthof the tumour causes at a relatively earlyphase, an alteration of the endoluminalsurface; via push enteroscopy it is thuspossible to identify small lesions and totake biopsies. Push enteroscopy is also agood diagnostic method to diagnosetumours causing occult bleeding {1495,1619}.Exploration of the ampulla of Vaterrequires a lateral viewing fibroscope,adapted to tissue sampling and endo-scopic sphincterotomy. The terminalileum may be visualized through retro-grade ileoscopy during colonoscopy.Sonde enteroscopy can identify tumoursthroughout the small bowel, but it is ham-pered by the inability to take biopsies{1064}.

MacroscopyThe macroscopic pathology of smallbowel carcinomas is determined by anumber of factors, of which stage and siteare the most significant. Many carcinomasof the jejunum and ileum are detected atan advanced stage {498, 189}. A furtherdeterminant of the macroscopic featuresis the presence or absence of predispos-

N.H. Wright M. PennazioJ.R. Howe L.H. SobinF.P. Rossini N.J. CarrN.A. Shepherd I. Talbot

Carcinoma of the small intestine

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ing factors, namely, an associated adeno-ma, coeliac disease, Crohn’s disease,radiotherapy, previous surgery (notablypouch surgery and ileostomy), polyposissyndromes, Meckel‘s diverticulum, andintestinal duplication.Carcinomas may be polypoid, infiltratingor stenosing. Jejunal and ileal carcino-mas are usually relatively large, annular,constricting tumours with circumferentialinvolvement of the wall of the intestine{189}. Most have fully penetrated themuscularis propria and there is ofteninvolvement of the serosal surface {16}.Adenocarcinoma of the ileum may mimicCrohn’s disease clinically, radiologically,endoscopically, and at macroscopicpathological assessment {745}.Although circumferential involvementcan occur, duodenal carcinomas areusually more circumscribed, with amacroscopically demonstrable adeno-matous component in 80% of cases{966, 496}. Thus, they are often protuber-ant or polypoid, and the central carcino-matous component may show ulceration{1267}. Carcinomas arising at the ampul-la of Vater tend to cause obstructivejaundice before they have reached alarge size; they are usually circum-scribed nodules measuring not more

than 2-3 cm in diameter. They may bewithin the wall of the duodenum or proj-ect into the lumen as a nodule.Unusual macroscopic features, e.g., thelack of ulceration, the predominance ofan extramural component and the pres-ence of multicentricity, should alert thepathologist to the possibility that thetumour is a metastasis.

MicroscopyHistologically, small bowel carcinomasresemble their more common counter-parts in the colon, but with a higher pro-portion of poorly differentiated tumours{496, 1006}. Some are adenosquamouscarcinomas {624, 1345, 1525}.Carcinomas with prominent neoplasticendocrine cells {821} and with tripartitedifferentiation, i.e. with glandular, squa-mous, and neuroendocrine components{111, 207}, have also been reported.Small cell carcinomas (poorly differenti-ated endocrine carcinomas) are rare{2196} (see next chapter).In metastatic carcinoma of the smallintestine, evidence of a pre-existingadenomatous component can be mim-icked by the ability of the intestinalmucosa to cause differentiation of themetastatic tumour {1732}; this phenome-non can give the erroneous impression ofa primary carcinoma of the small intes-tine.

Tumour spread and stagingSpread of small bowel carcinomas issimilar to that of the large bowel. Directspread may cause adherence to adja-cent structures in the peritoneal cavity,usually a loop of small intestine, althoughthe stomach, colon or greater omentummay also be involved. Lymphatic spreadto regional lymph nodes is common.Haematogenous and transcoelomicspread also occur. Diffuse involvement of

the ovaries, Krukenberg tumour, hasbeen reported {1089}. Staging of carci-nomas of the small intestine is by theTNM classification {1, 66}. For tumours ofthe ampulla of Vater, because of thecomplicated anatomy at this site, a sep-arate TNM classification is used.Alternative staging systems have beenproposed {1888}.

GradingGrading of small intestinal carcinomas isidentical to that used in the large bowel,namely, well, moderately and poorly dif-ferentiated, or high- and low-grade.

Precursor and associated lesionsAdenomasThere is good evidence for an adenoma-carcinoma sequence in the small intes-tine as in the colon {1506, 1709}.Residual adenomatous tissue at the mar-gins is seen in 80% of duodenal adeno-carcinomas {966}. Perzin and Bridge{1505} described 51 patients with adeno-mas of the small intestine – 65% had co-existing carcinoma. In patients withfamilial adenomatous polyposis (FAP),38/45 (84%) of duodenal carcinomasharboured adenomatous tissue {1709};whereas 30% of 185 sporadic adenomasshowed carcinoma {1706}. The age atdiagnosis of adenomas without carcino-ma is lower than for adenomas with car-cinoma or for carcinomas, and there is anearly identical spatial distribution ofthese three types of tumour in the smallintestine {1706}.Since the advent of endoscopic tech-niques, the earliest stages of malignantchanges can be followed in adenomas ofthe duodenum and peri-ampullary region{147}, where often the size of the lesionmay warrant extensive sampling. In astudy of post-colectomy patients withFAP, random biopsy specimens of ilealmucosa showed foci of abnormal, dys-plastic crypts resembling dysplasticaberrant crypt foci of the colon in somepatients, supporting the concept that, atleast in patients with FAP, oligocryptaladenomas are a step in the developmentof epithelial neoplasms of the small intes-tine {132}.Although adenomas can occur through-out the small intestine {399}, the com-monest site is the ampullary and peri-ampullary region {1366}. Adenomas canbe multiple, even in patients without ahistory of FAP {958, 1317, 685}.

A BFig. 4.01 A Tubulovillous adenoma of the duodenum and the ampulla of Vater which is greatly distended.B Villous adenoma of duodenum adjacent to normal mucosa.

Fig. 4.02 Adenocarcinoma of small intestine.

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73Carcinoma

Histologically, adenomas in the smallintestine are similar to those in the colon,but with a propensity to be more villousor tubulovillous in architecture {2127A,1342}. The adenomatous cells resemblethose of colonic adenomas, with varyingdegrees of dysplasia, but the columnarcells are unequivocally enterocytic innature; goblet cells are frequent andsome lesions have Paneth and endocrinecells {500, 1237}.

Other associated conditionsJuvenile polyposis and Peutz-Jegherssyndrome have a recognized associationwith small intestinal carcinoma {1830,1604, 1506}.

Genetic susceptibilityThese include: familial adenomatouspolyposis (FAP), hereditary non-polypo-sis colorectal cancer (HNPCC), Crohn’sdisease, coeliac disease, ileostomies,ileal conduits and pouches (especially

after colectomy for FAP), Peutz-Jegherssyndrome and juvenile polyposis. Thehighest risk is in FAP. Duodenal adeno-mas develop in a high proportion of FAPpatients {228}, and the relative risk ofduodenal carcinoma is over 300 timesthat of the normal population {1397};these carcinomas represent a majorcause of death in FAP patients after totalcolectomy.In FAP, carcinomas are usually associat-ed with a macroscopically definable ade-nomatous component and are usuallyaccompanied by many other adenomasin the second and third parts of the duo-denum {1808, 204}. Adenomas do occurelsewhere in the small bowel in FAP,including the ileum and the pelvic ilealreservoir {1376}, but carcinomas are dis-tinctly unusual.It has been proposed that patients withcarcinoma of the small intestine have anincreased incidence of multicentric car-cinomas of the gastrointestinal tract, with

an increased incidence of gastric andcolonic carcinomas in first-degree rela-tives {1830}. Primary small bowel carci-noma can be the presenting neoplasm inhereditary non-polyposis colorectal can-cer (HNPCC), occurring at an earlier agethan sporadic cases and carrying a bet-ter prognosis {1604, 125}.

GeneticsPatients with HNPCC and germline muta-tions of hMSH2 or hMLH1 have anapproximately 4% lifetime risk of smallbowel cancer, which exceeds the risk ofthe normal population 100 fold {2005}. InPeutz-Jeghers syndrome, the most com-mon site of polyps is in the small intes-tine, and 2-3% of patients are at risk fordeveloping intestinal carcinoma {431,721}. In juvenile polyposis, small intestin-al polyps occur with less frequency, butduodenal carcinoma has been reported{749}. Genes mutated in the germline ofpatients with inherited syndromes that

BAFig. 4.03 Adenocarcinoma. A Well differentiated, invasive. B Poorly differentiated, infiltrating fat.

BAFig. 4.04 Mucinous adenocarcinoma of the ileum arising in a patient with Crohn’s disease. A Large mucin filled lakes. B More mucin than neoplastic epithelium.

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DefinitionPeutz-Jeghers syndrome (PJS) is aninherited cancer syndrome with autoso-mal dominant trait, characterized bymucocutaneous melanin pigmentationand hamartomatous intestinal polyposis,preferentially affecting the small intes-tine. Associated extra-intestinal neo-plasms are less common and includetumours of the ovary, uterine cervix,testis, pancreas and breast.

MIM No. 175200

Synonyms and historical annotationThe syndrome was first described byPeutz {1512} and Jeghers {850}. Severaldesignations have been used synony-mously, including Peutz-Jeghers polypo-sis, periorificial lentiginosis, and polyps-and-spots syndrome.

IncidenceAs the condition is rare, well documenteddata on the incidence are not available.Based on numbers of families registeredin the Finnish Polyposis Registry, the inci-dence of PJS is roughly one tenth of thatof familial adenomatous polyposis.

Diagnostic criteriaThe following criteria are recommended:(1) three or more histologically confirmedPeutz-Jeghers polyps, or (2) any numberof Peutz-Jeghers polyps with a family his-tory of PJS, or (3) characteristic, promi-nent, mucocutaneous pigmentation witha family history of PJS, or (4) any numberof Peutz-Jeghers polyps and character-istic, prominent, mucocutaneous pig-mentation.Some melanin pigmentation is oftenpresent in unaffected individuals, hence

the emphasis on the prominence of thepigmentation.

Intestinal neoplasmsPenetrance appears to be high, and bothsexes are equally affected {691}. Polypsare most common in the small intestine,

L.A. Aaltonen M. BillaudH. Järvinen J.R. JassS.B. Gruber

Peutz-Jeghers syndrome

Fig. 4.05 Peutz-Jeghers syndrome. Pigmentation oflips, peri-oral skin, tongue and fingers.


predispose to small bowel neoplasia(APC, hMSH2, hMLH1, LKB1, andSmad4) may therefore play a role in thegenesis of these tumours.Studying the genetics of small boweladenocarcinomas has been difficult dueto the rarity of these tumours {1715}.There is evidence supporting a multisteppathway of carcinogenesis similar to thatdescribed for colorectal carcinomas{2018}. The incidence of KRAS mutationis 14-52% {83, 2185, 14}, p53 overex-pression 40-67%, 17p loss 38-67%, and18q loss 18-30% {14, 1562}. One reportfound no 5q loss {1562} while anotherfound the frequency to be 60% {14}. 15-45% of small bowel tumours havehigh levels of microsatellite instability{14, 1562, 705}, and mutations in theTGF beta-RII gene have been identified

in some of these tumours {14}. In one study of Crohn-associated smallbowel cancers, 43% had KRAS muta-tions, 57% had p53 overexpression, 33%had 17p loss, 17% had 5q loss, none had18q loss, 1 had microsatellite instability,and none had TGF beta-RII mutations{1562}. These findings were similar tothose seen in sporadic small bowel carci-noma, and indicate that the transforma-tion from intraepithelial neoplasia to carci-noma may occur in a similar fashion.

Prognosis and predictive factorsIn SEER data, the overall 5-year survivalfor adenocarcinoma of the small bowelwas 28%, and for mucinous adenocarci-noma 22% {1928}. 5-year survival forlocalized adenocarcinomas (63%) washigher than for gastric adenocarcinoma

(56%) and lower than for colon (87%)and rectum (79%). This relation is reflect-ed in survival figures for all stages.Another recent population-based studyfrom Sweden showed 5- and 10-year sur-vival rates for small intestinal adenocarci-noma of 39% and 37% for duodenaltumours and 46-41% for jejuno-ilealtumours {2201}. The survival of patientsundergoing curative resection is 63%when regional lymph nodes are notinvolved, and 52% when there are nodalmetastases {2011}. Long-term survival isassociated with well differentiatedtumours and local invasion only {1888,1336}.One study found a significant inverseassociation between immunoreactivity forc-neu and survival in duodenal adeno-carcinoma {2208}.

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75Peutz-Jeghers syndrome

but may occur anywhere in the gastroin-testinal tract.

Signs and symptomsThese include abdominal pain, intestinalbleeding, anaemia, and intussusception.Typical age at clinical manifestation isfrom two to twenty years. Characteristicpigmentation allows diagnosis of asymp-tomatic patients in familial cases.

ImagingThe presence of polyps may be demon-strated by upper gastrointestinal andsmall bowel contrast radiography, and byair contrast barium enema. Periodicsmall bowel X-ray examination at two tofive-year intervals is advisable in the fol-low-up of the affected patients.Endoscopy is superior to radiologicalimaging in that it enables polypectomyfor diagnostic and therapeutic purposes.Upper gastrointestinal tract endoscopyand colonoscopy every two years withsnare excision of all polyps detected ispresently recommended. Small bowelpolyps may be reached by an entero-scope but rarely for the full bowel length;thus, imaging remains an integral com-ponent of clinical management.

MacroscopyPeutz-Jeghers polyps occur within thestomach, small and large intestines, andrarely within oesophagus, nasopharynxand urinary tract. The small intestine isthe site of predilection. The polyps arelobulated with a darkened head andclosely resemble adenomas. The stalk isshort and broad or absent. Size is typi-cally 5 to 50 mm.

HistopathologyA typical Peutz-Jeghers polyp has adiagnostically useful central core of

smooth muscle that shows tree-likebranching. This is covered by themucosa native to the region, heaped intofolds producing a villous pattern. Diag-nostic difficulty occurs when there is sec-ondary ischaemic necrosis. This compli-cation arises when a polyp has causedintussusception, a common form of pres-entation. Some polyps may lack diagnos-tic features.Epithelial misplacement involving all lay-ers of the bowel wall (pseudoinvasion)has been described in up to 10% ofsmall intestinal Peutz-Jeghers polyps{1728}. Mechanical forces associatedwith intussusception or raised intralumi-nal pressure due to episodic intestinalobstruction are the likely explanation forthis observation. Epithelial misplacementmay be florid and extend into the serosa,thereby mimicking a well differentiatedadenocarcinoma. Useful diagnostic fea-tures are the lack of cytological atypia,presence of all the normal cell types,mucinous cysts and haemosiderin depo-sition {1728}.

Dysplasia and cancer in Peutz-JegherspolypsWhile the Peutz-Jeghers syndrome isassociated with a 10 to 18-fold excess ofgastrointestinal and non-gastrointestinal

cancers {579, 154}, the question ofwhether or not the Peutz-Jeghers polypis itself precancerous has proved difficultto resolve. Epithelial misplacement hasapparently been overdiagnosed as can-cer in the past {1728}, but it is likely thatthe increased risk of malignancy in thestomach, small bowel and colon {154,1807} is due to malignant progressionfrom hamartoma to adenocarcinoma.The evidence is threefold: (1) intraepithe-lial neoplasia (dysplasia), though uncom-mon, has been described in Peutz-Jeghers polyps {1506, 2017}; (2) carci-nomas may occur in contiguity withPeutz-Jeghers polyps {317, 1506}; (3)the responsible gene LKB1 (STK11) islocated on chromosome 19p, and loss ofheterozygosity at this locus has beendemonstrated in the majority of Peutz-Jeghers polyps and associated intestinalcancers {633, 691, 2052}.

Extraintestinal manifestationsPredisposition to cancer of multipleorgan systems is an important feature ofthe syndrome {579, 154}. The most welldocumented extra-intestinal neoplasmsinclude sex cord tumours with annulartubules (SCTAT) of the ovary {2188}, ade-noma malignum of the uterine cervix{2188}, Sertoli cell tumours of the testis

BAFig. 4.07 A A lobulated pedunculated Peutz-Jeghers polyp of the small intestine. B This small intestinalPeutz-Jeghers polyp exhibits haemorraghic infarction due to intussusception.

BAFig. 4.08 Peutz-Jeghers polyps. A Small intestine. B Colon.

Fig. 4.06 Peutz-Jeghers polyp of the colon. Arbor-izing smooth muscle separating colonic glands intolobules (Masson trichrome stain).

04 19.7.2006 7:45 5


{231, 2118}, carcinoma of the pancreas{579}, and carcinoma of the breast{1587, 1952}. The cutaneous melanin pigmentationoccurs typically around the mouth asfreckle-like spots. Other sites commonlyaffected are digits, palms and feet, buc-cal mucosa, and anal region. While dra-matic pigmentation is a helpful sign, itmay fade with time, and some affectedindividuals never display pigmentation.

GeneticsChromosomal location and mode ofinheritancePJS is an autosomal dominant trait withnearly complete penetrance. The PJSgene, LKB1 (STK11), maps to 19p13.3,and there is some evidence suggestiveof locus heterogeneity {1210}.

Gene structureLKB1 consists of 9 coding exons. Theopen reading frame consists of 1302base pairs, corresponding to 433 aminoacids. Codons 50 to 337 encode the cat-alytic kinase domain of the gene.

Gene productThe human LKB1 gene is ubiquitouslyexpressed in adults {853, 690}. Itencodes a protein of 433 amino acidswhich possesses a serine/threoninekinase domain framed by a short N-ter-minus sequence (48 residues) and amore extended C-terminus region of 122amino acids {853, 690}. LKB1 shares asignificant sequence similarity with theSaccharomyces cerevisiae SNF1 kinasewhich phosphorylates transcriptionalrepressor and regulates glucose-repressible genes. Homologs of LKB1have been identified in several speciesincluding mouse, Xenopus, andCaenorhabditis elegans {1852, 1768,

2072}. Sequence alignments revealedthat these proteins are most conservedwithin the kinase domain, with 96% ofidentity between human and mouse and42% identity between human and thenematode. Human LKB1 contains anuclear localization signal (NLS) flankingthe N-terminus part of the catalyticdomain {1343, 1768} and a putativeprenylation motif within the C-terminus{325}. The LKB1 gene product is locatedboth in the nucleus and in the cytoplasm{1343}. LKB1 displays an autocatalyticactivity in vitro, and is the substrate of the

cAMP-dependent protein kinase (PKA){325}. Although the function of LKB1remains to be determined, it is worth not-ing that PAR-4, the C.elegans orthologueof LKB1, is required for establishingpolarity during the first cell cycles of theembryo {2072}. PAR-4 expression is alsoessential for embryonic viability and forintestinal organogenesis. Since the car-dinal clinical feature of PJS is the pres-ence of intestinal hamartomatous polyps,it appears plausible that the function ofLKB1 has been conserved across evolu-tion as it exerts a key regulatory role dur-ing intestinal development.

Gene mutations and their relationship toclinical manifestationsGermline mutations are usually truncat-ing, but missense type mutations havealso been described {853, 690}. Wildtype LKB1 is capable of autophosphory-lation {1210, 2176}, and the effect of mis-sense mutations occurring in the kinasedomain can be evaluated observing thisproperty in autophosphorylation assays.Somatic mutations of LKB1 in tumourshave been reported but are rare.

PrognosisWhile intussusception has been a majorsource of mortality in PJS kindreds{2093} surgery constitutes an effectivetreatment. Thus, prognosis of the affect-ed individuals is mainly related to the riskof malignancy in PJS {579, 154}. Due tothe rarity of the syndrome, there is littleinformation on prognosis, but one reportsuggests that PJS-associated cancersare particularly aggressive {1807}.

Fig. 4.11 Structure of the LKB1 gene. Germlinemutations in Peutz-Jeghers patients are most fre-quent in the kinase domain.

BAFig. 4.09 Peutz-Jeghers polyp of small intestine. Pseudoinvasion characterized by benign mucinous cystsextending through bowel wall into mesentery. Patient was well ten years after removal.

Fig. 4.10 Peutz-Jeghers polyp of small intestine.Pseudoinvasion. Islands of mucosa are separatedby smooth muscle.

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77Endocrine tumours

Endocrine tumours of the small intestine C. CapellaE. SolciaL.H. SobinR. Arnold

DefinitionEndocrine tumours of the small intestineexhibit site-related differences, depend-ing on their location in the duodenumand proximal jejunum or in the distaljejunum and ileum. They include carci-noid tumours (well differentiated neo-plasms of the diffuse endocrine system),small cell carcinomas (poorly differentiat-ed endocrine neoplasms) identical tosmall cell carcinomas of the lung andmalignant large cell neuroendocrine car-cinomas. The classification used here isadapted from the WHO histological clas-sification of endocrine tumours {1784}.

ICD-O CodesCarcinoid 8240/3Gastrin cell tumour 8153/1Somatostatin cell tumour 8156/1EC-cell, serotonin-producing

neoplasm 8241/3L-cell, glucagon-like peptide and PP/PYY producing tumourGangliocytic paraganglioma 8683/0Small cell carcinoma 8041/3

Endocrine tumours of the duode-num and proximal jejunum

EpidemiologyIncidence and time trendsEndocrine tumours of the duodenumwere rare in some older series, accoun-ting for 1.8-2.9% of gastrointestinalendocrine tumours {587, 2016}. However,in recent histopathology series, duodenaltumours amount to 22% of all gastroin-testinal endocrine neoplasms {1780}.Jejunal tumours account for about 1%{587, 1780} of all gut endocrine tumours.Gastrin-cell (G-cell) tumours representthe largest group (62%) in reportedseries of endocrine tumours arising inthe upper small intestine, followed bysomatostatin-cell tumours (21%), gan-gliocytic paragangliomas (9%), unde-fined tumours (5.6%) and PP-celltumours (1.8%) {1780}.

An extensive review of all cases record-ed in the Zollinger-Ellison Syndrome(ZES) registry showed 13% of patients tohave duodenal wall gastrinomas, whilethe majority of patients had a pancreatictumour {726}. More recent studies haveshown a higher proportion of duodenaltumours (38-50%), possibly related toimproved diagnostic tools {429, 2076}.

Age and sex distributionIn a series of 99 cases of endocrinetumours of the duodenum, males weremore frequently affected (M/F ratio:1.5:1), with a mean age at manifestationof 59 years (range, 33 to 90 years) {208}.G-cell tumours associated with overt ZES(gastrinomas) differ from their apparentlynonfunctioning counterpart in arising ear-lier in life (mean age at diagnosis is 39years, as opposed to 66 years) {1780}.Somatostatin-cell tumours affect femalesslightly more frequently than males(1.2:1) and become clinically manifest ata mean age of 45 years (range 29 to 83years) {1780}. Gangliocytic paragan-gliomas are slightly more common inmales than in females and affect patientsranging in age from 23 to 83 years, withan average of 54 years {210}. The fewcases of small cell carcinoma recorded inthe literature were in males ranging inage from 51 to 76 years.

AetiologyApart from genetic susceptibility (seebelow), there is little knowledge aboutpossible aetiological factors involved inthe pathogenesis of duodenal and proxi-mal jejunal endocrine tumours. An isolat-ed report demonstrates that a sporadicgastrin-cell tumour of the duodenum orig-inated from hyperplastic and differentiat-ed G-cells located in the mucosal crypts{1114}. A case of a small multifocalsomatostatin-cell tumour of the proximalduodenum has been reported in a patientwith celiac sprue, showing somatostatin-cell hyperplasia in the mucosa, suggest-ing a relationship between D-cell growth

and a long standing chronic inflammato-ry process {233}.

LocalizationIn a series of duodenal endocrinetumours {208}, 43 lesions were located inthe first part, 41 in the second part, 2 inthe third part, and 2 in the fourth part.Nonfunctioning G-cell tumours are locat-ed in the duodenal bulb, while the site ofabout 1/3 gastrinomas associated withovert ZES is in the first, second or thirdpart of the duodenum or in the upperjejunum {1780}. The preferential locationof somatostatin-cell tumours, gangliocyt-ic paragangliomas and small cell carci-nomas is at, or very close to, the ampullaof Vater {206, 210, 233, 1149, 1780,1870, 2196}.

Clinical featuresEndocrine tumours of the duodenumproduce symptoms either by virtue oflocal infiltration causing obstructive jaun-dice, pancreatitis, haemorrhage, andintestinal obstruction (nonfunctioningtumours) or, less frequently, by secretedpeptide hormones (functioning tumours).The prevalent position of somatostatin-cell tumours, gangliocytic paraganglio-mas, and small cell carcinomas in theampullary region explains their frequentassociation with obstructive biliary dis-ease. About 20% of the tumours, espe-cially those located in the duodenal bulb,are asymptomatic and often incidentallydiscovered, e.g. by imaging analysis,endoscopy or pathological examinationof gastrectomy and duodenopancreate-ctomy specimens removed for gastricand pancreatic cancers.Zollinger-Ellison Syndrome (ZES) withhypergastrinaemia, gastrin hypersecre-tion, and refractory peptic ulcer disease,is the only syndrome of endocrine hyper-function consistently observed in associ-ation with endocrine tumours of the duo-denum and upper jejunum {208, 429,726, 1780, 2076}. The association withZES is found in about 15% of duodenal

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gastrin-cell tumours {1780}. Tumoursassociated with overt ZES differ fromtheir apparently nonfunctioning counter-part in arising earlier in life and having ahigher incidence of metastatic and non-bulbar cases {1780}.Argentaffin, serotonin-producing, carci-noids are unusual in the upper smallintestine. It follows that duodenal carci-noids only exceptionally give rise to aclinical carcinoid syndrome, associatedwith liver metastases of the tumour {233,1816}. In none of the cases of somato-statin-cell tumours, so far reported, didthe patients develop the full ‘somato-statinoma’ syndrome (diabetes mellitus,diarrhoea, steatorrhoea, hypo- or achlor-hydria, anaemia and gallstones) that hasbeen described in association with somepancreatic somatostatin-cell tumours{1780}.

MacroscopyEndocrine tumours of the duodenumand upper jejunum usually form small (< 2 cm in diameter), grey, polypoidlesions within the submucosa with anintact or focally ulcerated overlyingmucosa. However, some examplesappear as infiltrative intramural nodulesof rather large size (up to 5 cm in diam-eter). The tumours are multiple in about13% of cases {208}. In a large series of96 cases, the mean size was 1.8 cm(range, 0.2 to 5.0 cm) {208}. The meansize was 0.8 cm for gastrin-cell tumours{233}, 2.3 cm for somatostatin-cell

tumours {1816} and 1.7 cm for ganglio-cytic paragangliomas {233}. Small cellcarcinomas typically measure 2-3 cm,and present as focally ulcerated, or pro-tuberant lesions {1870, 2196}.

MicroscopyGastrin cell tumours. These tumours areformed by uniform cells with scanty cyto-plasm, arranged in broad gyriformtrabeculae and vascular pseudo-rosettesand show predominant immunoreactivityfor gastrin. Other peptides detected intumour cell sub-populations are chole-cystokinin, pancreatic polypeptide (PP),neurotensin, somatostatin, insulin, andthe α-chain of human chorionic gona-dotrophin {233}. Interestingly, somato-statin, which is known to inhibit gastrinrelease from gastrinomas, is detectedmore frequently in nonfunctioning G-celltumours than in tumours associated withZES {233}. Ultrastructurally, typicalG–cells with vesicular granules are found{233}.Somatostatin cell tumours. These neo-plasms usually exhibit a mixed architec-tural pattern with a predominant tubulo-glandular component admixed with avariable proportion of insular and trabec-ular areas. Concentrically laminatedpsammoma bodies are detected mostlywithin glandular spaces. The glandularpattern and psammoma bodies may beso prominent that these tumours havebeen misdiagnosed as well differentiat-ed ampullary adenocarcinomas. Unlike

adenocarcinomas, however, the somato-statin cell tumours are composed of uni-form cells with rather bland nuclei andfew mitotic figures. Grimelius silver stainand chromogranin A are not very usefulto diagnosis this tumour, because theyare negative in about 50% of cases. Thepresence of somatostatin in tumour cellscan be demonstrated by immunohisto-chemistry. In addition to the somatostatincells, some tumours have minor popula-tions positive for calcitonin, pancreaticpolypeptide and ACTH {233, 381}. Inaddition, the apical cytoplasm of glandular structures binds WGA andPNA lectins and expresses epithelialmembrane antigen {233, 1780}. Ultra-structural examination shows large,moderately electron dense secretorygranules, similar to those found in nor-mal D–cells of the intestinal mucosa{233}.EC-cell, serotonin-producing carcinoid.The classic argentaffin 'midgut' EC-cellcarcinoid, with its characteristic patternof solid nests of regular cells with bright-ly eosinophilic serotonin-containing gran-ules and other morphological character-istics of ileal argentaffin EC-cell carci-noid, is very rare both in the duodenumand upper jejunum.Gangliocytic paraganglioma This tumourappears as an infiltrative lesion com-posed of an admixture of three cell types:spindle cells, epithelial cells, and gan-glion cells. The spindle cells, which usu-ally represent the major component, areneural in nature. They form small fasci-cles or envelop nerve cells and axonsand show intense immunoreactivity forS–100 protein. The epithelial cells arelarger cells with eosinophilic or ampho-philic cytoplasm and uniform ovoidnuclei that are arranged in ribbons, solidnests, or pseudo-glandular structures.These are non-argentaffin and frequentlynon-argyrophil endocrine cells, oftencontaining somatostatin {233, 1816}.In addition, PP cells and rare glucagon orinsulin cells have been detected in gan-gliocytic paragangliomas, suggesting thatthey may be a hamartoma of pancreaticanlage {655, 1502}. The ganglion cellsmay be scattered singly or aggregatedinto clusters. The three components of thegangliocytic paraganglioma also inter-mingle with the normal smooth muscleand small pancreatic ducts at the ampul-la to produce a very complex lesion.Ultrastructurally, the epithelial cells have

Tumours of the small intestine78

Fig. 4.12 Gastrin cell tumour with typical gyriform trabecular pattern.

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79Endocrine tumours

abundant cytoplasm packed with dense-core secretory granules, while the gan-glion cells are larger and contain a smallnumber of neuroendocrine granules ofsmall size and more numerous second-ary lysosomes. The spindle cells arepacked with intermediate filaments andresemble either sustentacular cells orSchwann cells {1502}.

Genetic susceptibilityMEN-1. This inherited tumour syndromeis significantly associated with gastrin-cell tumours, but not with other types ofendocrine tumours of the duodenum andupper jejunum. The prevalence of MEN-1in all gastrin cell tumours of the duode-num-upper jejunum has been reported tobe 5.3% {1780}. Among duodenal-upperjejunal cases with an overt ZES, theassociation with MEN-1 syndrome isfound in 7 to 21% of cases {1780, 2076}.Loss of heterozygosity (LOH) at MEN-1gene locus has been found in 4/19 (21%)duodenal MEN-1 gastrin cell tumours{1105}, while a slightly higher 11q13LOH rate for MEN-1 gastrinomas (41%;14 of 34 tumours) was reported in anextended study of MEN-1 and sporadicgastrinomas {395}. A low incidence ofLOH on 11q13 in MEN-1-associatedgastrinomas suggests that thesetumours could arise due to inactivation ofthe wild-type allele via point mutations orsmall deletions rather than via a loss of alarge segment of chromosome 11{1105}.Neurofibromatosis type I. Patients withvon Recklinghausen disease are at sig-nificant risk for development of peri-ampullary neoplasms {210, 233, 933,1780}. The majority of these lesions aresomatostatin cell tumours, gastrointesti-nal stromal tumours or gastrointestinalautonomic nerve tumours, but other neo-plasms of neural crest and non-neuralcrest origin are known to occur. Soma-tostatin cell tumours were the most com-mon periampullary neoplasms identifiedin one review {933}, whereas carcinoidsaccount for only 2-3% of periampullarytumours in the general population{1149}.Some patients with neurofibromatosisand ampullary somatostatin cell tumouralso have a phaeochromocytoma involv-ing one or both adrenal glands, a clinicalsituation that can have considerableimplications for complicated patientmanagement {210}. Association of gan-

gliocytic paraganglioma with neurofibro-matosis type I {906} and somatostatin-cell tumour has been reported {1832}.

GeneticsPoint mutations of KRAS at codon 12,which are detected in small bowel adeno-carcinomas, are absent in endocrinetumours of the small intestine, includingthe duodenal ones {2185}. Incidental gas-trin cell tumours do not overexpress eitherbasic fibroblast growth factor (bFGF),acidic fibroblast growth factor (aFGF),transforming growth factor-α (TGFα), ortheir respective receptors FGFR4 andEGFR {995}. On the contrary, thesetumours overexpress the βA-subunit ofactivin, which may be involved in the reg-ulation of proliferation of tumour cells{994}.

Prognosis and predictive factorsAggressive endocrine tumours includegastrin cell, somatostatin cell, and EC-cell tumours that invade beyond the sub-mucosa or show lymph node or distant(liver) metastases. Aggressive tumourshave been reported to be 10% of all gas-trin cell duodenal-upper jejunal tumours{233}, 58% of sporadic ZES cases {429}and 45% of ZES-MEN-1 cases {429}. Inthe case of somatostatin cell tumours,about two-thirds were aggressive in onestudy {381}.

Gastrin cell tumours associated with anovert ZES are prognostically lessfavourable than their nonfunctioningcounterparts, having a higher incidenceof metastases (3 of 14 cases as against0 of 28), and being deeply infiltrative (7of 14 as against 3 of 19) {1780}. Thesefindings suggest a different natural histo-ry of gastrin cell tumours in the two con-ditions. Nonfunctioning tumours repre-sent a generally benign condition, whileZES tumours have a low-grade malig-nancy, especially when arising in siteswhere gastrin cells are not normallypresent, such as in the jejunum or pan-creas {233}. Metastases in regionallymph nodes have been reported in 4 of8 cases of duodenal gastrinomas withZES-MEN-1 syndrome {1521}, in 2 of 3

BA

Fig. 4.13 Gangliocytic paraganglioma. A Distortion of duodenal glands by stromal infiltrate. B Massontrichrome stain highlights islands of epithelial cells (red). C Spindle cells and epithelial cells. D Ganglion cellswith pale nuclei and prominent nucleoli.

Fig. 4.14 Somatostatin cell tumour exhibiting char-acteristic tubuloglandular pattern and a psammo-ma body.

DC

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cases of jejunal gastrinomas {233} andin 25% of 103 cases of duodenaltumours with ZES, 24% of which alsohad MEN-1 syndrome {724}. Locallymph node metastases seem to have lit-tle influence on survival of patients withZES {398, 2076}. In a study focusing onmetastatic rate and survival in patientswith ZES, no difference was found in thefrequency of metastases to lymph nodes{429}, when comparing primary pancre-atic (48%) and duodenal (49%) tumours.In contrast, the same study found a sig-nificantly higher frequency of metas-tases to the liver in patients with pancre-atic gastrinomas than in patients withduodenal gastrinomas (52% vs. 5%).The 10-year survival rate of patients withduodenal gastrinomas (59%) is signifi-cantly better than for patients with pan-creatic gastrinomas (9%) {2076}. Themore favourable prognosis of duodenaltumours is mainly linked to their smallersize and less frequent association withliver metastases.Somatostatin cell tumours are oftenmalignant, despite their rather bland his-tological appearance {1780, 210, 381}.Malignant somatostatin cell tumours are

2 cm in diameter {381}, invade the duo-denal muscularis propria, the sphincterof Oddi, and/or the head of the pancreas,and can metastasise to paraduodenallymph nodes and liver.Gangliocytic paragangliomas are usuallybenign, in contrast to gastrin andsomatostatin cell tumours that arise in thesame area. However, occasional largetumours (size > 2 cm) may spread tolocal lymph nodes, mainly attributable tothe endocrine component of the lesion{197, 783}.

Small cell carcinomas show histologicalsigns of high-grade malignancy (highmitotic rate, tumour necrosis, deep muralinvasion, angioinvasion, and neuroinva-sion). Metastases are present in all cases{2196} and patients die usually within 7-17 months of diagnosis.

Endocrine tumours of the distal jejunum and ileum

Endocrine tumours of this segment of thesmall intestine are mainly EC-cell, sero-tonin-producing carcinoids, and, less fre-quently, L-cell, glucagon-like peptideand PP/PYY-producing tumours.

EpidemiologyIncidence and time trendsEndocrine tumours of the lower jejunumand ileum have an incidence of 0.28-0.89per 100,000 population per year {60,587}. Jejuno-ileal lesions account for23–28% of all gastrointestinal endocrinetumours, making this site the secondmost frequent location for endocrinetumours, following the appendix {587,2016}. A recent SEER analysis of 5468cases found an increase in the proportionof ileal and jejunal carcinoids anddecrease in the proportion of appen-diceal carcinoids {60}.

Age and sex distributionEndocrine tumours of lower jejunum andileum are distributed more or less equal-ly between males and females. Patientsrange in age from the third to the tenthdecade, with a peak in the 6th and 7thdecades {211, 587, 1253, 1780}.

AetiologyAt present, there is little knowledge aboutthe aetiology of jejuno-ileal EC-cell carci-noids. Although endocrine tumours oflower jejunum and ileum are not general-ly associated with preneoplastic lesions,there have been reports of focal micro-proliferations of EC-cells in cases of mul-tiple ileal tumours {1736} and of intraep-ithelial endocrine cell hyperplasia in themucosa adjacent to jejuno-ileal carci-noids {1291}.Approximately 15% of carcinoid tumoursof the small intestine are associated withnon-carcinoid neoplasms, most frequent-ly adenocarcinomas of the gastrointesti-nal tract {1251, 1253}, supporting thehypothesis that secretion of growth fac-tors is involved in their aetiopathogenesis{1251}.

LocalizationIn the AFIP series of 167 jejuno-ilealendocrine tumours {211}, 70% werelocated in the ileum, 11% in the jejunum,3% in Meckel diverticulum. These datasuggest that small bowel endocrinetumours occur 6.5 times more frequentlyin the ileum than in the jejunum. Themajority of the tumours are located in thedistal ileum near the ileocaecal valve.

Clinical featuresPatients with jejuno-ileal endocrinetumours present most commonly withintermittent crampy abdominal pain, sug-gestive of intermittent intestinal obstruc-tion {1253}. Patients frequently havevague abdominal symptoms for severalyears before diagnosis, reflecting theslow growth rate of these neoplasms{1253}. Preoperative diagnosis is difficult

Fig. 4.15 Gangliocytic paraganglioma. A Immunoreactivity for cytokeratin (CAM 5.2) in epithelial cells. B Immunoreactivity for S100 in spindle cells.

BA

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81Endocrine tumours

since standard imaging techniques rarelyidentify the primary tumour. Scintigraphicimaging with radiolabeled somatostatin(octreotide) is widely used to localise pre-viously undetected primary or metastaticlesions {991}. The 'carcinoid syndrome' is found in5–7% of patients with EC-cell carcinoidtumours {587, 1253} that typically arise inthe ileum, all of which metastasise, most-ly to the liver. Symptoms include cuta-neous flushing, diarrhoea, and fibrousthickening of the endocardium andvalves of the right heart.

MacroscopyJejuno-ileal endocrine tumours are multi-ple (ranging from 2 to 100 tumours) inabout 25-30% of cases {211, 1253,1845}. The size of the tumours is < 1 cmin 13% and 2 cm in 47% of cases {211}.They usually appear as deep mucosal-submucosal nodules with apparentlyintact or slightly eroded overlyingmucosa. Deep infiltration of the muscularwall and peritoneum is frequent.Extensive involvement of the mesenterystimulates considerable fibroblastic ordesmoplastic reaction, with consequentangulation, kinking of the bowel andobstruction of the lumen. Infarction of theinvolved loop of the small intestine mayoccur as a consequence of fibrous adhe-sions, volvulus, or occlusion of themesenteric blood vessels.

MicroscopyEC-cell, serotonin-producing carcinoidsare formed by characteristic roundednests of closely packed tumour cells,often with peripheral palisading (Type A){1775}. Often, within the solid nests,rosette type, glandular-like structures aredetected. This variant of the fundamentalstructure designated as mixed insular +glandular (A + C) structure seems prog-nostically more favourable than the pure

type A structure {1780}. In areas of deepinvasion with abundant desmoplasticreaction, the cell nests may be orientedinto cords and files. Mesenteric arteriesand veins located near the tumour, oraway from it, may be thickened and theirlumen narrowed or even occluded by apeculiar elastic sclerosis, which maylead to ischaemic lesions in the intestine{72}. Most tumour cells are intenselyargyrophilic and reactive with chromo-granin A and B antibodies. In about 30%of cases, a variable number of cells isalso reactive for prostatic acid phos-phatase {211}.The identification of tumour cells as EC-cells can be accomplished using histo-chemical methods for serotonin, includ-ing argentaffin, diazonium, and immuno-histochemical tests. Because serotoninoccurs in some non EC-cell and related

tumours {655}, electron microscopicexamination of serotonin-immunoreactivetumours (particularly those failing toreact with histochemical tests) can con-firm their EC-cell nature by detectingcharacteristic pleomorphic, intenselyosmiophilic granules {1778}.Substance P and other tachykinins, suchas neurokinin A, are reliable markers of afraction of jejuno-ileal EC-cell tumours{144, 1173}; foregut (gastric, pancreaticand duodenal) EC-cell tumours remainmostly unreactive {1780}. Minor popula-tions of enkephalin, somatostatin, gastrin,ACTH, motilin, neurotensin, glucagon/gli-centin, and PP/PYY immunoreactive cells,unassociated with pertinent hyperfunc-tional signs, have been reported in someileal and jejunal tumours mostly com-posed of EC-cells {1173, 2168}.Dopamine and norepinephrine have also

Fig. 4.16 Multiple carcinoids of the ileum with mesenteric lymph node metastases.

B CAFig. 4.17 EC-cell carcinoid. A Typical mixed insular-acinar structure. B Positive Grimelius silver reaction. C Immunoexpression of TGFα.

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been detected in addition to serotonin ina type A (insular) argentaffin carcinoid ofthe ileum {588}. In many cases of jejuno-ileal EC-cell tumours, however, no otherhormones apart from serotonin and sub-stance P or related tachykinins aredetected {1173}.The main criteria for considering ajejuno-ileal carcinoid to have an aggres-sive potential are deep invasion of thewall (muscularis propria or beyond)and/or presence of metastases.According to these criteria, in the largeAFIP series {211}, 141 of 159 cases(89%) of jejuno-ileal carcinoids were con-sidered aggressive.

Genetic susceptibilityUnlike gastric ECL-cell tumours and duo-denal gastrin cell tumours, jejuno-ilealcarcinoids are only occasionally associ-ated with MEN-1 {1444}. Rare examplesof familial occurrence of ileal EC-cell car-cinoids have been reported {1252A}.

GeneticsA recent study {829} reported frequent(78%) LOH on chromosome 11q13 insporadic carcinoids of both foregut (lungand thymic) and midgut/hindgut (intes-tinal, including EC-cell tumours, and rec-tosigmoidal) origin. Other studies, how-ever, have shown retention of heterozy-gosity on 11q13 in sporadic carcinoids ofmidgut and hindgut origin {394, 1938},suggesting that LOH of the MEN-1 gene,unlike gastric and duodenal endocrinetumours, is not involved in the pathogen-esis of EC-cell tumours.Accumulation of p53 has not beendetected in EC-cell tumours examinedimmunohistochemically, suggesting that

this tumour suppressor gene is not impli-cated in the pathogenesis of thesetumours {1780, 2044, 2077}.Several growth factors and relatedreceptors have been localised in tumourcells of EC-cell carcinoids, includingtransforming growth factor-α (TGFα) andepidermal growth factor (EGF)-receptor,insulin-like growth factor-1 (IGF-1), andIGF-1 receptors, platelet-derived growthfactor (PDGF), transforming growth fac-tor-β (TGFβ), basic fibroblast growth fac-tor (bFGF), acidic fibroblast growth factor(aFGF), and fibroblast growth factorreceptor-4 (FGFR4) {22, 284, 993, 995,1291}.Some of these growth factors, such asTGFα, exert a proliferative effect reflectedby an increased mitotic index and signifi-cantly increased DNA levels in primarycell cultures of midgut carcinoids. Thesefindings suggest the involvement of anautocrine loop {22}. A similar growth pro-moting role in midgut carcinoid tumourcells is assigned to IGF-1 {22}. PDGF,TGFα, bFGF, and aFGF seem to be main-ly involved in tumour stromal reaction,including stromal desmoplasia {22, 993,995}, by acting on receptors expressedon fibro-blasts or stimulating the promo-tion of new vasculature and tumour pro-gression {22, 993, 995}.Neural adhesion molecule (NCAM), amember of the immunoglobulin super-family of cell adhesion molecules, ishighly expressed in midgut carcinoidtumours {22}. Because NCAM has not been shown innormal gut endocrine cells, the novelexpression of this adhesion molecule incarcinoids may be of importance forgrowth and metastases.

Prognosis and predictive factorsA recent report revealed a 21% mortalityrate for jejuno-ileal carcinoids, comparedwith 4% for duodenal, 6% for gastric, and3% for rectal carcinoids {211}. In two stud-ies, the overall 5-year survival rate ofpatients with jejuno-ileal endocrinetumours was about 60% and the 10-yearsurvival rate was 43% {211, 1845}. Inpatients with no liver metastases, the 5- and 10-year survival rates were 72%and 60%, respectively, as opposed to35% and 15% for patients with livermetastases {1845}, demonstrating the rel-atively slow rate of growth of some EC-celltumours. Metastases are generally con-fined to regional lymph nodes and liver.Extra-abdominal metastases were foundin only 0.5% of the cases reported byMoertel et al. {1253}. In one study, univari-ate analysis showed that survival wasnegatively correlated with distant metas-tases at the time of surgery, mitotic rate,tumour multiplicity, the presence of carci-noid syndrome, depth of intestinal wallinvasion, and female gender; by multivari-ate analysis, survival was negatively asso-ciated with distant metastases, carcinoidsyndrome, and female gender {211}.In summary, jejuno-ileal carcinoidtumours that are clinically nonfunctioning,1 cm or less in diameter, confined to themucosa/submucosa and non-angioinva-sive, are generally cured by completelocal excision. Invasion beyond submu-cosa or metastatic spread indicates thatthe lesion is aggressive. If the lesion,although confined to the mucosa/submu-cosa, shows angioinvasion, or is over1 cm in size, it is of uncertain malignantpotential.

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83B-cell lymphoma

DefinitionPrimary small intestinal lymphoma isdefined as an extranodal lymphoma aris-ing in the small bowel with the bulk of dis-ease localized to this site. Contiguouslymph node involvement and distalspread may be seen, but the primaryclinical presentation is the small intes-tine, with therapy directed to this site.

ICD-O codesMALT lymphoma 9699/3IPSID 9764/3Mantle cell lymphoma 9673/3Burkitt lymphoma 9687/3Diffuse large B-cell lymphoma 9680/3

EpidemiologyIn contrast to lymphomas involving thestomach, primary small intestinal lym-phomas are uncommon in Western coun-tries {792}. However, since epithelial andmesenchymal tumours are uncommon inthe small bowel, lymphomas constitute asignificant proportion (30-50%) of allmalignant tumours at this site.Lymphomas of mucosa-associated lym-phoid tissue (MALT) type are the mostfrequent lymphomas of both the smallintestine and the colorectum, althoughcontroversy surrounds the histogenesisof de novo diffuse large B-cell lymphomaarising along the gastrointestinal tract. A unique form of intestinal MALT lym-phoma occurs predominantly in theMiddle East and Mediterranean areas,and is referred to as immunoproliferativesmall intestinal disease (IPSID) {1649}.This entity represents part of a spectrumof small intestinal lymphoproliferations,including alpha heavy chain disease(αHCD) and may represent differentmanifestations or phases of the samedisease. αHCD and IPSID occur pre-dominantly in the Mediterranean area,but may be seen outside this region.They typically affect young adults,whereas small intestinal lymphomas inthe Western world increase in frequencywith age with a peak incidence in the 7thdecade. Most studies have shown aslight male predominance {424}.

AetiologyIn contrast to the well-established rela-tionship between Helicobacter pylori andgastric MALT lymphoma, no infectiousorganism has been clearly implicated inthe pathogenesis of small intestinalMALT lymphoma. IPSID appears to berelated to bacterial infection, as antibiot-ic responsiveness is typical of the earlyphases of the disease. However, no spe-cific organism has been identified. Lymphomas involving the small intestineor colorectum may occur in distinct clini-cal settings. Chronic inflammatory boweldisease, including Crohn disease andulcerative colitis, are recognized risk fac-tors for non-Hodgkin lymphoma at thissite. Importantly, the risk is much lessthan that associated with gluten-sensitiveenteropathy and primary T-cell lym-phomas of the small bowel (see T-celllymphoma section). Crohn disease ismore often implicated in the develop-ment of lymphoma in the small intestine,while ulcerative colitis is associated withlymphomas of the colorectum {1733}. Anincreased incidence of lymphoma hasbeen associated with both acquired andcongenital immunodeficiency states,including congenital immune deficiency,iatrogenic immunodeficiency associatedwith solid organ transplantation, andacquired immunodeficiency syndrome(AIDS) {357}. In general, lymphomasassociated with immunodeficiency showa predilection for extranodal sites, partic-ularly the gastrointestinal tract, irrespec-tive of the cause of the immunodeficien-cy {1057, 787}.

Clinical featuresSymptoms produced by small intestinallymphomas depend upon the specifichistological type. Indolent lymphomas ofB-cell lineage typically present withabdominal pain, weight loss and bowelobstruction {424}. Occasional casespresent with nausea and vomiting, whilerare cases are discovered incidentally.More aggressive tumours, such as thoseof T-cell lineage (described separately)or Burkitt lymphoma, may present as a

large intra-abdominal mass or acutelywith intestinal perforation. IPSID oftenmanifests as abdominal pain, chronicsevere intermittent diarrhoea and weightloss {1649}. The diarrhoea is mainly theresult of steatorrhoea, and a protein-los-ing enteropathy can be seen. Peripheraloedema, tetany and clubbing areobserved in as many as 50% of patients.Rectal bleeding is uncommon in smallbowel lymphoma, but a common pre-senting sign in primary colonic lym-phoma.Burkitt lymphoma is most frequently seenin the terminal ileum or ileocaecal region,and may cause intussusception.

Imaging and endoscopyRadiological studies are useful adjunctsto the diagnosis of small intestinal lym-phomas, including barium studies andcomputerized tomography scans. T-celllymphomas are typically localized in thejejunum, presenting as thickenedplaques, ulcers, or strictures. Most B-celllymphomas manifest as exophytic orannular tumour masses in the ileum {792}.B-cell lymphomas of both low- and inter-mediate-grade may produce nodules orpolyps that can be seen both endoscopi-cally and by imaging. Most small intestin-al lymphomas are localized to oneanatomic site, but multifocal tumours aredetected in approximately 8% of cases. Multiple lymphomatous polyposis con-sists of numerous polypoid lesionsthroughout the gastrointestinal tract{791}. Most often, the jejunum and termi-nal ileum are involved, but lesions canappear in the stomach, duodenum,colon, and rectum. This entity producesa characteristic radiological picture thatis virtually diagnostic. As discussedbelow, the majority of such cases iscaused by mantle cell lymphoma, butother subtypes of lymphoma may pro-duce a similar radiological pattern{1034}.IPSID. The macroscopic appearance ofIPSID depends on the stage of disease.Early on, the bowel may appear endo-scopically normal, with infiltration appar-

R.D. GascoyneH.K. Müller-HermelinkA. ChottA. Wotherspoon

B-cell lymphoma of the small intestine

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ent only on intestinal biopsy. The diseasemay then progress to thickening of theupper jejunum together with enlargementof the mesenteric lymph nodes and thedevelopment of lymphomatous masses.Typically, the spleen is not involved andmay even be small and fibrotic, asdescribed in coeliac disease. Distalspread beyond the abdomen is uncom-mon {1649, 798}.

HistopathologyMALT lymphomaThe majority of intestinal lymphomasinvolving the small bowel are B-cell lym-phomas of MALT type, including bothlow-grade and aggressive types {792,793, 796}. These so-called ‘Western’types are distinct from IPSID and αHCD.The histological features of Western typesmall intestinal lymphoma are similar togastric MALT lymphoma, except thatlymphoepithelial lesions are less promi-nent {792}. In contrast to gastric MALT lymphomas,diffuse large B-cell lymphomas arising inthe small bowel are much commonerthan low-grade B-cell lymphomas ofMALT-type {796}. Some of these lym-phomas may have a low-grade MALTcomponent, providing evidence that theirhistogenesis is related to the mucosalimmune system. Precise criteria fordefining a MALT lymphoma of large celltype are lacking, as are the criteria fordistinguishing transformation within alow-grade MALT lymphoma {383}. Whenboth histologies are evident, the lesion isbest described as composite. Whensmall foci of large transformed cells orearly sheeting-out of large cells aredetected within a background of low-grade intestinal MALT lymphoma, theirpresence should be noted. Currently, theprognostic impact of these findings andtheir effect on treatment are undeter-mined. Diffuse large B-cell lymphomasarising in the small bowel that lack abackground of low-grade MALT lym-phoma are currently best classified asextranodal diffuse large B-cell lym-phoma, not otherwise specified {670}.

IPSID / αHCD Immunoproliferative small intestinal dis-ease and α heavy chain disease are partof a spectrum of lymphoproliferative dis-eases prevailing in the Middle East andMediterranean countries {792}. They aresubtypes of small intestinal MALT lym-

phoma characterized by the synthesis ofα heavy chain. The histology is charac-teristic of MALT lymphoma with markedplasma cell differentiation. Three stages of IPSID are recognized. Instage A, the lymphoplasmacytic infiltrateis confined to the mucosa and mesen-teric lymph nodes, and cytological atyp-ia is not present. Although the infiltratemay obliterate the villous architecture,endoscopic examination appears nor-mal. Resection specimens reveal reac-tive lymphoid follicles, lymphoepitheliallesions and small clusters of parafollicu-lar clear cells. This phase of the diseaseis typically responsive to antibiotic thera-py. In stage B, nodular mucosal infiltratesdevelop and there is extension below themuscularis mucosae. A minimal degreeof cytological atypia is apparent. Thisstage appears to represent a transitionalphase, can be seen macroscopically asthickening of mucosal folds, and is typi-cally not reversible with antibiotics. The

characteristic features of MALT lym-phoma are now evident, and follicularcolonization may be so marked as tomimic follicular lymphoma. Stage C ischaracterized by the presence of largemasses and transformation to frank largecell lymphoma. Numerous centroblastsand immunoblasts are present. Plasma-cytic differentiation is still evident, butmarked cytological atypia is usuallyfound, including Reed-Sternberg-likecells. Mitotic activity is increased.Mesenteric lymph node involvementoccurs early in the course of disease,with both plasma cell infiltration of nodalsinuses and marginal-zone areas dis-tended by small atypical lymphoma cellswith moderate amounts of pale, clearcytoplasm.Immunohistochemical studies demon-strate the production of α heavy chainwithout light chain synthesis {798}. TheIgA is almost always of the IgA1 type,with intact carboxy-terminal regions and

BAFig. 4.19 Malignant lymphomatous polyposis. A Typical polypoid mucosa. B Polypoid mantle cell lymphoma.

Fig. 4.18 High-grade B-cell lymphoma of the small intestine.

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85B-cell lymphoma

deletion of most of the V and all of theCH1 domains. The molecular characteri-zation of individual cases is variable. Thesmall lymphoma cells express CD19 andCD20, but fail to express CD5, CD10 andCD23.

Mantle cell lymphomaMantle cell lymphoma (MCL) typicallyinvolves both spleen and intestines andmay present as an isolated mass or asmultiple polyps throughout the gastroin-testinal tract where it is referred to asmultiple lymphomatous polyposis {424,791, 1292}. Importantly, other histologi-cal subtypes of non-Hodgkin lymphomacan also produce this clinico-pathologi-cal entity. The polyps range in size from 0.5 cm to2 cm with much larger polyps found inthe ileocaecal region. The histology ofMCL involving the small bowel is identi-cal to MCL at nodal sites {110}. Thearchitecture is most frequently diffuse,but a nodular pattern and a less com-mon true mantle-zone pattern are alsoobserved. Reactive germinal centersmay be found and are usually com-pressed by the surrounding lymphomacells, thereby appearing as replacingthe normal mantle zones. Intestinalglands may be destroyed by the lym-phoma, but typical lymphoepitheliallesions are not seen. The low powerappearance is monotonous with frequentepithelioid histiocytes, mitotic figuresand fine sclerosis surrounding smallblood vessels. The lymphoma cells aresmall to medium sized with irregularnuclear outlines, indistinct nucleoli andscant amounts of cytoplasm. Largetransformed cells are typically not pres-ent. The lymphoma cells are mature B-cells and express both CD19 andCD20. Characteristically the cells co-express CD5 and CD43. Surfaceimmunoglobulin is found including bothIgM and IgD. Light chain restriction ispresent in most cases, with some studiesdemonstrating a predominance of lamb-da. CD10 and CD11c are virtually alwaysnegative. Bcl-1 (cyclin D1) is found in vir-tually all cases and can be demonstrat-ed within the nuclei of the neoplasticlymphocytes in paraffin sections. MCL is an aggressive lymphoma, whichtypically presents in advanced stagewith involvement of mesenteric lymphnodes and spread beyond the abdomen,including peripheral lymph nodes,

spleen, bone marrow and peripheralblood involvement {84}.

Burkitt lymphomaBurkitt lymphoma occurs in two majorforms, defined as endemic and spo-radic. Endemic Burkitt is found primarilyin Africa and typically presents in the jaw,orbit or paraspinal region, and is strong-ly associated with Epstein-Barr virus(EBV).In other endemic regions however, it isrelatively common for Burkitt lymphomato present in the small intestine, usuallyinvolving the ileum, with preferentiallocalization to the ileocaecal region{792}. In parts of the Middle East, pri-mary gastrointestinal Burkitt lymphoma isa common disease of children. Sporadicor non-endemic Burkitt lymphoma is arare disease, not associated with EBVinfection, that frequently presents as pri-mary intestinal lymphoma. Burkitt lym-phoma is also seen in the setting of HIVinfection when it often involves the gas-trointestinal tract {236}.The histology in all cases is identical andis characterized by a diffuse infiltrate ofmedium-sized cells with round to ovalnuclear outlines, 2-5 small but distinctnucleoli and a small amount of intenselybasophilic cytoplasm. Numerous mitoticfigures and apoptotic cells are present.The prominent starry-sky appearance iscaused by benign phagocytic histiocytesengulfing the nuclear debris resultingfrom apoptosis. Thin sections often show

an unusual finding for lymphomas,whereby the cytoplasmic borders of indi-vidual cells ‘square-off’ against eachother.Burkitt lymphoma may rarely demon-strate a true follicular architecture, con-sistent with the proposed germinal cen-ter histogenesis of this neoplasm. It is amature B-cell lymphoma and the neo-plastic cells express pan-B-cell antigens

A

Fig. 4.20 Burkitt lymphoma. A Large ileocecalmass. B Starry-sky effect due to phagocytic histio-cytes.

B

Fig. 4.21 Follicular lymphoma of terminal ileum.

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CD19, CD20, CD22, and CD79a. Inapproximately 60-80% of cases, the neo-plastic cells co-express CD10, but fail toexpress CD5 or CD23. Surface immuno-globulin expression is moderatelyintense and is nearly always IgM witheither kappa or lambda light chainrestriction. The growth fraction, asassessed by Ki-67 or the paraffin equiva-lent MIB-1, is typically in excess of 90%of tumour cells. Burkitt lymphoma cellsuniformly fail to express bcl-2.

Burkitt-like lymphomaThis group of atypical Burkitt lymphomasappears to represent a morphologicaloverlap between Burkitt lymphoma anddiffuse large B-cell lymphoma. The over-all cell size is similar to Burkitt, but withgreater pleomorphism {827}. Thesecases lack the typical monomorphicappearance of Burkitt lymphoma anddemonstrate slight variation in both cellsize and shape. The cells may have mul-tiple nucleoli as in Burkitt lymphoma or asingle distinct nucleolus. A starry-skypattern may be evident and the mitoticrate is usually significantly increased.These lymphomas have a predilectionfor the gastrointestinal tract of adults,and also occur in the setting of HIV infec-tion.

Other B-cell lymphomasAny subtype of B-cell lymphoma canpresent as a primary small intestinal lym-phoma, including those thought to arisefrom peripheral lymph node equivalents.De novo diffuse large B-cell lymphomasare the commonest lymphomas in thesmall bowel, and may develop from low-grade MALT lymphomas.Indolent lymphomas such as small lym-phocytic lymphoma, lymphoplasmacyticlymphoma and follicular lymphoma (cen-troblastic/centrocytic) can present as pri-mary small intestinal disease. The lattersubtype can occasionally produce theclinico-pathological entity of multiplelymphomatous polyposis, but can usual-ly be distinguished from MCL by immu-nophenotypic and molecular geneticanalysis {1034}. Lymphoblastic lymphoma may underliesmall intestinal lymphoma and frequentlyproduces a mass in the ileocaecalregion. Characteristic nuclear featuresand the expression of terminalnucleotidyl transferase may aid in estab-lishing the diagnosis.

GeneticsMALT lymphomaCytogenetic and molecular features ofintestinal MALT lymphomas are incom-pletely understood; the presence of eithert(1;14)(p22;q32) or t(11;18)(q21;q21) andthe corresponding molecular abnormali-ties, rearrangement of bcl-10 or AP12-MLT, have not been described at this site;thus their relationship to gastric MALTlymphomas is unclear {2116, 412}.Trisomy 3 is common in gastric MALTlymphomas, but the frequency of thiscytogenetic abnormality in primary intes-tinal lymphomas is unknown {413}.

IPSIDAlthough cytogenetic abnormalities havebeen detected in IPSID, no consistentchanges have been described. Southernblot analysis reveals clonal immunoglob-ulin heavy-chain (IgH) gene rearrange-ments, but consensus IgH polymerasechain reaction (PCR) strategies mayyield false negative results.

Mantle cell lymphomaMCL is cytogenetically characterized bya t(11;14)(q13;q32) translocation whichderegulates expression of the bcl-1 onco-gene on chromosome 11. Rearrange-ment can be detected using Southernblot analysis, PCR or fluorescent in situhybridization (FISH).

Burkitt lymphomaBurkitt lymphoma demonstrates a con-sistent cytogenetic abnormality in allcases, with rearrangement of the c-myconcogene on chromosome 8. The char-acteristic translocation, t(8;14)(q24;q32),is seen in most cases; the remaindershows variant translocations includingthe immunoglobulin light chain loci,t(2;8)(p12;q24) or t(8;22)(q24;q11), invol-ving kappa and lambda light chaingenes, respectively. In the classicalt(8;14), the c-myc oncogene is translo-cated from chromosome 8 to the heavychain locus on chromosome 14. In thevariant translocations, a part of the lightchain constant region is translocated tochromosome 8, distal to the c-myc gene.Thus, in the variant translocations, c-mycremains on chromosome 8 and is dereg-ulated by virtue of its juxtaposition to theimmunoglobulin light chain genes. Themolecular characteristics of the c-myctranslocation also differ between endem-ic and sporadic cases. In endemic

Burkitt lymphoma, the chromosome 8breakpoints are usually far 5’ of the c-myc gene, while their chromosome 14breakpoints most often occur in the loca-tion of the IgH gene joining segments.The variable chromosome 8 breakpointsand their location far from the c-myc cod-ing sequences make it impossible inmost cases to demonstrate c-mycrearrangements by Southern blot analy-sis. In contrast, sporadic cases frequent-ly have c-myc breakpoints within non-coding introns and exons of the geneitself, typically in the first exon or intron,or in the 5’ flanking regions of the gene.In most of these cases, c-myc rearrange-ments can be demonstrated usingSouthern analysis {670}.

Burkitt-like lymphoma/Atypical Burkitt lymphomaThis category is cytogenetically hetero-geneous and may contain three or morebiological groups {1387}. Importantly, thefrequency of variant c-myc translocationsprecludes the accurate recognition ofcases using molecular techniques alone.

Prognostic factorsThe main determinants of clinical out-come in small intestinal lymphomas arehistological grade, stage, and resectabil-ity {424}. Advanced age at diagnosis, anacute presentation with perforation, andthe presence of multifocal tumours havean adverse impact on survival. Thebehaviour of diffuse large B-cell lym-phoma is not affected by the presence ofa low-grade MALT component {424}. Theexpression of bcl-2 protein and the pres-ence of TP53 mutations may adverselyaffect outcome in this group, but a sys-tematic study of small intestinal lym-phomas is lacking {567, 770}.MCL is an aggressive neoplasm. A blas-toid cytology, increased mitotic indexand peripheral blood involvement arerecognized as adverse factors {84}.Mutations in the p53 gene and homozy-gous deletions of p16 have recently beenshown to be associated with poor prog-nosis {1099, 700}. Burkitt-like lymphomaswith ‘dual translocation’ of both bcl-2 andc-myc oncogenes have a markedlyshortened overall survival {1137}.

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87T-cell lymphoma

DefinitionA peripheral T-cell lymphoma arising inthe intestine, usually as a complication ofcoeliac disease (gluten sensitive entero-pathy), histologically characterised bydifferentiation towards the intestinalintraepithelial T-cell phenotype.

ICD-O codesT-cell lymphoma 9702/3Enteropathy associated 9717/3

Epidemiology and aetiologyIntestinal T-cell lymphoma (ITL) is rare,accounting for only about 5% of all gas-trointestinal lymphomas, and is normallyassociated with coeliac disease {305}.There is marked geographic variation inthe incidence of ITL, with a high inci-dence in Northern Europe, reflecting thenotion that ITL arises against the samegenetic background as that predispos-ing to coeliac disease {753}. There is no clear sex predominance andin Europe, the median age at diagnosis isaround 60 years {305, 424, 374}. In con-trast, a small series of Mexican patientshad a median age of 24 years and therewas circumstantial evidence for a possi-ble aetiological role of the Epstein Barrvirus, which is absent in European cases{1552, 795}. Congenital or acquiredimmunodeficiency disorders are notknown to be associated with ITL.

LocalizationThe proximal jejunum is the most frequentsite of disease, although it may occur

elsewhere in the small intestine and,rarely, in the stomach and colon {305}.

Clinical featuresThe most frequent symptoms are abdom-inal pain and weight loss {303}. About40% of patients present as acute abdom-inal emergencies due to intestinal perfo-ration and/or obstruction {305, 424}.Patients may have a short history of mal-absorption, sometimes diagnosed asadult coeliac disease which is usuallygluten-insensitive or, less frequently, along history of coeliac disease lasting foryears or even decades {796}. Signs and symptoms of the disease maymimic inflammatory bowel disease (IBD),particularly Crohn disease. Radiographicstudies may be helpful, but they are ofteninterpreted as consistent with a segmen-tal or diffuse inflammatory process.Except for leukocytosis, laboratory dataare usually unremarkable, including nor-mal levels of lactate dehydrogenase{303}.Refractory coeliac disease and ulcera-tive jejunitis are two conditions that fre-quently have a history of coeliac diseasefor years, become resistant to gluten-freediet and may, but not necessarily,progress to ITL {1385, 92}. In ulcerativejejunitis, patients develop non-specificinflammatory ulcers without overt histo-logical evidence of lymphoma.

MacroscopyThe affected bowel segment is oftendilated and oedematous, and usually

shows multiple circumferential ulcers,ulcerated plaques and strictures, withoutthe formation of large tumour masses{424}. The intact mucosa between thelesions may contain thickened folds orappear completely normal. Loops ofbowel may adhere to each other or addi-tionally to the left or right colon, causingpalpable conglomerate tumours.

Tumour spread and stagingAbout 70% of the patients present withlocalized intestinal disease with or with-out contiguous lymph node involvement{305}. Disseminated disease involvesliver, spleen, lung, testes, and skin, butrarely the bone marrow {303, 794}.

HistopathologyThe histological appearances of ITL arevariable both between cases andbetween different tumour sites in thesame patient. The most frequentlyencountered type is composed of highlypleomorphic, medium to large cells, fol-lowed by a lymphoma type that shows amorphology most consistent with ana-plastic large cell lymphoma. The borderbetween these two histologies is notsharp and transition from one to the othermay occur, even within the same tumour{307}.About 20% of ITL are characterized bythe monotonous appearance of denselypacked small to medium-sized cellsalmost without any recognizable stromacomponents. Most of the rathermonomorphic cells contain only slightly

R.D. GascoyneH.K. Müller-HermelinkA. ChottA. Wotherspoon

Intestinal T-cell lymphoma

B CFig. 4.22 Intestinal T-cell lymphoma. Histological features of the most common variants. A Pleomorphic medium and large cells. B Anaplastic large cells. CMonomorphic small to medium cells.

A

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irregular nuclei with small nucleoli andmoderately wide, pale or sometimesclear cytoplasm {307}. Rare variants ofITL are composed predominantly of pleo-morphic small cells or immunoblasts.Irrespective of morphology, the lym-phoma cells often invade and destroy theoverlying epithelium. Most frequently, theenterocytes of the upper and intermedi-ate villous regions, or in cases of severevillous atrophy, the epithelium of theupper parts of the elongated crypts arethe preferential targets of lymphoma cellattack. These features are best appreci-ated at the borders of ulcerated tumours.However, they may also be present as

band-like or patchy microscopic lesionsentirely confined to the mucosa {303}.Fibrosis and admixed inflammatory cellsare constant features of the pleomorphicmedium and large cell and the anaplas-tic large cell ITL types; in the former, anabundance of eosinophils may mask theneoplastic infiltrate {1731}. In contrast,the monomorphic small to medium-sizedvariant characteristically lacks fibroticchanges and inflammatory background{307}.

Histopathology of the enteropathic mucosaIn the vast majority of cases, the macro-scopically normal intestinal mucosashows features of coeliac disease, i.e.increase in normal appearing intraepithe-lial lymphocytes (IEL), villous atrophy, andcrypt hyperplasia {794}, which hasprompted O’Farrelly and co-workers tocoin the term ‘enteropathy associated T-cell lymphoma’ {1383}. An increase innormal appearing IEL (duodenum /jejunum, 40/100 enterocytes; ileum,

20/100 enterocytes) represents the sin-gle most important feature suggestive ofcoeliac disease {1172}. The severity ofthese enteropathic changes is highly vari-able and similar to coeliac disease; theyare most pronounced proximally andimprove distally so that the lower jejunumand ileum may appear normal. Further-more, enteropathy may be minimal orabsent if the patient is on a gluten freediet, or if enteropathic sites are missedbecause of their patchy distribution. Occasionally, the non-neoplastic mucosain ITL shows a strikingly intense or floridintraepithelial lymphocytosis {2142}.

Immunological phenotypingSimilarities of the immunophenotypes innormal or activated (reactive) intraep-ithelial lymphocytes (IEL) and the tumourcells in ITL provide an important part ofevidence that ITL cells are the neoplasticcounterpart of IEL. The expression of theHML-1 defined αEβ7 (CD103) on non-neoplastic IEL and in > 50% of ITL, butnot in resting peripheral blood T-cells,strongly supports this view {1802}. Thevast majority of normal IEL are restingcytotoxic CD3+CD8+CD4-CD2+CD7+CD5low TIA-1+ T-cells using the αβ T-cellreceptor, but minor subsets such asCD4-CD8- or CD56+ are present as wellas predominantly CD4-CD8- γδ T-cells{1113, 304}. In ITL, most cases are

CD3+CD4-CD8-CD7+CD5- and co-express the cytotoxic granule-associatedprotein TIA-1, often together with the acti-vation-dependent cytotoxic moleculegranzyme B {305, 382}. Some correla-tions between ITL morphology and phe-notype exist; pleomorphic medium andlarge cell lymphomas and lymphomas ofanaplastic large cell histology are oftenCD4-CD8-, the latter express CD30+ butare always ALK1 negative; the monomor-phic small to medium-sized variant is fre-quently associated with a CD56+CD8+phenotype {307}. Cytologically normal IEL abundantlypresent in the intact enteropathicmucosa in ITL, in ulcerative jejunitis, andin refractory coeliac disease share anidentical aberrant phenotype with ITLand are monoclonal, as demonstrated byPCR {103}. They therefore are consid-ered a neoplastic population which, inthe absence of concurrent overt ITL, mayrepresent the first step in ITL lymphoma-genesis (‘intraepithelial lymphoma’) andmay have already persisted for years{238}.

ITL diagnosis of endoscopic biopsiesMost cases of ITL are diagnosed on sur-gical resection specimens. In a minorityhowever, endoscopic biopsies, usuallytaken from the stomach, duodenum, orcolon, are available. These patients fre-quently have a longer than 6 months his-tory of abdominal pain and weight loss.Some of them are clinically suspected tohave inflammatory bowel disease, andoccasionally patients had already beenbiopsied with the diagnosis of IBD or anunclear inflammatory process, thusemphasizing the challenging task of ITLdiagnosis in endoscopic biopsies. Theimmunohistochemical demonstration ofan aberrant phenotype is essential indiagnosing ITL, especially in caseswhich lack overt cytological atypiaand/or invasiveness. Furthermore, theneoplastic infiltrate may be subtle orsuperficial and therefore easily over-looked in routinely stained sections.

GeneticsVery few data on chromosomal abnor-malities in ITL exist. Deletion of the Ychromosome and chromosome 9 abnor-malities were found among a phenotypi-cally aberrant intraepithelial T-cell popu-lation {2142}; a t(4;16)(q26;p13) translo-cation was present in a mesenteric

B

C

A

Fig. 4.23 Coeliac disease. The non-neoplasticmucosa distant from an anaplastic large cell intes-tinal T-cell lymphoma displays villous atrophy, crypthyperplasia (A) and an increase in cytologicallyunremarkable intraepithelial lymphocytes (B) with-out evidence of lymphoma. Both the lymphoma(ALCL) and the intraepithelial lymphocytes (IEL)share the same dominant T-cell clone (C) and thesame aberrant immunological phenotype.

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89T-cell lymphoma

lymph node associated with extensiveITL {239}. In two cases of anaplasticlarge cell ITL very complex abnormalitieswere detected in ascitic fluid and lymphnode, respectively {1436}.Southern blotting and PCR studiesdemonstrated monoclonal rearrange-ments of the T-cell receptor (β-chain) inITL, consistent with the derivation fromαβ T-cells {799}. ITL using the γδ T-cellreceptor are rare {86}, but neverthelessseem to outnumber the few well docu-mented cases of true intestinal naturalkiller (NK) cell lymphomas {1176}. Thelatter finding is not surprising as NK cellsare not present among IEL.

Prognosis and predictive factorsThe clinical course is very unfavorabledue to complications from peritonitis andmalnutrition and later from progressivedisease typically characterized by intes-tinal recurrences. The malabsorption dueto underlying coeliac disease is detri-mental to these patients, particularlywhen recovering from surgery or receiv-ing multiagent chemotherapy {444}.Consequently, only one half of thepatients is amenable to chemotherapy

and only a proportion of these is able tofinish the complete course. The overallmedian survival in the largest publishedseries is only 3 months, and 5-year sur-vival in this and other series ranges from

8-25% {305, 424, 444}. The small groupof long-term survivors usually receivedchemotherapy and, interestingly, nonehad a previous diagnosis of coeliac dis-ease {305, 444}.

Fig. 4.24 CD3 immunoexpression in a T-cell lymphoma of the small intestine.

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DefinitionA variety of benign and malignant mes-enchymal tumours can arise in the smallintestine, but the neoplasms that occur inany appreciable numbers are gastroin-testinal stromal tumours (GISTs).

EpidemiologySarcomas account for approximately14% of malignant small intestinal tumours{1928}. Males are affected somewhatmore than females (M:F 1.2:1). The peakincidence is in the 6th to 8th decade. Ageof onset for sarcomas was lower than forcarcinomas, with black females showingthe lowest median age, 50 years. In theU.S. SEER database, the incidence ratefor sarcoma was 0.2 per 100,000 per yearcompared to 0.3 for lymphomas, 0.4 foradenocarcinomas and 0.4 for carcinoids,and appears to be stable.

LocalizationSarcomas show a much more even dis-tribution throughout the small bowelcompared to adenocarcinomas and car-cinoids {1928}. GISTs have been specifi-cally identified in duodenum, jejunum,and ileum {183, 594, 1980}.

Clinical featuresVague abdominal discomfort is the usualcomplaint. Mesenchymal neoplasms ofsmall bowel are more difficult to diag-nose by endoscopy or imaging studiesthan those in the stomach.

MacroscopySmall bowel sarcomas generally appearmacroscopically as those in the stom-ach. Some small intestinal tumours maycause aneurysmal bowel dilatation, whileothers have a diverticulum-like appear-ance.

Histopathology Gastrointestinal stromal tumours Small bowel GISTs resemble those of thestomach histologically, although epithe-lioid lesions are uncommon. Globoidextracellular collagen accumulations (so-called skeinoid fibers) are frequently

observed, especially in benign smallintestinal GISTs {1235}. Factors that cor-relate with malignancy are tumour size> 5 cm, mitotic count > 5 per 50 HPF,dense cellularity, and mucosal invasion(rarely observed). Even with low orabsent mitotic activity, tumours largerthan 5 cm are considered to have malig-nant potential. Small intestinal GISTs arepositive for KIT (CD117) and usually forCD34, and a subset (30-50%) are posi-tive for α–smooth muscle actin; mosttumours are negative for desmin andalmost all are negative for S100-protein.

Leiomyomas and leiomyosarcomas arerare in the small intestine, and can beidentified immunohistochemically bytheir smooth muscle actin and desminexpression and lack of KIT.

Angiosarcomas are recognized by ananastomosing proliferation of atypicalendothelial cells. Immunohistochemicaldemonstration of CD31, less consistentlyvon Willebrand factor, is diagnosticallyuseful {1904}.

Kaposi sarcomas may involve smallintestine, either the mucosa alone ormore extensively. Histologically typicalare elongated spindle cells with vascularslits. Cytoplasmic PAS-positive hyalineglobules are present in some tumourcells. Immunohistochemically, the lesion-al cells are positive for CD31 and CD34.Human herpesvirus 8 can be demon-strated by PCR.

Lipomas exhibit the same morphologicalfeatures as their colonic counterparts.

GeneticsSmall intestinal GISTs show similar c-kitmutations in exon 11 as observed in gas-tric GISTs, and most mutations occur inthe malignant cases. Comparativegenomic hybridization shows commonlosses in chromosomes 14 and 22 similarto those seen in gastric GISTs.

PrognosisThe prognosis of small bowel sarcomasis largely dependent on the mitotic count,size, depth of invasion, and presence orabsence of metastasis. In the SEER data-base, 5-year survival for localizedtumours was 45% for sarcomas, com-pared to 92% for carcinoids and 63% forcarcinomas {1928}. In a study of overone thousand stromal/smooth musclesarcomas, the 5-year survival rate was55% for sarcomas of small bowel, 60%for colorectum, 70% for stomach and75% for oesophagus {462}.

M. MiettinenJ.Y. BlayL.H. Sobin

Mesenchymal tumours of the small intestine

Fig. 4.25 A Stromal tumour of small intestine. B Cutsurface of lesion illustrated in A.

B

A

Fig. 4.26 Small intestinal stromal tumour. Extra-cellular accumulation of skeinoid fibres produceseosinophilic globules.

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91Secondary tumours

DefinitionTumours of the intestines that originatefrom an extra-intestinal neoplasm or whichare discontinuous with a primary tumourelsewhere in the gastrointestinal tract.

EpidemiologyMetastatic spread to the small intestine ismore frequent than to any other site in thegastrointestinal tract (see Table 3.02).Secondary carcinomas of the smallbowel are as common as primary carci-nomas at this site {1234}.

OriginFor small intestine, melanoma, lung,breast, colon and kidney are the most

frequent primary sites (see Table 3.02){130, 1022, 1378, 1209, 1457, 458}.Metastatic spread from primary lungcancer to the small intestine is more fre-quent than to stomach and colon (Table4.01). Virtually all primary cancers canoccasionally lead to metastases in thesmall intestine and, because of the lowfrequency of primary small bowel cancer,a high proportion of small intestinalmalignancies are metastatic.The pathogenesis of intestinal metastasisusually involves haematogenous spreadof tumour cells. Invasion from neighbour-ing primary tumours also occurs, e.g.pancreatic carcinoma to duodenum andprostate carcinoma to rectum.

Primary melanomas of the intestine arevery rare. Although most melanomasfound in the small bowel have no history

C. NiederauL.H. SobinSecondary tumours of the

small and large intestines

Table 4.01Frequency of metastasis from breast (695 cases)and lung (747 cases) to gastrointestinal tract {130}.

Fig. 4.27 Metastatic adenocarcinoma, small intestine. A Tumour is beneath swollen mucosa. B Tumour in muscularis propria. Submucosa is oedematous.

BA

Metastasis

Fig. 4.28 A, B Metastatic malignant melanoma, small intestine.BA

Primary Stomach Small Colonsite intestine

Breast 3.6% 1.7% 1.4%

Lung 1.3% 4.4% 1.9%

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of a primary tumour, the general consen-sus is that they are virtually all secondary,usually from misdiagnosed or regressedprimary melanomas {458}.

Clinical featuresSmall intestinal metastases can causebleeding and obstruction as well as non-specific symptoms such as abdominaldiscomfort, gas distension, and diar-rhoea {1378, 580}.

ImagingThe identification of a small bowel tumouralways raises the question of whether thetumour is primary or secondary. Contrastradiography shows narrowing andabnormalities of the small intestinal wall.Advanced cases result in stenosis withdistension due to obstruction.

MacroscopyTypical features of intestinal metastasesinclude intestinal wall thickening, submu-cosal spread, and ulcers. Melanomasmay not be pigmented and may appearas nodules or polyps.

HistopathologyMetastases are typically submucosal orsubserosal making the distinctionbetween primary and secondary tumoursrelatively easy. Cytokeratin immunohisto-chemistry may help to differentiatebetween primary colon cancer (positivefor cytokeratin 20), metastases fromovary and breast (usually positive forcytokeratin 7) and those from liver, kidneyand prostate (usually negative for bothcytokeratins 7 and 20) {2047, 129}. Onthe other hand, the distinction between

multiple primary small bowel carcinoidsand their metastases may not be possi-ble. This also applies to leiomyosarco-mas/stromal tumours of the small intes-tine.

PrognosisIntestinal metastases usually represent alate stage of disease in which otherhaematogenous metastases are also fre-quently found. Therefore, the prognosisis poor. Exceptions are melanoma andrenal cancer in which metastases con-fined to the bowel may be associatedwith prolonged survival after resection.

Fig. 4.30 Metastatic breast carcinoma, colon.Tumour cells expand submucosa.

Fig. 4.31 Metastatic breast carcinoma, caecum,diastase-PAS stain. Many tumour cells are mucinpositive.

Fig. 4.29 Metastatic adenocarcinoma, small intes-tine. Muscularis propria contains tumour. Mucosais free of neoplasia.

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