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Definition

Endocrine tumours of the large intestine are defined as in the small intestine.

Epidemiology

Incidence and time trends

Endocrine tumours of the colon have an incidence of 0.07-0.11 up to 0.21 cases per 100,000 population per year {1251}. In a recent series, carcinoids from caecum to transverse colon (midgut) represented about 8% and descending colon and rectosigmoid (hindgut) carcinoids about 20% of 5973 gastrointestinal carci-noids {1251}. Rectal carcinoids had a reported incidence of 0.14-0.76 cases per 100,000 population per year. In the 40-year time period (from 1950 to 1991) the percentage of caecal carcinoids, among carcinoids of all sites, nearly doubled, as did the percentage of rectosig-moid lesions {1251}.

Age and sex distribution

The reported average age at diagnosis is 58 years, for rectal, and 66 years, for colonic carcinoids, and the M/F ratio is 1.06, for rectal, and 0.66, for colonic carcinoids {1251}.

Aetiology

Some colorectal carcinoids have been reported in the large bowel of patients with ulcerative colitis {584, 622} or Crohn disease {722, 622}. In association with these conditions, the tumours tend to be multiple {1208}. However, there appears to be no evidence to substantiate a direct association between inflammatory bowel

Fig. 6.77 Endoscopically resected carcinoid tumour of rectum.

disease and carcinoid tumours, because almost all cases were found incidentally after surgery for inflammatory bowel disease {622}.

Localization

Endocrine tumours are more common in the rectum (54% of the cases), followed by the caecum (20%), sigmoid colon (7.5%), rectosigmoid colon (5.5%) and ascending colon (5%) {1251, 1784}.

Clinical features

Patients with colonic carcinoid tumours most commonly present in the seventh decade with symptoms of abdominal pain and weight loss, though some present late with liver metastases {1616}. Less than 5% of patients present with the carci-noid syndrome {1616, 128}. Carcinoids of the colon are associated with metachro-nous or synchronous non-carcinoid neoplasms in 13% of cases {1251}. Half of rectal endocrine tumours are asymptomatic and are discovered at rou-

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Fig. 6.78 A, B Carcinoid tumour of rectum. Trabecular pattern, typical of L-cell tumour.

tine rectal examination or endoscopy, while the other half give rise to symptoms, typically rectal bleeding, pain or constipation {857, 1836}. Rectal carcinoids are practically never associated with the carcinoid syndrome {857, 1836, 212}. Small cell carcinomas are aggressive neoplasms and can present with symptoms due to local disease or to widespread metastases.

Macroscopy

The majority of colonic carcinoids are detected in the right colon {1616, 128} and are larger than carcinoids of the small intestine, appendix, and rectum. The average size was 4.9 cm in cases reviewed by Berardi {128}. Rectal carcinoids appear as submucosal nodules, sometimes polypoid, often with apparently intact overlying epithelium {968}. Larger lesions tend to be somewhat fixed to the rectal wall. In the great majority of cases the tumour is found 4 to 13 cm above the dentate line and on the anterior or lateral rectal walls {222}. The majority of rectal endocrine tumours are solitary and measure less than 1 cm in diameter {222}. Reviewing 356 cases reported in the literature, Caldarola et al. {222} found that only 13% of rectal carcinoids measured more than 2 cm in diameter.

Histopathology

Carcinoid - well differentiated endocrine neoplasm

Colonic serotonin-producing EC-cell tumours show histological, cytological, cytochemical, and ultrastructural features that are identical to those of jejuno-ileal EC-cell tumours, including the absence of S100 protein positive susten-tacular cells {1784}.

L-cell, glucagon-like peptide and PP/PYY-producing tumours are characterized his-tologically by a predominance of a type B {1775} ribbon pattern, often admixed with type C (tubuloacini or broad, irregular tra-beculae with rosettes) and only occasionally with areas of type A solid nest structures. These patterns are different from

Fig. 6.79 Rectal carcinoid showing prostatic acid phosphatase immunoreactive cells.

those of EC-cell tumours, in which type A structures prevail. The argentaffin reaction is usually negative {146}, while consistently positive results are obtained with Grimelius stain {488}. Immunohisto-chemically, they stain for panendocrine markers (neuron-specific enolase, synap-tophysin, chromogranins) and for a variety of peptide hormones {488}. Among 62 rectal carcinoids derived from surgical pathology files, about 80% displayed more or less abundant glucagon-like peptide (GLP-1, GLP-2, glicentin) and/or PP/PYY immunoreactivities typical of intestinal L-cells, whereas only 30% showed serotonin immunoreactivity and 20% somatostatin immunoreactivity, usually in only few cells {1780, 507}. Although there is a prevalence of L-cells in these tumours, minority populations of substance P, insulin, enkephalin, beta-endorphin, neurotensin, and motilin immunoreactive cells have also been identified {1780, 488, 212}. The vast majority (82%) of colorectal carcinoids tested in one series of 84 cases showed immunoreactivity for prostatic acid phos-

phatase, a finding that is unusual in other gut carcinoids and possibly is related to the common origin of the rectum and prostate from cloacal hindgut {488}. Ultrastructurally, rectal L-cells show round to slightly angular secretory granules similar to those of L-cells of the normal human intestine {506}. Small (< 2 cm) benign L-cell rectal carci-noids show an immunohistochemical Ki-67 index < 1%, while large (> 2 cm) L-cell carcinomas show a Ki-67 index > 5% (La Rosa S, Capella C, Solcia E, unpublished observations, 1999).

Small cell carcinoma (poorly differentiated neuroendocrine neoplasm)

These are morphologically identical to small cell carcinomas of the lung, and correspond to grade 3 tumours according to Rindi et al. {1589}. They are usually found in the right colon, and are frequently associated with an overlying adenoma or adjacent adenocarcinoma {2085}, but are not associated with carci-noid tumours. Small cell carcinomas typically express neuroendocrine markers (e.g. chromogranin, synaptophysin) by immunohistochemistry. Patients usually have liver metastases at the time of original surgery, and the prognosis is poor {207}.

Large cell neuroendocrine carcinoma is a malignant neoplasm composed of large cells having organoid, nesting, trabecu-lar, rosette-like and palisading patterns that suggest endocrine differentiation, which can be confirmed by immunohis-tochemistry and electron microscopy. In contrast to small cell carcinoma, cyto-

Fig. 6.80 Small cell carcinoma arising in a tubulovil-lous adenoma of the sigmoid colon.

plasm is more abundant, nuclei are more vesicular and nucleoli are prominent {1954}. These tumours have not been well described in the gastrointestinal tract because of their apparent low frequency.

Genetics

Loss of heterozygosity at MEN-1 locus has been reported in two sporadic colonic and two sporadic rectosigmoidal carcinoids {829}. However, this finding has not been confirmed by more recent studies {394, 1938}. Colorectal carci-noids do not represent an integral part of MEN-1 {1444}. A case of rectal carcinoid tumour associated with Peutz-Jeghers syndrome has been reported {2032}.

Prognosis

Colonic EC-cell carcinoids are frequently malignant, local spread of the tumours was found in 36-44% of patients and distant metastases in 38% {1251, 1616}. The reported 5-year survival rate was 25-42% and the 10-year survival rate was 10% {1251, 1616}. Modlin found malig

nant (non-localized) tumours represented 71% of the cases among colonic car-cinoids, and 14% of cases among rectal carcinoids {1251}. The alleged poor prognosis of colonic carcinoids has been questioned as possibly the result of a proportion actually being poorly differentiated adenocarcinomas with carcinoid-like growth patterns {1928}.

For rectal carcinoids, an overall malignancy rate of 11% to 14% has been calculated in some studies {1251, 488}. Recognised malignancy criteria include: a size of the tumour greater than 2 cm {857, 1328, 930}, invasion of the muscu-laris propria {857, 212, 1328}, atypical histology {964}, presence of more than 2 mitoses per 10 high power (X 400) micro scopic fields, and DNA aneuploidy {1963}. Patients with rectal carcinoids generally have a good prognosis, showing a 5-year survival rate of 72%-89% {1251, 1931}, which is better than the 5-year survival rate of 60% for patients with jejuno-ileal carcinoids {211}. The prognosis is excellent if the tumour diameter is 1 cm or less {294}.

B-cell lymphoma of the colon and rectum

H.K. Müller-Hermelink A. Chott R.D. Gascoyne A. Wotherspoon

Definition

Primary lymphoma of the colorectum is defined as an extranodal lymphoma arising in either the colon or rectum with the bulk of disease localized to this site {796}. Contiguous lymph node involvement and distal spread may be seen, but the primary clinical presentation is the colon and/or rectum.

Epidemiology

Primary lymphomas arising in the large intestine are less frequent than either gastric or small bowel lymphomas {792}. Primary colorectal lymphomas account for about 0.2% of all neoplasms at this site. The lymphoma subtypes that present in the colorectum are similar to those that involve the small intestine, with the exception of immunoproliferative small intestinal disease (IPSID). Mucosa-asso-ciated lymphoid tissue (MALT) lymphomas of both small and large cell type account for the majority of lymphomas of the colorectum {1733}. Mantle cell lymphoma (MCL), often in the form of multiple lymphomatous polyposis, is less frequent but accounts for a larger propor tion of primary lymphomas in the colorectum than in the small bowel {1733}.

Most colorectal lymphomas occur in older patients without a clear sex predominance. Amongst aquired immunodeficiency syndrome (AIDS) patients, the median age is lower and the majority of cases occur in homosexual men. Involvement of the colorectum by Burkitt lymphoma is distinctly uncommon in immunocompetent individuals.

Aetiology

The factors involved in the aetiology of colorectal lymphomas are similar to those in the small intestine. Inflammatory bowel disease, particularly ulcerative colitis, is a recognized predisposing factor {1733}. Diverticular disease does not appear to be a risk factor for the development of lymphoma. Immunodeficiency disorders giving rise to lymphoma have a predilection for the gastrointestinal tract. The frequency of colorectal lymphomas has significantly increased, partly due to the AIDS epidemic.

Localization

Most colorectal lymphomas involve the distal large bowel, rectum and anus. There is a preference for rectal lymphoma in patients infected with the human immunodeficiency virus (HIV) {787, 1057}. Multifocal involvement is uncommon with the exception of multiple lymphomatous polyposis {1733}.

Clinical features

The presenting features are very similar to epithelial neoplasms at this site. Rectal bleeding is the most common symptom, followed by diarrhoea, abdominal pain, passage of mucus per rectum, constipation, abdominal mass, weight loss, irregular bowel habit, anal pain and worsening of ulcerative colitis symptoms. Occasional cases are found incidentally, while an acute presentation with rupture of the colon is distinctly uncommon {1733, 611}.

Similar to gastric lymphomas, colorectal lymphomas can be diagnosed using endoscopy and biopsy. Computerized tomography and barium enema have a role in diagnosis and determining the extent of disease. Multiple lymphoma-tous polyposis has a characteristic radiological picture with numerous polyps of variable size throughout the colon. Transrectal ultrasonography may also be a useful adjunct for diagnosis.

Macroscopy

Most low-grade lymphomas present as well defined protuberant growths that deeply invade the bowel wall. Diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma tend to form larger masses with stricture and ulcer formation involving long segments of the colorec-tum. Low-grade and aggressive MALT lymphomas typically remain localized for prolonged periods, but may spread to involve loco-regional lymph nodes. Mantle cell lymphoma (MCL) may present as an isolated mass or as multiple polyps producing the clinical picture of multiple lymphomatous polyposis {2084}. In most cases, the colon is more significantly involved than the small bowel. Importantly, other histological subtypes of lymphoma can produce this clinicopathological entity (see below). The polyps range in size from 0.5 cm to 2 cm with much larger polyps found in the ileocaecal region {791, 1292}. MCL frequently spreads to involve the spleen, extra-abdominal lymph nodes, bone marrow and peripheral blood.

Histopathology

MALT lymphoma

The majority of intestinal lymphomas involving the large bowel are B-cell lymphomas of MALT type, including both low-grade and aggressive histologies {796}. The histological and immunophe-notypic features are discussed in detail in the section describing lymphomas of the stomach. Colorectal low-grade MALT

Fig. 6.82 MALT lymphoma of rectum with lym-phoepithelial lesions.

Fig. 6.83 Malignant lymphoma of rectum.

lymphomas resemble those of the small intestine in that lymphoepithelial lesions are less prominent than in the stomach. Precise criteria for defining a MALT lymphoma of large cell type are lacking, as are the criteria for distinguishing transformation within a low-grade MALT lymphoma. When both histologies are evident, the neoplasm is best described as composite. When small foci of large transformed cells or early sheeting-out of large cells are detected within a background of low-grade intestinal MALT lymphoma, their presence should be noted {383}. Currently, the prognostic impact of these findings and their effect on treatment are undetermined. DLBCLs arising in the large bowel that lack a background of low-grade MALT lymphoma are best classified as extranodal diffuse large B-cell lymphoma, not otherwise specified, until such time as confirmatory tests can be established to clearly determine the histogenesis of these neoplasms from the mucosal immune system.

Mantle cell lymphoma

The morphology of MCL involving the large bowel is identical to MCL at nodal sites {110}. The architecture is most frequently diffuse, but a nodular pattern and a less common true mantle-zone pattern are also seen. Reactive germinal centers may be found and are usually compressed by the surrounding lymphoma cells, imparting the appearance of replacing the normal mantle zones. Intestinal glands may be destroyed by the lymphoma, but typical lymphoepithelial lesions are not seen. The low power appearance is monotonous with frequent epithelioid histiocytes, mitotic figures and fine sclerosis surrounding small blood vessels. The lymphoma cells are small to medium sized with irregular nuclear outlines, indistinct nucleoli and scant amounts of cytoplasm. Large transformed cells are typically not present.

The lymphoma cells are mature B-cells and express both CD19 and CD20. Characteristically the cells co-express CD5 and CD43. Surface immunoglobulin is found including both IgM and IgD. Light chain restriction is present in most cases, with some studies demonstrating a predominance of lambda. CD10 and CD11c are virtually always negative. Bcl-1 (cyclin D1) is found in virtually all cases and can be demonstrated within the nuclei of the neoplastic lymphocytes in paraffin sections.

Burkitt lymphoma

The details of the histology, immunophe-notype, cytogenetics and molecular genetics are described in detail in the small intestinal lymphoma section (Chapter 4).

Burkitt-like lymphoma

The histological and cytogenetic features have been previously described in the small intestinal lymphoma section. AIDS patients have a preponderance of cases with this histology. Many are of small non-cleaved cell type with the typical molecular and cytogenetic changes associated with classical Burkitt lymphoma, and

Fig. 6.84 Burkitt lymphoma of colon. The malignant cells infiltrate the lamina propria and produce lym-phoepithelial lesions.

Fig. 6.82 MALT lymphoma of rectum with lym-phoepithelial lesions.

Fig. 6.85 Mantle cell lymphoma infiltrating the submucosa predominantly , thereby causing a polypoid lesion.

are best considered to be part of the same biological entity {236}. However patients with AIDS have also been recognized to have another lymphoma, with features intermediate between small non-cleaved cell lymphoma with plas-mablastic differentiation and immuno-blastic lymphoma, plasmacytoid type. This latter lymphoma subtype is strongly associated with EBV infection and TP53 mutations {236}.

Other B-cell lymphomas Any subtype of B-cell lymphoma can arise in a colorectal site, including those thought to arise from peripheral lymph node equivalents. De novo DLBCLs are equal in frequency to low-grade MALT lymphomas in the colorectum {1733}, and are particularly common in the setting of HIV infection. Rectal involvement in AIDS patients typically demonstrates DLBCL with either centroblastic or immunoblastic cytomorphology. These lymphoma subtypes can be distinguished using phenotypic markers including Bcl-6, CD138 (syndecan-1) and EBV-related protein, latent membrane protein (LMP-1). Small non-cleaved and centroblastic lymphomas express Bcl-6, but fail to express CD138 or LMP-1 in the majority of cases. Immunoblastic lymphomas in the HIV setting do not express Bcl-6, but are positive for both CD138 and LMP-1, in keeping with a non-germinal center histogen-esis {237}.

Genetics

MALT lymphoma

Cytogenetic and molecular features of intestinal low-grade MALT lymphomas are incompletely understood. The presence of either t(1 ;14)(p22;q32) or t(11;18)(q21;q21) and the corresponding molecular abnormalities, rearrangement of bcl-10 or AP12-MLT, have not been described at this site, thus the relationship of these lesions to gastric MALT lymphomas is unclear {2116, 412}.

Furthermore, trisomy 3 is common in gastric MALT lymphomas, but the frequency of this cytogenetic abnormality in primary intestinal lymphoma is unknown. Some of these DLBCLs may have a low-grade MALT component evident, providing compelling evidence that their histogenesis is related to the mucosal immune system.

Mantle cell lymphoma

MCL is characterized by a recurrent cytogenetic abnormality, the t( 11; 14) (q13;q32). This translocation deregulates expression of the bcl-1 oncogene on chromosome 11. Rearrangement can be detected using Southern blot analysis, PCR or fluorescent in situ hybridization (FISH).

Prognosis

The relevant prognostic factors in colorectal lymphomas are similar to those for the small intestine, and have been described in detail in that section. MCL is an aggressive lymphoma, which typically presents in advanced stage; there is often involvement of mesenteric and peripheral lymph nodes, spleen, bone marrow and peripheral blood {670}.

Fig. 6.86 Mantle cell lymphoma.

Mesenchymal tumours Jv.JS™

of the colon and rectum LG K'nbdblom

Definition

A variety of benign and malignant mes-enchymal tumours that arise in the large intestine as a primary site.

Classification

The morphological definitions of these lesions follow the WHO histological classification of soft tissue tumours {2086}. Stromal tumours are described in detail in the chapter on gastric mesenchymal tumours.

Epidemiology

Sarcomas accounted for 0.1% of malignant large intestinal tumours in SEER data {1928}. Males were affected slightly less than females. Adults between the 6th and 8th decades were primarily affected.

Aetiology

Aetiological factors are poorly understood for most colorectal mesenchymal tumours. Kaposi sarcoma usually occurs in association with AIDS, but it has also been described in connection with inflammatory bowel disease, in one case following immunosuppressive therapy {1930, 1584}. Human herpesvirus 8 is usually demonstrable by PCR in Kaposi sarcoma cells. An angiosarcoma has been reported in the colon, related to a persistent foreign body {149}.

Fig. 6.87 Leiomyoma of rectum.

Pathological features

Lipomas are composed of mature adipose tissue and are surrounded by a fibrotic capsule. They usually arise in the submucosal layer of the caecum or the sigmoid colon. When ulcerated, the lipocytes may become irregular and hyperchromatic. Lipomas should be distinguished from lipohyperplasia of the ileocaecal valve {1726}. Neurofibromas and schwannomas occur in the colorectum. Most patients with the former have neurofibromatosis, and in these cases plexiform neurofibromas are common. Ganglioneuromas occur rarely in the mucosa.

Vascular tumours are classified into benign (such as haemangiomas, lym-phangiomas and angiomatosis) and malignant (such as haemangioendothe-liomas and angiosarcomas). Kaposi sarcoma is mostly asymptomatic; a few present with GI-bleeding {319}. Intestinal lesions may be observed without cutaneous disease {114}. The tumours are often multiple mucosal or submucosal nodules. Histologically typical are sheets of spindle cells interspersed by clusters of extravasated erythrocytes. Cytoplas-mic hyaline PAS-positive globules are usually seen. The spindle cells are generally positive for CD31 and CD34 and are negative for actin, desmin and c-kit.

Leiomyomas usually are detected in the rectum and colon as small polyps arising from the muscularis mucosae, and consist of well-differentiated smooth muscle cells with a similar immunohistochemical profile as observed in oesophageal leiomyomas {1227}. Leiomyomatosis has been described in the colon with a circumferential semiconstrictive growth in a 35 cm long segment {529}. It is not known whether colorectal leiomyomas and leiomyomatosis have the same colla-

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