Pnu

Fig. 3.41 Low-grade B-cell MALT lymphoma. The centrocyte-like cells show prominent plasma cell differentiation with (A) extracellular immunoglobulin deposition, and (B) prominent Dutcher bodies.

Fig. 3.42 A, B, C Low-grade B-cell MALT lymphoma. A, B Lymphoepithelial lesions. C Immunostaining for cytokeratin highlights lymphoepithelial lesions. D Diffuse large B-cell lymphoma; the neoplastic cells focally infiltrate glandular epithelium to form structures reminiscent of lymphoepithelial lesions.

Fig. 3.42 A, B, C Low-grade B-cell MALT lymphoma. A, B Lymphoepithelial lesions. C Immunostaining for cytokeratin highlights lymphoepithelial lesions. D Diffuse large B-cell lymphoma; the neoplastic cells focally infiltrate glandular epithelium to form structures reminiscent of lymphoepithelial lesions.

eradication are characteristic. The lamina propria appears 'empty' with gland loss. Scattered lymphocytes and plasma cells are seen within the lamina propria and there are usually focal nodular collections of small lymphocytes. These collections frequently contain a mixture of B- and T-cells and may be based on follicular dendritic cell networks. In most cases, the appearances are insufficient for a diagnosis of residual lymphoma. The significance of these lymphoid nodules remains uncertain. In cases showing partial regression or no change following H. pylori eradication, the lamina propria contains an infiltrate morphologically indistinguishable from that seen at diagnosis, but in these treated cases lymphoepithelial lesions may be very scanty or absent. In some cases of partial regression and in cases with relapsed low-grade MALT lymphoma following H. pylori eradication, the lymphoma may be largely confined to the sub-mucosa with only minimal involvement of the mucosa.

PCR based diagnosis

The role of genetic analyses in the diagnosis and follow up of low-grade MALT lymphoma remains controversial. Up to 10% of well characterized cases of MALT lymphoma identified as clonal through demonstration of rearrangement of the immunoglobulin heavy chain gene by Southern blot fail to show a clonal pattern when examined for immunoglobulin heavy chain gene rearrangement by PCR using fresh frozen tissue {418}. This false negative rate increases if paraffin embedded material is studied {417}. Several studies have revealed by PCR the presence of clonal B-cell populations in biopsies from patients with uncomplicated chronic gastritis and no morphological evidence of lymphoma {1677, 225, 388}. In conjunction with histological assessment, PCR studies may be useful in monitoring regression of MALT lymphomas following conservative therapy {25}. However, PCR detected clonal B-cell populations may still be detected in cases showing complete histological regression. Some, but no all of these will eventually show molecular regression but there may be a prolonged time lag between histological and molecular regression {1677}. In the absence of his-tological evidence of residual lymphoma, the clinical significance of a persistent clonal population remains uncertain.

Progression to high-grade lymphoma

The emergence of clusters of large transformed 'blastic' B-cells reflects transformation to high-grade lymphoma {383}. Eventually, these areas become confluent to form sheets of cells indistinguishable from the cells of a diffuse large B-cell lymphoma. As long as a low-grade component remains, these tumours may be termed high-grade MALT lymphomas but during further progression, all traces of the pre-existing low-grade lymphoma are lost, making it impossible to distinguish the lesion from a diffuse large B-cell lymphoma of unspecified type. In cases with both low- and high-grade components, genetic studies have con firmed the transformation of low-grade to high-grade lymphoma in the majority of cases {1263} while in other cases both components appear clonally unrelated, suggesting the development of a second primary lymphoma {1184, 1491}.

Molecular genetics of MALT lymphomas

Early studies confirmed the presence of immunoglobulin gene rearrangement in each case {1803} and suggested that there was no involvement of the bcl-1or bcl-2 oncogenes {2136}. The translocation t(11;18)(q21;q21) has been identified in a significant number of low-grade MALT lymphomas and may be the sole genetic alteration in these cases. However, this translocation appears to be less common in high-grade lesions {1435, 95}. Trisomy 3 has been detected in up to 60% of cases in some studies using both metaphase and interphase techniques {2134, 2137}, but this finding has not been confirmed by other studies {1434}. The translocation t(1;14) (p22; q32) has also been described in a small proportion of cases {2138} and this is associated with increased survival of tumour cells in unstimulated cell culture. Cloning of the breakpoint involved in this translocation has led to the discovery of a novel gene, bcl-10, on chromosome 1 that may be significant in determining the behaviour of MALT lymphomas {2116}. Studies of the immunoglobulin gene of MALT lymphoma cells has shown the sequential accumulation of somatic mutations, consistent with an ongoing, antigen driven selection and proliferation {279, 434, 1546}. Study of the third complementary determining region of the immunoglobulin heavy chain gene shows a pattern of changes associated with the generation of antibody diversity and increased antigen binding affinity {131}. Transformation of low-grade MALT lymphoma to a high-grade lesion has been associated with several genetic alterations. While the t(11; 18) chromosomal translocation is not seen in high-grade MALT lymphoma and may be protective against transformation, alterations in the genes coding for p53, p16, c-myc and trisomy 12 have all been identified in high-grade lesions {1489, 1490, 1341, 270, 435, 1992}. Bcl-6 protein has also been described in high-grade lymphomas while being absent from low-grade lesions {1425}. Some studies have shown a high level of bcl-6gene hyper-

mutations in diffuse large B-cell lymphomas independent of a rearrangement of the gene {1070}. Epstein-Barr virus is not associated with low-grade lymphomas and has only been seen in some high-grade lymphomas {1038, 1437}.

Mantle cell lymphoma

Mantle cell lymphoma of the stomach is typically a component of multiple lym-phomatous polyposis of the gastrointestinal tract and infrequently encountered outside this clinical context {1380}. Morphologically and immunophenotypi-cally, the lymphoma is indistinguishable from mantle cell lymphomas of lymph nodes, with a diffuse and monotonous infiltrate of cells with scanty cytoplasm and irregular nuclei that express B-cell markers together with CD5 and cyclinD1.

Other low-grade B-cell lymphomas

Although the lymphoid tissue in the stomach contains all the B-cell populations encountered in nodal lymphoid tissue, other low-grade B-cell lymphomas, such as follicle centre cell lymphomas, are very rare and usually indistinguishable from their nodal counterparts.

Diffuse large B-cell lymphoma

These lymphomas are morphologically indistinguishable from diffuse large B-cell lymphomas that arise within lymph nodes. There is complete destruction of the gastric glandular architecture by large cells with vesicular nuclei and prominent nucleoli. Variants of large B-cell lymphoma (e.g. plasmablastic lymphoma) may also be encountered {1541}.

Burkitt lymphoma

Although rare, classical Burkitt lymphomas may be encountered in the stomach {55}. The morphology is identical to that of Burkitt lymphoma encountered elsewhere, with diffuse sheets of medium sized cells with scanty cytoplasm and round/oval nuclei containing small nucleoli. Within the sheets there are numerous macrophages, giving a 'starry-sky' appearance. Mitoses are frequent and apoptotic debris abundant. The cells express CD10 in addition to pan-B-cell markers. Close to 100% of nuclei are immunoreactive for Ki-67.

T-cell lymphoma

Primary gastric T-cell lymphomas are rare. Most have been reported from areas of endemic HTLV-1 infection and probably represent gastric manifestations of adult T-cell leukemia/lymphoma (ATLL). In these regions, T-cell lymphoma may represent up to 7% of gastric lymphomas {1741}. Most of the remainder are similar to peripheral T-cell lymphomas encountered in lymph nodes but occasionally, gastric NK cell lymphomas are also seen {1741}. It has recently been demonstrated that some gastric T-cell lymphomas display features of intraepithelial T lymphocyte differentiation (e.g. expression of the human mucosal lymphocyte 1 antigen, CD103), similar to those seen in intestinal T-cell lymphomas {520}.

Hodgkin disease

Hodgkin disease may involve the gastrointestinal tract but this is usually secondary to nodal disease. Primary gastric Hodgkin disease is very rare {2210}.

Prognosis and predictive factors

Studies on the regression of low-grade MALT lymphoma through H. pylorieradi-cation have shown remission in 67-84% of cases {1926, 1520, 2133}, but this applies only to low-grade lesions and is most effective for lesions showing superficial involvement of the gastric wall. Although remission following H. pylori eradication has occasionally been seen in advanced tumours, the highest success rate of 90-100% is seen in tumours confined to the mucosa and superficial submucosa. The time taken to achieve remission in these patients varies from 4-6 weeks to 18 months. The stability of these remissions remains to be determined; one study has reported a relapse in 10% of patients after a mean follow-up period of 24 months {1338} while others have found sustained remissions for up to six years {801}.

Surgical resection is associated with prolonged survival {552} in many cases. Involvement of the resection margins and advanced stage are poor prognostic features, but not with the addition of chemotherapy {1262}. Irrespective of treatment modality, the only significant independent prognostic variables are stage and tumour-grade {260, 1653, 1262, 320, 383}.

Mesenchymal tumours of the stomach J^™

L.H. Sobin

Definition

Most gastrointestinal mesenchymal neoplasms are gastrointestinal stromal tumours (GIST) or smooth muscle types. They are predominantly located in the stomach. The definitions of other mesenchymal lesions follow the WHO histo-logical classification of soft tissue tumours {2086}.

Terminology

The designation GIST was originally introduced as a neutral term for tumours that were neither leiomyomas nor schwannomas. The term GIST is now used for a specific group of tumours comprising the majority of all gastrointestinal mesenchy-mal tumours. These tumours encompass most gastric and intestinal mesenchymal tumours earlier designated as leiomyoma, cellular leiomyoma, leiomyoblastoma and leiomyosarcoma {80, 76, 78, 79, 1227}. Currently, the terms leiomyoma and leiomyosarcoma are reserved for those tumours that show smooth muscle differentiation, histologically or by immunohis-tochemistry, e.g. with strong and diffuse actin and desmin positivity. Most tumours historically called leiomyosarcoma {31, 1559, 1750} are now classified as GISTs; hence the old literature on gastric (and intestinal) leiomyosarcomas largely reflects GISTs.

Epidemiology

GIST accounts for 2.2% of malignant gastric tumours in SEER data. There is no gender preference (M:F, 1.1:1), in contrast to carcinomas which have a M:F of 2:1 {1928}. Adults between the 6th and 8th decade are primarily affected. The ratio of the age-adjusted incidence rates for Blacks and Whites is greater for sarcomas (3 to 1) than for carcinomas (2 to 1). Black women are affected six times more frequently than white women (0.6 versus 0.1 per 100,000 per year, analogous to the ratio for uterine leiomyosarcomas) {1584}.

Localization

GISTs occur at every level of the tubular gastrointestinal tract and additionally may be primary in the omentum and mesentery. They are most common in the stomach (60-70%), followed by small intestine (20-30%), colorectum and oesophagus (together < 10%) {1227}.

Clinical features

GISTs present a spectrum from clinically benign, small to medium-sized tumours, to frank sarcomas. According to our estimate, approximately 30% of GISTs are clinically malignant, and a substantial number of patients with apparent radical surgery will relapse {1344, 462}. Typical of the malignant GISTs at all locations is intra-abdominal spread as multiple tumour nodules, and distant metastases most commonly to liver followed by lung and bone in decreasing frequency {478A, 1984, 1855}. Vague abdominal discomfort is the usual complaint in symptomatic tumours. Both benign and sarcomatous GISTs that project into the lumen may ulcerate and be a source of bleeding {80, 78, 79}.

Macroscopy

Small gastric GISTs appear as serosal, submucosal or intramural nodules that are usually incidental findings during abdominal surgery or endoscopy. Some tumours may ulcerate, especially the epithelioid stromal tumours. The larger tumours protrude intraluminally or to the serosal side, and may have a massive extragastric component that masks the gastric origin. Intraluminal tumours are often lined by intact mucosa, but ulcera-

Fig. 3.43 Cajal cells immunoexpress KIT antigen (CD117) in fetal small intestine.

tion occurs in 20-30% of cases. Infiltration by direct extension to the pancreas or liver occurs. On sectioning GISTs vary from slightly firm to soft, tan, often with foci of haemorrhage. Larger tumours may undergo massive haemorrhagic necrosis and cyst formation leaving only a narrow rim of peripheral viable tissue; malignant tumours may form complex cystic masses. Multinodular peritoneal seeding is typical of malignant GISTs.

Histopathology

Typically GISTs are immunohistochemi-cally positive for KIT tyrosine kinase receptor (stem cell factor receptor), which is perhaps their single best defining feature {920, 713, 1665, 1762}. The c-kit positivity of GISTs parallels that seen in the interstitial cells of Cajal, the pacemaker cells regulating autonomic motor activity {1139, 1654}. Based on this, and on the expression of an embryonic form of smooth muscle myosin heavy chain in GISTs and Cajal cells {1648} the origin from Cajal cells has been proposed {920, 1762}. However, considering the origin of Cajal cells and smooth muscle from a common precursor cell {1035, 2186}, the hybrid Cajal cell and smooth muscle differentiation seen in many GISTs, and the occurrence of GISTs in the omentum and mesentery {1225}, their origin from such a precursor cell pool with differentiation towards a Cajal cell phenotype is more likely. Electron microscopic observations showing hybrid autonomic nerve and smooth muscle features in many GISTs are also consistent with origin from a multipotential precursor cell {474, 1227}. Morphology. GISTs may resemble smooth muscle tumours histologically as well as grossly. The majority of gastric GISTs are spindle cell tumours that show a variety of histological patterns {1866}. Some, including many of the smaller ones, are collagen-rich and paucicellular. A perinuclear vacuolization pattern is common. Tumours with moderate cellu-larity and focal nuclear palisading can resemble nerve sheath tumours. Peri-

Fig. 3.44 Radiograph demonstrating mass defect in stomach due to a stromal tumour.

vascular hyalinization can accompany myxoid change. The epithelioid pattern occurs in approximately one-third of gastric GISTs and corresponds to tumours previously designated as leio-myoblas-toma or epithelioid leiomyosarcoma. Some of the epithelioid tumours show mild pleomorphism. Marked pleomor-phism is rare.

Immunohistochemistry. Most GISTs are positive for KIT (CD117), which may show membrane, diffuse cytoplasmic or a perin-uclear accentuation pattern. Approximately 70-80% of GISTs are positive for CD34 (typically membrane pattern). 30-40% are focally or diffusely positive for a-smooth muscle actin, very few show reactivity for desmin (< 5%), and very few for S100-protein (< 5%, usually weak reactivity) {526, 1229, 1260, 1991, 1227, 1232}. Assessment of malignancy and grading. Histological assessment of malignancy is essentially based on mitotic counts and size of the lesion. Tumours less than 5 cm are usually benign. Different limits have been applied for low-grade malignant tumours. This designation has been used for tumours showing mitotic counts greater than 5 per 50 HPF, or tumours showing as many as 5 mitoses per 10 HPF. Tumours over 5 cm, but with fewer than 5 mitoses per 50hpf, are often assigned to the category of 'uncertain malignant potential'. However, large tumours (especially over 10 cm) with no detected mitotic activity may develop late recurrences and even metastases. DNA-aneuploidy, high proliferative index (over > 10%) by proliferation markers (especially Ki67 analogs, such as MIB1) may reflect higher malignant potential {338, 362, 929, 525, 1048, 1632, 461, 462}.

Histological grading follows the systems commonly used for soft tissue sarcomas. Mitotic activity is the main criterion, namely those tumours with over 10 mitoses per 10 hpf are considered highgrade. Lower mitotic activity (over 1-5 mitoses/10 HPH) is considered low-grade.

Genetics

Both benign and malignant GISTs commonly show losses in chromosomes 14 and 22 in cytogenetic studies and by comparative genomic hybridization. Losses in 1p and chromosome 15 have been shown less frequently. Gains and high level amplifications occur in malignant GISTs in 3q, 8q, 5p and Xp {450, 451}. A proportion of GISTs, more commonly the malignant examples, show mutations in the regulatory juxtamembrane domain (exon 11) of the c-kit gene. A family with germline KIT mutations and GISTs has also been described. These c-kit mutations have been shown to represent gain-of-function mutations leading to lig-and-independent activation (autophos-

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