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Intestinal T-cell lymphoma

1. GENERAL INFORMATION

1.1 Definition

Intestinal T-cell lymphoma (ITCL) is a rare malignancy usually arising in patients with a history of gluten-sensitive enteropathy. However, patients without evidence of enteropathy have also been affected by this malignancy. This disorder was originally termed “malignant histiocytosis of the intestine”, but has since been conclusively shown to be a T-cell lymphoma (Isaacson 1985). This lymphoma has not been listed neither in the Kiel, nor in the Working Formulation classifications. However, it mostly corresponded to T-zone, pleomorphic lymphoma according to the Kiel classification (Banks 1992; Lennert 1978), and to diffuse small cleaved cell, diffuse mixed small and large cells, diffuse large cell, or large-cell immunoblastic lymphomas in the Working Formulation. Intestinal intraepithelial alpha beta T cells, in various stages of transformation, have been postulated as the normal-cell counterpart for ITCL. This seems to be supported by immunophenotypic and genotypic data, as well as by the cytotoxic differentiation observed in the neoplastic cells of almost all cases of ITCL (Daum 1997).

1.2 Incidence

Intestinal T-cell lymphoma (ITCL) is an extremely rare malignancy in the United States and Northern Europe, but is seen with increased frequency in areas in which gluten-sensitive enteropathy is more common, that is the Mediterranean and Middle East. It represents 10% to 25% of all primary lymphomas of the small bowel.

1.3 Risk factors

Intestinal T-cell lymphoma (ITCL) is the most common neoplastic complication of coeliac disease. Usually, these tumours have aggressive clinical behavior (Wright 1995); however, low-grade lymphomas secondary to coeliac disorder have also been reported (Wright 1997). Ten percent of patients affected by coeliac disease will develop an intestinal lymphoma, and 65% of them will have T-immunophenotype. The interval between diagnosis of coeliac disease and the development of lymphoma is extremely variable, oscillating from 2 months to more than 5 years (Ilyas 1995). Human leukocyte antigen (HLA) genotyping shows that patients with enteropathy-associated T-cell lymphoma (EATCL) have the coeliac disease-associated DQA1*0501, DBQ1*0201 phenotype, and additional HLA-DR/DQ alleles may increase the risk of lymphoma (Wright 1995). Another condition associated with EATCL is ulcerative jejunitis. T-cell monoclonality has been detected in this disorder using PCR for TCR gamma gene rearrangement. This has also been detected in inflammatory and lymphomatous lesions in patients affected by coeliac disease and lymphoma (Murray 1995). This supports the concept that T-cell lymphoma arises against a background of gluten-sensitive enteropathy from the initial reactive T-cell population present in the enteropathic bowel (Murray 1995). Small bowel is the most frequent extranodal site of presentation among NHLs developing in solid-organ graft recipients who did not receive cyclosporine (Thomas 1991). In these patients, in contrast to cases that occur in individuals treated with cyclosporine, the time interval between grafting and lymphoma development is longer than 12 months (Penn 1987). In this group of patients, gastrointestinal involvement is common, especially among renal graft recipients. Epstein-Barr virus infection appears to play a minor role in ITCL in Western countries, and a significant geographical difference in incidence has been reported (Quintanilla-Martinez 1998b; Quintanilla-Martinez 1998a;Quintanilla-Martinez 1997; Walsh 1995).

2. PATHOLOGY and BIOLOGY

2.1 Morphology

The pathological presentation of intestinal T-cell lymphoma is different from that seen with intestinal B-cell lymphomas. The former type presents with jejunal ulcers, often multiple, and frequently with perforation; a mass or stricture may or may not be present, and the most commonly involved intestinal segment is the proximal small intestine. In contrast, B-cell lymphomas tend to involve the distal or terminal ileum, with annular or polypoid masses (Domizio 1993; Quintanilla-Martinez 1997). The tumours contain a variable admixture of small, medium, large or anaplastic tumour cells, often with a high content of intraepithelial T cells in adjacent mucosa. Villous atrophy may not be present. Early lesions may show mucosal ulceration with only scattered atypical cells and numerous reactive histiocytes, without formation of large masses.

2.2 Immunophenotype

The cells of intestinal T-cell lymphoma are CD3+, CD7+, CD8+/-, CD4-, CD103+. (MLA: HML-1, LFG1, Bly7, Ber-ACT8) (Spencer 1988). ITCL appears to show cytotoxic differentiation in the majority of cases, with reactivity for granzyme B, TIA-1/GMP-17, and perforin in 84%, 95%, and 94% of cases, respectively.

2.3 Genetic features

TCRb genes are clonally rearranged (Isaacson 1985).

3. DIAGNOSIS

3.1 Clinical presentations

Usually, intestinal T-cell lymphoma (ITCL) occurs in adults, often with a history of gluten-sensitive enteropathy, but occasionally as the initial event in a patient found to have the typical histologic features of sprue in the resected intestine. Less commonly, it arises in patients without evidence of enteropathy. Patients present with abdominal pain, often associated with jejunal perforation, weight loss, diarrhoea, or bowel obstruction. ITCL is characterized by multifocal presentation in 10% to 25% of cases (Levine 1997). Small-bowel lymphoma is more common than large-bowel or rectal lymphomas. The higher frequency of intestinal perforation at diagnosis may account for the high perioperative complication rate in this lymphoma. The prognosis of enteropathy-associated T-cell lymphoma is very poor compared with B-cell intestinal lymphoma (Domizio 1993). Usually, ITCL shows low chemosensitivity, rapid tumour growth and a tendency to dissemination. Moreover, the high incidence of severe postsurgical complications and the poor nutritional and immunological conditions lead to progressive deterioration of these patients, preventing the use of an adequate and opportune treatment.

3.2 Diagnostic criteria

Intestinal T-cell lymphoma (ITCL) occurs in adults, often with a history of gluten-sensitive enteropathy, but occasionally as the initial event in a patient found to have the typical histologic features of sprue in the resected intestine. Less commonly, it arises in patients without evidence of enteropathy. Patients present with abdominal pain, often associated with jejunal perforation, weight loss, diarrhoea, or bowel obstruction. Pathological presentation of intestinal T-cell lymphoma consists of jejunal ulcers, often multiple, and frequently with perforation; a mass or stricture may or may not be present, and the most commonly involved intestinal segment is the proximal small intestine. (Domizio 1993; Quintanilla-Martinez 1997). The tumours contain a variable admixture of small, medium, large or anaplastic tumour cells, often with a high content of intraepithelial T cells in adjacent mucosa. Villous atrophy may not be present. Early lesions may show mucosal ulceration with only scattered atypical cells and numerous reactive histiocytes, without formation of large masses. The cells of intestinal T-cell lymphoma are CD3+, CD7+, CD8+/-, CD4-, CD103+. (MLA: HML-1, LFG1, Bly7, Ber-ACT8) (Spencer 1988). TCRb genes are clonally rearranged (Isaacson 1985).

3.3 Additional useful tests

No reliable molecular markers are available for monitoring of minimal residual disease in intestinal T-cell lymphoma.

4. STAGING

4.1 Staging procedures

Complete staging work-up for intestinal T-cell lymphoma (ITCL) includes an accurate physical examination (Waldeyer’s ring involvement should be excluded), complete haematological and biochemical exams, total-body computerized tomography, gastrointestinal tract examination, and bone marrow aspirate and biopsy. Unlike primary gastric lymphoma, where a surgical approach is progressively being replaced by conservative management, most patients with ITCL still undergo exploratory laparotomy for diagnosis and staging. In patients with ITCL who have not had a surgical exploration, barium studies of the small and large intestine and pancolonscopy with biopsy sampling of all macroscopically evident lesions should be performed because of the frequent multifocal nature of this malignancy. Abdominal staging, with evaluation of potential hepatic or splenic involvement in ITCL is usually performed during exploratory laparotomy. In patients managed with a conservative approach, abdominal staging should follow the general principles as for all NHL. Bone marrow assessment in ITCL should follow general statements for all NHL.

4.2 Staging system

4.2.1

The Ann Arbor staging system (Carbone 1971), currently used for the majority of non-Hodgkin’s lymphomas, has been considered unsatisfactory for intestinal T-cell lymphomas (ITCL). Several alternative staging systems have been used for this malignancy (Musshoff 1977; Blackledge 1979;Rohatiner 1994). An International Workshop of 1994 recommended the following classification (Rohatiner 1994): Stage I: lymphoma confined to the gastrointestinal tract. Single primary site or multiple noncontiguous lesions. Stage II: lymphoma extending in abdominal lymph nodes from primary gastrointestinal site
Stage II1: involvement of local (paragastric or paraintestinal) lymph nodes
Stage II2: involvement of distant (mesenteric, para-aortic, paracaval, pelvic, inguinal) lymph nodes
Stage IIE: penetration of serosa to involve adjacent organs or tissues Stage IV: diffuse or disseminated involvement of one or more extralymphatic organs, or a gastrointestinal tract lesion with supradiaphragmatic nodal involvement
Patients should be divided in two subsets according to the presence (A) or absence (B) of systemic symptoms. Fever of no evident cause, night sweats and weight loss of more than 10% of body weight are considered systemic symptoms. These symptoms must be meticulously evaluated because they are frequently due to causes other than intestinal lymphoma. Several ITCL patients have remarkable weight loss due to severe associated enteropathy; fever can be secondary to a concomitant but not obvious sepsis in an immunocompromised individual. The presence of bulky mass, such as a lesion of 10 cm or more in the longest diameter, is designated as “X”.

4.3 Molecular analysis of minimal residual disease

No reliable molecular markers are available for monitoring of minimal residual disease in intestinal T-cell lymphoma.

4.4. Restaging procedures

Restaging should include all the diagnostic procedures positive at time of diagnosis and initial staging.

5. PROGNOSIS

5.1 Natural history

Intestinal T-cell lymphoma (ITCL) is an aggressive malignancy which, if untreated, leads invariably to death due to multifocal intestinal perforation caused by refractory malignant ulcers. ITCL occurs often in adults with a history of gluten-sensitive enteropathy, that is patients who are extremely compromised from an immunological and nutritional point of view. The most common presenting symptoms are abdominal pain, often associated with jejunal perforation, weight loss, diarrhoea, or bowel obstruction. ITCL is characterized by multifocal presentation in 10% to 25% of cases (Levine 1997) . Most patients with ITCL are managed with a surgical approach as the primary strategy. Even if surgical operation is not a curative treatment, debulking and resection of masses with high-risk of perforation or occlusion are frequently indicated in these patients. The higher frequency of intestinal perforation at diagnosis may account for the high perioperative complication rate in this lymphoma. The prognosis of enteropathy-associated T-cell lymphoma is very poor compared with B-cell intestinal lymphoma (Domizio 1993). Usually, ITCL shows low chemosensitivity, rapid tumour growth and a tendency to dissemination. Moreover, the higher incidence of severe postsurgical complications and the poor nutritional and immunological conditions of these patients lead to progressive clinical deterioration, preventing the use of adequate and opportune therapeutic modalities.

5.2 Prognostic factors

Considering the heterogeneity and the small number of patients reported in any single series, reliable prognostic factors for intestinal T-cell lymphoma (ITCL) have not been established. In effect, the majority of ITCL patients have been reported as part of large series of patients with different primary gastrointestinal lymphomas. These series were usually managed heterogeneously and included patients with all stages of disease. Stage is the main prognostic factor in ITCL, with a 5-year cause-specific survival higher than 60% for patients with limited disease and 25% for those with advanced ITCL (Chott 1992; d’Amore 1994). In the largest series of gastrointestinal lymphoma, bulky lesion, stage, histology, immunophenotype, B symptoms, and LDH ratio have been reported as the main prognostic indicators (Chott 1992; d’Amore 1994; Liang 1991; Morton 1993). In a large series of intestinal lymphomas, perforation, high-grade histology, multiple tumours and advanced stage have been identified as the main adverse prognostic features (Domizio 1993).

6. TREATMENT

6.1 Treatment of limited disease (Stage I-II)

A standard treatment for patients with stage I-II intestinal T-cell lymphoma (ITCL) has not been established. Combined treatment with primary systemic conventional-dose anthracycline-containing chemotherapy which may or may not be followed by radiation therapy is suitable for individual clinical use on a type 3 level of evidence (d’Amore 1994; Morton 1993). The role of surgery is limited to debulking or resection of masses with high-risk of obstruction or perforation and is suitable for individual clinical use on a type R basis. The use of chemotherapy in cases of incomplete resection is associated with a 5% – 15% incidence of intestinal perforation and other complications. Many patients with ITCL present with obstruction or perforation and, for this reason, many cases are diagnosed at laparotomy. A better prognosis in patients who have undergone macroscopically complete resection compared with those who have residual disease has been reported, but these data come from retrospective small series and cannot be considered definitive (Stewart 1991; Zinzani 1997; Shih 1994). Patients who have undergone complete resection as primary treatment should receive adjuvant anthracycline-based chemotherapy. Radiation therapy is usually indicated in patients presenting with bulky disease, rectal lymphoma or incomplete resection. Involved-field delivering 35 Gy in 1.5 to 2-Gy daily fractions, 5 fractions a week is suitable for individual clinical use on a type R basis.

6.2 Treatment of advanced disease (Stage IV)

A standard therapeutic option for patients with stage IV disease is conventional-dose anthracycline-containing chemotherapy which may or may not be followed by radiotherapy on a type R basis. The role of surgery is limited to debulking or resection of masses with high-risk of occlusion or perforation. Primary debulking resection and anthracycline-based chemotherapy, with or without subsequent radiotherapy, have been associated with a 5-yr survival of 25% (d’Amore 1994; Domizio 1993; Morton 1993).

6.3 Treatment of relapsed or refractory disease

A standard therapeutic option for patients with relapsed or refractory disease has not been established. High-dose chemotherapy supported by bone marrow transplantation should be taken into account in these patients considering the aggressive behavior of relapsed T-cell lymphomas and the lack of valid therapeutic alternatives. However, the worldwide experience is very limited, and this remains an investigational option (Jaffe 1999). Special attention should be paid to eligibility criteria for intensive therapeutic strategies, considering the poor performance status of these patients at relapse. In some cases, whole-abdomen irradiation with 20 to 25 Gy delivered in 1- to 1.25-Gy daily fractions may be indicated for palliative treatment (Crump 1999).

INDEX

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Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
mail: ferreri.andres@hsr.it

Dr. Emilio Montserrat (Reviewer)
Hospital Clinic, Hemato-Oncology Institute – Barcelona, Spain
mail: emontse@clinic.ub.es

Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy
mail: carlo.tondini@ospedaliriuniti.bergamo.it