—  SHORT COURSE #26  —

Hematopathology Diagnoses Too Easy to Miss!

VII. Quiz

Marsha Kinney, James Cook and Steven Swerdlow


Case 13: The Quiz Case

Diagnosis: Enteropathy-associated T-cell lymphoma

Case history: 60 year old male with nausea, pain, celiac sprue and lesions in his stomach and small intestine. Gastric ulcer was biopsied. Following his diagnosis, the patient was treated with CHOP chemotherapy; however, he expired after a short course and after he was discovered to have a metastatic squamous cell carcinoma of the lung.

Histopathology : Gastric mucosal infiltrate with epitheliotropism composed of large, occasionally pleomorphic cells. Also neutrophils, some plasma cells and lymphocytes present.

Flow cytometric immunophenotypic studies: None performed.

Paraffin section immunohistochemistry:
  • CD20 – Rare positive small cells, abnormal cells negative.

  • CD3 – Abnormal cells positive.

  • CD5 – Few positive cells, abnormal cells negative (ie, abnormal T-cell or natural killer cell phenotype!)

  • CD4 – Abnormal cells negative

  • CD8 – Most abnormal cells positive.

  • TIA-1 – Many abnormal cells positive.

  • Granzyme B – Many abnormal cells positive.

  • CD56 – Most abnormal cells positive.

  • Other stains were as follows: CD7 positive on abnormal cells, anti-kappa and lambda showed a few polyclonal plasma cells, bcl-2 mostly negative on abnormal cells, bcl-6 and CD10 negative on abnormal cells, CD30 and ALK1 negative, H. pylori negative.

Genotypic & Cytogenetic studies: None performed.

Diagnostic pathway: The atypical infiltrate in these biopsies suggests the diagnosis of a definite neoplasm that is composed of cells that are too large and associated with too many mitotic figures to represent a MALT lymphoma, in spite of the epitheliotropism that is clearly present. The patient's history should raise the question of an enteropathy associated T-cell lymphoma. The phenotype suggests an "aberrant" T-cell or a natural killer cell phenotype and excludes one of the large B-cell lymphomas (or an epithelial neoplasm). The diagnosis of a T-cell lymphoma of enteropathy-associated type was rendered here, knowing that the patient had celiac disease, having a compatible histopathology including the epitheliotropism, and knowing that enteropathy type T-cell lymphomas are typically CD5 negative. A minority of cases are reported to be CD56 positive. These cases are designated as being of "type II" and have been described as being of monomorphic type. [1] They are considered to have either less of an association with celiac disease and its risk factors or no association, although they do share the most characteristic cytogenetic abnormalities. If there were any concern for a natural killer cell neoplasm, this would be a very appropriate situation to perform genotypic studies using DNA from the paraffin embedded material and PCR looking for a clonal T-cell receptor gamma chain gene rearrangement.

This case illustrates the following:
  • Paying attention to the clinical history goes a long way since enteropathy-associated T-cell lymphoma frequently arises in adults with celiac disease.

  • Not everything in the stomach is a MALT lymphoma or even a B-cell lymphoma.

  • Conversely, enteropathy-associated T-cell lymphomas are most common in the small intestine but can very rarely involve the stomach.

  • One of major differences between the WHO (and REAL) classifications and those that preceded it is the recognition of a group of aggressive extranodal cytotoxic T-cell and natural killer cell lymphomas (TIA-1 and granzyme B positive).

  • Diagnosing lymphomas in 2009 is best accomplished by integrating histopathologic findings with the results of appropriately selected ancillary studies.

  • Don't be overly influenced by any single piece of information. Just because this was a gastric biopsy didn't mean it had to be one of the lymphomas you usually associate with the stomach. Also beware, not all lymphomas in patients with celiac disease are of this type.

  • Be aware not only of the classical features for the lymphomas you need to diagnose, but also know what "exceptions" are allowable. For example, it is acceptable to diagnose CD56+ enteropathy associated T-cell lymphomas; however, the finding of TdT expression would be totally unacceptable. Know that there is current interest in considering the CD56+ monomorphic cases as a distinct subtype of EATL. [2]

  • While we try to be as certain as possible about all of our diagnoses, sometimes we do need to deal with some degree of uncertainty in diagnostic hematopathology.

  • Knowing the clinical implications of the diagnoses you render makes you a much more useful consultant to your clinical colleagues. It is also useful to understand the implications of your diagnoses to avoid undue mental anguish. If you cannot decide between two diagnoses and their treatment and prognosis are similar enough, it may not be worth losing lots of sleep over your decision (and then making other errors due to fatigue).

Extranodal cytotoxic T-cell and natural killer cell lymphomas: The subject of the extranodal cytotoxic T-cell and natural killer cell lymphomas was briefly reviewed in the handout for case 7. [3]

Enteropathy-associated T-cell lymphoma: Enteropathy-associated T-cell lymphoma (EATL, aka enteropathy type T-cell lymphoma) occurs in adults, often with a history of celiac disease, who present with abdominal symptoms. [2, 4, 5, 6, 7] It has also been described in post-transplantation patients. Radiologic procedures demonstrate small bowel abnormalities with or without a major mass lesion. Most typically, EATL arises in the jejunum. Extraintestinal involvement also occurs with common involvement of mesenteric lymph nodes. [8] Gastric involvement has been described but is very rare. [9] Recognition is important because these are very aggressive even when treated appropriately. [10] It should also be recognized that patients with celiac disease also have an increased risk for other lymphomas as well. [11]

Histopathology: EATL demonstrates small bowel infiltration by a cytologically heterogeneous proliferation that includes varying numbers of small, medium and large lymphoid cells although, in most cases, small cells do not predominate. [4, 5] Biopsies with predominantly small cells may be confused with indolent MALT lymphomas. Ulcerated and inflamed lesions may be present and biopsies in these areas may not be clearly neoplastic-appearing. Some of these lesions may fulfill the criteria for what has been called "ulcerative jejunitis". Ulcerative jejunitis is an ulcerated polymorphous lesion that used to be considered a benign complication of celiac disease; however the lesions are clonal and at least most lesions are now considered neoplastic. Some consider these to be a part of refactory celiac disease-II (RCD with aberrant phenotype). The 2008 WHO monograph discusses two types of refractory celiac disease – one that is polyclonal and where the intraepithelial lymphocytes have a normal phenotype and another that is monoclonal and where the intraepithelial lymphocytes have an abnormal CD8 negative phenotype. The latter cases, that also can have chromosomal abnormalities are considered as "intraepithelial T-cell lymphoma or alternatively, EATL in situ". [2] EATL was originally recognized as "malignant histiocytosis of the intestine" because of the numerous admixed lysozyme positive macrophages/histiocytes present. Intravascular tumor cells are frequently seen but not usually angioinvasion or necrosis. The adjacent bowel often, but not invariably, demonstrates villous atrophy consistent with celiac disease. There may be striking epitheliotropism. The CD56+ cases are described as usually being composed of medium-sized round cells often with striking intraepithelial infiltration and without admixed inflammatory cells (type II EATL).

Immunophenotype: Immunophenotypic studies, most of which can be performed on paraffin embedded tissue sections, are important in diagnosing EATL, especially in problematic cases. [4, 5, 12] They demonstrate an "aberrant" cytotoxic T-cell phenotype. Pan-T-cell markers are usually expressed except for CD5. Most are CD4 and CD8 negative (most of remaining cases are CD8 positive). Most express the -T-cell receptor rather than the -T-cell receptor although some describe loss of beta chain expression. CD103 is expressed, a feature characteristic of intraepithelial T-cells (and hairy cell leukemia). The cells express cytotoxic markers such as TIA-1 and granzyme B. A minority express the NK-associated CD56 antigen (N-CAM) and are CD8+. These latter cases have been reported to have a distinct morphologic appearance with a predominance of monomorphic medium sized cells. [1, 2, 4] Some cases are CD30/Ki-1 positive. Many of these antigens can be detected in paraffin embedded tissue sections, with the major exception being CD103. The marked phenotypic variation that is present between cases is not considered particularly important. For example, cases derived from T cells expressing the -T-cell receptor are not currently considered distinct from those expressing the -T-cell receptor. With the current suggestion that intestinal gamma-delta T-cell lymphomas may be a part of a distinct entity of mucocutaneous gamma-delta T-cell lymphomas, the precise type of T-cell present might be considered to be of greater importance in the future. [13] Epstein-Barr virus may be present depending on where the patients are from or if they are immunosuppressed.

Cytogenetic studies: Approximately half of ETCL are reported to have characteristic chromosome 9q gains with amplification of 9q34. [12, 14, 15] The primary target of this amplification may be the NOTCH1 gene. [14] Loss of heterozygosity at 9p21 is also reported particularly in cases with a large cell morphology. [16] There may be other characteristic chromosomal abnormalities as well and differences between the monomorphic and other cases. [15] The 2008 WHO monograph note the frequent presence of +9q31.3 or -16q12.1 in both types of EATL, +1q32.3-q41 and +5q34-q35.2 more frequently in the type I versus type II cases and +8q24 (MYC amplifications) more frequently in the type II than the type I cases. [2]

The stomach in patients with celiac disease: Celiac disease can be associated with non-neoplastic lymphoid proliferations in the stomach with an increased incidence of lymphocytic gastritis or simply increased intraepithelial T-cells. [17, 18] Furthermore, the lymphocytes in lymphocytic gastritis are reported to demonstrate an aberrant phenotype similar to that seen in the enteropathy-associated T-cell lymphomas (surface CD3-, CD8-). [18] In addition, particularly in patients with refractory celiac disease, clonal T-cells are reported in gastric biopsies, most of which will demonstrate lymphocytic gastritis. [18] This, together with the report of clonal T-cells in the peripheral blood of 44% of patients with refractory celiac disease, suggests that EATL is a widely disseminated disorder. As noted above, gastric involvement by EATL rarely occurs, usually in association with small intestinal disease. [9, 19]

References:
  1. Chott A, Haedicke W, Mosberger I, et al. Most CD56+ intestinal lymphomas are CD8+CD5-T-cell lymphomas of monomorphic small to medium size histology. Am J Pathol 153: 1483-1490, 1998.

  2. Isaacson PG, Chott A, Ott G, et al., Enteropathy-associated T-cell lymphoma. in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Swerdlow SH, Campo E, Harris NL, et al., [Eds.] IARC: Lyon. 2008, 289-291.

  3. Jaffe ES, Krenacs L, Raffeld M. Classification of cytotoxic T-cell and natural killer cell lymphomas. Semin Hematol 40: 175-184, 2003.

  4. Chott A, Vesely M, Simonitsch I, et al. Classification of intestinal T-cell neoplasms and their differential diagnosis. American Journal of Clinical Pathology 111: S68-74, 1999.

  5. Isaacson PG. Gastrointestinal lymphomas of T- and B-cell types. Modern Pathology 12: 151-158, 1999.

  6. Isaacson P, Wright DH. Intestinal lymphoma associated with malabsorption. Lancet 1: 67-70, 1978.

  7. Gale J, Simmonds PD, Mead GM, et al. Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment of 31 patients in a single center. J Clin Oncol 18: 795-803, 2000.

  8. Isaacson PG, Du MQ. Gastrointestinal lymphoma: where morphology meets molecular biology. J Pathol 205: 255-274, 2005.

  9. Palacio A, Tamariz L, Berger J, et al. Enteropathy-associated T-cell lymphoma and its immunocarcinogenic correlates: case report and review of the literature. Crit Rev Oncog 9: 63-81, 1998.

  10. Al-Toma A, Verbeek WH, Hadithi M, et al. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut 56: 1373-1378, 2007.

  11. Smedby KE, Akerman M, Hildebrand H, et al. Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma. Gut 54: 54-59, 2005.

  12. Zettl A, Ott G, Makulik A, et al. Chromosomal gains at 9q characterize enteropathy-type T-cell lymphoma. Am J Pathol 161: 1635-1645, 2002.

  13. Arnulf B, Copie-Bergman C, Delfau-Larue M-H, et al. Nonhepatosplenic gamma delta T-Cell Lymphoma: A Subset of Cytotoxic Lymphomas With Mucosal or Skin Localization. Blood 91: 1723-1731, 1998.

  14. Cejkova P, Zettl A, Baumgartner AK, et al. Amplification of NOTCH1 and ABL1 gene loci is a frequent aberration in enteropathy-type T-cell lymphoma. Virchows Arch 446: 416-420, 2005.

  15. Baumgartner AK, Zettl A, Chott A, et al. High frequency of genetic aberrations in enteropathy-type T-cell lymphoma. Lab Invest 83: 1509-1516, 2003.

  16. Obermann EC, Diss TC, Hamoudi RA, et al. Loss of heterozygosity at chromosome 9p21 is a frequent finding in enteropathy-type T-cell lymphoma. J Pathol 202: 252-262, 2004.

  17. Feeley KM, Heneghan MA, Stevens FM, et al. Lymphocytic gastritis and coeliac disease: evidence of a positive association. J Clin Pathol 51: 207-210, 1998.

  18. Verkarre V, Asnafi V, Lecomte T, et al. Refractory coeliac sprue is a diffuse gastrointestinal disease. Gut 52: 205-211, 2003.

  19. Katoh A, Ohshima K, Kanda M, et al. Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells. Leuk Lymphoma 39: 97-111, 2000.