Clinicopathologic features of primary colonic enteropathy-associated T cell lymphoma type II in an elderly Asian male with diarrhea
A 76-year-old Asian man with a 6-month history of intractable watery diarrhea proceeded to colonoscopic examination that revealed diffusely dull-appearing colonic mucosa with focal areas of superficial ulceration. Mucosal biopsies demonstrated a neoplastic population of monomorphous small-to-intermediate-sized CD8+/CD56+ cytotoxic T cells that densely infiltrated the surface epithelium and crypts in a near pan-colonic distribution without tumor formation. Clinical staging revealed no disease elsewhere. The patient was treated aggressively with chemotherapy but died from disease five and a half months after presentation. In all likelihood, the patient had primary colonic involvement by enteropathy-associated T cell lymphoma (EATL) type II, a rare and aggressive extranodal non-Hodgkin lymphoma that occurs more commonly in Asians in whom celiac disease is infrequent. Widespread colonic disease in the absence of a mass-forming infiltrate has not been characterized in EATL type II and highlights an expanded clinical and pathological spectrum of the disease.
KeywordsEnteropathy-associated T cell lymphoma (EATL) Primary intestinal T cell lymphoma (ITL) Monomorphic Cytotoxic T cells Natural killer (NK) cells
Enteropathy-associated T cell lymphoma
Primary intestinal T-cell lymphoma
Primary intestinal T cell lymphoma (ITL) is a rare group of extranodal non-Hodgkin lymphoma of which enteropathy-associated T cell lymphoma (EATL) is the most common. Two types of EATL are currently recognized by the World Health Organization. Type I disease occurs primarily in Caucasians, is frequently associated with celiac disease and malabsorption, and is characterized by polymorphous intermediate-to-large-sized neoplastic cells. Type II disease, by contrast, is more common among Asians, is characterized by monomorphous small-to-intermediate-sized cells positive for cytotoxic T/natural killer (NK) cell markers, and is only infrequently associated with celiac disease or malabsorption. Herein, we describe a 76-year-old Asian man who presented with diarrhea due to a primary colonic T cell lymphoma with clinicopathologic similarities to EATL type II. The neoplasm involved the colonic mucosa in a near pan-colonic distribution with striking epitheliotropism but was without an intestinal mass-forming infiltrate which in all probability is consistent with primary colonic manifestation of EATL type II.
Materials and methods
The biopsy samples were fixed in 10 % neutral buffered formalin and processed and stained with routine hematoxylin and eosin. Immunostains for CD3 (Ventana Medical System, 2GV6, 0.4 μg/mL), CD20 (Ventana Medical System, L26, 0.3 μg/mL), CD56 (Dako, 123C3, 1:100), CD4 (Leica Biosystems, 4B12, 1:250), CD8 (Dako, C8/144B, 1:100), CD2 (Leica Biosystems, AB75, 1:50), CD5 (Leica Biosystems, 4C7, 1:100), CD7 (Biocare Medical, 272, 1:25), CD57 (PhenoPath, HNK-1, 1:5), CD30 (Ventana Medical System, Ber-H2, 1 μg/mL), CD103 (Epitomics, EPR4166(2), 1:1000), TIA-1 (Immunotech Laboratories, 2G9A10F5, 1:1000), and TCR-βF1 (Thermo Fisher Scientific, 8A3, 1:25) following antigen retrieval were visualized using polymer-based immunoperoxidase reaction and counterstained with hematoxylin. In situ hybridization for Epstein-Barr virus-encoded small RNA using fluorescein-conjugated oligonucleotide probes (Leica Biosystems, EBER, 0.1 μg/mL) was performed in conjunction with positive and negative reagent controls. T cell receptor gamma (TCRγ) gene rearrangement studies were performed on purified genomic DNA (Qiagen, Puregene), amplified by multiplex PCR using fluorescently labeled primers for the VγI and VγII variable regions and for the Jγ1/2 and JγP1/2 joining regions of TCRγ, and size fractionated on an ABI 3130 Sequence Analyzer (Applied Biosystems).
Disease staging with a positron emission tomography/computed tomography (PET/CT) scan revealed increased SUV activity in the colon and rectum, but no appreciable activity elsewhere. There was no lymphadenopathy or organomegaly. His serum LDH was within normal limits. A staging bone marrow biopsy was deferred. The patient was treated with an attenuated chemotherapy regimen of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) at 3-week intervals, resulting in symptomatic improvement including a decrease in diarrhea. Unfortunately, within 4 months following 5 cycles of CHOP therapy, the patient developed progressive fatigue, anorexia, recurrent diarrhea, and a marked decline in his performance status. A repeat colonoscopic evaluation revealed recurrent/persistent disease. The patient was transitioned to hospice care and expired five and half months following his diagnosis. An autopsy was not requested.
Primary intestinal T cell lymphoma (ITL) is a rare, heterogeneous group of extranodal non-Hodgkin lymphoma of which the most common and best characterized is enteropathy-associated T cell lymphoma (EATL) [1, 2]. EATL is clinically aggressive, associated with 70 % mortality within 6 months of diagnosis, and typically presents as a mass-forming infiltrate in the small intestine with histological features of enteropathy in the surrounding non-tumorous mucosa. The tumor is often multifocal, involves the intestine transmurally, and exhibits a high tendency toward ulceration, bowel obstruction, and/or perforation. Based on clinical, serological, histopathologic, and genetic features, two types of enteropathy-associated T cell lymphoma are currently recognized by the World Health Organization [3, 4, 5]. Type I, or the classical form of EATL, is frequently associated with celiac disease and malabsorption and occurs primarily in the Caucasian population of northern European descent. It is typically limited to the small intestine, often associated with histological features of enteropathy in the adjacent mucosa, and characterized by polymorphous medium-to-large sized neoplastic cells with immunoblastic and/or high-grade features and an immunophenotypic profile that is negative for CD4, CD8, and CD56. Type II, by contrast, is less commonly associated with an enteropathy or malabsorption and has a broader geographic and ethnic distribution. It mainly involves the small intestine but can also involve the colon and is characterized by monomorphous small-to-medium-sized lymphocytes that co-express CD8 and CD56 in the majority of cases and lack high-grade histologic features or angioinvasive properties [4, 5, 6, 7, 8, 9, 10].
Since the refinement in the classification of EATL, there has been growing interest in ITL and EATL in the Asian population in whom the frequency of celiac disease is low and Epstein-Barr virus (EBV) infection and extranodal T/NK cell lymphoma are more prevalent [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. In European patients, EATL comprises the majority of ITL and is composed of approximately 80–90 % type I and 10–20 % type II disease, reflecting the high prevalence of celiac disease in this population. In Asians of the Far East, in whom celiac disease has only been rarely reported, EATL comprises a smaller proportion of ITL and is composed predominantly, if not exclusively, of type II disease. Although the clinicopathologic and genetic features of EATL type II in Asian and Western patients are similar in many respects, including an absence of an etiologic association with celiac disease in most cases, there appears to be more variable clinical and/or histopathological association with an enteropathy or malabsorption, greater prevalence of colonic involvement, and a higher frequency of neoplastic T cells expressing TCR-γδ in the Asian population [4, 5, 6, 7, 10, 12, 13, 14, 15, 18].
This patient’s ITL shares many clinicopathologic similarities with EATL type II. It was a clinically aggressive neoplasm that presented insidiously as diarrhea in an elderly Asian man who had no prior history of celiac disease or malabsorption. The neoplastic T cells were monomorphous, small-to-intermediate in size, demonstrated prominent epitheliotropism, and expressed CD103, the human mucosal lymphocyte-1 antigen that is commonly expressed in intraepithelial T lymphocytes and cytotoxic T/NK cell-associated markers CD8, CD56, and TIA-1 with loss of the pan-T cell marker CD5 and absent CD30 expression. Nevertheless, the patient’s near pan-colonic disease involvement and absence of an intestinal mass-forming infiltrate are dissimilar to the characteristic mass-forming and zonal features of EATL type II. Although EATL is defined as a neoplasm of intraepithelial T cells, the clinicopathologic studies of EATL type II have largely been focused on clinical or surgically resected small intestinal masses [5, 7, 8, 9, 10, 13, 15, 16, 19]. While type II disease limited to the colon is uncommon, comprising at most 18 % in one study , the clinicopathologic colonic manifestations have not been well characterized and there has been no reported case to date of type II disease without a clinically apparent intestinal mass. Secondly, epitheliotropic neoplastic cells are typically limited to the small intestinal mucosa immediately adjacent to a central tumor-forming zone [7, 13, 16]. Although reports of discontinuous or distant intraepithelial involvement away from a mass are emerging [7, 13, 20], this disease pattern appears to be an infrequent finding.
In all likelihood, this patient had primary colonic involvement by EATL type II due to the similarities in their aggressive clinical course, monomorphic small-to-intermediate cell size, expression of cytotoxic T/NK cell immunophenotypic profile, and epitheliotropism. The clinical and endoscopic features of our patient’s disease are reminiscent of primary colonic T cell lymphoma in Korean patients in whom there was a high association with diarrhea, diffuse colonic disease involvement, endoscopic impression of an ulcerative/infiltrative process, and low association with a mass-forming infiltrate . In the absence of an intestinal mass, the patient’s neoplasm may represent an “early” (i.e., epitheliotropic) manifestation of EATL type II; however, the patient’s rapid clinical decline suggests that intraepithelial-predominant disease may be as clinically aggressive as those associated with an intestinal mass-forming neoplasm.
Conflict of interest
The authors declare that they have no conflict of interest.
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