Biology and genetics of extranodal mature T-cell and NKcell lymphomas and lymphoproliferative disorders

Abstract

The extranodal mature T-cell and NK-cell lymphomas and lymphoproliferative disorders represent a unique group of rare neoplasms with both overlapping and distinct clinicopathological, biological, and genomic features. Their predilection for specific sites, such as the gastrointestinal tract, aerodigestive tract, liver, spleen, and skin/soft tissues, underlies their classification. Recent genomic advances have furthered our understanding of the biology and pathogenesis of these diseases, which is critical for accurate diagnosis, prognostic assessment, and therapeutic decision-making. Here we review clinical, pathological, genomic, and biological features of the following extranodal mature T-cell and NK-cell lymphomas and lymphoproliferative disorders: primary intestinal T-cell and NK-cell neoplasms, hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma, nasal type, and subcutaneous panniculitis-like T-cell lymphoma.

Figure 1.

Enteropathy-associated T-cell lymphoma. (A-H) This case was composed of intermediate-sized to large cells with high mitotic activity, abundant apoptotic debris, and angioinvasion (A, H&E). Although the patient had not reported a history of gastrointestinal symptoms prior to presentation, the small bowel distant from the mass showed villous blunting and marked intraepithelial lymphocytosis (B, H&E) while serological evaluation detected anti-gliadin IgA, anti-gliadin IgG, anti-tissue transglutaminase IgA, and anti-endomysial IgA antibodies, consistent with subclinical celiac disease. The neoplastic cells showed a typical phenotype of enteropathy-associated T-cell lymphoma, expressing CD30 (C), and CD103 (D), and lacking CD4 (E), CD8 (F), TCRβ (G), and TCRδ (H) expression. H&E: hematoxylin and eosin.

Figure 2.

Monomorphic epitheliotropic intestinal T-cell lymphoma. (A-E) A dense infiltrate of monotonous small to intermediate-sized neoplastic cells with condensed chromatin and a rim of pale cytoplasm which infiltrates the small bowel epithelium is typical of monomorphic epitheliotropic intestinal T-cell lymphoma (A, hematoxylin and eosin). The cells expressed CD8 (B), CD56 (C), and TCRδ (D), and overexpressed SYK (E). (F, G) Another case showed increased MYC expression (F) and gain of the MYC locus on chromosome 8q24, as determined by fluorescence in situ hybridization (G).

Figure 3.

Hepatosplenic T-cell lymphoma. (A-F) Bone marrow biopsy in this patient with hepatosplenic T-cell lymphoma showed an infiltrate of intermediate-sized atypical lymphoid cells with condensed chromatin and pale cytoplasm involving and expanding the sinusoids (A, hematoxylin and eosin, black arrows). The cells expressed CD3 (B), CD56 (C), TIA1 (D), and TCRδ (E). Karyotyping detected multiple characteristic chromosomal abnormalities, including isochromosome 7q (red arrow) and trisomy 8 (black arrow) (F). (G-I) In another case of hepatosplenic T-cell lymphoma, both isochromosome 7q and trisomy 8 were detected by single nucleotide polymorphism array analysis (G, red arrow indicates 7p loss, purple arrow indicates 7q gain, black arrow indicates gain of 8) and fluorescence in situ hybridization (H, 3 signals of 7q31 [red probe] and 2 signals of CEP 7 [green probe] indicate gain of 7q; I, 3 signals of CEP 8 [red probe] indicates gain of 8). BAF: B-allele frequency.

Figure 4.

Extranodal NK/T-cell lymphoma, nasal type. (A-E) This extranodal NK/T-cell lymphoma, nasal type showed sheets of atypical lymphoid cells ranging from small to large in size with irregular nuclei (A, hematoxylin and eosin). The cells were diffusely positive for CD3 (B), CD56 (C), and EBER (D). High PD-L1 expression was also present (E).

Figure 5.

Subcutaneous panniculitis-like T-cell lymphoma. (A-E) A panniculitic lymphoid infiltrate composed of intermediatesized atypical lymphoid cells with irregular nuclei and hyperchromatic chromatin are seen rimming individual adipocytes in this case of subcutaneous panniculitis-like T-cell lymphoma (A, hematoxylin and eosin). Foamy macrophages are present in the background. The atypical lymphocytes expressed CD3 (B), CD8 (C), and TCRα (D), and showed a high Ki-67 proliferative index (E). (F) Another similar case showed atypical cytoplasmic granular/paranuclear dot-like TIM3 staining, instead of the normal membranous/cytoplasmic staining pattern, raising suspicion of misfolded TIM3 protein, although HAVCR2 mutational testing was not performed.