Discussion
Primary gastrointestinal (GI) tract lymphoma is uncommon and only accounts for 1–4 % of all GI malignances [
8]. According to Dawson et al. [
9], the diagnosis of GI lymphoma should meet the following 5 criteria: (1) absence of palpable superficial lymphadenopathy; (2) no evidence of enlarged mediastinal lymph nodes; (3) normal total and differential white blood cell counts; (4) a predominance of bowel lesions at laparotomy with only the lymph nodes obviously affected in the immediate vicinity; (5) absence of tumor involvement of the liver and spleen. Small intestine is the second most common site affected by primary GI lymphoma which ranks after stomach [
10]. Intestinal B-cell lymphomas occur more frequently than T-cell lymphomas at the ratio of 6:1 [
11]. As reported, the most common subtype of primary intestinal lymphoma is diffuse large B-cell lymphoma and extra-nodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) [
10‐
12]. Among the T-cell lymphomas of GI tract, peripheral T-cell lymphomas (PTCL), enteropathy-associated T-cell lymphoma (EATL) and NK/T-cell lymphoma (NK/TL) are the common subtypes [
12,
13]. In a retrospective Korean study, 42 primary GI T-cell lymphomas were assessed out of which 17 cases are located in small intestine. Among the 17 small intestinal T-cell lymphomas, 10 lesions (58.8 %) could be classified as EATL type II, 4 cases (23.5 %) as NK/TL, 2 cases (11.8 %) as PTCL, and only 1 case (9.5 %) as ALCL [
5]. Another study from Japan reported only 1 case of ALCL (6.7 %) among 15 intestinal T-cell lymphomas in small intestine [
6]. Hence, ALCL primarily occurred from small intestine is very rare.
According to WHO classification of tumors of hematopoietic and lymphoid tissues (4th Edition), ALCL was divided into ALK-positive and ALK-negative subtypes based on expression of ALK or ALK gene rearrangement [
2]. ALK/Nucleophosmin (NPM1) gene fusion was the most common genetic alteration. In addition, variant ALK rearrangement partners have been recognized subsequently including TPM3, ATIC, and TFG. Mechanistically, rearrangements of these genes result in the up-regulation of ALK protein. Moreover, the pattern of ALK immunostaining depends on different types of genetic alterations [
14,
15]. In this regard, ALK/NPM1 fusion is characterized by both nucleus and cytoplasm staining, whereas fusions of ALK with other partners lead to diffuse cytoplasmic staining only [
16]. Compared with ALK-negative ALCL, ALK positive ALCL occurs more frequently in younger patients with favorable outcomes [
17,
18]. Most of the patients diagnosed with ALK negative ALCL are reported to have cutaneous, hepatic, or gastrointestinal lesions [
18]. In this regard, Kim identified 4 ALK negative ALCL in GI tract including 2 in duodenum, 1 in large intestine, and 1 in small intestine [
5]. In another report by Carey MJ, only 3 ALK negative cases were found out of 4 small intestinal ALCL [
4]. Based on our observations and other reports, it seems that ALK negative ALCL tends to invade intestine. However, since the number of cases is very small, a larger patient cohort is needed to make a solid conclusion.
Moreover, diagnosis of intestinal ALCL should be made after exclusion of other lymphomas which show similar cell morphology and/or ALK positive staining. The most important differential diagnosis was ALK positive diffuse large B cell lymphoma (ALK positive DLBCL), which was now considered as a distinct entity [
2,
19]. It was characterized by monomorphic large plasmablast- or immunoblast-like cells with large central nucleoli. It is histologically very close to ALCL and metastatic carcinoma in lymph node at low magnification because of its sinusoidal growth pattern. The neoplastic cells often lack the expression of lineage-associated leukocyte antigens as CD3, CD5, CD20, or CD79a, but express ALK [
2,
19,
20]. Therefore it could lead to the diagnosis of ALCL “null cell” phenotype. However, ALK positive DLBCL constantly lack the expression of CD30 in immunohistochemistry, and strongly express plasma cell markers such as CD138 and CD38, which demonstrates the features of terminally differentiated B-lineage origin of the tumor cells. Moreover, unlike both the nucleus and cytoplasm staining in ALCL, the staining of ALK in DLBCL exhibits granular cytoplasmic staining indicating the CLTC/ALK fusion protein [
19,
20]. In the present case, besides ALK and CD30 expression, the neoplastic cells were also positive for T lymphocyte lineage markers as CD5, TIA-1, and Granzyme B, while negative for CD20, CD79a, CD38, CD138, suggesting the T-cell origin of these cells and the diagnosis of ALK positive ALCL.
Plasmablastic Lymphoma (PBL) should also be considered as one of the differential diagnosis because of the morphology of the neoplastic cells mimicking centroblastic and immunoblastic cells. The neoplastic cells of plasmablastic lymphoma expressed markers characterizing plasma cell phenotype including CD 138, CD38, Vs38c either kappa or lambda light chain, and IRF4/MUM1, whereas without the expression of T cell phenotype. Although the neoplastic cells frequently expressed EMA or CD30, they did not express ALK [
2,
21]. Moreover, EBV EBER in situ hybridization is positive in 60–75 % of the cases of PBL [
2,
21]. Based on the immunophenotype in this case, the diagnosis as PBL was not correct.
Peripheral T-cell lymphoma, not other specified (PTCL, NOS) deserves additional attention in terms of differential diagnosis. It encompassed all mature T-cell neoplasms lacking specific features that would allow its categorization in any of the better-defined subtypes of post-thymic T-cell lymphoma. In some cases, tumor cells infiltrate lymphatic sinuses and consist of CD30 positive large cells predominantly, which result in difficulty of distinguishing it from ALK negative ALCL. In fact, diagnostic criteria for ALK negative ALCL are still evolving, particularly in distinguishing it from other CD30 positive PTCL, NOS [
15,
22]. In ALK negative ALCL, all tumor cells are positive for CD30, mainly on the cell membrane and in the Golgi region. Particularly, the staining of CD30 are strong and of equal intensity in all the tumor cells [
16,
23]. By contrast, CD30 staining in PTCL, NOS is usually heterogeneous and comparatively weaker than that in ALK negative ALCL [
23]. Additionally, the diagnosis of ALK negative ALCL should be reserved for cases with the morphology of ALCL accompanied with a cytotoxic T-cell phenotype including TIA-1, perforin and Granzyme B [
24]. Nevertheless, other pathologists consider ALK negative ALCL as an anaplastic variant of PTCL, NOS, in light of its poor prognosis and partially overlapping phenotype [
18,
25,
26].
In addition, ALCL occured in the GI tract must be distinguished from enteropathy associated T-cell lymphoma (EATL), type I, which is considered as a complication of celiac disease (gluten-sensitive). In Type I EATL, the cytological composition of tumor cells is varied, and more polymorphous than Type II lymphomas [
25,
27]. In this regard, ALK negative ALCL may closely resemble CD30 positive EATL. However, unlike ALCL, usually EATL is not positive for both EMA and ALK. In addition, EATL is mainly CD8 positive rather than CD4 positive. Its association with celiac disease or villous atrophy further distinguishes itself with ALK positive ALCL [
2,
28].
Since some of the tumor cells in ALCL resemble classic Reed-Sternberg cells which are “hallmark” cells in Hodgkin’s lymphoma (HL), differential diagnosis should also include HL. Fortunately, it is not difficult to differentiate HL from ALCL if it is ALK positive, but at times it may be a challenge when it comes to ALK negative ALCL. In this case, expression of EMA, clusterin, or CD56 in tumor cells may help to support a diagnosis of ALK negative ALCL, as the staining of these markers are known to be absent in HL [
29]. Jaffe have suggested that HL-like ALK negative ALCL should be diagnosed only when tumor cell morphology closely resemble Hodgkin’s lymphoma but immunohistochemical study show characteristics of ALCL (positive staining for CD30, EMA, CD3 but negative for EBV and B-cell markers) [
24].
In addition to lymphatic tissue tumor, ALK rearrangements can also be detected in other malignancies, including inflammatory myofibroblastic tumors [
30,
31], non-small cell lung cancers [
32], neuroblastomas [
33] and embryonal rhabdomyosarcomas [
34]. However, these malignancies are readily distinguishable from ALCL is based on their distinct morphology. Moreover, some specific immunohistochemistry markers which were not known to be expressed in ALCL but in the other malignancies can support the diagnosis, including rhabdomyosarcoma markers MyoD1 and Myogenine and non-small cell lung cancers marker TTF-1.
In general, we reported a rare case of primary intestinal ALK positive large cell lymphoma and highlighted the clinicopathological features and differential diagnosis.