Malignant lymphoma, peripheral T-Cell type, with features of ALK-1 negative anaplastic large cell lymphoma.
Anaplastic large cell lymphoma (ALCL) is a subgroup of lymphomas believed to be of cytotoxic T or NK cell origin and is characterized by the presence of characteristic large anaplastic cells. According to the WHO 2008 classification  and the proposed 2016 update of hematologic malignancies , ALCL is divided into two primary variants, based on whether or not the characteristic translocation involving the anaplastic lymphoma kinase-1 (ALK-1) gene on chromosome 2 is present . ALK-1 is generally translocated with the nucleophosmin (NPM) gene on chromosome 5, although a few variant translocations have also been described.
Although many peripheral T-cell lymphomas of cytotoxic T/NK origin demonstrate aggressive clinical behavior, ALK-positive ALCL has a characteristic survival curve that is generally better than that of most peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS). Although some controversy exists regarding the classification of ALK-negative ALCL, expression profiling studies and survival data indicate they share more overlapping features with ALK-1 positive ALCL, and patient survival is generally intermediate to that of ALK-1 positive ALCL and PTCL-NOS .
ALK-negative ALCL generally occurs in adults between 40 and 65 years of age, with a male-to-female ratio of approximately 1.5:1. Patients frequently present with peripheral or abdominal lymphadenopathy and B symptoms such as fever, night sweats, and weight loss. The primary site tends to be the lymph nodes; however, there is typically stage III-IV disease at the time of initial diagnosis, and bone, soft tissue, and skin may be involved .
When lymph nodes are involved, solid sheets of neoplastic cells may efface the normal tissue architecture, or cells may infiltrate sinuses or T-cell areas with a cohesive pattern similar to that of carcinoma. ALK-negative ALCL has numerous histological patterns, and more than one can be seen in a given specimen. The common theme among these is the presence of "hallmark" cells, which are multinucleated large cells in a "wreath-like" arrangement around the cell periphery. The pattern seen in our patient's specimen is the "common pattern." It contains large pleomorphic cells with abundant eosinophilic cytoplasm, multiple nuclei in a wreath-like formation, and basophilic nucleoli. Large cells may occasionally appear similar to Hodgkin-Reed-Sternberg (HRS) cells. Other frequently seen patterns are the "lymphohistiocytic" pattern, with numerous reactive histiocytes that mask the malignant cells, and the "Hodgkin-like" pattern, which mimics the nodular sclerosis variant of Hodgkin lymphoma .
With regard to molecular and genetic studies, it is very important to demonstrate the lack of ALK-1 gene rearrangement by using classical cytogenetic analysis or appropriate fluorescence in situ hybridization (FISH) studies with ALK-1 break-apart probes. In the future, further subclassification of ALK-negative ALCLs may also be plausible. A 2014 study of 105 ALCL specimens identified DUSP22 (IRF4) (6p25.3) and TP63 (3q28) chromosomal rearrangements in 30% and 8% of ALK-negative ALCLs, respectively . These rearrangements occurred in isolation and were not seen in ALK-positive ALCLs. Other findings include clonal rearrangement of T-cell receptors and secondary genetic imbalances, such as gains of 1q, 6p, 8q, 12q or deletions of 6q, 4q, 13q .
Immunohistologic studies are useful for diagnosing ALK-negative ALCL. The large neoplastic cells generally stain strongly and homogenously with CD30 in Golgi and membranous regions, although diffuse cytoplasmic staining also occurs. Smaller tumor cells are infrequently positive or even negative. Similar to ALK-positive ALCL, ALK-negative ALCL is almost always positive for the pan T-cell marker CD43 and is frequently positive for cytotoxic T-cell markers such as perforin, granzyme B, and/or TIA1. Most neoplastic populations express at least one T-cell marker, but loss of CD3, CD5 or CD8 is common, and some cases have complete loss of T-cell receptor expression . Also, staining with ALK is, by definition, negative.
There are four main entities in the differential diagnosis of ALK-negative ALCL:
The International Peripheral T-cell lymphoma (IPTL) Project  is thus far the largest retrospective study to analyze outcomes of ALCL specimens. 181 samples were utilized, and a significant relationship was found between ALK status and five-year overall survival, with the International Prognostic Index (IPI) as an independent predictor of outcome after stratifying patients into four risk groups based on clinical factors. Five-year overall survival in the lowest risk factor group was found to be around 90%, 70%, and 49% for patients with PCALCL, ALK-positive ALCL, and ALK-negative ALCL, respectively. In a more recent study , ALK and DUSP22 rearrangements had similar favorable five-year survival of 85% and 90%, respectively, while TP63 and cases without translocations identified had 15%, and 42% five-year survival, respectively. These results were similar when restricted to patients receiving chemotherapy, but not for those who received stem cell transplants. More studies are currently in progress to characterize the morphologic , immunohistochemical, and genetic findings [5, 15, 16] characteristic of these tumors and their responses to treatment.
Contributed by Christopher Suciu, MD and Raymond E. Felgar, MD, PhD