ALK-positive Large Cell Lymphomas Research Articles

Lung carcinoma–‘nonsmall cell’ is no longer an option

Current diagnostic issues concerning nonsmall cell lung carcinoma (NSCLC) include subtyping as encountered in cytology and small biopsy samples, and the requirement to strike a balance between histology and immunohistochemistry (IHC) for discrimination between squamous (SCCs) and adenocarcinomas (ADCs), versus the requirement for conservation of material for molecular studies (i.e., for recognition of ADCs with EGFR, EML4-ALK, or other mutations). There is a problem for pathologists in subtyping of NSCLC from small biopsies, in relation to: (i) a minimal sample of poorly differentiated tumour for histological and IHC assessment; (ii) biopsy artefact; (iii) conservation of tissue for molecular studies. A minimalist IHC workup of p63 and TTF1 can facilitate discrimination between SCC versus nonmucinous ADC, respectively. However, about one-third of proven ADCs show expression of p63, so that a p63+/TTF1+ immunoprofile is still considered to favour ADC. Alternatively, p40 can be substituted for p63 and labels ADCs less often than p63, or CK5 or CK5/6 can be added to p63 to facilitate diagnosis of SCC. Invasive mucinous ADC has an immunoprofile different from nonmucinous ADC (usually CK7+/CK20+/TTF1–). Other pitfalls exist: TTF1+/p63– in small cell carcinoma and metastatic thyroid carcinoma; TTF1–/p63– in lymphomas and melanoma; and TTF1–/p63+ in metastatic uro-thelial carcinoma. In this context, IHC studies need to take into account the clinical background and medical history for each case. Even now, up to about 30% NSCLCs are not further classifiable beyond NSCLC NOS, on the basis of IHC on small biopsy samples. EGFR antibodies are commercially available, and can be used to screen for such mutations, whereas ALK antibodies used at present for diagnosis of ALK positive large cell lymphomas are insensitive for diagnosis of most EML4-ALK ADCs. ALK positive ADCs reported to date have been positive for TTF1, and positive/negative TTF1 labelling may represent an inclusionary/exclusionary boundary for molecular testing. Even so, EGFR and ALK ADCs represent a small proportion of ADCs in Western societies, so that histological/IHC subtyping appears to retain prognostic and clinical relevance for most ADCs.

Anaplastic Lymphoma Kinase (ALK)-Positive Diffuse Large B-Cell Lymphoma Presenting with CNS Involvement: A Case Report

Abstract 5225 IntroductionAnaplastic lymphoma kinase (ALK)- positive large B-cell lymphoma is a rare form of large B-cell lymphoma originally described in 19971. Since its initial description, approximately fifty cases have been reported in the literature, none of which describe extranodal involvement of the CNS as we will present below. CaseThe patient is a 30 year old previously healthy male who presented with visual changes described as decreased acuity and headaches. Papilledema was present on exam, but exam was otherwise negative. Imaging showed an enhancing mass posterior to the Torcula Herophili. With the working diagnosis of meningioma, the lesion was embolized and then debulked. Final pathology, however, revealed an ALK-positive large B-cell lymphoma with cytoplasmic granular ALK staining. Immunohistochemistry was positive for CD 138, CD 45, CD 38, CD 4, MUM1, epithelial membrane antigen (EMA) and monoclonal IgA lambda, and negative for CD 20, CD30, CD 3, and CD 8. FISH revealed ALK rearrangement (likely with clathrin, but pending at time of abstract) and c-MYC amplification, but not translocation. Serum immunoglobulins were normal. PET/CT showed skeletal metastasis but no additional visceral disease. DiscussionALK-positive large cell lymphomas described previously show immunoblastic/plasmablastic-like phenotypes (CD138+, CD 45+, CD 20-, and cytoplasmic IgA expression), but are CD30-negative and have uniform EMA expression and ALK translocations, as did our patient. The majority of ALK-positive DLBCL exhibit an ALK translocation with the long arm of the clathrin gene to form t(2;17)(p23;q23)2.ALK-positive large cell tumors typically present nodally, but cases have been reported extranodally in the nasopharynx, tongue, bone, soft tissue, and stomach. There is a 3:1 male predominance and a poor overall prognosis with a median survival of 12.2 months, with isolated cases having longer survival. Most patients were treated with CHOP-based regimens with or without radiation therapy2,3. The need for more intense or biologically directed therapy in these cases, including early intensification with or without autologous stem cell rescue is recognized. Gambacorti-Passerini and Poglinani recently described lymphoma sensitivity with crizotinib, an anaplastic lymphoma tyrosine kinase inhibitor, in relapsed anaplastic large cell lymphoma after standard treatment with promising results. Investigation into the use of crizotinib in ALK-positive large cell lymphomas as salvage therapy is potentially warranted4.This case presents an interesting treatment dilemma given the ALK mutation, c-myc amplification, and CNS disease. Crizotinib is likely not a salvage option for this patient given unclear CNS availability and the possibility of this tumor being motivated by c-myc as well as ALK. Disclosures:No relevant conflicts of interest to declare.