Direct immunofluorescence is of limited utility in patients with low clinical suspicion for an oral autoimmune bullous disorder

ObjectivesOral autoimmune bullous disorders show clinical overlap with diseases such as lichen planus and others that may cause desquamative gingivitis. As direct immunofluorescence is expensive, we sought to determine if routine histology alone would be sufficient to distinguish between oral autoimmune bullous disorders and mimics.MethodsWe searched the records for patients with a suspected oral autoimmune bullous disorder who underwent biopsies for concurrent routine histologic evaluation and direct immunofluorescence and who had at least one followâ up visit. Cases were separated into high and low suspicion subgroups based on clinical findings.ResultsWithin 148 cases, the sensitivity of routine histology alone was 0.810, with a negative predictive value of 0.889. However, the specificity was 0.989 with a positive predictive value of 0.979. Of the high suspicion cases, 57 (47.1%) were found to be consistent with an oral autoimmune bullous disorder, with a total of 11 histologic false negatives. 8 cases, all in the high suspicion subgroup, showed indeterminate direct immunofluorescence results. There were no histologic false negatives or inconclusive direct immunofluorescence results in the low suspicion subgroup.ConclusionsIn patients with a low clinical suspicion for an oral autoimmune bullous disorder, it is reasonable and more costâ effective to evaluate the lesion with routine histology alone.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153107/1/odi13159_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153107/2/odi13159.pd

Regulation and inhibition of the anaplastic lymphoma kinase

Activating mutations in the anaplastic lymphoma kinase (ALK) gene were recently discovered in neuroblastoma, a cancer of the developing autonomic nervous system that is the most commonly diagnosed malignancy in the first year of life. The most frequent ALK mutations in neuroblastoma cause amino acid substitutions in regulatory regions of the intracellular catalytic domain of the intact ALK receptor tyrosine kinase (F1174L and R1275Q). The identification of ALK as an oncogenic driver in neuroblastoma suggests that crizotinib (PF-02341066), a dual-specific inhibitor of the ALK and Met tyrosine kinases, will be useful in treating this malignancy. We assessed the ability of crizotinib to inhibit proliferation of neuroblastoma cell lines expressing mutated (F1174L or R1275Q) or wild-type (overexpressed) ALK. Growth of cells expressing R1275Q-mutated ALK or high levels of wild-type ALK (due to genomic amplification) was inhibited by crizotinib, whereas cells expressing F1174L-mutated ALK were resistant. These in vitro observations were recapitulated in xenograft studies of crizotinib sensitivity. Through detailed biochemical analyses, we show that the reduced susceptibility to crizotinib inhibition of F1174L-mutated ALK results from an increased ATP-binding affinity (by Km, ATP measurement), as also seen in the development of resistance to EGFR inhibitors in non-small cell lung cancer by \u27gatekeeper\u27 residue mutation. In addition to mutations observed at the R1275 and F1174 positions, our sequencing efforts have defined the full spectrum of ALK mutations in a panel of 1597 primary neuroblastoma tumor samples. We extended our biochemical analysis to these mutations. Our results indicate that many of these novel mutation variants are constitutively activating, developing our structural understanding of the ALK catalytic domain and suggesting that they are clinically relevant. We conclude that, in several cases, the in vitro crizotinib sensitivity of these variants correlate with Km, ATP values, like R1275Q and F1174L. However, inhibitor affinity also appears to be altered for select mutant variants. These results have direct relevance to the future development and clinical application of inhibitors for ALK-driven malignancies, and suggest a need for higher-affinity ALK inhibitors

Fat necrosis with an associated lymphocytic infiltrate represents a histopathologic clue that distinguishes cellular dermatofibroma from dermatofibrosarcoma protuberans

BackgroundCellular dermatofibromas (CDFs) and dermatofibrosarcoma protuberans (DFSP) can be challenging to differentiate from one another. Morphologically, both entities commonly extend into the subcutis, exhibit high cellularity with limited cytologic atypia and have a mixed fascicular‐to‐storiform growth pattern. We sought to evaluate the significance of fat necrosis with an associated lymphocytic infiltrate as a histopathologic clue for distinguishing CDFs from DFSP.MethodsWe identified cases in our pathology database with a primary diagnosis of CDF or DFSP. Punch or excisional biopsy specimens with extension into the subcutis were selected. Previously biopsied lesions and specimens that did not interact with the subcutis were excluded. Histopathologic features were evaluated in hematoxylin and eosin stained sections.ResultsFat necrosis with lymphocytic infiltrate was present in 20/20 cases of CDF. None of the 20 DFSP cases had fat necrosis with lymphocytic infiltrate although 4/20 had fat necrosis alone.ConclusionsFat necrosis with associated lymphocytic response can aid in the distinction between CDF and DFSP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162705/2/cup13744_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162705/1/cup13744.pd

Primary cutaneous follicle center lymphoma with extensive plasmacytic differentiation and t(14;18) in both the lymphoid and plasma cell components

Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B‐cell lymphoma. The typical immunophenotype includes expression of both CD20 and BCL6, with the majority of cases lacking expression of CD10, BCL2, and the characteristic t(14;18)/IGH‐BCL2 rearrangement seen in systemic follicular lymphoma (FL). Plasmacytic differentiation (PD) is an uncommon finding in both systemic and cutaneous FLs and presents a diagnostic challenge when present, leading to the potential for misdiagnosis as marginal zone lymphoma (MZL). Limited reports have described light chain restriction in the plasma cell component of FLs with PD, and rare cases of PCFCL with PD have been described. While the IGH‐BCL2 translocation has been identified in a subset of FLs with PD, the presence of the BCL2 translocation in monotypic plasma cells of PCFCL has not been previously described to our knowledge. Here, we report a case of PCFCL with extensive PD in a 77‐year‐old woman that was favored to represent primary cutaneous MZL on an initial punch biopsy. Excisional biopsy, however, revealed that the atypical lymphocytes expressed CD10, BCL6, and BCL2, while the plasma cell component demonstrated light‐chain lambda restriction. FISH studies showed the presence of an IGH‐BCL2 translocation in both the lymphocytic and plasmacytic components.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168335/1/cup14020_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168335/2/cup14020.pd

Two cases of challenging cutaneous lymphoid infiltrates presenting in the context of COVID-19 vaccination: A reactive lymphomatoid papulosis-like eruption and a bona fide lymphoma

COVID-19 infection and vaccination may be associated with a wide variety of cutaneous and immune manifestations. Here, we describe two patients who presented with monoclonal cutaneous T-cell infiltrates that showed cytologic and immunophenotypic features concerning for lymphoma shortly following COVID-19 vaccination. In one case, the eruption completely resolved. The second patient showed initial resolution, but her disease recurred and progressed following a breakthrough SARS-CoV-2 infection. These cases suggest that immune stimulation following exposure to SARS-Cov-2 protein(s) in vaccine or infection may facilitate the development of a lymphoma or lymphoproliferative disorder in susceptible individuals. Moreover, they show that separating these cases from pseudolymphomatous reactive conditions is often challenging and requires close clinical correlation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175916/1/cup14371_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175916/2/cup14371.pd

PRAME expression is similar in scar and desmoplastic melanoma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/174781/1/cup14286.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/174781/2/cup14286_am.pd