Distinctive genomic features of human T-lymphotropic virus type 1-related adult T-cell leukemia-lymphoma in Western populations.

Adult T-cell leukemia-lymphoma (ATLL) is an aggressive Human T-cell Leukemia Virus Type 1 (HTLV-1)-driven malignancy. Although Western hemisphere (Afro-Caribbean and South American) patients face worse prognoses, our understanding of ATLL molecular drivers derives mostly from Japanese studies. We performed multi-omic analyses to elucidate the genomic landscape of ATLL in Western cohorts. Recurrent deletion and/or damaging mutations involving FOXO3, ANKRD11, DGKZ, and PTPN6 implicate these genes as potential tumor suppressors. RNA-seq, published functional data and in vitro assays support the roles of ANKRD11 and FOXO3 as regulators of T-cell proliferation and apoptosis in ATLL, respectively. Survival data suggest ANKRD11 mutation may confer a worse prognosis. Japanese and Western cohorts, in addition to acute and lymphomatous subtypes, demonstrated distinct molecular patterns. GATA3 deletion was associated with unfavorable chronic cases. IRF4 and CARD11 mutations frequently emerged in relapses after interferon therapy. Our findings reveal novel putative ATLL driver genes and clinically relevant differences between Japanese and Western ATLL patients.

Rosai-Dorfman Disease: A Less Common Cause of Leptomeningeal and Nerve Root Enhancement.

A 46-year-old male experienced progressive neurocognitive decline, weight loss, intermittent headaches, and weakness over 6 months. Magnetic resonance imaging of the brain revealed hydrocephalus and the spinal cord imaging showed diffuse leptomeningeal enhancement with prominent nerve root involvement. Intradural biopsy of lumbar arachnoid tissue found mixed inflammatory infiltrate consisting predominantly of histiocytes, S100 and CD68 positivity, and lymphocytophagocytosis (emperipolesis) consistent with extranodal Rosai-Dorfman disease. Rosai-Dorfman disease, a non-Langerhans cell histocytic disorder, can mimic the appearance of neurosarcoidosis and leptomeningeal carcinomatosis and should remain on the differential of a patient presenting with diffuse leptomeningeal enhancement, a common occurrence on a neurohospitalist service.

Chromosomal microarray analysis of benign mesenchymal tumors with RB1 deletion.

Spindle cell lipomas/pleomorphic lipomas, mammary-type myofibroblastomas, and cellular angiofibromas are benign mesenchymal tumors that demonstrate histologically overlapping features but with varying anatomic locations and an uncertain etiologic relationship. These tumors have also been found to have an overlapping molecular profile with shared 13q14 deletions, which is the location of the tumor suppressor gene RB1 that encodes the retinoblastoma protein. Molecular studies thus far have largely focused on the RB1 locus, using primarily immunohistochemistry and fluorescence in situ hybridization to characterize RB1 status. However, further characterization of the molecular profile of these lesions, including genome-wide copy number variation, remains to be well defined. The goal of this study is to further characterize the specific RB1 deletions seen in spindle cell lipomas/pleomorphic lipomas, cellular angiofibromas, and mammary-type myofibroblastomas as well as to evaluate these neoplasms for additional molecular abnormalities using the OncoScan™ CNV Plus Assay, which is used for clinical use as a whole-genome copy number microarray-based assay. Ten of eleven cases demonstrated deletion of the RB1 gene with varying deletion size and breakpoints. The majority of additional genetic alterations were chromosomal losses and loss of heterozygosity with rare chromosomal gains. Although only a small subset of mesenchymal neoplasms was evaluated, the principle of creating a novel pairing of the molecular method with the tumor type represents a promising avenue for further study in a variety of tumors.

High-Grade Squamous Intraepithelial Lesion of the Gastroesophageal Junction Secondary to High-Risk Human Papillomavirus.

OBJECTIVES: Although the role of human papillomavirus (HPV) in the development of some carcinomas (eg, anogenital and oropharyngeal squamous cell carcinomas) is nondebatable, there is still significant controversy regarding the relationship of HPV and esophageal squamous cell carcinomas (SCCs). METHODS: All cases were sampled at or near the gastroesophageal junctions in patients with reflux and/or known Barrett esophagus and appear to have been initially sampled "incidentally." Patients were all men, aged 56 to 80 years. None had a known history of other HPV-related disease. RESULTS: We present four cases of high-grade squamous intraepithelial lesion of the gastroesophageal junction secondary to high-risk HPV that have identical histologic features to similar lesions of the anogenital tract. CONCLUSIONS: Whether such lesions are at risk for developing into invasive SCC remains unclear.

PD-L1 expression in tumor cells and the immunologic milieu of bladder carcinomas: a pathologic review of 165 cases.

Programmed death ligand 1 (PD-L1) is a transmembrane protein that plays a major role in immune suppression. Its interaction with the receptor PD-1 results in downregulation of antitumoral immunity. Humanized monoclonal antibodies that interrupt the PD-L1/PD-1 interaction have shown therapeutic efficacy in patients with advanced urothelial cancer. However, immunohistochemical staining of PD-L1 in bladder tumors and its relationship to tumor histologic type, grade, and overall survival has been incompletely analyzed. Slides from 165 cystectomy specimens were reviewed for tumor type, grade of urothelial carcinoma, pathologic stage, and overall survival. A tissue microarray (TMA) using four 0.6 mm cores from each case was constructed. Immunohistochemistry was performed on the TMA using a variety of new PD-L1 antibodies and platforms now widely available. For each case, the percent of tumor cells positive for PD-L1 and the percent of positive immune cells were scored. The overall number of bladder cancers positive for PD-L1 depended on the antibody/platform combination used and the threshold for considering a tumor "PD-L1-positive." Squamous cell carcinomas (SCCs) of the bladder demonstrated PD-L1 positivity more frequently than urothelial cell carcinomas (UCCs). High-grade UCCs were positive for PD-L1 on tumor cells more frequently than low-grade UCCs. There was no difference in survival between PD-L1-positive and PD-L1-negative bladder cancers in our study. Further studies should consider examining the predictive significance of PD-L1 IHC in bladder cancers.

Indeterminate Dendritic Cell Tumor: A Report of Two New Cases Lacking the ETV3-NCOA2 Translocation and a Literature Review.

Indeterminate dendritic cell tumor (IDCT) is a cutaneous proliferation of histiocytes that share morphologic and immunophenotypic properties with Langerhans cells. IDCT was recently included in the updated WHO classification of tumors of hematopoietic and lymphoid tissues. Recent studies have shown that some cases of IDCT demonstrate an ETV3-NCOA2 translocation, supporting the idea that IDCT is a clonal neoplasm. We report 2 new cases of IDCT at our institution lacking the ETV3-NCOA2 translocation. We also present a comprehensive review of reported cases of IDCT in the medical literature. Eighty-five cases of IDCT were reported in the literature between 1985 and 2016. The median age at diagnosis was 45 years. In contrast to Langerhans cell histiocytosis, IDCT is limited to the skin in the majority of cases (88%) and generally follows an indolent clinical course. Most reported lesions are cured with complete excision. However, the histologic features of IDCT and langerhans cell histiocytosis are similar. Conjoint immunostaining for CD1a and langerin is necessary for optimal classification.

Primary Cutaneous Small/Medium CD4+ T-CELL Lymphoproliferative Disorder Occurring in a Patient With Metastatic Melanoma.

Therapeutic agents designed to stimulate the immune system are now cornerstones in the treatment of metastatic melanoma. These drugs promote lymphocyte growth and survival, which could plausibly result in clinical lymphoproliferative disorders. We report the case of a 62-year-old female with metastatic melanoma who developed primary cutaneous small/medium CD4 T-cell lymphoproliferative disorder (PC-SMTCL) after treatment with vemurafenib and recombinant high-dose interleukin-2 (IL-2). The patient developed a painless red papule behind the ear. A biopsy showed a dense population of CD4 lymphocytes with a T-follicular helper cell phenotype. Molecular studies confirmed the presence of a clonal population of T cells, and the process was classified as PC-SMTCL. The patient was diagnosed with metastatic melanoma approximately 3 years before the development of the cutaneous lymphoma and had been treated with vemurafenib followed by 2 courses of IL-2. The patient's last course of IL-2 was completed in April of 2013. She developed the cutaneous lymphoma behind her ear in December of 2015. An association between PC-SMTCL and vemurafenib treatment for advanced melanoma has been reported previously in one patient; however, an association between PC-SMTCL and IL-2 treatment has not been documented. The immunostimulatory properties of IL-2 or vemurafenib may be responsible for the development of PC-SMTCL in our patient. Additionally, antigenic stimulation of the immune system by melanoma itself could contribute to clonal selection of lymphocytes.

Development of a biclonal cutaneous T-cell lymphoproliferative process during treatment with immune checkpoint inhibitors for metastatic melanoma.

The immune checkpoint inhibitors targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and the programmed death protein 1 (PD-1)/PD-L1 pathway have recently shown promising therapeutic results in patients with metastatic melanoma. Dermatologic side effects of these agents occur in ∼30-40% of cases. Here, we report the development of a biclonal cutaneous T-cell lymphoproliferative disorder in a patient being treated with ipilimumab (a CTLA-4 inhibitor) for metastatic melanoma. Nivolumab (a PD-1 inhibitor) had also been administered to him previously. An 8 mm reddish papule appeared on the skin of the left forearm. A biopsy of that lesion showed an atypical population of predominantly CD4-positive, CD30-positive T-cells that also expressed PD-1 and PD-L1 immunohistochemically. PCR studies for T-cell receptor rearrangements showed the presence of two distinct clonal T-cell populations. The lesion was completely excised and the patient had no local recurrences. There was also no subsequent evidence of a systemic lymphoproliferative process. Although the development of a lymphoid skin lesion in our patient may have only been coincidentally related to his treatment, immunostimulatory drugs could theoretically cause clonal expansion of a population of lymphocytes that leads to a lymphoproliferative disorder.

Disseminated CD8-positive, CD30-positive cutaneous lymphoproliferative eruption with overlapping features of mycosis fungoides and primary cutaneous anaplastic large cell lymphoma following remote solitary lesional presentation.

CD8-positive, CD30-positive cutaneous lymphoproliferative disorders constitute a rare subset of T-cell lymphoproliferative conditions, including variants of primary cutaneous anaplastic large cell lymphoma (ALCL), mycosis fungoides, lymphomatoid papulosis type D, cutaneous gamma-delta T-cell lymphoma and cutaneous peripheral T-cell lymphoma. These entities share overlapping clinical, histopathologic and immunophenotypic features, presenting both a clinical and pathological diagnostic challenge. Presented here is a 73-year-old man with a disseminated, indolent CD30+, CD8+ cutaneous lymphoproliferative disorder with overlapping clinical and histopathological features of both mycosis fungoides and primary cutaneous ALCL, as well as features of lymphomatoid papulosis. To our knowledge, this is the first case of a generalized CD8+, CD30+ eruption with features of both mycosis fungoides and primary cutaneous ALCL arising following an episode of solitary primary cutaneous CD8-positive ALCL.