Primary Well-Differentiated Neuroendocrine Tumor/Carcinoid of the Prostate: Case Report and Review of Literature.

Primary well-differentiated neuroendocrine tumor (WDNT)/carcinoid of the genitourinary tract is rare. Many WDNT reported in the prostate gland have been seen in close association with conventional prostatic adenocarcinoma and/or label for prostate-specific immunohistochemical markers and are best considered prostatic adenocarcinomas with "carcinoid-like" features. We present a case of primary WDNT/carcinoid incidentally detected in a 67-year-old man who underwent radical prostatectomy for Grade group 2 prostatic adenocarcinoma. Morphologically, the neuroendocrine (NE) lesion appeared distinct from the prostatic adenocarcinoma, labeled for NE markers, was negative for prostatic markers (NKX3.1, PSA, and ERG), and showed an overall low Ki-67 proliferation index (<1%). Follow-up was uneventful with no evidence of residual disease or metastasis.

Proteogenomic Profiling of High-Grade B-Cell Lymphoma With 11q Aberrations and Burkitt Lymphoma Reveals Lymphoid Enhancer Binding Factor 1 as a Novel Biomarker.

High-grade B-cell lymphomas with 11q aberrations (HGBL-11q) represent a World Health Organization-defined group of lymphomas that harbor recurrent chromosome 11q aberrations involving proximal gains and telomeric losses. Although a limited number of HGBL-11q cases evaluated thus far appear to show a similar course and prognosis as Burkitt lymphoma (BL), many molecular differences have been appreciated, most notably the absence of MYC rearrangement. Despite biological differences between BL and HGBL-11q, histomorphologic and immunophenotypic distinction remains challenging. Here, we provide a comparative whole proteomic profile of BL- and HGBL-11q-derived cell lines, identifying numerous shared and differentially expressed proteins. Transcriptome profiling performed on paraffin-embedded tissue samples from primary BL and HGBL-11q lymphomas was additionally performed to provide further molecular characterization. Overlap of proteomic and transcriptomic data sets identified several potential novel biomarkers of HGBL-11q, including diminished lymphoid enhancer-binding factor 1 expression, which was validated by immunohistochemistry staining in a cohort of 23 cases. Altogether, these findings provide a comprehensive multimodal and comparative molecular profiling of BL and HGBL-11q and suggest the use of enhancer-binding factor 1 as an immunohistochemistry target to distinguish between these aggressive lymphomas.

POU2F3 in SCLC: Clinicopathologic and Genomic Analysis With a Focus on Its Diagnostic Utility in Neuroendocrine-Low SCLC.

INTRODUCTION: POU2F3 is a recent marker of a small cell lung carcinoma (SCLC) subtype related to chemosensory tuft cells (SCLC-P). The characteristics of SCLC-P have not been fully defined, and the data on POU2F3 expression in other lung tumors are scarce. METHODS: We screened 254 SCLC for POU2F3 expression and comprehensively analyzed histopathologic, genomic, and clinical characteristics of POU2F3-positive tumors. We also explored POU2F3 expression in other major lung cancer types (n = 433) and a targeted set of potential diagnostic mimics of SCLC (n = 123). RESULTS: POU2F3 was expressed in 30 of 254 (12%) SCLC and was strongly associated with low expression of standard neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1). Notably, POU2F3 was expressed in 75% of SCLC with entirely negative or minimal neuroendocrine marker expression (15/20) and was helpful in supporting the diagnosis of SCLC in such cases. Broad targeted next-generation sequencing revealed that SCLC-P (n = 12) exhibited enrichment in several alterations, including PTEN inactivation, MYC amplifications, and 20q13 amplifications, but similar rates of RB1 and TP53 alterations as other SCLC (n = 155). Beyond SCLC, POU2F3 expression was exclusively limited to large cell neuroendocrine carcinoma (12%) and basaloid squamous cell carcinoma (22%). CONCLUSIONS: This is the largest cohort of SCLC-P clinical samples to date, where we describe the diagnostic utility of POU2F3 in a challenging subset of SCLC with low or absent expression of standard neuroendocrine markers. The distinct genomic alterations in SCLC-P may offer a novel avenue for therapeutic targeting. The role of POU2F3 in a narrow subset of other lung cancer types warrants further study.

CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience.

BACKGROUND: Waldenström macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM. METHODS AND RESULTS: We performed preclinical studies demonstrating CAR T cell activity against WM cells in vitro, and developed an in vivo murine model of WM which demonstrated prolonged survival with use of CAR T therapy. We then report the first three patients with multiply relapsed and refractory WM treated for their disease with CD19-directed CAR T cells on clinical trials. Treatment was well tolerated, and observed toxicities were consistent with those seen in CAR T treatment for other diseases, and no grade 3 or higher cytokine release syndrome or neurotoxicity events occurred. All three patients attained at least a clinical response to treatment, including one minimal residual disease-negative complete response, though all three eventually developed recurrent disease between 3 and 26 months after initial treatment. CONCLUSIONS: This report summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.

Current Knowledge in Genetics, Molecular Diagnostic Tools, and Treatments for Mantle Cell Lymphomas.

Mantle Cell lymphoma (MCL) is a mature B-cell lymphoma with a well-known hallmark genetic alteration in most cases, t (11,14)(q13q32)/CCND1-IGH. However, our understanding of the genetic and epigenetic alterations in MCL has evolved over the years, and it is now known that translocations involving CCND2, or cryptic insertion of enhancer elements of IGK or IGL gene, can also lead to MCL. On a molecular level, MCL can be broadly classified into two subtypes, conventional MCL (cMCL) and non-nodal MCL (nnMCL), each with different postulated tumor cell origin, clinical presentation and behavior, mutational pattern as well as genomic complexity. This article reviews both the common and rare alterations in MCL on a gene mutational, chromosomal arm, and epigenetic level, in the context of their contribution to the lymphomagenesis and disease evolution in MCL. This article also summarizes the important prognostic factors, molecular diagnostic tools, and treatment options based on the most recent MCL literature.

Biphenotypic sinonasal sarcoma: Report of 3 cases with a review of literature.

Biphenotypic sinonasal sarcoma (BSNS) is a rare recently described distinct spindle cell sarcoma which arises exclusively in the sinonasal region and is characterized by concomitant neural and myogenic differentiation. Before this neoplasm was characterized, most were classified as other entities including adult fibrosarcoma, monophasic synovial sarcoma and malignant peripheral nerve sheath tumor. By immunohistochemistry, these tumors characteristically express S100 and smooth muscle actin (SMA) and/or muscle specific actin (MSA). Most cases harbor rearrangements of PAX3 (paired box gene 3), and the most frequent translocation partner is MAML3 (mastermind like transcriptional coactivator 3). Herein, we described three cases of BSNS involving the nasal cavity with or without paranasal sinus involvement. We also did a literature review of the clinical features, histologic and immunophenotypic findings, cytogenetics, pathogenesis and behavior of this rare entity.

Clinicopathologic Characteristics of Young Patients with Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) occasionally occurs in young patients and is likely to be distinct from OSCC in older patients. In this retrospective study, we described the clinicopathologic features and outcome of 150 OSCCs that were diagnosed in patients 40-year-old or younger. Most patients (63%) were non-smokers. The most common site of the primary tumor was oral tongue (n = 131, 87%), followed by gingiva (n = 9), buccal mucosa (n = 8) and lip (n = 2). The median patients' age at presentation was 34 (range: 16-40). Seven patients (5%) had Fanconi anemia with the gingiva being the most common location (4/7, 57%). All OSCCs were of keratinizing type. All cases tested for high-risk HPV (n = 34) were negative. On univariate analysis, high tumor budding was associated with decreased overall survival (OS) and distant metastasis free survival (DMFS), pattern of invasion correlated with OS and tumors with high stromal tumor infiltrating lymphocytes (sTIL) were associated with improved locoregional recurrence free survival (LRFS). Compared with patients 31 to 40-year-old, OSCC in the younger group was associated with significant less alcohol consumption (p = 0.011) and decreased DSS (p = 0.003) and DMFS (p = 0.023). On multivariate analysis, younger age (30 years or younger) was an independent prognostic factor for worse OS and DSS, whereas histologic grade was an independent prognostic factor for DSS. In summary, most OSCC in young patients occurred in non-smokers and did not occur in association with Fanconi anemia. Independent prognostic factors included age at presentation (30 years or younger) for OS and DSS, and histologic grade for DSS.

Mycobacterium Spindle Cell Pseudotumor Caused by Mycobacterium xenopi: A First Described Association of a Rare Entity Presenting in the Lung.

Mycobacterial spindle cell pseudotumor (MSP) is a rare benign lesion characterized by a proliferation of bland spindle-shaped histiocytes with vague granulomatous formation, positive for acid-fast bacilli staining. This lesion is usually reported in the lymph nodes and skin of immunocompromised patients; only 6 cases primary in the lung have been reported in the English literature to this date. In this article, we present the case of a 42-year-old female status post failed kidney-pancreas transplant with subsequent multiple kidney transplants, on chronic immunosuppression, who developed a mass in the left lower lobe consistent with MSP. Mycobacterium xenopi was identified in lung tissue culture, an association never previously described in literature. This case report alerts for the possible association of this rare form of non-tuberculous mycobacteria in the pathogenesis of MSP and highlights the importance of this differential diagnosis in lung masses of immunocompromised patients.

Cytologic and clinical features of NIFTP: Can we diagnose based on preoperative fine-needle aspiration.

BACKGROUND: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is considered an indolent neoplasm of the thyroid. Currently, this entity presents a diagnostic challenge on preoperative fine-needle aspiration (FNA) cytology. METHODS: Cases of NIFTP and noninvasive encapsulated follicular variant of papillary thyroid carcinoma from January 1994 to August 2018 were retrieved from our institution's pathology databases, and their clinical and cytopathologic features were reviewed. RESULTS: A total of 45 patients with NIFTP were identified. Thirty-nine of 45 patients had presurgical thyroid FNAs, 27 of which showed abnormal cytology (27/39). NIFTPs were most often classified in the indeterminate diagnostic categories on presurgical FNAs (78%), including suspicious for follicular neoplasm (8/27), atypia of undetermined significance (8/27) and suspicious for malignancy (5/27). Six patients had a cytologic diagnosis of papillary thyroid carcinoma (6/27) on thyroid FNAs. Fourteen out of 27 cases with abnormal FNAs had in-house cytology available for review. The most frequent cytologic features observed in NIFTPs included architectural abnormalities, such as crowded clusters (13/14), nuclear overlapping (13/14), predominance or presence of individual microfollicles (11/14), and abundant to scattered isolated cells (10/14). The papillary-like nuclear features observed included nuclear enlargement (14/14), eccentric nucleoli (13/14), nuclear membrane irregularity (12/14), pale chromatin (12/14), nuclear grooves (10/14), and elongated nuclear contour (8/14). CONCLUSIONS: The NIFTPs were most frequently categorized as atypia of undetermined significance and suspicious for follicular neoplasm on cytology. Recognition of the architectural and nuclear features of NIFTP can be helpful in distinguishing NIFTPs from other entities, such as papillary thyroid carcinoma and follicular neoplasms.

Light Chain Amyloidosis Presenting as Bilateral External Auditory Canal Obstructing Masses.

: A morbidly-obese 57-year-old diabetic and hypertensive man with chronic kidney disease, diastolic heart failure, and bilateral hearing loss was found to have soft tissue masses/densities in the lateral aspect of both auditory canals on local examination and on imaging. He underwent biopsies of both ear canal masses and histologic examination revealed amyloid deposits in the dermis. These deposits were confirmed as AL (amyloid light chain) kappa-type amyloid by laser mass spectrometry. A systemic work-up showed plasma cell dyscrasia with 9% kappa light chain restricted plasma cells in the bone marrow as well as amyloid deposits on a kidney biopsy.Involvement of the external auditory canals is a rare manifestation of systemic amyloidosis with only 13 cases reported so far, of which four cases had bilateral external auditory canal involvement, associated with multiple myeloma. Interpretation of small biopsies can be challenging especially with early, scant amyloid deposits, but a sufficient biopsy to type amyloid by immunohistochemistry or laser mass spectrometry is imperative for further management. Early diagnosis and treatment of systemic light chain amyloidosis translates to better patient outcomes, while delay in management could lead to dismal prognosis.

Umbilical Lesions: Clinicopathologic Features of 99 Tumors.

BACKGROUND: Umbilical lesions are rare, and can be benign or malignant. This retrospective study was conducted to assess the epidemiological, clinical, and histologic characteristics of umbilical masses. METHODS: Cases of umbilical masses from January 1994 to August 2016 were retrieved from our institution's pathology databases, and their clinicopathological features were reviewed. RESULTS: There were a total of 99 cases of umbilical masses, 78 women (78.8%) and 21 men (21.2%). Of these, 59 were malignant (59.6%) and 40 were benign (40.4%). Among the malignant cases, 48 were women with a mean age of 65 years and 11 were men with a mean age of 66 years. All malignant lesions were secondary tumors. Twenty-five patients (42.3%) had a metastatic tumor to the umbilicus with an average of 7 months from the original diagnosis (12 gynecological, 8 pancreatic/gastrointestinal, 2 lymphomas, and a case each of breast, prostate, and melanoma). Of the patients with a benign diagnosis, 30 were women (75%) with a mean age of 52 years and 10 were men (25%) with a mean age of 43 years. The benign lesions included epidermal inclusion cysts (15/40), endometriosis (11/40), lipomas (3/40), neurofibromas (3/40), fibromas (3/40), abscesses (2/40), and 1 case each of tubular apocrine adenoma, serous cystadenoma, and calcified nodule. CONCLUSION: The most common metastatic tumors to the umbilicus are from the adjacent organs with the gynecologic tract as the most frequent primary followed by the gastrointestinal system. Primary malignant tumors of the umbilical region are rarely identified in clinical practice.

A Novel Complication of the Dall-Miles Cable Grip System Mimicking Recurrent Synovial Chondromatosis: A Case Report and Review of the Literature.

CASE: A 25-year-old man with synovial chondromatosis of the hip was treated with a synovectomy through a transtrochanteric approach; the repair was made with use of a Dall-Miles cable. Approximately 13 years later, the patient returned with a massive bursal reaction and a cyst containing "rice bodies." Although the physical examination and imaging were suggestive of recurrent synovial chondromatosis, the bursal reaction actually represented a novel complication of the Dall-Miles system. CONCLUSION: When a patient who has had prior orthopaedic instrumentation presents with pain and imaging that demonstrates formation of a bursal cyst, a cyst containing rice bodies secondary to bursal irritation by the implant should be considered.