Mir Alikhan

Discrepant serum and urine β-hCG results due to production of β-hCG by a cribriform-morular variant of thyroid papillary carcinoma.

BACKGROUND Although patients with medullary thyroid cancer are known to present with paraneoplastic hormone production, this is much less common with papillary thyroid cancer. METHODS We present a patient with the cribriform morular variant of papillary thyroid cancer in association with familial adenomatous polyposis who developed a positive pregnancy test in the absence of known pregnancy. The patient had developed vaginal bleeding, and her laboratory testing was characterized by elevated serum human chorionic gonadotropin (β-hCG) concentrations, but negative qualitative urine results. After a thorough gynecological evaluation to exclude unexpected normal, ectopic, or molar pregnancy, we pursued an evaluation for other sources of β-hCG production. RESULTS We showed that the elevated serum β-hCG concentrations were not the result of heterophile antibody interferences, and ultimately we proved that her recurrent tumor produced the ectopic β-hCG. This is the first report of β-hCG production by papillary thyroid cancer. Thus, the possibility of ectopic production of β-hCG by papillary thyroid cancer needs to be included in the differential diagnosis of elevated hCG concentration in the absence of pregnancy. CONCLUSIONS This study of an unusual paraneoplastic syndrome highlights the importance of investigating discrepancies in the clinical laboratory.

Melanotic Translocation Renal Cell Carcinoma With a Novel ARID1B-TFE3 Gene Fusion

A 36-year-old male was found to have a 7.0 cm left upper pole renal mass on renal ultrasound. Following nephrectomy, the mass was grossly ill-demarcated, friable and red-brown, invading renal parenchyma, hilar fat and the renal vein. Microscopically, the tumor had a nested and papillary architecture. The cells demonstrated abundant clear and eosinophilic cytoplasm and focal intracytoplasmic melanin pigment. Nucleoli were prominent. By immunohistochemistry, the tumor was positive for TFE3; HMB-45 stained approximately 5% of tumor cells corresponding to the histologic melanin pigment, which was confirmed with Fontana-Masson stain with bleach. Immunostains for PAX8, CD10, MiTF, and CAIX were negative; keratins Cam 5.2 and AE1/AE3 were focally positive. Targeted next-generation sequencing revealed an ARID1B-TFE3 gene fusion. Melanotic Xp11 renal cell carcinoma is a rare, pigment containing translocation variant demonstrating overlapping features with melanoma and is usually associated with an SFPQ-TFE3 gene fusion. The patient is alive and without evidence of disease 7 years after his diagnosis. The combination of high grade histopathology, the presence of melanin, absent PAX8, keratin positivity, and relatively indolent clinical behavior with a unique translocation may warrant recognition as a distinct renal cell carcinoma translocation subtype.

Melanotic PEComa of the Sinonasal Mucosa With NONO-TFE3 Fusion: An Elusive Mimic of Sinonasal Melanoma

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal tumors with features of both smooth muscle and melanocytic differentiation, with or without true melanin pigment. The highly variable morphology of PEComas results in a broad differential diagnosis that is also dependent on anatomic site. A subset demonstrates rearrangements involving the TFE3 (Xp11) locus, which can be used in diagnostically difficult cases. Here we describe a case of a melanotic PEComa with NONO-TFE3 fusion occurring in the sinonasal mucosa, as demonstrated by both next-generation sequencing and molecular cytogenetic studies. This case is the first of its kind in the literature and only the second documented PEComa harboring a NONO-TFE3 rearrangement. In light of unequivocal molecular ancillary studies, this case illustrates that PEComa must enter the differential for pigmented lesions of the sinonasal mucosa, where malignant melanoma would be much more likely to occur.

Peripheral T-cell lymphomas of follicular helper T-cell type frequently display an aberrant CD3 −/dim CD4 + population by flow cytometry: an important clue to the diagnosis of a Hodgkin lymphoma mimic

Nodal follicular helper T-cell-derived lymphoproliferations (specifically the less common peripheral T-cell lymphomas of follicular type) exhibit a spectrum of histologic features that may mimic reactive hyperplasia or Hodgkin lymphoma. Even though angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma of follicular type share a common biologic origin from follicular helper T-cells and their morphology has been well characterized, flow cytometry of peripheral T-cell lymphomas of follicular type has not been widely discussed as a tool for identifying this reactive hyperplasia/Hodgkin lymphoma mimic. We identified 10 peripheral T-cell lymphomas of follicular type with available flow cytometry data from five different institutions, including two cases with peripheral blood evaluation. For comparison, we examined flow cytometry data for 8 classical Hodgkin lymphomas (including 1 lymphocyte-rich classical Hodgkin lymphoma), 15 nodular lymphocyte predominant Hodgkin lymphomas, 15 angioimmunoblastic T-cell lymphomas, and 26 reactive nodes. Lymph node histology and flow cytometry data were reviewed, specifically for the presence of a CD3−/dimCD4+ aberrant T-cell population (described in angioimmunoblastic T-cell lymphomas), besides other T-cell aberrancies. Nine of 10 (90%) peripheral T-cell lymphomas of follicular type showed a CD3−/dimCD4+ T-cell population constituting 29.3% (range 7.9–62%) of all lymphocytes. Five of 10 (50%) had nodular lymphocyte predominant Hodgkin lymphoma or lymphocyte-rich classical Hodgkin lymphoma-like morphology with scattered Hodgkin-like cells that expressed CD20, CD30, CD15, and MUM1. Three cases had a nodular growth pattern and three others exhibited a perifollicular growth pattern without Hodgkin-like cells. Epstein–Barr virus was positive in 1 of 10 cases (10%). PCR analysis showed clonal T-cell receptor gamma gene rearrangement in all 10 peripheral T-cell lymphomas of follicular type. By flow cytometry, 11 of 15 (73.3%) angioimmunoblastic T-cell lymphomas showed the CD3−/dimCD4+ population (mean: 19.5%, range: 3–71.8%). Using a threshold of 3% for CD3−/dimCD4+ T cells, all 15 nodular lymphocyte predominant Hodgkin lymphoma controls and 8 classical Hodgkin lymphomas were negative (Mann–Whitney P=0.01, F-PTCL vs Hodgkin lymphomas), as were 25 of 26 reactive lymph nodes. The high frequency of CD3−/dimCD4+ aberrant T cells is similar in angioimmunoblastic T-cell lymphomas and peripheral T-cell lymphomas of follicular type, and is a useful feature in distinguishing peripheral T-cell lymphomas of follicular type from morphologic mimics such as reactive hyperplasia or Hodgkin lymphoma.

Morphology and Immunophenotype of Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is an indolent mature B-cell lymphoproliferative disorder that often presents with bone marrow and peripheral blood involvement. Lymphadenopathy and proliferation in extramedullary tissues are often seen. The key to the precise diagnosis of CLL begins with assessment of the cytomorphology of the neoplastic cells, often from peripheral blood, but also the architectural patterns of involvement from tissue sections in bone marrow and lymph node biopsies. Although not 100% sensitive and specific, these morphologic features are strong clues in the broad differential diagnosis. Immunophenotyping complements and aids the morphologic impressions. Although often an indolent disease, some patients tend to have progressive disease and an aggressive clinical course. Staining for CD38 and 70 kD zeta-associated protein (ZAP-70) helps to prognosticate the patient’s disease and predict the tumor’s mutational status for the immunoglobulin heavy-chain, variable region (IGHV). Since defining the disease in the mid-nineteenth century, the workup of CLL now combines multiple disciplines, from basic characterization of morphology to immunophenotyping, and now molecular genetics that all aid in arriving at a precise diagnosis and help to choose the proper therapies for affected patients. In this section, the morphology and immunophenotype of CLL are discussed, with special emphasis on differential diagnosis and transformation (Richter syndrome). The issue of monoclonal B-cell lymphocytosis is also addressed, the criteria and description of which have recently been modified in the new 2016 WHO revision.

Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas with Unique Molecular Signatures

Despite the relatively high prevalence of thyroid cancer, the occurrence of multiple synchronous, distinct subtypes of primary thyroid carcinoma is uncommon. The incidental finding of papillary thyroid microcarcinoma in a gland with a biologically relevant follicular or medullary carcinoma is more frequent than the synchronous occurrence of multiple clinically significant carcinomas. We report a case of synchronous papillary and follicular thyroid carcinomas metastatic to lymph node and bone, respectively. Next generation sequencing showed BRAF V600E mutation in the primary papillary carcinoma and NRAS Q61R mutation in the primary follicular carcinoma and bony metastasis. To our knowledge, this is the first reported case of synchronous and metastatic primary papillary and follicular carcinomas, and the first report of synchronous BRAF V600E mutated papillary and NRAS mutated follicular carcinoma.

Burkitt leukemia limited to the bone marrow has a better prognosis than Burkitt lymphoma with bone marrow involvement in adults

Abstract Burkitt lymphoma patients with bulky disease often have bone marrow involvement. However, leukemic presentation of Burkitt lymphoma in the absence of a mass (pure Burkitt leukemia; PBL) is uncommon. Both PBL and Burkitt lymphoma/leukemia, presenting with a tumor mass and marrow involvement (BLL), are considered stage IV disease, which is associated with a poor prognosis. However, there is limited information on the prognosis in adults with PBL because they have typically been included in cohorts of patients with BLL. This study identified 23 patients, which included 10 PBL and 13 BLL cases. Complex karyotypes (100%) were seen in all BLL cases compared to the PBL group (40%; p = 0.061). Patients with PBL had a significantly better 5-year overall survival of 87.5% vs only 24.3% in the BLL group (p = 0.005). The 5-year overall survival of patients with PBL treated with intensive chemotherapy is superior to those with BLL who are similarly treated.

Cytomegalovirus Infection of Seminal Vesicles.

Cytomegalovirus (CMV) infection is a common pathogen in the immunocompromised patient and usually presents as pneumonitis, enteritis, retinitis, or central nervous system infection. A 56-year-old HIV-positive male was diagnosed with prostatic adenocarcinoma on needle biopsies. He reported long-standing lower urinary tract symptoms that included urgency, nocturia, and weak stream. Medical history included herpes simplex type 1 dermatitis. The radical prostatectomy specimen showed prostatic adenocarcinoma Gleason 7 (3 + 4) with extraprostatic extension. The seminal vesicles and ejaculatory ducts were negative for carcinoma, but showed numerous markedly enlarged cells (Figure 1A) with large intranuclear inclusions indicative of the viral cytopathic changes of CMV (Figure 1B). There was background lymphoplasmacytic inflammation. An immunohistochemical stain for CMV supported the impression of CMV infection (Figure 1C). No involvement of the prostate or prostatic urethra was identified. Although there are reports of CMV prostatitis, none have indicated synchronous involvement of the seminal vesicles. CMV restricted to the seminal vesicles and ejaculatory ducts has not been reported in the English language literature. The significance of this incidental finding in this immunocompromised patient is unknown.