Deborah J. Chute

Cytologic features of parathyroid fine-needle aspiration on ThinPrep preparations: Cytology of Parathyroid FNA on ThinPrep

Previous studies have provided cytologic criteria that aid in the recognition of parathyroid tissue on aspirate smears, including high cellularity, the presence of naked nuclei, loose 2‐dimensional clusters, and papillary architecture. However, to the authors knowledge, the cytomorphologic features of parathyroid fine‐needle aspiration (FNA) on liquid‐based preparations have not been previously described.

Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas

Sinonasal undifferentiated carcinoma (SNUC) is a high‐grade malignancy with limited treatment options and poor outcome. A morphological spectrum of 47 sinonasal tumours including 17 (36.2%) SNUCs was analysed at genomic level. Thirty carcinomas (cohort 1) were subjected to a hybridization exon‐capture next‐generation sequencing assay (MSK‐IMPACTTM) to interrogate somatic variants in 279 or 410 cancer‐related genes. Seventeen sinonasal tumours (cohort 2) were examined only for the presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in two (20%) poorly‐differentiated carcinomas with glandular/acinar differentiation, and in one of two high‐grade neuroendocrine carcinomas, large cell type (HGNECs). No IDH2 mutation was detected in any of five olfactory neuroblastomas or in any of five SMARCB1‐deficient carcinomas. Among 12 IDH2‐mutated cases in cohort 1, five (41.7%) harboured co‐existing TP53 mutations, four (33.3%) CDKN2A/2B loss‐of‐function alterations, four (33.3%) MYC amplification, and three (25%) had concurrent SETD2 mutations. AKT1 E17K and KIT D816V hotspot variants were each detected in one IDH2‐mutated SNUC. The vast majority of SNUCs and variable proportions of other poorly‐differentiated sinonasal carcinomas may be amenable to IDH2‐targeted therapy. Copyright

A Rare Case of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Presenting in the Thyroid Gland

BACKGROUND Lymphoma involving the thyroid gland is rare. Diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma are the two most common histologic subtypes of primary thyroid lymphoma. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) presenting initially as a thyroid abnormality is extremely rare, with very few reported cases in the literature. SUMMARY We report a case of a patient with a long history of Hashimotos thyroiditis and goiter who presented with a recent enlargement of her thyroid gland. The sonographic finding of a distinct thyroid nodule in the heterogeneous background of chronic lymphocytic thyroiditis led to the performance of a fine-needle aspiration biopsy and flow cytometry, with a high index of suspicion for thyroid lymphoma. Subsequent surgical removal of the thyroid gland, prompted by the patients history of head and neck radiation, confirmed the diagnosis of CLL/SLL. The patients systemic illness was recognized only after the management of her thyroid disease. Although thyroiditis has long been associated with lymphoma arising in the thyroid gland, CLL/SLL involving the thyroid has not been linked to chronic lymphocytic thyroiditis. Therefore, the patient also had coexisting thyroiditis. CONCLUSIONS Due to the rarity of thyroid lymphomas, our experience in the detection and management of this disease is limited. Primary thyroid lymphoma should be suspected in a patient with a history of chronic lymphocytic thyroiditis presenting with a rapidly enlarging neck mass. The initial diagnostic method for thyroid lymphoma should consist of a fine-needle aspiration biopsy with the use of ancillary techniques such as flow cytometry and immunohistochemistry for improved diagnostic accuracy. Although controversial, the treatment of thyroid lymphoma is typically guided by the histologic subtype and extent of disease. CLL/SLL is one of the rarest subtypes of lymphoma that can involve the thyroid gland. Diagnosis of this entity is difficult, particularly before the recognition of systemic involvement, requiring the expertise of a multidisciplinary team for early detection and optimal management.

LEF-1 is a Sensitive Marker of Cribriform Morular Variant of Papillary Thyroid Carcinoma

Cribriform morular variant of PTC (CMV-PTC) frequently shows activation of the CTNNB1/Wnt pathway with nuclear accumulation of beta catenin. The utility of LEF-1, also in the CTNNB1/WNT pathway, in the diagnosis of CMV-PTC has not been previously studied. LEF-1 immunohistochemistry was performed on seven CMV-PTC, 52 benign cases and 101 malignant thyroid neoplasms. LEF-1 was scored by stain intensity (0 = no nuclear stain, 1 = weak nuclear stain, less than lymphocyte and 2 = strong nuclear stain, intense as lymphocyte) and percentage of positive cells at each intensity, for a maximum total score of 200. Sensitivity and specificity of LEF-1 stain for all cases and to differentiate between regular PTC and CMV-PTC was also calculated. Six of the seven CMV-PTCs showed ≥ 30% strong (2+) nuclear LEF-1 staining and a total score over 100. Beta catenin also showed strong and diffuse nuclear staining in these cases. One CMV-PTC was negative for both LEF-1 and beta catenin and did not have a history of FAP. All control PTC cases uniformly lacked LEF-1 staining at 2+ intensity. LEF-1 had a sensitivity of 86% and specificity of 98% for the diagnosis of CMV-PTC. LEF-1 is highly sensitive and specific marker for CMV-PTC, especially when used in the setting of a PTC neoplasm. The pattern of staining is important with ≥ 30% of cells showing strong 2+ nuclear staining having the highest combined sensitivity and specificity.

PROGNOSTIC VARIABLES AFFECTING PRIMARY TREATMENT OUTCOME FOR MEDULLARY THYROID CANCER.

OBJECTIVE Identifying prognostic risk factors and determining the efficacy of common surgical treatments is critical to determine optimal treatment strategies for patients with medullary thyroid carcinoma (MTC). The objective of this study was to review a contemporary institutional experience with MTC primary treatment with 2 goals: to identify prognostic factors that impact survival and to study the effect of neck dissection on those outcomes. METHODS This study was a retrospective case series of patients with MTC who underwent at least a total thyroidectomy with curative intent. Clinical parameters including tumor and nodal staging with corresponding pathology findings were identified. Survival endpoints included overall survival, disease-free survival, and biochemical cure. RESULTS Sixty-seven patients were included. The majority presented with early T-stage disease. Fifty (76%) patients were N0 at presentation. Seventeen (24%) had some evidence of neck disease on clinical examination or imaging. Forty (71%) achieved biochemical cure, and the 5-year biochemical recurrence-free survival for those cases was 86.5%. Among patients who had successful resection of all gross disease, 92% had no evidence of structural disease at 5 years. Overall survival was 91% at 5 years. Increased pre-operative calcitonin (Ct) level, primary tumor size, extrathyroidal extension, and neck metastases decrease the rate of biochemical cure. Larger tumor size increases the risk of structural disease recurrence and biochemical relapse after initial cure. The presence and number of neck metastases correlate with biochemical relapse. The presence of lateral neck nodes (pN1b) does not have different survival implications than centrally confined disease (pN1a). CONCLUSION This study shows increasing tumor size, increased Ct level, and cervical metastases are poor prognostic factors. Patients with large tumors, high Ct level, or unfavorable pathologic findings may warrant more aggressive initial treatment, although limitations of the study prevent any conclusion regarding the effect of neck dissection. ABBREVIATIONS ATA = American Thyroid Association BRFS = biochemical recurrence-free survival CND = central neck dissection Ct = calcitonin DFS = disease-free survival MTC = medullary thyroid carcinoma OR = odds ratio OS = overall survival pCND = prophylactic CND.

Unknown primary mucoepidermoid carcinoma: Diagnosis and treatment

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. The majority of MECs occur in major or intraoral minor salivary glands. Herein, we present a case of MEC metastatic to cervical lymph nodes with an unknown primary site and discuss diagnostic and treatment options.

Evaluation of Carcinoma of Unknown Primary on Cytologic Specimens

Carcinoma of unknown primary is defined as metastatic carcinoma without a clinically obvious primary tumor. Determining the tissue of origin in carcinoma of unknown primary is important for site-directed therapy. Immunohistochemistry is the most widely used tool for the work-up of metastases, but molecular profiling assays are also available. This review provides an overview of immunohistochemical stains in the work-up of metastatic carcinoma, with a focus on newer site-specific markers, and discusses the role of gene expression profiling assays for determining tissue of origin. The utility of cytopathology specimens in the evaluation of carcinoma of unknown primary also is highlighted.

The role of a monoclonal antibody 11C8B1 as a diagnostic marker of IDH2 -mutated sinonasal undifferentiated carcinoma

IDH2 R172 mutations occur in >80% sinonasal undifferentiated carcinomas (“SNUC”) and ~80% of these are R172S and R172T variants. We examined the utility of the monoclonal antibody 11C8B1 to IDH2 R172S in IDH2 R172-mutated tumors to establish an immunohistochemistry protocol as a surrogate method for IDH2 R172S mutation detection. Eighty-eight formalin-fixed paraffin-embedded tumors including 42 sinonasal tumors and a variety of IDH1/2-mutated malignancies were tested by immunohistochemistry. The IDH1/2 mutation status was determined in 86 cases by a targeted massively parallel sequencing MSK-IMPACTTM assay. Interestingly, monoclonal antibody 11C8B1 was reactive with all IDH2 R172S (N = 15) mutated tumors including 12 sinonasal carcinomas, 2 high-grade sarcomas and one intrahepatic cholangiocarcinoma, and with all R172T (N = 3) mutated sinonasal carcinomas displaying a distinct granular cytoplasmic labeling in all R172S/T mutated malignancies. 11C8B1 immunohistochemistry was also positive in 2 of 6 IDH1 R132S-mutated tumors, including one intrahepatic cholangiocarcinoma and one chondrosarcoma showing a smooth homogeneous cytoplasmic staining pattern. All IDH2 R172G/K/M/W (N = 22) and IDH1 132H/C/G/L (N = 15) mutated tumors, and all IDH1/2-wild-type tumors (N = 25), including a histologic variety of 23 sinonasal tumors, were immunonegative. Importantly, 11 sinonasal undifferentiated carcinomas (N = 14, 79%) and 3 (100%) high-grade neuroendocrine carcinomas, large cell type were 11C8B1 immunopositive. Literature search revealed a virtual absence of IDH2 R172 and IDH1 R132S mutations in >1000 cases of 8 different malignancies included in the differential diagnosis of sinonasal undifferentiated carcinoma. Our study suggests that positive IDH2 11C8B1 immunohistochemistry in sinonasal carcinomas would be highly predictive of the presence of IDH2 R172S/T mutations and could serve as a reliable adjunct diagnostic marker of sinonasal undifferentiated carcinomas in >70% cases.

Cytologic findings of an adult rhabdomyoma in the parapharyngeal space: A report of a case and review of the literature

Adult extracardiac rhabdomyomas are rare benign mesenchymal tumor arising from skeletal muscle. While they are often located in the larynx and pharynx, the incidence in the parapharyngeal area is extremely rare with only 1 documented cytology case report to date. We report a case of an adult extracardiac rhabdomyoma in the parapharyngeal space diagnosed cytologically with subsequent histologic confirmation. The patient is a 57‐year‐old man with history of weight loss, hematuria, dysphagia, and airway encroachment. Computerized tomography of his abdomen showed a large left renal mass. While the patient was in the operating room for the resection of his renal mass, a fine‐needle aspiration from left the parapharyngeal mass was performed. The smears showed uniform bland polygonal cells with abundant eosinophilic cytoplasm and peripherally located nuclei. Immunohistochemical stains performed on the cell block showed the tumor cells were desmin positive and negative for S‐100 and PAX‐8, supporting the diagnosis of an adult rhabdomyoma. Subsequent resection of the mass confirmed the diagnosis of an adult extracardiac rhabdomyoma.

Barriers to the recognition of medullary thyroid carcinoma on FNA: Implications relevant to the new American Thyroid Association guidelines: Barriers to MTC Recognition on FNA

The 2016 American Thyroid Association guidelines recommend multiple endocrine neoplasia testing and evaluation for pheochromocytoma before thyroidectomy after a thyroid fine‐needle aspiration biopsy (FNA) is positive for medullary thyroid carcinoma (MTC). In the current study, the authors examined the reasons why FNA was unable to definitively diagnose MTC preoperatively, with attention to morphologic patterns that can be misleading.