Deborah J. Chute

Background Nested is defined as “cellular clusters arranged in small groupings with intervening vascular or stromal networks, lacking lumens or glandular formation.” Using this definition, multiple neoplastic and non-neoplastic lesions of the head and neck come into the differential. We have broadly organized the differential diagnosis of “nested” tumors into entities with neuroendocrine differentiation, squamous differentiation, thyroid follicular cell differentiation, and other lesions. Methods Review. Results Many different entities have a nested appearance and the morphologic, immunohistochemical, clinical, and radiographic features contribute to the differential diagnosis. The different tumors covered in this review include neuroendocrine neoplasms, paraganglioma, middle ear neuroendocrine tumor (formerly known as middle ear adenoma), medullary thyroid carcinoma, poorly differentiated thyroid carcinoma, olfactory neuroblastoma, ectopic pituitary neuroendocrine tumor, hyalinizing trabecular tumor, solid subtype of papillary thyroid carcinoma, solid cell nests/C-cell hyperplasia, necrotizing sialometaplasia, and meningioma. Conclusion In this review, we discuss the morphologic and immunohistochemical features of the covered entities as a guide to differential diagnosis when nested-patterned head and neck lesions are encountered.

BACKGROUND. Patients with p16⁺ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16⁺ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16⁺ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability. METHODS. We present a deep-learning–based metric, the multinucleation index (MuNI), for prognostication in p16⁺ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16⁺ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI. RESULTS. The MuNI was prognostic for DFS, overall survival (OS), or distant metastasis–free survival (DMFS) in p16⁺ OPSCC, with HRs of 1.78 (95% CI: 1.37–2.30), 1.94 (1.44–2.60), and 1.88 (1.43–2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately. CONCLUSION. MuNI holds promise as a low-cost, tissue-nondestructive, H&E stain–based digital biomarker test for counseling, treatment, and surveillance of patients with p16⁺ OPSCC. These data support further confirmation of the MuNI in prospective trials. FUNDING. National Cancer Institute (NCI), NIH; National Institute for Biomedical Imaging and Bioengineering, NIH; National Center for Research Resources, NIH; VA Merit Review Award from the US Department of VA Biomedical Laboratory Research and Development Service; US Department of Defense (DOD) Breast Cancer Research Program Breakthrough Level 1 Award; DOD Prostate Cancer Idea Development Award; DOD Lung Cancer Investigator-Initiated Translational Research Award; DOD Peer-Reviewed Cancer Research Program; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award (CTSA) program, Case Western Reserve University; NCI Cancer Center Support Grant, NIH; Career Development Award from the US Department of VA Clinical Sciences Research and Development Program; Dan L. Duncan Comprehensive Cancer Center Support Grant, NIH; and Computational Genomic Epidemiology of Cancer Program, Case Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of VA, the DOD, or the US Government.

Objectives: Fine-needle aspiration (FNA) of thyroid bed lesions after thyroidectomy is challenging to evaluate. We determined the sensitivity, specificity, and positive and negative predicative value of thyroid bed FNA (TB-FNA) for detecting local recurrence of thyroid carcinoma. Methods: A retrospective search was conducted for TB-FNAs from patients with a prior thyroid resection and subsequent ipsilateral FNA from the thyroid bed. Clinical and pathologic data were retrieved from the medical record. Patients were ultimately classified as “malignant” or “benign” based on the worst pathology identified and follow-up available. Results: Forty-two cases were included, and the prior thyroidectomy pathology included 36 papillary thyroid carcinomas, two follicular carcinomas, one medullary carcinoma, and three benign cases. TB-FNA was adequate in 38 (90.5%) cases and interpreted as positive for malignancy (n = 22; 52.4%), suspicious for follicular neoplasm (n = 3; 7.1%), atypia of unknown significance (n = 2; 4.8%), and benign (n = 10; 23.8%). Twenty-seven patients had histologic follow-up, and 24 (87.5%) showed recurrent malignancy. The cytology sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 96%, 100%, 100%, 92.3%, and 97.4%, respectively, for identification of recurrent malignancy. Conclusions: Most TB-FNA cases ultimately were diagnosed with malignancy on follow-up, although there may be sampling bias, as not all clinically benign cases had surgical follow-up.

BACKGROUND: 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.METHODS: Cases of MTC diagnosed on thyroid surgical resection for which there was a prior FNA and slides available for review were included (28 cases). Clinicopathologic data were collected. Slides were reviewed for numerous features blinded to the original FNA interpretation. Morphologic features were compared between concordant cases (20 cases) (“positive for MTC” or “suspicious for MTC”) and discordant cases (4 cases) (any other interpretation). Three cases of microscopic MTC (measuring Cancer Cytopathol 2018;126:397‐405. © 2018 American Cancer Society.

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.

CMYC regulates approximately 15% of human genes and is involved in up to 20% of all human cancers. Reports discussing cMYC protein expression in thyroid carcinomas are limited, with controversies pertaining to cMYC expression patterns noted in the literature. The aims of the current study were to clarify patterns and intensities of cMYC expression in follicular cell-derived thyroid carcinomas across a spectrum of cancer morphologies and disease aggressivities, to correlate cMYC with BRAFV600E expression, and to evaluate the potential role of cMYC in progression of well-differentiated thyroid carcinomas into less well-differentiated carcinomas. Immunohistochemical studies using specific monoclonal antibodies for cMYC and BRAFV600E were performed on tissue microarrays built from follicular cell-derived thyroid carcinomas (25 papillary, 24 follicular, 24 oncocytic variant of follicular, and 21 undifferentiated). In addition, cMYC IHC testing was also performed on whole tissue tumor sections from a subset of patients. Nodular hyperplasia cases were used as non-neoplastic controls. Appropriate positive and negative controls were included. cMYC was expressed almost exclusively in a nuclear fashion in both thyroid carcinomas and nodular hyperplasias. cMYC expression was weakly positive in both nodular hyperplasias and well-differentiated carcinomas. The majority of undifferentiated carcinomas (UDCs) showed strong nuclear cMYC positivity. PTC cases that were positive for cMYC (6/25) harbored the BRAF V600E mutation. A correlation was confirmed between cMYC intensity and tumor size in UDCs. UDC cases that developed out of well-differentiated thyroid carcinomas showed frank overexpression of cMYC in the undifferentiated tumor components. Our study suggests that nuclear overexpression of cMYC correlates with tumorigenesis / dedifferentiation in follicular cell derived thyroid carcinomas, a concept that has not been shown before on whole tissue sections.

Malignant mesothelioma (MM) is a rare neoplasm, which is most commonly encountered in cytology through effusion specimens. Fine needle aspiration biopsy of MM, particularly the epithelioid subtype, can be a source of diagnostic difficulty and may mimic sampling of an adenocarcinoma. This is the first case report to demonstrate abundant extracellular myxoid material and numerous intracellular vacuoles, including signet ring cells, in a fine needle aspirate of metastatic MM. A review of the literature for myxoid change and vacuoles in fine needle aspiration biopsies of MM discloses that vacuoles are found in up to 35% of aspirates of MM, but myxoid change is very rare, reported in