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Standardized pathologic reporting for cancers improves patient care and prognostic determination. However, access in many countries is limited. To address this issue, the International Collaboration on Cancer Reporting (ICCR), a not-for-profit organization, has the mission to develop and disseminate standardized data sets for global use. Within endocrine organs, the parathyroid gland has rarely been included in formal pathologic data sets. Utilizing an expert international panel of eleven members, an evidence-based data set was developed for parathyroid carcinoma and atypical parathyroid neoplasms. This data set consists of sixteen core (required) elements viewed as essential for documentation of these conditions. Characterizing parathyroid carcinomas and atypical neoplasms begins with correlative clinical information, the operative procedure, specimens submitted, and site of the disease. The pathologic features essential to document include parathyroid weight, size, classification, and, when a carcinoma, the tumor grade. Histologic grade of parathyroid carcinoma incorporates other core elements including necrosis, mitotic count, perineural invasion, and lymphovascular invasion. Documenting the extent of disease locally into adjacent organs, regionally, and distally is critical for staging. Pathologic staging is now included as part of the American Joint Committee on Cancer 8th edition and is included in this data set. Ancillary studies should be recorded when performed as noncore elements. Standardized pathologic data sets for endocrine organs including the parathyroid gland are now available through the ICCR website. These essential resources enhance international standardization for documenting these rare tumors for both patient care and future guidelines.

Successful BRAF inhibitor therapy depends on the accurate assessment of the mutation status of the BRAF V600 residue in tissue samples. In melanoma, immunohistochemical (IHC) analysis with monoclonal anti-BRAF V600E has emerged as a sensitive and specific surrogate of BRAF V600E mutation, particularly when BRAF V600E protein expression is homogeneous and strong. A subset of melanomas exhibit heterogeneous labeling for BRAF V600E, but our understanding of the significance of heterogeneous BRAF V600E IHC expression is limited. We used next-generation sequencing to compare BRAF V600E IHC staining patterns in 154 melanomas: 79 BRAF(WT) and 75 BRAF (including 53 V600E) mutants. Agreement among dermatopathologists on tumor morphology, IHC expression, and intensity was excellent (ρ = 0.99). A predominantly epithelioid cell phenotype significantly correlated with the BRAF V600E mutation (P = .0085). Tumors demonstrating either heterogeneous or homogeneous IHC expression were significantly associated with the BRAF V600E mutation (P < .0001), as was increased intensity of staining (P < .0001). The positive predictive value was 98% for homogenous IHC expression compared with 70% for heterogeneous labeling. Inclusion of both heterogeneous and homogeneous BRAF V600E IHC expression as a positive test significantly improved IHC test sensitivity from 85% to 98%. However, this reduced BRAF V600E IHC test specificity from 99% to 96%. Cautious evaluation of heterogeneous BRAF V600E IHC expression is warranted and comparison with sequencing results is critical, given its reduced test specificity and positive predictive value for detecting the BRAF V600E mutation.

Primary lingual adenocarcinomas are rare and typically of salivary or seromucinous glands origin. Similarly, metastatic adenocarcinoma from distant primary sites to the tongue is an uncommon event, with only three cases from a colonic primary site reported. We present, for the first time, two primary colonic-type adenocarcinomas of the base of the tongue and discuss their putative origin and the clinicopathologic characteristics.

Anaplastic thyroid carcinoma is a rare and universally fatal disease. Therefore, novel biomarkers are needed as surrogate end points in triaging patients for novel and selective biologic treatments. Up-regulation of several growth factor receptors has been shown to be associated with the biologic progression and response to targeted therapy of several malignancies. To determine the role of growth factor receptors in the biologic stratification of anaplastic thyroid carcinoma, we studied the expression of epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor beta, and HER-2 receptor in a large cohort of anaplastic thyroid carcinomas by immunohistochemical techniques. The percentage of positive cells, staining intensity and localization of staining in the anaplastic component, and coexisting well-differentiated thyroid carcinoma and adjacent nonneoplastic thyroid were evaluated for these markers. EGFR, platelet-derived growth factor receptor beta, and HER-2 were overexpressed in 58%, 16%, and 16% of anaplastic carcinomas, respectively. In tumors with adjacent normal thyroid parenchyma and/or differentiated carcinoma components, overexpression of all 3 markers was noted exclusively in the anaplastic component. Mutational analysis of exons 18, 19, and 21 of the EGFR gene showed no mutations in all anaplastic carcinomas. We conclude that the expression of these markers (1) may play a role in a subset of thyroid tumorigenesis and anaplastic transformation and (2) can be validated for potential use in the stratification of patients for targeted therapy.

The classification of follicular thyroid neoplasms requires surgical resection for histologic evaluation of malignancy. Because variable clinical behavior exists, genomic expression profiling may lead to the identification of novel markers that facilitate better biologic classification. We performed for the first time gene expression analysis on clinically aggressive and nonaggressive follicular carcinomas (FCs) from patients for whom long-term follow-up data were available. We examined matched fresh-frozen tissue from 15 histopathologically diagnosed follicular carcinomas (7 patients with documented distant metastasis and/or death from disease and 8 patients without recurrence). For categorical comparison, we analyzed 4 follicular adenomas (FAs). The biologic control comprised 11 normal thyroid tissue specimens. High-quality RNA was extracted from the tissues, labeled, and hybridized to an Affymetrix (Santa Clara, CA) oligonucleotide microarray (HG-U133A). With the exceptions of 1 follicular adenoma and 1 follicular carcinoma, unsupervised hierarchical cluster analysis revealed 2 distinct groups--one containing normal thyroid tissue and follicular adenomas and another containing follicular carcinomas. We identified 421 genes that were differentially expressed between histologically normal thyroid tissues and all follicular neoplasms (P0.01; fold-change2), 94 genes that distinguished follicular carcinomas from follicular adenomas (including PBP and CKS2), and 4 genes that distinguished aggressive follicular carcinomas from nonaggressive follicular carcinomas (NID2, TM7SF2, TRIM2, and GLTSCR2). Comparative genomic groupings identified differentially expressed genes that may lead to better classification of follicular thyroid neoplasms. Such genes may be used in future prospective validation studies to establish clinically useful and complementary diagnostic markers.

Primary poorly differentiated (small round and non-small) sinonasal neoplasms comprise histogenetically and biologically diverse entities with overlapping morphologic features. Because of the limited initial biopsy tissue materials, differential diagnostic difficulties may arise and complicate timely management of some cases. We used immunohistochemical and molecular marker analyses in a large cohort of these tumors to optimize their early diagnosis and classification. Fifty-two tumors of the skull base and sinonasal regions and, for comparison, 19 poorly differentiated neoplasms of other head and neck sites were analyzed by a panel of immunohistochemical markers including those of epithelial, mesenchymal, melanocytic, and neuroectodermal origin using tissue microarray. Reverse transcriptase-polymerase chain reaction analysis of messenger RNA for EWS-FLI1 and PAX-FKHR fusion transcripts and the human achaete-scute homolog-1 gene was performed on 24 of the 52 sinonasal tumors and the 19 tumors of other sites for comparison. The immunohistochemical results substantiated the phenotypic assessment and the initial diagnosis in 49 of the 52 tumors. In 4 instances the integrated markers and phenotypic analyses led to reclassification of 3 tumors and confirmed the histogenesis of a mesenchymal tumor with aberrant cytokeratin expression. Molecular analysis of the EWS-FLI1 fusion gene transcript revealed 4 (9.3%) of the 43 tumors to be positive; all were Ewing sarcomas. The human achaete-scute homolog-1 gene transcript was identified in 10 (23.8%) of 42 tumors: 3 of 6 neuroblastomas, all 4 neuroendocrine carcinomas, and 1 each in sinonasal undifferentiated carcinoma, rhabdomyosarcoma, and melanoma. The PAX-FKHR fusion transcript was not detected in any tumors. We conclude that (1) an integrated morphologic and biomarker algorithm may better optimize the early diagnosis of poorly differentiated sinonasal and skull-base tumors; (2) molecular analysis may assist in future biological stratification of certain classes of these tumors; and (3) the human achaete-scute homolog-1 gene transcript is a nonspecific marker for the diagnosis of neuroblastoma.

To determine the association between the expression of p63 gene isoforms (TA and DeltaN) and salivary gland tumorigenesis, we performed reverse transcription-polymerase chain reaction analysis of these markers in 71 benign and malignant salivary gland neoplasms. The results were correlated with the expression of Notch ligand JAG1 gene and the clinicopathologic features and the full-length p63 protein expression by immunohistochemistry. Both p63 isoforms were either negative or weakly expressed in normal salivary gland tissues. TAp63 was highly expressed in most benign tumors and was either negative or weakly positive in most carcinomas. Conversely, DeltaNp63 was negative or faintly positive in most benign neoplasms and was highly expressed in adenoid cystic, mucoepidermoid, and myoepithelial carcinomas. Immunohistochemical analysis using anti-full-length p63 protein showed ubiquitous nuclear staining in basal and myoepithelial cells in both benign and malignant neoplasms. JAG1 was expressed in most benign and malignant tumors and did not correlate with p63 isoforms expression. We conclude that (1) p63 isoforms are differentially expressed in most benign and malignant tumors and may play distinct biological roles in certain salivary gland neoplasms; (2) p63 immunostaining do not correlate with the isoforms expression; and (3) isoform-specific antibodies are required for better cellular localization and biological correlations.

Most hospitals microscopically examine all routine tonsil and adenoid specimens from healthy pediatric patients with recurrent infections or obstructive sleep apnea. Concern over missing the rare unsuspected, significant diagnosis propagates this practice. Careful gross examination for asymmetry and clinical findings should obviate the need for routine microscopic examination of tonsil and adenoid specimens in patients age 21 years and younger. A retrospective study was conducted using the SNOMED database of 4070 patients age 21 years or younger who underwent tonsillectomy and/or adenoidectomy between 1970 and July 2001 at the University of Florida. The age distribution of the study group was 0 to 5 years (52%), 6 to 12 years (37%), and 13 to 21 years (11%). Specimens consisted of tonsils only (15%), tonsils and adenoids (40%), and adenoids only (45%). Clinically significant diagnoses were diagnoses that impacted the care of patients and included malignancies and some infections. Non-clinically significant diagnoses included normal, acute or chronic tonsillitis, and tonsillar hyperplasia. Clinically significant pathological processes were seen in the tonsil or adenoid specimens of 3 of the 4070 patients. These 3 cases included a 2-year-old male with Burkitt's lymphoma, a 19-year-old male with non-Hodgkin's lymphoma (small noncleaved cell, non-Burkitt's type), and an 11-year-old male with a probable viral process but in whom a lymphoma could not be absolutely excluded. All 3 of these patients had signs and symptoms, including significant cervical lymphadenopathy, meriting microscopic analysis of the specimens. In conclusion, microscopic examination of all routine tonsils and adenoids for individuals 21 years or younger is not indicated. Gross examination is still recommended. Clinical suspicion and specimen asymmetry should be used to determine when thorough histological examination is merited.