Clinical course of atypical parathyroid neoplasm with soft tissue extension.

BACKGROUND AND OBJECTIVES: The American Joint Committee on Cancer (AJCC) TNM staging system defines atypical parathyroid neoplasia (APN) as tumor in situ (Tis) and reserves the definition of parathyroid carcinoma (PC) to parathyroid tumor with invasion into surrounding structures. Because the parathyroid gland has no true capsule, "extension" with APN versus microscopic "invasion" of surrounding soft tissue can be difficult and confusing for clinicians. We aimed to determine the clinical course of atypical parathyroid neoplasm with and without soft tissue extension and parathyroid carcinoma with only soft tissue invasion (pT1) and to report the outcomes. METHODS: Following an IRB-approved protocol, we identified all patients treated for parathyroid neoplasm or cancer at our single tertiary care cancer center from 1990 to 2021. We excluded all patients with evidence of clinical or pathologic gross invasion into surrounding structures (pT2 or higher), lymph node involvement, or metastatic disease. By definition, this excluded all cases where the distinction was clinically evident to the surgeon at the time of the operation based on finding a hard, firm, sticky, or discolored parathyroid gland. Only patients with pathologic T1 (pT1) parathyroid carcinoma or APN were included. All pathologic examinations were independently re-reviewed by a single designated expert senior endocrine pathologist. The definition of APN strictly followed the WHO definition of a clinically worrisome lesion having features including fibrous bands or increased mitotic rate, necrosis, or trabecular growth that did not meet robust criteria for frank invasion. Pathologic T1 disease was defined as invasion limited to soft tissue. Analyses were performed using R version 4.0.2 and Jamovi. RESULTS: Of all PC patients at our institution, only 71 met the strict inclusion criteria of APN or pT1. Forty-four patients had pT1 disease and 27 had APN: 12 of the APN had soft tissue extension, and 15 had no soft tissue extension. The groups were similar with regard to age at diagnosis (p = 0.328). The average follow-up duration was 84 months from initial surgical intervention. Of the 12 with APN, one patient (1/12; 8%) with soft tissue extension recurred, developed distant metastases, and subsequently died during follow up. Of the 44 patients with pT1 PC, six developed distant metastases and 13 (13/44; 30%) died during the follow-up period. One patient with APN and soft tissue extension recurred and died and no patient with APN and no soft tissue extension died. CONCLUSIONS: Patients with APN and extension into soft tissue have a clinical course similar to that of APN without soft tissue extension. APN with soft tissue extension is a different disease from pT1 disease with invasion of soft tissue. The pTis classification appears justified for APN with and without soft tissue extension.

Deep learning extended depth-of-field microscope for fast and slide-free histology.

Microscopic evaluation of resected tissue plays a central role in the surgical management of cancer. Because optical microscopes have a limited depth-of-field (DOF), resected tissue is either frozen or preserved with chemical fixatives, sliced into thin sections placed on microscope slides, stained, and imaged to determine whether surgical margins are free of tumor cells-a costly and time- and labor-intensive procedure. Here, we introduce a deep-learning extended DOF (DeepDOF) microscope to quickly image large areas of freshly resected tissue to provide histologic-quality images of surgical margins without physical sectioning. The DeepDOF microscope consists of a conventional fluorescence microscope with the simple addition of an inexpensive (less than $10) phase mask inserted in the pupil plane to encode the light field and enhance the depth-invariance of the point-spread function. When used with a jointly optimized image-reconstruction algorithm, diffraction-limited optical performance to resolve subcellular features can be maintained while significantly extending the DOF (200 µm). Data from resected oral surgical specimens show that the DeepDOF microscope can consistently visualize nuclear morphology and other important diagnostic features across highly irregular resected tissue surfaces without serial refocusing. With the capability to quickly scan intact samples with subcellular detail, the DeepDOF microscope can improve tissue sampling during intraoperative tumor-margin assessment, while offering an affordable tool to provide histological information from resected tissue specimens in resource-limited settings.

Emerging Entities and New Diagnostic Markers for Head and Neck Soft Tissue and Bone Tumors.

Bone and soft tissue tumors of the head and neck are relatively uncommon tumors that often represent a diagnostic challenge because of the wide range of entities that must be considered in the differential diagnosis. Over the past few years, classification of bone and soft tissue tumors has evolved primarily because of substantial contributions from molecular genetics, with the identification of new markers that are increasingly used to complement histopathologic findings in the routine diagnostic workup. This review focuses on the recently described mesenchymal tumors that preferentially involve the head and neck region, with a focus on the most relevant novel immunohistochemical and molecular findings, including gene fusions and mutations, that can help in the diagnosis and in the assessment of clinical behavior.

Risk of Distant Metastasis in Parathyroid Carcinoma and Its Effect on Survival: A Retrospective Review from a High-Volume Center.

BACKGROUND: Development of distant metastases (DM) is associated with markedly decreased survival in parathyroid carcinoma (PC). We sought to identify factors associated with development of DM and to quantify the effect that development of DM had on overall survival (OS). METHODS: Patients with surgically resected local/regional PC treated or surveilled at a tertiary-referral cancer hospital from 1980 to 2017 were included. We assessed the association between biochemical and clinicopathologic factors (preoperative parathyroid hormone (PTH) levels, sex, race, age, preoperative serum calcium levels, serum calcium levels at 6 months postop, tumor size, and extent of resection) with the development of DM. We also assessed the effect of development of DM on OS. RESULTS: Seventy-five patients with PC were assessed; 17 (22.7%) developed DM at a median follow-up of 77 months. The cumulative incidence of DM in the cohort was 20, 30, and 38% at 5, 10, and 20 years respectively. Tumor size > 3.2 cm based on recursive partitioning analysis was the only significant predictor for development of DM (hazard ratio (HR) = 3.51; 95% confidence interval [CI] 1.04-11.91; p = 0.04). Median OS for the entire cohort was 17 years compared with 40 months for the cohort who developed DM. The HR for death after distant metastasis was 9.6 (95% CI 4.2-22.3; p < 0.0001). CONCLUSIONS: Development of distant metastasis during surveillance is associated with decreased OS, including late recurrences. Primary tumor size should be considered in future interval surveillance and development of treatment algorithms.

Extrathyroidal Extension: Does Strap Muscle Invasion Alone Influence Recurrence and Survival in Patients with Differentiated Thyroid Cancer?

BACKGROUND: According to the 8th edition American Joint Committee on Cancer staging system, extrathyroidal extension (ETE) and primary tumor size remain the principle determinants of T stage. However, impact of gross ETE into strap muscles on survival remains controversial. PATIENTS AND METHODS: A retrospective review of 2084 patients with ≤ 4 cm nonmetastatic differentiated thyroid cancer who underwent surgery between 2000 and 2015 was conducted. Patients were divided into three groups according to degree of ETE: no ETE (group 1), ETE into perithyroidal soft tissue (group 2), and gross ETE into strap muscle (group 3). Survivals were analyzed using Kaplan-Meier method and compared using log-rank test. Factors predictive of survival were analyzed using Cox proportional hazard model. RESULTS: Ten-year disease-free survival (DFS) of patients in groups 1-3 was 90, 82, and 83%, respectively (p = 0.003). On multivariate analysis, age ≥ 55 years, male sex, and pathologic N1b category predicted significantly worse DFS, while ETE into perithyroidal soft tissue or gross strap muscle invasion did not predict worse DFS. Overall survival (p = 0.957) and disease-specific survival (p =0.910) were not significantly different between the three groups. There was a statistically significant difference in locoregional recurrence-free survival between groups 1 and 2 [HR 2.02, 95% CI 1.06-3.94]. CONCLUSION: Gross strap muscle invasion may not be an important survival prognostic factor for staging purposes. Although both gross strap muscle invasion and perithyroidal soft tissue extension may be predictive for locoregional recurrence, the distinction between them may not be as important for postoperative risk stratification.

Molecular markers in well-differentiated thyroid cancer.

PURPOSE: Thyroid nodules are of common occurrence in the general population. About a fourth of these nodules are indeterminate on aspiration cytology placing many a patient at risk of unwanted surgery. The purpose of this review is to discuss various molecular markers described to date and place their role in proper perspective. This review covers the fundamental role of the signaling pathways and genetic changes involved in thyroid carcinogenesis. The current literature on the prognostic significance of these markers is also described. METHODS: PubMed was used to search relevant articles. The key terms "thyroid nodules", "thyroid cancer papillary", "carcinoma papillary follicular", "carcinoma papillary", "adenocarcinoma follicular" were searched in MeSH, and "molecular markers", "molecular testing", mutation, BRAF, RAS, RET/PTC, PAX 8, miRNA, NIFTP in title and abstract fields. Multiple combinations were done and a group of experts in the subject from the International Head and Neck Scientific Group extracted the relevant articles and formulated the review. RESULTS: There has been considerable progress in the understanding of thyroid carcinogenesis and the emergence of numerous molecular markers in the recent years with potential to be used in the diagnostic algorithm of these nodules. However, their precise role in routine clinical practice continues to be a contentious issue. Majority of the studies in this context are retrospective and impact of these mutations is not independent of other prognostic factors making the interpretation difficult. CONCLUSION: The prevalence of these mutations in thyroid nodule is high and it is a continuously evolving field. Clinicians should stay informed as recommendation on the use of these markers is expected to evolve.

Radiation therapy dose is associated with improved survival for unresected anaplastic thyroid carcinoma: Outcomes from the National Cancer Data Base.

BACKGROUND: The outcomes of patients with unresected anaplastic thyroid carcinoma (ATC) from the National Cancer Data Base (NCDB) were assessed, and potential correlations were explored between radiation therapy (RT) dose and overall survival (OS). METHODS: The study cohort was comprised of patients who underwent either no surgery or grossly incomplete resection. Correlates of OS were explored using univariate analysis and multivariable analysis (MVA). RESULTS: In total, 1288 patients were analyzed. The mean patient age was 70.2 years, 59.7% of patients were women, and 47.6% received neck RT. The median OS was 2.27 months, and 11% of patients remained alive at 1 year. A positive RT dose-survival correlation was observed for the entire study cohort, for those who received systemic therapy, and for those with stage IVA/IVB and IVC disease. On MVA, older age (hazard ratio [HR], 1.317; 95% confidence interval [CI], 1.137-1.526), ≥ 1 comorbidity (HR, 1.587; 95% CI, 1.379-1.827), distant metastasis (HR, 1.385; 95% CI, 1.216-1.578), receipt of systemic therapy (HR, 0.637; 95% CI, 0.547-0.742), and receipt of RT compared with no RT (<45 grays [Gy]:HR, 0.843; 95% CI, 0.718-0.988; 45-59.9 Gy: HR, 0.596; 95% CI, 0.479-0.743; 60-75 Gy: HR, 0.419; 95% CI, 0.339-0.517) correlated with OS. The RT dose-survival correlation for patients who received higher (60-75 Gy) versus lower (45-59.9 Gy) therapeutic doses was confirmed by propensity-score matching. CONCLUSIONS: Survival was poor in this cohort of patients with unresected ATC, and more effective therapies are needed. However, the association of RT dose with OS highlights the importance of identifying patients with unresected ATC who may still yet benefit from multimodal locoregional treatment that incorporates higher dose RT. Cancer 2017;123:1653-1661. © 2017 American Cancer Society.

How phenotype guides management of non-conventional squamous cell carcinomas of the larynx?

Although the majority of laryngeal malignancies are the conventional squamous cell carcinomas (SCC), a wide variety of malignant epithelial tumors can affect the larynx. Current treatment guidelines are designed to guide clinicians in management of conventional laryngeal SCC. Less is known about the biological behavior and responsiveness to therapy and overall outcomes of other malignant epithelial lesions. Because a spectrum of disease biology is represented by these rare phenotypes, an understanding of the basic biology can help direct management to optimize clinical outcome in this group of patients. This review provides a critical analysis of literature relating to the diagnosis, management, and outcome of patients with non-conventional squamous malignant epithelial neoplasms of the larynx. Particular attention is paid to features which are at variance with the conventional SCC and how these impact on management of these rare tumors.

A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis.

The RET proto-oncogene, a tyrosine kinase receptor, is widely known for its essential role in cell survival. Germ line missense mutations, which give rise to constitutively active oncogenic RET, were found to cause multiple endocrine neoplasia type 2, a dominant inherited cancer syndrome that affects neuroendocrine organs. However, the mechanisms by which RET promotes cell survival and prevents cell death remain elusive. We demonstrate that in addition to cytoplasmic localization, RET is localized in the nucleus and functions as a tyrosine-threonine dual specificity kinase. Knockdown of RET by shRNA in medullary thyroid cancer-derived cells stimulated expression of activating transcription factor 4 (ATF4), a master transcription factor for stress-induced apoptosis, through activation of its target proapoptotic genes NOXA and PUMA. RET knockdown also increased sensitivity to cisplatin-induced apoptosis. We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. Moreover, chromatin immunoprecipitation assays revealed that ATF4 occupancy increased at the NOXA promoter in TT cells treated with tyrosine kinase inhibitors or the ATF4 inducer eeyarestatin as well as in RET-depleted TT cells. Together these findings reveal RET as a novel dual kinase with nuclear localization and provide mechanisms by which RET represses the proapoptotic genes through direct interaction with and phosphorylation-dependent inactivation of ATF4 during the pathogenesis of medullary thyroid cancer.

Uveal melanoma: From diagnosis to treatment and the science in between.

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.

Differentiating Atypical Parathyroid Neoplasm from Parathyroid Cancer.

INTRODUCTION: The differentiation of benign parathyroid gland atypia and true parathyroid carcinoma (PC) can be challenging. In some instances, patients are classified as having 'atypical parathyroid neoplasms' (APNs), explicitly acknowledging that the distinction between benign and malignant disease appears impossible to determine. This 'grey area' diagnosis makes rendering an accurate prognosis difficult, and clouds clinical management and treatment planning. METHODS: We performed a retrospective chart review of all patients undergoing operation for primary hyperparathyroidism in our institution (2000-2014). Patients with a histopathological diagnosis of PC or APN were included. Demographics, clinical characteristics, and survival rates were analyzed, and analysis was conducted using SAS 9.4 (SAS Institute, Inc., Cary, NC, USA). RESULTS: Fifty-four patients were included in the study-31 (57.41 %) with PC and 23 (42.59 %) with APN. PC versus APN was associated with higher parathyroid hormone (PTH) (p = 0.005) and with males (p = 0.002). Five-year overall survival (OS) from diagnosis was 82.64 % [95 % confidence interval (CI) 59.82-93.17] for the PC group and 93.33 % (95 % CI 61.26-99.03) for the APN group, while the 5-year recurrence-free survival rate was 59.63 % (95 % CI 36.32-76.81) in the PC group and 90.91 % (95 % CI 50.81-98.67) in the APN group. CONCLUSION: PC and APN are distinct clinical entities with differences in tumor biology reflected in overall recurrence rates, disease-free survival, and OS. APNs present with a less accentuated biochemical profile and demonstrate an indolent clinical course compared with PCs. Efforts to improve categorization and staging of PC and APN are needed.

Oncologic progress for the treatment of parathyroid carcinoma is needed.

BACKGROUND AND OBJECTIVES: Parathyroid carcinoma (PC) is rare but potentially lethal. No standardized staging system or treatment guidelines have been established. We aimed to determine whether management of PC and patient outcomes have changed at our institution over the past 35 years. METHODS: Retrospective review of patients with PC at our institution between 1980 and 2015. Patients were grouped by date of initial surgery: group 1, 1980-2001; group 2, 2002-2015. RESULTS: About 57 patients (26 in group 1; 31 in group 2) were included. Group 2 had more female patients (61%) than group 1 (31%; P = 0.033). Patients in group 2 were older at the time of initial operation (mean age 48 years in group 1 (SD:14.3) and 56 years (SD:14.6) in group 2; P = 0.034). The 5-year OS rates were 82% (95%CI 59.6%, 93%) for group 1 and 72% (95%CI 45.0%, 87.7%) for group 2. The 5-year DFS rates were 62% (95%CI 36.4%, 79.9%) for group 1 and 66% (95%CI 40.6%, 82.2%) for group 2. CONCLUSION: Management of PC and patient outcomes (OS and DFS) have not significantly changed over the past 35 years at our institution. This rare malignancy needs oncologic improvement. J. Surg. Oncol. 2016;114:708-713. © 2016 Wiley Periodicals, Inc.

Determining Adequate Margins in Head and Neck Cancers: Practice and Continued Challenges.

Margin assessment remains a critical component of oncologic care for head and neck cancer patients. As an integrated team, both surgeons and pathologists work together to assess margins in these complex patients. Differences in method of margin sampling can impact obtainable information and effect outcomes. Additionally, what distance is an "adequate or clear" margin for patient care continues to be debated. Ultimately, future studies and potentially secondary modalities to augment pathologic assessment of margin assessment (i.e., in situ imaging or molecular assessment) may enhance local control in head and neck cancer patients.

Paraneoplastic syndromes in patients with laryngeal neuroendocrine carcinomas: clinical manifestations and prognostic significance.

Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the larynx. There are a total of ten patients reported with paraneoplastic syndromes associated with laryngeal neuroendocrine carcinomas in the literature. Of these, nine died and the tenth is alive with liver metastases. There were five cases of small-cell neuroendocrine carcinoma, four cases of moderately differentiated neuroendocrine carcinoma, and one case of well-differentiated neuroendocrine carcinoma associated with paraneoplastic syndromes. As these syndromes have significant clinical relevance, physicians should be aware of the possible presence of paraneoplastic syndromes in the diagnostic process of patients with neuroendocrine carcinoma of the larynx.

Incidental findings of thyroid tissue in cervical lymph nodes: old controversy not yet resolved?

The clinical significance of papillary or follicular thyroid tissue incidentally discovered in cervical lymph nodes during pathological assessment of neck dissections for non-thyroid cancers of the upper aero-digestive tract is critically reviewed. Special emphasis is given to controversies over normal-looking, nodal, thyroid follicles. Arguments for and against the benign nature of these follicles are considered together with processes that could be involved in their formation. The admittedly limited evidence suggests that benign, thyroid follicular inclusions rarely occur in cervical lymph nodes. Histological criteria that could be helpful in recognizing the inclusions, which include assessing their extent in conjunction with the size of the node, are discussed. Finally, an algorithm based on collaboration between specialists, correlating histological findings with imaging and loco-regional control of the upper aero-digestive tract cancer, is suggested for the management of patients with incidentally discovered, nodal thyroid tissue.

Landscape of DNA virus associations across human malignant cancers: analysis of 3,775 cases using RNA-Seq.

Elucidation of tumor-DNA virus associations in many cancer types has enhanced our knowledge of fundamental oncogenesis mechanisms and provided a basis for cancer prevention initiatives. RNA-Seq is a novel tool to comprehensively assess such associations. We interrogated RNA-Seq data from 3,775 malignant neoplasms in The Cancer Genome Atlas database for the presence of viral sequences. Viral integration sites were also detected in expressed transcripts using a novel approach. The detection capacity of RNA-Seq was compared to available clinical laboratory data. Human papillomavirus (HPV) transcripts were detected using RNA-Seq analysis in head-and-neck squamous cell carcinoma, uterine endometrioid carcinoma, and squamous cell carcinoma of the lung. Detection of HPV by RNA-Seq correlated with detection by in situ hybridization and immunohistochemistry in squamous cell carcinoma tumors of the head and neck. Hepatitis B virus and Epstein-Barr virus (EBV) were detected using RNA-Seq in hepatocellular carcinoma and gastric carcinoma tumors, respectively. Integration sites of viral genes and oncogenes were detected in cancers harboring HPV or hepatitis B virus but not in EBV-positive gastric carcinoma. Integration sites of expressed viral transcripts frequently involved known coding areas of the host genome. No DNA virus transcripts were detected in acute myeloid leukemia, cutaneous melanoma, low- and high-grade gliomas of the brain, and adenocarcinomas of the breast, colon and rectum, lung, prostate, ovary, kidney, and thyroid. In conclusion, this study provides a large-scale overview of the landscape of DNA viruses in human malignant cancers. While further validation is necessary for specific cancer types, our findings highlight the utility of RNA-Seq in detecting tumor-associated DNA viruses and identifying viral integration sites that may unravel novel mechanisms of cancer pathogenesis.

Adrenal ganglioneuroma: features and outcomes of 27 cases at a referral cancer centre.

BACKGROUND: Adrenal ganglioneuroma (AGN) is a rare neurogenic tumour that can mimic other adrenal neoplasms. Limited information, mostly derived from small cases series, is available for AGN. METHODS: A retrospective review for AGNs seen at a tertiary referral centre describing important features to distinguish AGN from other adrenal neoplasms. RESULTS: Of 53 ganglioneuromas, 27 were AGNs. Median age was 31 years (range, 1·7-64 years) and median tumour size was 8 cm (range, 1·5-20 cm). Seventeen AGNs (63%) were detected incidentally and nine patients (33%) presented with abdominal/back discomfort. Catecholamine levels, available for 21 patients, were normal. On computed tomography (CT), most AGNs were homogenous and well circumscribed with a median density of 32·5 Hounsfield units (HU) on unenhanced CT; 40 HU on postcontrast venous phase; and 66·5 HU on delayed postcontrast phase. On magnetic resonance imaging (MRI), AGNs had hypo-intense signal on T1-weighted images with heterogeneous hyperintense signal on T2-weighted images. In four patients, there was no tumour growth during median follow-up of 48 months (range, 21-60 months). One patient had malignant peripheral nerve sheath tumour arising from AGN. Thirteen patients with resected AGN had no recurrence during a median follow-up of 50 months (range, 2-135 months). CONCLUSIONS: We herein describe the largest AGN series reported to date. Isolated AGNs do not produce catecholamines and have CT imaging characteristics that can help in distinguishing them from other adrenal and para-adrenal neoplasms. The natural history of AGNs is usually benign, although local extra-adrenal extension or malignant transformation can rarely occur.

The association between thyroid differentiation score and survival outcomes in papillary thyroid carcinoma.

BACKGROUND: Thyroid differentiation score (TDS), calculated based on mRNA expression levels of 16 genes controlling thyroid metabolism and function, has been proposed as a measure to quantify differentiation in PTC. The objective of this study is to determine whether TDS is associated with survival outcomes across patient cohorts. METHODS: Two independent cohorts of PTC patients were used: 1) the Cancer Genome Atlas (TCGA) thyroid cancer study (N=372), 2) MD Anderson Cancer Center (MDACC) cohort (N=111). The primary survival outcome of interest was progression-free interval (PFI). Association with overall survival (OS) was also explored. The Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. RESULTS: In both cohorts, TDS was associated with tumor and nodal stage at diagnosis as well as tumor driver mutation status. High TDS was associated with longer PFI on univariable analyses across cohorts. After adjusting for overall stage, TDS remained significantly associated with PFI in the MDACC cohort only (aHR 0.67, 95%CI 0.52-0.85). In subgroup analyses stratified by tumor driver mutation status, higher TDS was most consistently associated with longer PFI in BRAFV600E-mutated tumors across cohorts after adjusting for overall stage (TCGA: aHR 0.60, 95% CI: 0.33-1.07; MDACC: aHR 0.59, 95% CI: 0.42-0.82). For OS, increasing TDS was associated with longer OS in the overall MDACC cohort (aHR=0.78, 95% CI:0.63-0.96), where the median duration of follow-up was 12.9 years. CONCLUSION: TDS quantifies the spectrum of differentiation status in PTC and may serve as a potential prognostic biomarker in PTC, mostly promisingly in BRAFV600E-mutated tumors.

Metastatic cutaneous squamous cell carcinoma accounts for nearly all squamous cell carcinomas of the parotid gland.

Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic.