Update of newly-recognized salivary gland neoplasms: molecular and immunohistochemical findings and clinical importance.

With the advancement of molecular testing and the routine use of immunohistochemical stains, salivary gland tumours previously categorized as adenoma or adenocarcinoma, not otherwise specified, are being reclassified with distinct diagnoses. Newly recognized benign entities include: sclerosing polycystic adenoma, keratocystoma, intercalated duct hyperplasia and adenoma, and striated duct adenoma. Newly recognized malignant salivary gland tumours include: microsecretory adenocarcinoma, sclerosing microcytic adenocarcinoma, and mucinous adenocarcinoma. Additionally, rare subtypes of mucoepidermoid carcinoma have been described, including Warthin-like and oncocytic. Understanding of intraductal carcinoma continues to evolve. Correctly distinguishing these lesions from mimickers can be crucial for appropriate patient care and prognostication, as well as future conceptualization of salivary disease.

Small biopsies in the head and neck: Bone and soft tissue.

Bone and soft tissue lesions in the head and neck encompass not only a broad morphologic spectrum but also significant inherent clinicopathologic overlap. Epidemiology, radiology, and location - similar to the diagnostic assessment in other sites - are especially important considerations in the context of an established mesenchymal proliferation. Herein, the approach towards diagnosis is stratified by morphology (spindle, sarcomatoid, epithelioid, round cell), cellular lineage (fibroblastic, nerve sheath, rhabdomyogenic), and tumor grade (benign, low- to high-grade malignant) as the basis of further immunohistochemical or molecular investigation.

Secretory carcinoma of the salivary gland: a multi-institutional clinicopathologic study of 90 cases with emphasis on grading and prognostic factors.

Secretory carcinoma (SC) is a rare form of salivary carcinoma that was first described in 2010 and is characterized by ETV6::NTRK3 fusion in most cases. In this large retrospective study, we aimed to identify adverse clinicopathologic factors and propose a prognostically relevant grading scheme for SC. METHODS: A detailed clinicopathologic review was conducted on 90 SCs from the major and minor salivary glands. RESULTS: The median age at presentation was 50 years (range: 7-93). Sixty-nine (77%) tumours originated from major salivary glands, whereas the remaining 21 involved minor salivary glands.Six cases (7%) had cervical nodal metastasis. Only lymphovascular invasion (LVI) was associated with a risk of nodal metastasis (P < 0.05). The 5-year disease-specific survival and disease-free survival (DFS) were 98% and 87%, respectively. On univariate survival analysis, adverse prognostic factors associated with decreased DFS included minor salivary gland origin, atypical mitosis, high mitotic index, high-grade transformation (HGT), necrosis, nuclear pleomorphism, infiltrative tumour border, fibrosis at the invasive front, LVI, positive margin, and advanced pT stage (P < 0.05). When adjusted for pT stage and margin status, mitotic index, LVI, nuclear pleomorphism, and HGT remained as independent prognostic factors. CONCLUSION: We therefore propose a two-tiered grading system for SC. The low-grade SC is defined as those with <5 mitoses /10 high-power fields and no tumour necrosis, and high-grade SC as those with ≥5 mitoses /10 high-power fields and/or necrosis. This proposed grading system can be useful to risk stratify patients with SC for appropriate clinical management.

Graves' disease and papillary thyroid carcinoma: case report and literature review of a single academic center.

BACKGROUND: Graves' disease (GD) and papillary thyroid cancer (PTC) can be concomitant. The existence of a link between these entities has long been investigated, but a clear correlation hasn't been established. We report a case of GD resistant to medical treatment in which surgery revealed unsuspected PTC and we aim to study the prevalence of PTC in Graves' disease, its clinical characteristics and review of the literature. CASE PRESENTATION: Report of a 32 yo man who presented with weight loss and was found to be biochemically hyperthyroid. Antibodies were positive. Incremental doses of methimazole provided no improvement in thyroid tests. Hypervascularity and a spongiform nodule were noted on ultrasound. Thyroid uptake and scan showed 70.2% uptake. Thyroidectomy was performed due to inadequate therapeutic response. Pathology revealed PTC with extrathyroidal extension and positive lymph nodes. A retrospective review (2000-2021) and literature review of PTC in GD was performed. Clinical data were reviewed. Statistical analysis was calculated to identify correlations. 243 GD patients had total thyroidectomy at an academic center, 50 (20%) had PTC, 14% were microcarcinomas. 76% of cases were less than 55yo, 82% female, 78% stage 1, PTC diagnosis was incidental in 48%, hyperthyroidism was difficult to treat in 10% and only 2% had recurrence of PTC. There was no correlation between demographic or clinical data. CONCLUSIONS: Evidence is controversial with some studies showing GD does not affect PTC prognosis. PTC may not be well recognized in GD, pre-operative assessment should consider risk of cancer.

Practical immunohistochemistry in the classification of salivary gland neoplasms.

Diagnosis of salivary gland neoplasms can be challenging for surgical pathologists due to low incidence of tumors as well as overlapping histologic features. On small biopsy, the most important information to be conveyed for clinical management is the distinction between a benign/low grade tumor and a high grade carcinoma. This review will discuss the differential diagnosis of salivary gland tumors based on four broad morphologic patterns: basaloid/tubular/cribriform, (micro)cystic/secretory/mucinous, solid-nested/clear-spindled, and oncocytic/oncocytoid. With the assistance of immunohistochemistry, demonstration of the number of cell types (mainly epithelial versus myoepithelial/basal) can further subclassify tumors within these morphologic categories. Additional tumor-specific immunomarkers are useful in some cases. Underlying tumor-specific genetic anomalies can be of value, however, immunohistochemical correlates are only available for some. When used judiciously, in the correct morphologic context, and with knowledge of their limitations, immunohistochemical stains can aid in differentiating tumors with similar morphology.

Laryngeal and pharyngeal actinomycosis: a systematic review and report of 3 cases.

INTRODUCTION: Actinomycosis is a granulomatous infection that rarely involves the larynx or pharynx. Three cases of actinomycosis of the larynx or pharynx from our institution were reviewed and a systematic literature review was performed to better define surgical management, antibiotic therapy, risk factors, and incidence of recurrence or complications. MATERIALS AND METHODS: PubMed/Medline, Cochrane, Embase, and Google Scholar were searched on November 30, 2021 using the terms "laryngeal actinomycosis", "pharyngeal actinomycosis", "actinomycosis AND larynx", and "actinomycosis AND pharynx." Articles which did not describe appropriate sites or were non-English were excluded. Results were collected for demographic information, site(s) of infection, comorbidities, lesion characteristics and treatments. RESULTS: Along with three cases reported from our institution, 40 unique cases were reviewed from 37 studies for a total of 43 patients (Table 1). 34 (81.0 %) of the patients were male with the highest incidence of infection in the seventh decade (54.8 %). The most common site for the infection was the larynx (69.0 %) followed by the pharynx (16.7 %). Risk factors included a history of radiation therapy, immunosuppression, inhalational irritant, and diabetes (Table 3). The duration of antibiotic therapy varied greatly, from one month to one year and total follow up ranged from 1 month to 2.5 years (Table 1). CONCLUSIONS: A comprehensive review of the literature on pharyngolaryngeal actinomycosis shows that this infection has increased prevalence within the head and neck cancer patient population. Similar to cervicofacial actinomycosis, these atypical sites have shown favorable responses to extended antibiotic therapy and generally do not require aggressive surgical management.

Deep learning prediction of BRAF-RAS gene expression signature identifies noninvasive follicular thyroid neoplasms with papillary-like nuclear features.

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RAS mutations, rather than BRAFV600E mutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor's expression profile resembles a BRAFV600E or RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P < 0.0001). To test the hypothesis that BRS may serve as a surrogate for biological processes that determine tumor subtype, a separate model was trained on TCGA slides to predict BRS as a linear outcome. This model performed well in cross-validation on the training set (R2 = 0.67, dichotomized AUC = 0.94). In our internal cohort, NIFTPs were near universally predicted to have RAS-like BRS; as a sole discriminator of NIFTP status, predicted BRS performed with an AUC of 0.99 globally and 0.97 when restricted to follicular-patterned neoplasms. BRAFV600E-mutant PTC-EFG had BRAFV600E-like predicted BRS (mean -0.49), nonmutant PTC-EFG had more intermediate predicted BRS (mean -0.17), and NIFTP had RAS-like BRS (mean 0.35; P < 0.0001). In summary, histologic features associated with the BRAF-RAS gene expression spectrum are detectable by deep learning and can aid in distinguishing indolent NIFTP from PTCs.

Mesenchymal lesions of the vulva.

Mesenchymal lesions of the vulva include site-specific entities limited to the lower genital tract, as well as a range of non-site-specific tumors that are more common at extragenital sites. Site-specific lesions include fibroepithelial stromal polyp, cellular angiofibroma, angiomyofibroblastoma, and aggressive angiomyxoma. Non-site-specific tumors that may occur in the vulva include those of smooth muscle, skeletal muscle, vascular, neural, adipocytic, and uncertain differentiation. This review discusses both site-specific and non-site-specific vulvar mesenchymal lesions including non-neoplastic proliferations, benign neoplasms, locally aggressive neoplasms with a predilection for local recurrence, neoplasms of indeterminate biologic potential, and frankly malignant neoplasms with a high risk of distant metastasis and death. Accurate diagnosis is essential for proper management, and is facilitated by correlation with clinical findings and targeted application of immunohistochemical and molecular studies.

Pituitary Adenoma Deposit in the Nasolabial Region Following Sublabial Transsphenoidal Surgery in the Setting of Nelson Syndrome.

Pituitary adenomas are a group of tumors arising from the anterior pituitary gland, and with the exception of prolactin-secreting adenomas, transsphenoidal resection is the cornerstone of treatment. Although most adenomas are located within the pituitary fossa, ectopic adenomas have been reported, primarily occurring along the route of embryologic development. In this article, we present the case of an ectopic pituitary adenoma in the nasolabial fold that likely resulted from seeding during transsphenoidal resection via sublabial approach.

Histological features and prognostic significance of treatment effect in lymph node metastasis in head and neck squamous cell carcinoma.

AIMS AND OBJECTIVES: Cervical lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) is common. Pre-operative chemoradiotherapy (preCRT) and postoperative chemoradiotherapy (postCRT) is frequently employed in such patients. The prognostic value of viable SCC, treatment effect or no SCC in resected lymph nodes in patients who received or did not receive preCRT and postCRT was investigated. METHODS AND RESULTS: Resected cervical lymph nodes from 146 patients with HNSCC were evaluated for viable SCC, treatment effect or no SCC. Immunostains for Ki67, cyclin D1, caspase 3 and H2AFX were performed on viable SCC or nucleate keratin debris. Clinical and histological data were correlated with tumour recurrence or persistence. Patients with nucleate keratin debris in lymph nodes had outcomes similar to those with diffuse treatment effect and no SCC. Viable tumour in lymph nodes was associated with worse prognosis in patients who received preCRT (P = 0.01). This relative worsening of prognosis was not observed in patients with oropharyngeal SCC or recurrent disease. Lower proliferation index in lymph node SCC was associated with preCRT and with worse outcomes (P = 0.0002). Overall, patients who received preCRT or postCRT had outcomes not significantly different from those who did not. CONCLUSION: The presence of viable SCC in cervical lymph nodes has prognostic import when taken in context with the patient's history. Viable SCC in lymph nodes was significantly associated with worse outcome among patients with non-oropharyngeal SCC who received preCRT. Nucleate keratin debris should not be considered viable SCC in lymph nodes.

Factors associated with false-negative pathologic diagnosis of calciphylaxis.

BACKGROUND: Calciphylaxis is a rare, painful, and debilitating disorder of vascular calcification and skin necrosis that typically affects patients with advanced kidney disease. During our routine pathology practice, we noted several missed diagnoses on calciphylaxis consultation cases originating from outside institutions and sought to explore factors associated with false-negative pathologic diagnosis of calciphylaxis. METHODS: The pathology database of a large tertiary academic medical center was retrospectively searched for "calciphylaxis" in inside reports on outside surgical consultation cases between 2007 and 2017. Inside and outside pathology reports were compared and medical records were searched for calciphylaxis clinical diagnosis and risk factors. RESULTS: Twenty-four calciphylaxis patients were identified, with median age of 63.5 years. Seven of 24 (29%) of specimens were inadequate (e.g., lack of subcutaneous adipose tissue for evaluation). Eight of 17 (47%) of adequate specimens had a first false-negative pathologic diagnosis of calciphylaxis. Histochemical staining for calcium significantly correlated with true-positive diagnosis (93% vs 55%, P = 0.004). Dermatopathology fellowship training significantly correlated with true-positive diagnosis (82% vs 38%, P = 0.047). CONCLUSIONS: Adequate sampling, dermatopathology training, and use of histochemical stains to identify calcium associate with decreased false-negative rate for calciphylaxis diagnosis. These findings need further evaluation in larger prospective studies.

p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a comparison of antibody clones using patient outcomes and high-risk human papillomavirus RNA status.

High-risk human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas have a more favorable prognosis than HPV-negative ones. p16 immunohistochemistry has been recommended as a prognostic test in clinical practice. Several p16 antibodies are available, and their performance has not been directly compared. We evaluated three commercially available p16 antibody clones (E6H4, JC8 and G175-405) utilizing 199 cases of oropharyngeal squamous cell carcinoma from a tissue microarray, read by three pathologists with three different cutoffs for positivity: any staining, >50% and >75%. Positive predictive values for high-risk HPV status by RNA in situ hybridization for the E6H4, JC8 and G175-405 clones were 98%, 100% and 99% at the 75% cutoff, but negative predictive values were much more variable at 86%, 69% and 56%, respectively. These improved using the 50% cutoff, becoming similar for all three antibodies. Intensity varied substantially, with 85% of E6H4, 72% of JC8 and 67% of G175-405 showing strong (3+) intensity. With Kaplan-Meier survival plots at the 75% cutoff, the E6H4 clone showed the largest differential in disease specific and overall survival between p16-positive and -negative results. Decreasing the cutoff to 50% increased correlation with HPV in situ hybridization and improved the survival differential for the JC8 and G175-405 clones without worsening of performance for the E6H4 clone. Interobserver agreement was also assessed by kappa scores and was highest for the E6H4 clone. Overall, these study results show modest but important performance differences between the three different p16 antibody clones, suggesting that the E6H4 clone performs best because of strongest staining intensity, greatest differential in outcomes between positive and negative results, lowest interobserver variability, and lowest background, nonspecific staining. The results also suggest that a 75% cutoff is very functional but that, in this patient population with high HPV incidence, 50% and any staining cutoffs may be more effective, particularly for the non-E6H4 clones.

NUT midline carcinoma of the larynx: an international series and review of the literature.

AIMS: NUT midline carcinoma (NMC) is a rare undifferentiated and aggressive carcinoma that locates characteristically to the midline of the head and neck, and mediastinum. NMC is characterized by chromosomal rearrangements of the gene NUT, at 15q14. The BRD4 gene on 19q13 is the most common translocation partner forming a fusion oncogene, BRD4-NUT. By the end of 2014, the International NUT Midline Carcinoma Registry had 48 patients treated for NMC. Laryngeal NMC are exceedingly rare, and we report a case series of seven cases. METHODS AND RESULTS: We searched for cases in files of different hospitals as well as a thorough search of the English language literature. The diagnosis of NMC is made by demonstration of NUT rearrangement either by immunohistochemistry, fluorescence in-situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR). We found three previously published cases, and in this series add four cases of our own. CONCLUSIONS: NMC consists of monomorphic, often discohesive, cells with an epithelioid appearance and distinct nucleoli. The tumours typically show abrupt squamous differentiation. The mean age of the patients was 34 years, hence significantly lower than that for conventional laryngeal carcinoma. All tumours were located in the supraglottis and five patients died of the disease after 3, 7, 8, 9 and 11 months. Laryngeal NMC may be underdiagnosed, and an increased awareness among pathologists is warranted. NMC has characteristic morphological features, and positive immunostaining with the NUT antibody is diagnostic. Its aggressive behaviour demands a very intense treatment strategy and the need for its recognition is emphasized further by new promising treatment strategies.

High prevalence of MiTF staining in undifferentiated pleomorphic sarcoma: caution in the use of melanocytic markers in sarcoma.

AIMS: The diagnosis of undifferentiated pleomorphic sarcoma (UPS) may be challenging, as other lesions with undifferentiated spindle cell morphology must be excluded, including melanoma. Microphthalmia-associated transcription factor (MiTF) stains naevi and epithelioid melanomas, as well as some mesenchymal neoplasms. The aim of this study was to evaluate the prevalence of MiTF and melanocytic markers in UPS and a subset of atypical fibroxanthoma (AFX). METHODS AND RESULTS: MiTF, SOX10, Melan-A, HMB45 and S100 immunostaining was performed on resection specimens from 19 UPSs and five AFXs. Next-generation sequencing of 50 genes was performed in UPSs to exclude dedifferentiated melanoma. In 17 of 19 UPSs (89%), tumour cells showed nuclear positivity for MiTF that was not eliminated by casein block. Three showed focal nuclear staining for HMB45, which was eliminated by casein block. One showed focal nuclear vacuole staining for S100 with red but not brown chromogen. None expressed SOX10 or Melan-A. Mutational analysis of 15 UPSs with adequate DNA showed no mutations within hotspot regions of BRAF, KIT, or NRAS. Four of five AFXs (80%) stained with MiTF; other markers were negative. CONCLUSION: There is a high prevalence of nuclear MiTF expression in UPSs (89%) and AFXs (80%). Rare UPSs showed non-specific nuclear HMB45 or S100 staining. These findings argue against using MiTF in isolation to differentiate between UPS or AFX and melanoma, and caution in interpreting focal staining for a single additional melanocytic marker. Casein block may eliminate non-specific staining. MiTF should be used to support a diagnosis of melanoma only if multiple melanocytic markers are positive.

BRAF mutation in 'sarcomas': a possible method to detect de-differentiated melanomas.

AIMS: BRAF is mutated in 50-60% of melanomas, but BRAF mutation in sarcomas has not been systematically evaluated. Some melanomas are spindled and may show no immunohistochemical evidence of melanocytic differentiation. Similarly, many sarcomas are undifferentiated, i.e. undifferentiated pleomorphic sarcomas (UPS). Diagnosing melanoma versus sarcoma in an undifferentiated spindle cell malignancy can be challenging. Our aim was to evaluate the prevalence of BRAF mutation in sarcomas and the use of BRAF mutational status in the diagnosis of spindle cell malignancies. METHODS AND RESULTS: BRAF mutational analysis was performed on tissue from 104 patients: 90 with sarcoma only (50 UPS) and 14 with sarcoma and melanoma (seven UPS). In the sarcoma-only group, BRAF mutation was absent. In the sarcoma-melanoma group, three sarcomas showed BRAF mutation; all were UPS, occurred after the melanomas and did not stain for melanocytic markers. One melanoma-sarcoma pair showed identical BRAF V600E mutations. CONCLUSIONS: The presence of BRAF mutation in these tumours raises the possibility that poorly differentiated spindle cell malignancies with BRAF mutation may represent melanomas, and BRAF mutational analysis should be considered in a patient with a spindle cell malignancy and a history of melanoma, as a positive result may indicate de-differentiated melanoma.

The Diagnostic Utility of Repeat Fine-needle Aspirations of Benign Thyroid Nodules.

Objective This study aims to analyze the diagnostic utility of multiple repeat FNA on thyroid nodules with initially benign diagnosis. Methods In a 5-year period, 1658 thyroid nodules with initially benign FNAs were retrospectively reviewed and followed for subsequent resection and repeat biopsy. Results Out of 2150 thyroid nodules, 1658 (77.1%) were diagnosed as benign on FNAs. The average age was 57.4 years (range 11-93 years), and most were females (83.8%). Repeat FNA was performed on 183 benign nodules, of which 141 (8.5%) were sampled a second time and 42 (2.5%) had 2 or more repeat samplings. For the benign nodules without repeat FNAs, 124 had benign resection. Of cases with one-time repeat FNA, most (n=101) remained benign on repeat FNAs, 13 of which were benign on resection. Eleven had atypical repeat FNAs, 5 were resected, 4 of which were benign and one was atypical follicular neoplasm with HRAS and TERT promoter mutations. Of cases with multiple repeat FNA, most (n=35) were still benign on repeat FNAs, one had benign resection. Two had atypical repeat biopsies, one was PTC on resection with CCD6::RET fusion. The positive predictive value significantly decreased from 41.1% on single FNA to 8.3% on one-time repeat (p<0.001) and 16.7% on multiple repeat (p=0.002). The total cost for workup of previously benign nodules was $285,454. Conclusions Repeat FNA biopsies did not provide an additional diagnostic value in the evaluation of benign thyroid nodules, and often led to unwarranted follow-up procedures and significantly increased health care cost.

Imaging features and surgical management of giant parathyroid adenoma with autoinfarction.

Autoinfarction of a parathyroid adenoma can have an atypical clinicoradiologic features that can mimic an inflammatory process or malignancy. In addition, the associated fibrosis makes surgical resection more challenging than for regular parathyroid adenomas. The implications of these findings are that while autoinfarction of parathyroid adenomas is a rare phenomenon, this entity should be considered when there are heterogeneous and cystic components on imaging in patients without hypercalcemia. Ultimately, histopathology is necessary for definitive diagnosis.

Adenoid Cystic Carcinoma with Sebaceous Differentiation and MYB::NFIB Fusion Arising in the External Auditory Canal.

Adenoid cystic carcinoma arising in the external auditory canal is rare, and even rarer are cases with sebaceous differentiation mimicking sebaceous carcinoma. This case with clinical, radiologic, gross, and histologic images exemplifies an unusual occurrence of adenoid cystic carcinoma in the external auditory canal with sebaceous differentiation, confirmed by MYB::NFIB fusion.

Columnar Cell Thyroid Carcinoma: A Heterogeneous Entity Demonstrating Overlap Between Papillary Thyroid Carcinoma and Follicular Neoplasms.

BACKGROUND: Columnar cell papillary thyroid carcinoma (CC-PTC) is a morphologic subtype of papillary thyroid carcinoma with a variable prognosis. It is characterized by neoplastic thyroid follicular-derived cells with pseudostratified columnar morphology arranged in papillary or follicular structures with supranuclear or subnuclear vacuoles. The molecular profile of this subtype has only recently come under scrutiny, with mixed results. The aim of this study is to further explore the morphologic, immunohistochemical, and genetic profile of CC-PTC, as well as to correlate these features with clinical outcomes. METHODS: CC-PTC cases were identified from 3 institutions. Immunohistochemistry (ER, CDX2) and molecular testing (DNA and RNA sequencing) were performed. Clinicopathologic parameters and patient outcomes were recorded. RESULTS: Twelve cases (2006-2023) were identified, all in adults (age 45-91). Two presented with disease outside the thyroid gland (neck and mediastinum) and two presented with distant metastasis. Four were high-grade differentiated thyroid carcinomas (necrosis or mitoses), one of which died of disease. Four were noninvasive or minimally invasive, one of which locally recurred. Three patients had lymph node metastases. ER and CDX2 were positive in 73% and 50%, respectively. Pathogenic mutations were found in TERT promoter (n = 3), RAS (n = 2), ATM, NOTCH1, APC, and ESR1, along with cases bearing AGK::BRAF fusion (n = 1), BRAF VE1 expression (n = 1), and NF2 loss (n = 1). CONCLUSIONS: This study represents the largest molecularly defined cohort of non-oncocytic thyroid carcinomas with columnar cell morphology. These tumors represent a genetically and behaviorally heterogeneous group of neoplasms, some of which have RAS-like or follicular neoplasm-like genetics, some of which have BRAF-p.V600E-like or classic papillary thyroid carcinoma-like genetics, and some of which remain unclear. Noninvasive or minimally invasive tumors showed an indolent course compared to those with angioinvasion, gross extrathyroidal growth, or high-grade morphology. Consideration could be given to reclassification of this neoplasm outside of the subtyping of papillary thyroid carcinoma in light of its genetic diversity, distinct morphology, and clinical behavior more closely aligned with follicular thyroid neoplasms.