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.

Seven years of Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Rate of Acceptance and Variation of Diagnostic Approaches Across Different Continents.

CONTEXT: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a new entity replacing the diagnosis of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC). Significant variability in the incidence of NIFTP diagnosed in different world regions has been reported. OBJECTIVE: To investigate the rate of adoption of NIFTP, change in practice patterns, and uniformity in applying diagnostic criteria among pathologists practicing in different regions. METHODS: Two surveys distributed to pathologists of the International Endocrine Pathology Discussion Group with multiple-choice questions on NIFTP adoption into pathology practice and whole slide images of 5 tumors to collect information on nuclear score and diagnosis. Forty-eight endocrine pathologists, including 24 from North America, 8 from Europe, and 16 from Asia/Oceania completed the first survey and 38 the second survey. RESULTS: A 94% adoption rate of NIFTP by the pathologists was found. Yet, the frequency of rendering NIFTP diagnosis was significantly higher in North America than in other regions (P = .009). While the highest concordance was found in diagnosing lesions with mildly or well-developed PTC-like nuclei, there was significant variability in nuclear scoring and diagnosing NIFTP for tumors with moderate nuclear changes (nuclear score 2) (case 2, P < .05). Pathologists practicing in North America and Europe showed a tendency for lower thresholds for PTC-like nuclei and NIFTP than those practicing in Asia/Oceania. CONCLUSION: Despite a high adoption rate of NIFTP across geographic regions, NIFTP is diagnosed more often by pathologists in North America. Significant differences remain in diagnosing intermediate PTC-like nuclei and respectively NIFTP, with more conservative nuclear scoring in Asia/Oceania, which may explain the geographic differences in NIFTP incidence.

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.

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.

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.

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.

Deep learning generates synthetic cancer histology for explainability and education.

Artificial intelligence methods including deep neural networks (DNN) can provide rapid molecular classification of tumors from routine histology with accuracy that matches or exceeds human pathologists. Discerning how neural networks make their predictions remains a significant challenge, but explainability tools help provide insights into what models have learned when corresponding histologic features are poorly defined. Here, we present a method for improving explainability of DNN models using synthetic histology generated by a conditional generative adversarial network (cGAN). We show that cGANs generate high-quality synthetic histology images that can be leveraged for explaining DNN models trained to classify molecularly-subtyped tumors, exposing histologic features associated with molecular state. Fine-tuning synthetic histology through class and layer blending illustrates nuanced morphologic differences between tumor subtypes. Finally, we demonstrate the use of synthetic histology for augmenting pathologist-in-training education, showing that these intuitive visualizations can reinforce and improve understanding of histologic manifestations of tumor biology.

Top 10 Clear Cell Head and Neck Lesions to Contemplate.

BACKGROUND: Optically clear cytoplasm may occur in neoplastic and non-neoplastic conditions, either as a characteristic feature of a disease entity or as a morphologic rarity, potentially creating diagnostic dilemmas in various organ systems. In the head and neck, clear cell change can occur in lesions of salivary, odontogenic, thyroid, parathyroid, or sinonasal/skull base origin, as well as in metastases to these regions. METHODS: This review elaborates the top ten clear cell lesions in the head and neck, emphasizing their distinguishing histologic, immunohistochemical, and molecular attributes, and presents a rational approach to arriving at an accurate classification. RESULTS: Cytoplasmic pallor or clearing may be caused by accumulations of glycogen, lipid, mucin, mucopolysaccharides, water, foreign material, hydropic organelles, or immature zymogen granules. Overlapping morphologic features may present a diagnostic challenge to the surgical pathologist. Similarity in immunohistochemical profiles, often due to common cell type, as well as rare non-neoplastic mimics, furthers the diagnostic conundrum. CONCLUSIONS: The top ten lesions reviewed in this article are as follows: (1) clear cell carcinoma (salivary and odontogenic), (2) mucoepidermoid carcinoma, (3) myoepithelial and epithelial-myoepithelial carcinoma, (4) oncocytic salivary gland lesions, (5) squamous cell carcinoma, (6) parathyroid water clear cell adenoma, (7) metastatic renal cell carcinoma (especially in comparison to clear cell thyroid neoplasms), (8) sinonasal renal cell-like adenocarcinoma, (9) chordoma, and (10) rhinoscleroma.

To Freeze or Not to Freeze? Recommendations for Intraoperative Examination and Gross Prosection of Thyroid Glands.

The use of intraoperative consultation for indeterminate thyroid lesions is not advocated but is still requested by some surgeons. Obscured cytomorphology and nonrepresentative sampling limit the specificity of intraoperative assessment. Formalin fixation of thyroid glands before sectioning also minimizes artifacts introduced by fresh sectioning. Inking of thyroid may vary based on institutional preferences and information desired by clinical teams. Sectioning may occur in the conventional transverse method or the modified transverse vertical method to more thoroughly evaluate the lesion's periphery. Gross examination of thyroid lesions should always consider possible high-grade features, such as necrosis or extrathyroidal extension.

High-Grade Non-Anaplastic Thyroid Carcinomas of Follicular Cell Origin: A Review of Poorly Differentiated and High-Grade Differentiated Carcinomas.

Poorly differentiated thyroid carcinoma (PDTC) and high-grade differentiated thyroid carcinoma (HGDTC) are considered high-grade follicular-derived thyroid carcinomas, with prognoses intermediate between well-differentiated and anaplastic thyroid carcinoma. Both share the presence of invasion, thyroid follicular-cell origin, and tumor necrosis or increased mitoses (≥ 3 mitoses per 2 mm2 in PDTC and ≥ 5 mitoses per 2 mm2 in HGDTC), without anaplastic dedifferentiation. PDTC must possess solid, trabecular, or insular growth and lack classic papillary-like nuclei; HGDTC can be of any architectural or nuclear morphology (follicular-like, papillary-like, oncocytic). Transformation may be accompanied by acquisition of high-risk mutations (such as TP53 or TERT promoter) on top of RAS-like or BRAF p.V600E-like (including NTRK-fusion) initial driver mutations. These carcinomas most frequently affect adults and often present with metastases (20-50%) or wide local invasion. As PDTC and HGDTC may be radioactive iodine resistant, post-surgical therapy may consist of external beam radiotherapy or targeted, mutation-dependent chemotherapy, such as tyrosine kinase inhibitors. Ten-year disease specific survival is as low as 50%. Awareness of high-grade features in the diagnostic setting is important for patient prognosis and triage of tissue for molecular analysis in order to guide relevant clinical management and therapy.

IgG4-related disease mimicking gynecologic malignancy.

Immunoglobulin G4 (IgG4) related disease is a systemic disease that causes fibrosis, tumor-like nodules, and lymphoid hyperplasia with infiltration of IgG4 positive plasma cells. It can manifest in many organ systems; however, there are few cases that report gynecologic organ involvement. It is crucial to correctly diagnose IgG4-related disease versus malignancy because the former is treated with glucocorticoids or rituximab. In this case report, we describe two patients in which IgG4-related disease mimics gynecologic cancer. In the first case, an 85 year old woman presented with diffuse lymphadenopathy and a uterine mass concerning for malignancy. Biopsies were negative for carcinoma. Inguinal lymph node biopsy demonstrated IgG4 positive plasma cells and the patient was treated with rituximab therapy given concurrent severe rheumatoid arthritis. In the second case, a 35 year old woman under surveillance for Stage IB2 squamous cell carcinoma of the cervix (status post definitive chemoradiation therapy) presented with fluorodeoxyglucose (FDG) avid paraaortic lymph nodes on positron emission tomography (PET) imaging with subsequent negative paraaortic lymph node biopsies. Serial imaging and biopsies remained inconclusive despite ongoing diffuse lymphadenopathy and clinical concern for recurrence. Supraclavicular lymph node excision was performed which demonstrated lymphoid hyperplasia with increased IgG4 plasma cells and no evidence of carcinoma, supporting the diagnosis of IgG4-related disease. The patient was treated with high dose steroids with clinical improvement and resolution of abnormal imaging findings. We demonstrate that IgG4-related disease can present with FDG-avid lesions on PET imaging and lymphadenopathy that mimics primary or recurrent gynecologic malignancy. While rare, we conclude the IgG4-related disease is an important differential diagnosis to consider in the workup of primary or recurrent gynecologic malignancy and highlights the value of PET imaging to identify unusual patterns of lymphadenopathy and guide histologic confirmation of disease.

Right Vocal Cord Paralysis Caused by Histoplasmosis: A Case Report.

OBJECTIVES: Histoplasma capsulatum is a prevalent dimorphic fungus, reaching an exposure rate of 90% in endemic areas such as the Midwest and Central United States. We report an unusual presentation of dysphonia due to right vocal cord paralysis caused by mediastinal lymphadenopathy from histoplasmosis. METHODS: A 73-year-old male presented to an otolaryngology clinic with 4 months of hoarseness. Flexible strobolaryngoscopy demonstrated right vocal cord paralysis in lateral position and a full length glottic gap. Computerized tomography (CT) scan showed enlargement of a right paratracheal node. RESULTS: A lymph node biopsy was obtained and showed histoplasmosis. He was treated with a 3-month course of pozaconazole. He then received a vocal cord medialization injection 2 months after symptom onset, which produced favorable improvement of his symptoms at 8-month follow up. CONCLUSIONS: One other case report in the literature has reported left vocal cord paralysis related to histoplasmosis. This first case of right vocal cord paralysis was extremely unusual and is not often included in the differential diagnosis of vocal cord paralysis.

The Significance of RAS-Like Mutations and MicroRNA Profiling in Predicting Malignancy in Thyroid Biopsy Specimens.

In cytologically indeterminate thyroid nodules undergoing molecular testing, estimated risk of malignancy is variable. Identification of a non-cancer-specific mutation (RAS-like) confirms a neoplastic process but does not differentiate between benign, malignant, and low-risk neoplasms. This study aims to retrospectively evaluate institutional experience of Interpace (ThyGeNEXT® and ThyraMIR®; Pittsburgh, PA) testing and to determine the rate of malignancy in resected nodules, stratified by mutational analysis and microRNA profile. Of 1917 fine need aspirations, 140 (7.3%) underwent Interpace testing: 47 (33.6%) were molecular-not-benign (harbored mutation, fusion, and/or positive miRNA) and 93 (66.4%) were molecular-benign (no mutations or fusions and negative microRNA). Surgery was spared in 79.6% of molecular-benign and 61.4% of all tested patients. Fifty-four (38.6%) underwent resection. Seventeen (89.5%) of the resected molecular-benign were benign and 2 were malignant. Thirteen (37.1%) of the resected molecular-not-benign were benign, 7 (20%) were noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and 15 (42.9%) were malignant (p < 0.05, negative predictive value (NPV) 89.4-95.6%, positive predictive value (PPV) 22.3-42.8%). Most molecular-not-benign (72.3%) had RAS-like mutation. Twenty-three were resected: 3 were malignant and 7 were NIFTP. Nodules with non-RAS-like mutations (BRAF V600E-like, others) were more likely to be malignant than RAS-like (H/N/KRAS, BRAF K601E) (p < 0.05, NPV 86.9-96.5%, PPV 100%). Most nodules had RAS-like mutations and most were benign or low-risk neoplasms (NIFTP). This study supports the role of histologic examination in the distinction of malignancy in RAS-like thyroid neoplasms and underscores the role of molecular testing in risk stratification, patient counseling, and operative management.

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.

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.

NUTM1 -rearranged Carcinoma of the Thyroid : A Distinct Subset of NUT Carcinoma Characterized by Frequent NSD3 - NUTM1 Fusions.

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC.

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.