Tert-expressing cells contribute to salivary gland homeostasis and tissue regeneration after radiation therapy.

Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (TertHigh) cell population located in the ductal region of the adult SMG. These TertHigh cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. TertHigh cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of "cell cycling" and "oxidative stress response" pathways in TertHigh cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of TertHigh cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy.

Promising Therapeutic Targets for Recurrent/Metastatic Anaplastic Thyroid Cancer.

OPINION STATEMENT: Anaplastic thyroid cancer presents formidable challenges, particularly in cases of recurrence or metastasis. Timely BRAF V600E testing is imperative at diagnosis, initially through immunohistochemistry, followed by comprehensive genomic profiling encompassing genes such as NTRK, RET, ALK, and assessment of tumor mutation burden (TMB). FDA-approved treatment options include dabrafenib and trametinib for patients with BRAF mutations, while those exhibiting high TMB may benefit from pembrolizumab. Further therapeutic decisions hinge upon mutational profile, urgency of response required, airway integrity, and access to targeted therapies There is growing use of immunotherapy for ATC based on published reports of activity, but currently there is no FDA approved agent for ATC. The off-label utilization of "precision medicine" combinations imposes a considerable financial strain, underscoring the necessity for further clinical trials to elucidate promising therapeutic avenues for this orphan disease. There is a pressing need for the development and support of clinical trials investigating genomically driven and immune-based therapies for anaplastic thyroid cancer.

A Novel Gene Fusion YLPM1::PRKD1 Identified in a Cribriform Subtype of Polymorphous Adenocarcinoma.

Cribriform adenocarcinoma of the salivary gland (CASG) is an entity that is currently classified under polymorphous adenocarcinoma (PAC), cribriform subtype per the 2022 WHO classification of head and neck tumours. There is debate about whether CASG should be considered a separate diagnostic entity, as CASG differs from conventional PAC in anatomic site, clinical behaviors, and molecular patterns. Herein we describe a challenging and unique case which shares histologic and behavioral features between CASG and conventional PAC with a YLPM1::PRKD1 rearrangement not previously reported in the literature.

How far are we off? Analyzing the accuracy of surgical margin relocation in the head and neck.

BACKGROUND: Positive surgical margin rates remain high in head and neck cancer surgery. Relocation is challenging given the complex, three-dimensional (3D) anatomy. METHODS: Prospective, multi-institutional study to determine accuracy of head and neck surgeons and pathologists relocating margins on virtual 3D specimen models using written descriptions from pathology reports. Using 3D models of 10 head and neck surgical specimens, each participant relocated 20 mucosal margins (10 perpendicular, 10 shave). RESULTS: A total of 32 participants, 23 surgeons and 9 pathologists, marked 640 margins. Of the 320 marked perpendicular margins, 49.7% were greater than 1 centimeter from the true margin with a mean relocation error of 10.2 mm. Marked shave margins overlapped with the true margin a mean 54% of the time, with no overlap in 44 of 320 (13.8%) shave margins. CONCLUSIONS: Surgical margin relocation is imprecise and challenging even for experienced surgeons and pathologists. New communication technologies are needed.

Patient With Dysphonia.

A male individual in his 60s presented with a hoarse and weak voice and a history of follicular lymphoma with multiple relapses treated with an allogeneic stem cell transplant complicated by graft-vs-host disease treated with sirolimus and steroids. What is your diagnosis?

Are 99mTC-Sestamibi Single Photon Emission Computed Tomography Scan Results Associated to the Parathyroid Cell Type in Primary Hyperparathyroidism?

INTRODUCTION: 99mTC-sestamibi scintigraphy (SPECT-CT) is a common imaging modality for parathyroid localization in primary hyperparathyroidism (PHPT). Prior studies have suggested that the cellular composition of parathyroid adenomas influences SPECT-CT imaging results. Other biochemical and anatomical factors may also play a role in false negative results. Therefore, after controlling for confounding variables, we sought to determine whether the histologic composition of parathyroid adenomas is associated to SPECT-CT results in patients with single gland disease causing PHPT. METHODS: A retrospective review of patients with PHPT due to confirmed single gland disease was performed over a 2-y period. A 1:1 propensity score matching was done between patients with positive and negative SPECT-CT results with regard to demographical, biochemical, and anatomical characteristics followed by blinded pathologic examination of cell composition in the matched pairs. RESULTS: Five hundred forty two patients underwent routine four gland exploration and 287 (53%) patients were found to have a single adenoma. Of those, 26% had a negative SPECT-CT result. There were significant differences between groups with regards to biochemical profile, gland location, and gland size. All of which became nonsignificant after propensity score matching. Adenomas were primarily composed of chief cells, with no difference between groups (95% versus 97%, P = 0.30). In the positive SPECT-CT group, chief cells were the dominant cell type in 68% of the cases, followed by mixed type (13%), oxyphil cells (12%), and clear cells (7%). This was similar to the negative SPECT-CT group (P = 0.22). CONCLUSIONS: While certain patient's clinical characteristics are associated with SPECT-CT imaging results, histologic cell type is not significantly associated.

Variability in Depth of Invasion Measurements in Carcinomas of the Oral Cavity and the Effect on Pathologic Tumor Staging.

Depth of invasion (DOI) was added to the staging criteria for carcinoma of the lip and oral cavity in the 8th edition of the American Joint Committee on Cancer Staging Manual (AJCC8). However, there are multiple practical challenges to obtaining an accurate DOI measurement with limited data regarding interobserver variability in DOI measurement. The aim of this study was to investigate interobserver variability in DOI measurement and its effect on tumor stage. We performed an electronic medical record search for excisions of squamous cell carcinoma of the oral cavity between January 1, 2010 and December 25, 2017. All slides containing significant tumor were selected for independent blinded DOI measurement by four head and neck pathologists per AJCC8 guidelines. Pathologic stage was assigned in conjunction with reported tumor greatest dimension. Observers recorded the slide used for measurement and potential issues limiting assessment of DOI. Results were compared for reproducibility in DOI and tumor stage using intraclass correlation coefficient (ICC) analysis. A total of 167 cases of oral squamous cell carcinoma with available slides were included. The ICC score for DOI between observers was 0.91339 (> 0.9 considered excellent). Only 7.2% of cases had uniform DOI amongst observers. Increasing overall tumor size and average DOI correlated with increasing range in DOI amongst observers. Differences in DOI resulted in differences in pathologic tumor staging (pT) for 15% of tumors. Use of different slides for DOI measurements was significantly associated with different pT staging. In contrast, ulceration and exophytic growth did not correlate with higher DOI or pT variability. Despite the excellent ICC score, differences in DOI measurement resulted in variable pT staging for a considerable number of cases. We therefore recommend consensus for DOI in at least some cases in which potential differences in DOI could alter pT stage assignment.

Salivary Duct Carcinoma: An Aggressive Salivary Gland Carcinoma with Morphologic Variants, Newly Identified Molecular Characteristics, and Emerging Treatment Modalities.

Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy with significant mortality. Morphologically, most tumors are characterized by apocrine differentiation with a typical immunophenotype of androgen receptor positive/gross cystic disease fluid protein positive/estrogen receptor negative/progesterone receptor negative. Several morphologic variants of SDC exist, representing diagnostic pitfalls. Several differential diagnoses should be considered because prognosis, treatment, and management may be different from SDC. For SDC, current treatment strategies are aggressive and commonly include surgical excision with lymph node dissection and adjuvant radiotherapy. Continued research is examining the utility of androgen deprivation therapy and targeted molecular therapy.

BRAFV600E, hypothyroidism, and human relaxin in thyroid carcinogenesis.

PURPOSE: BRAFV600E, a major driver of thyroid cancer, evaluated in the context of thyroid hormones and human relaxin. METHODS: Immunohistochemical expressions of BRAFV600E, TSH, TSH receptor (TSHR), T4, T3 receptor (T3R), RLNH2, and its receptor, RXFP1, were evaluated in thyroid tumors from a retrospective U.S. population of 481 cancer cases diagnosed in 1983-2004. RESULTS: BRAFV600E was expressed in 52% of all thyroid tumors; expression of other markers ranged from 25% for T4 to 98% for RLNH2. Tumors predominantly exhibited hypothyroid-like conditions characterized by elevated TSH and TSHR and reduced T4. BRAFV600E prevalence was significantly higher in tumors expressing TSH, TSHR, T3R, and RXFP1 and lower in tumors expressing T4. The proportion of BRAFV600E mutation in classic papillary tumors significantly increased from 56 to 72% over the 21-year period of diagnoses, while expression of RXFP1, TSH, TSHR, and T3R decreased in non-tumor. Racial/ethnic differences were observed in thyroid hormone marker expression. Non-tumor expression of TSH, TSHR, and T3R were each associated with shorter overall survival, but did not remain significant after adjustment for demographic and clinical factors. CONCLUSIONS: Our study provides the first evidence of the potential interaction of BRAFV600E mutation, relaxin, and thyroid hormones in thyroid carcinogenesis. Moreover, our results suggest that hypothyroidism, influenced by RLNH2 activity, may underlie the development of the majority of thyroid cancers and mediate the role of BRAFV600E in thyroid carcinogenesis. BRAFV600E mutation is increasing in papillary thyroid cancers and may be contributing to the rising incidence of this malignancy.

Clinical management of emerging sinonasal malignancies.

Several emerging sinonasal malignancies have recently been described in the pathology literature. Although not all distinctly classified by the World Health Organization, these rare tumors present a management challenge to surgeons and oncologists. While prior studies have summarized histologic details, a clinically focused review is currently lacking in the literature. This review describes the presentation, histopathology, imaging, treatment, and prognosis of newly described or recently evolving sinonasal malignancies while highlighting the distinguishing features of these entities. It includes teratocarcinosarcoma, human papillomavirus-related multiphenotypic carcinoma, biphenotypic sinonasal sarcoma, sinonasal renal cell-like adenocarcinoma, NUT-midline carcinoma, squamous cell carcinoma associated with inverted papilloma, sinonasal undifferentiated carcinoma, and INI-1-deficient sinonasal carcinoma. By describing the diagnosis, treatment, and prognosis of these recently defined entities, this clinical review aims to help guide oncologists in the clinical management of these patients.

Metastatic neoplasms to the thyroid diagnosed by fine-needle aspiration/core needle biopsy: Clinicopathologic and cytomorphologic correlation.

BACKGROUND: Although thyroid fine-needle aspiration (FNA) and core needle biopsy (CNB) are commonly utilized modalities in the evaluation of thyroid nodules, metastatic tumors to the thyroid are only rarely encountered. We aspired to determine the incidence and primary origin of metastases to the thyroid at our institution and to examine their clinicopathologic and cytomorphologic features. MATERIALS AND METHODS: A search of our database was undertaken to review all thyroid FNA and/or CNB examined between January 2004 and December 2013. RESULTS: During our 10 year study period, 7497 patients underwent 13,182 FNA and/or CNB. Four hundred sixty one (6%) patients were diagnosed with neoplasms. Only five (1.1%) were found to have metastatic tumors to the thyroid involving three females and two males. Two were diagnosed by FNA, one by CNB, and two by both FNA and CNB, with rapid on-site evaluation (ROSE) employed in all cases. The primary malignancies in the five cases were pulmonary and nasopharyngeal squamous cell carcinomas, renal cell carcinoma, pancreatic adenocarcinoma, and olfactory neuroblastoma. The cytomorphologic features of these metastases to the thyroid aided in their distinction from primary thyroid carcinoma. Two of these metastases, a renal cell carcinoma and pancreatic adenocarcinoma, were the first clinical manifestations of cancer. CONCLUSION: Metastases to the thyroid diagnosed by FNA and/or CNB are exceedingly rare in our institution, comprising only 0.04% of total FNA/CNB and only 1.1% of all thyroid neoplasms. We report the first known case of metastatic olfactory neuroblastoma to the thyroid diagnosed by aspiration cytology. In addition, an occult primary may present as a thyroid mass on FNA or CNB as occurred with two of our cases. FNA/CNB proved to be highly effective in the diagnosis of metastases to the thyroid, with ROSE proving valuable in assuring specimen adequacy. Thyroid FNA and CNB demonstrated great utility in the setting of metastatic disease, obviating the need for more invasive procedures.

Agreement of Different Methods for Tissue Based Detection of HER2 Signal in Invasive Breast Cancer.

Breast cancer is the second leading cause of cancer mortality amongst American women. The HER2 gene encodes a cell surface receptor that affects cell proliferation and has been recognized as a diagnostic factor in treatment selection for invasive breast cancer. Examine accuracy in HER2 detection between manual count, computer assisted, and automated tiling algorithm. 42 randomly selected invasive breast cancer specimens were enumerated by fluorescence in situ hybridization (FISH)for HER2 and CEP17 markers using the Vysis HER2 assay (AbbotLaboratory, North Chicago, IL). Specimens were tested using three methods: Manual, computer assisted nuclei selection (Tissue FISH MetaSystems, Newton, MA), and automated enumeration (MetaSystems, Newton, MA). The greatest bias and widest agreement limits for HER2 and CEP17 were seen in Automatic versus Manual, the gold standard. HER2 values greater than 6 possessed the greatest bias and widest agreement limits. CEP17 comparison showed similar bias and agreement limits for each comparison. Kappa values indicated good agreement for all methods although Tissue FISH and Manual possessed better agreement. Higher agreement at lower HER2 & CEP17 count maybe due to fewer chromosomal aberrations, in which selection of field of views has less variation between methods. Alternatively, increased background signals seen in polyploidy may be responsible for the variations in signal count. Manual and Tissue FISH demonstrated good agreement amongst by both Altman Bland and Cohen's Kappa. While the automatic method has good agreement at lower HER2, the sharp increase in variability at higher HER2 counts illustrates a limitation of the automatic method.

Sudden Development of Thrombocytopenia After Reversal of Anticoagulation for Surgery.

Herein, we report a case of post-transfusion purpura after the reversal of anticoagulation for surgical purposes in a 66-year old ethnic Asian man who was undergoing long-term warfarin therapy for antiphospholipid syndrome. The patient experienced a sudden decrease in platelet count, from 308,000 per µL from the day of admission to 38,000 per µL the following day. Follow-up testing revealed unremarkable red blood cell (RBC) morphology, no evidence of platelet clumping, and negative heparin-induced antibody test results. Platelet antibody testing revealed anti-HPA15a antibodies.

p16(INK4A) expression in invasive laryngeal cancer.

We examined p16 expression in tumors from a population-based sample of laryngeal cancer cases diagnosed in the U.S. Samples had been previously genotyped for HPV DNA. Overall, p16 expression was observed in laryngeal tissue from 8 of 101 (7.9%) cases. p16 expression was observed in 2 of 16 (12.5%) cases previously determined to be HPV DNA positive. The two cases dually positive for p16 and HPV DNA were non-keratinizing SCC and papillary SCC tumors that were positive for genotypes 18 and 35/89, respectively. Positivity for p16 and/or HPV DNA was not associated with 5-year survival (log-rank p value= 0.55). Our findings support a limited role of HPV in laryngeal carcinogenesis. p16 is not a reliable surrogate for HPV status in laryngeal cancers and is not a predictor of laryngeal cancer survival.