HMGA2-positive salivary gland neoplasms with prominent trabecular/canalicular morphology: a focus on carcinomas arising within this phenotype.

AIMS: Pleomorphic adenoma (PA) with a prominent trabecular/canalicular morphology has consistent HMGA2 protein expression, and association with HMGA2 fusions. We report our experience with this subtype, with emphasis on the carcinomas that can arise in this context. METHODS AND RESULTS: A retro- and prospective review (2013-2024) of major salivary gland tumours with prominent trabecular/canalicular morphology was performed. Twenty-one parotid tumours met the criteria: 14 benign (66.7%), six carcinomas (28.6%), and one of uncertain behaviour (4.7%). HMGA2 immunohistochemistry (IHC) was performed on all cases. Next-generation sequencing was successfully performed on 18. Seven benign cases had a conventional PA component. In all cases, the tumour cells in these trabecular/canalicular areas demonstrated variable papillary thyroid carcinoma-like nuclear changes, including chromatin clearing, overcrowding, membrane irregularities, and intranuclear pseudoinclusions. Benign tumours were well-demarcated, whereas carcinomas demonstrated either a multinodular pattern of invasion or subtle infiltration. Two carcinomas showed increased cytologic atypia and architectural complexity and one had perineural invasion. By IHC, all were positive for HMGA2. In the trabecular/canalicular areas, there was consistent strong expression of CAM5.2, S-100, and SOX-10 and variable expression of p63 but negative p40. HMGA2 alterations were detected in 16 of 18 cases (89%). Follow-up was available on two carcinomas, with one being locally recurrent. CONCLUSION: While most HMGA2-positive salivary gland neoplasms with a prominent trabecular/canalicular growth pattern are benign, they, like traditional PAs, may give rise to carcinomas that can locally recur. These carcinomas can be deceptively bland, subtly infiltrative, or have a multinodular pattern of invasion.

Challenging differential diagnoses in small biopsies from the sinonasal tract.

Sinonasal biopsy specimens are a challenging area in anatomic pathology. The small, often fragmented or crushed nature of these biopsies can hinder morphologic assessment. Additionally, many of the tumors in this area are rare and share morphologic, and sometime immunophenotypic similarities. In many cases, immunohistochemistry is helpful if not necessary to reach a specific diagnosis. In other cases, a specific diagnosis is not possible and a differential diagnosis must be given on a biopsy specimen despite access to a well-equipped immunohistochemistry laboratory. This review article groups some of the more challenging entities in the sinonasal region based on morphologic patterns. These include low grade squamoid lesions such as sinonasal (Schneiderian) papilloma and DEK::AFF2 rearranged carcinoma, glandular neoplasms such as intestinal and non-intestinal type sinonasal adenocarcinoma, high-grade carcinomas such as HPV-related multiphenotypic sinonasal carcinoma, NUT carcinoma and SWI/SNF deficient carcinomas, small round blue cell tumors such as teratocarcinosarcoma, neuroendocrine carcinoma and olfactory neuroblastoma, and finally, low grade spindle cell neoplasms such as glomangiopericytoma, biphenotypic sinonasal sarcoma and solitary fibrous tumor.

Neoplastic embolization to systemic and pulmonary arteries.

OBJECTIVE: Arterial neoplastic emboli are uncommon, accounting for <1% of thromboemboli in the current literature. Nonetheless, this event may be associated with significant morbidity and mortality. Herein, we report a series of 11 cases of arterial neoplastic emboli from a single tertiary care center along with a comprehensive review of the literature to date. The aim of this study was to document the incidence, clinical presentations, and complications of arterial neoplastic emboli as well as to highlight the importance of routine histologic examination of thrombectomy specimens. METHODS: Pathology archives from a single tertiary care institution were queried to identify cases of surgically resected arterial emboli containing neoplasm (1998-2014). Histopathology was reviewed for confirmation of diagnosis. Patient demographics and oncologic history were abstracted from the medical record. Comprehensive literature review documented 332 patients in 275 reports (1930-2016). RESULTS: Eleven patients (six men) with a median age of 63 years (interquartile range, 42-71 years) were identified through institutional archives. Embolism was the primary form of diagnosis in seven (64%) cases. Cardiac involvement (primary or metastasis) was present in more than half of the cohort. Comprehensive literature review revealed that pulmonary primaries were the most common anatomic origin of arterial neoplastic emboli, followed by gastrointestinal neoplasia. Cardiac involvement was present in 18% of patients, and sentinel identification of neoplasia occurred in 30% of cases. Postmortem evaluation was the primary means of diagnosis in 27%. CONCLUSIONS: This study highlights the importance of routine histopathologic evaluation of embolectomy specimens in patients with and without documented neoplasia.

No Longer Well-Differentiated: Diagnostic Criteria and Clinical Importance of Poorly Differentiated/High-Grade Thyroid Carcinoma.

Poorly differentiated thyroid carcinoma (PDTC) and differentiated high-grade thyroid carcinoma (DHGTC) are uncommon thyroid malignancies, recently (re)codified into distinct entities with overlapping clinical significance. Recognizing them may be challenging for the general practitioner and subspecialty pathologist alike. This article will describe the required features to diagnose PDTC and DHGTC, differential diagnostic considerations, molecular findings, and clinical implications. It is intended to be a general synopsis of the most critical elements of PDTC and DHGTC as well as a summary of points in approaching these challenging cases.

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.

Margin Assessment Methods in Oral Cavity Squamous Cell Carcinoma and Recurrence: Tumor Bed vs Resection Specimen Sampling.

Importance: Positive margins and margin clearance are risk factors for recurrence in oral cavity squamous cell carcinoma (OCSCC), and these features are used to guide decisions regarding adjuvant radiation treatment. However, the prognostic value of intraoperative tumor bed vs resection specimen sampling is not well defined. Objective: To determine the prognostic implications of intraoperative margin assessment methods (tumor bed vs resection specimen sampling) with recurrence among patients who undergo surgical resection for OCSCC. Design, Setting, and Participants: This was a retrospective study of patients who had undergone surgical resection of OCSCC between January 1, 2000, and December 31, 2021, at a tertiary-level academic institution. Patients were grouped by margin assessment method (tumor bed [defect] or resection specimen sampling). Of 223 patients with OCSCC, 109 patients had localized tumors (pT1-T2, cN0), 154 had advanced tumors, and 40 were included in both cohorts. Disease recurrence after surgery was estimated by the cumulative incidence method and compared between cohorts using hazard ratios (HRs). Data analyses were performed from January 5, 2023, to April 30, 2023. Main Outcome and Measures: Recurrence-free survival (RFS). Results: The study population comprised 223 patients (mean [SD] age, 62.7 [12.0] years; 88 (39.5%) female and 200 [90.0%] White individuals) of whom 158 (70.9%) had defect-driven and 65 (29.1%) had specimen-driven margin sampling. Among the 109 patients with localized cancer, intraoperative positive margins were found in 5 of 67 (7.5%) vs 8 of 42 (19.0%) for defect- vs specimen-driven sampling, respectively. Final positive margins were 3.0% for defect- (2 of 67) and 2.4% for specimen-driven (1 of 42) margin assessment. Among the 154 patients with advanced cancer, intraoperative positive margins were found in 29 of 114 (25.4%) vs 13 of 40 (32.5%) for defect- and specimen-driven margins, respectively. Final positive margins were higher in the defect-driven group (9 of 114 [7.9%] vs 1 of 40 [2.5%]). When stratified by margin assessment method, the 3-year rates of local recurrence (9.7% vs 5.1%; HR, 1.37; 95% CI, 0.51-3.66), regional recurrence (11.0% vs 10.4%; HR, 0.85; 95% CI, 0.37-1.94), and distant recurrence (6.4% vs 5.0%; HR, 1.10; 95% CI, 0.36-3.35) were not different for defect- vs specimen-driven sampling cohorts, respectively. The 3-year rate of any recurrence was 18.9% in the defect- and 15.2% in the specimen-driven cohort (HR, 0.93; 95% CI, 0.48-1.81). There were no differences in cumulative incidence of disease recurrence when comparing defect- vs specimen-driven cases. Conclusions and Relevance: The findings of this retrospective cohort study indicate that margin assessment methods using either defect- or specimen-driven sampling did not demonstrate a clear association with the risk of recurrence after OCSCC resection. Specimen-driven sampling may be associated with reduced surgical margin positivity rates, which often necessitate concurrent chemotherapy with adjuvant radiation therapy.

SSTR2 Expression in Olfactory Neuroblastoma: Clinical and Therapeutic Implications.

Somatostatin receptor 2 (SSTR2) expression has previously been documented in olfactory neuroblastoma (ONB). Here, we fully characterize SSTR2 expression in ONB and correlate staining results with clinicopathologic parameters including Hyams grade. We also assess SSTR2 immunohistochemistry expression in various histologic mimics of ONB to assess its diagnostic functionality. 78 ONBs (51 primary biopsies/excisions and 27 recurrences/metastases) from 58 patients were stained for SSTR2. H-scores based on intensity (0-3 +) and percentage of tumor cells staining were assigned to all cases. 51 histologic mimics were stained and scored in an identical fashion. 77/78 (99%) ONB cases demonstrated SSTR2 staining (mean H-score: 189, range: 0-290). There were no significant differences in staining between primary tumors and recurrences/metastases (mean H-score: 185 vs 198). Primary low-grade ONB had somewhat stronger staining than high-grade tumors (mean H-score: 200 vs 174). SSTR2 expression had no prognostic value when considering disease-free or disease-specific survival. SSTR2 staining is significantly higher in ONB than its histologic mimics (mean H-score: 189 vs 12.9, p < 0.001) suggesting a potential use of the marker in diagnosis of ONB. In conclusion, SSTR2 is consistently expressed in ONB suggesting a role for somatostatin-analog based imaging and therapy in this disease. More generally, SSTR2 may be another marker of neuroendocrine differentiation in ONB.

An Evaluation of CD61 Immunohistochemistry in Identification of Vascular Invasion in Follicular Thyroid Neoplasms.

The identification of vascular invasion in follicular thyroid neoplasms is essential for categorizing lesions as benign (follicular adenomas) or malignant (follicular thyroid carcinomas). Among the histologic criteria diagnostic of true vascular invasion is tumor-cell associated thrombosis, including fibrin deposition and platelet clumping. This study aims to evaluate whether an immunohistochemical stain for the platelet-associated protein CD61 could assist in identifying tumor-associated thromboses and thereby confirm vascular invasion in follicular thyroid neoplasms. Histologic review and CD61 immunostaining of 19 atypical follicular adenomas, 13 non-metastatic follicular thyroid carcinomas, and 11 metastatic follicular thyroid carcinomas was performed. Linear arrays or clustered groups of CD61-expressing intravascular platelets were present in 51% of cases overall, including 54% of follicular thyroid carcinomas and 47% of follicular adenomas, mostly within intracapsular or peritumoral vessels. In three follicular thyroid carcinomas (all with distant metastases), CD61-expressing platelets were present in association with intravascular tumor cells. This finding was not present in adenomas. CD61 staining alone did not distinguish between atypical follicular adenomas, non-metastatic carcinomas, and metastatic carcinomas. When present in association with intravascular tumor cells, however, CD61-expressing platelets may serve as a marker for vascular invasion and aid in the diagnosis of follicular thyroid carcinoma.

Follicular Thyroid Neoplasms: Comparison of Clinicopathologic and Molecular Features of Atypical Adenomas and Follicular Thyroid Carcinomas.

In follicular thyroid neoplasms without invasion, a diagnosis of atypical adenoma (AA) (follicular tumor of uncertain malignant potential) may be rendered if atypical features (indefinite capsular/vascular invasion, necrosis, solid growth, increased mitoses) are present. This study compares clinical, histologic, and molecular features of patients with AAs (n=31), nonmetastatic follicular thyroid carcinoma (nmFTC) (n=18), and metastatic follicular thyroid carcinoma (mFTC) (n=38). Patients with mFTC were older. Mitotic activity in areas of solid growth was greatest in mFTC (P=0.05). Oncocytic tumors tended to show solid growth (P=0.04). The presence or frequency of capsular and/or vascular invasion was not different between nmFTC and mFTC. TERT promoter mutations were higher in patients with mFTC (50%) than nmFTC (25%) and AA (10%) (P=0.02). TERT promoter mutation was associated with necrosis (P=0.01) and solid growth plus increased mitoses (P=0.03). Necrosis and TERT promoter mutations were identified in all groups, most frequently in mFTC. The combination of solid growth with increased mitoses, necrosis, and TERT promoter mutation was only seen in follicular carcinomas. Poorly differentiated features, vascular invasion, and TERT promoter mutation correlated with metastasis in FTC. Given the low frequency of necrosis and TERT promoter mutation in AAs, close clinical follow-up is recommended in patients with these findings, especially if additional atypical features (such as solid growth plus mitoses) are present.

Head and Neck Sinus Histiocytosis with Massive Lymphadenopathy Radiology-Pathology Correlation.

Sinus histiocytosis with massive lymphadenopathy, or Rosai-Dorfman disease, is a rare, benign type of non-Langerhans cell histiocytosis. The radiological findings are often nonspecific, potentially mimicking malignancies. The diagnosis is ultimately made based on pathology, in which the lymph nodes are characterized by a dilated subcapsular sinus filled with histiocytes that can exhibit emperipolesis. Immunohistochemically, the histiocytes are variably CD68 positive and reliably negative for CD1a. The features of head and neck sinus histiocytosis with massive lymphadenopathy are exemplified in this radiology-pathology correlation sine qua non article.

Art as a Learning Tool: Medical Student Perspectives on Implementing Visual Art into Histology Education.

Creating visual art to teach and learn histologic concepts is uncommon. A pilot visual art program was developed for use in first-year medical student courses that include histology with the hypothesis that creating visual art would subjectively improve the learning process and lead to learner-based personal incorporation of art into in future learning. Prior to the term, volunteers (n=25) were recruited from 89 first-year medical students. The volunteer group was given art supplies and encouraged to draw histologic images in a free-form setting without restrictions. The control group (n=64) consisted of non-volunteers. Pre- and post-term surveys were distributed to all students, of which 72% and 45% completed the surveys, respectively. Regardless of participation, a majority of students viewed art as a valuable tool to learn medicine prior to and following the term (73% and 82.5%, respectively), however less than half admitted to using art to learn medical concepts (42% and 40%, respectively). In the post-term survey, a higher percentage of students in the experimental group stated they will use art to learn medical concepts in the future (75% vs 40.6%). Most students considered art to be a valuable resource to learn concepts in medicine, including all the students who participated in the art program. Based on the number of students who reported intent to change behavior, the initial hypothesis is supported. Many students favor incorporation of visual art into medical education, we believe that creating visual art may be a worthwhile adjunct tool for histology education.

Clinicopathologic and Molecular Features of Metastatic Follicular Thyroid Carcinoma in Patients Presenting With a Thyroid Nodule Versus a Distant Metastasis.

Metastatic follicular thyroid carcinoma (FTC) is rare. The aim of this study was to determine the clinical, histologic, and molecular differences between patients with metastatic FTC who present with distant metastatic (DM) disease versus those who present with a primary thyroid nodule (PT). Clinical and pathologic information was extracted from the medical record and surgical pathology report. When available, slides were reviewed. Molecular testing was performed on available primary and/or metastatic lesions. Thirty-six patients with metastatic FTC were identified: 15 DM and 21 PT. DM patients were significantly older than those with PT (P=0.0001). In DM patients, bone was the most common site of initial metastasis (P=0.03), compared with lung in PT patients (P=0.03). Unique to primary carcinomas in DM patients was extensive intratumoral fibrosis (50%), occasionally reaching such a degree as to obscure histologic features of malignancy (2 cases). Oncocytic features were more common in those who presented with PT (P=0.03). Pathogenic mutations were identified in 85% of cases, most commonly in RAS (55%) and TERT promoter (45%); of these, combined RAS and TERT was present in 30%. Pathogenic PTEN, NF1, RET, and BRCA2 mutations were also identified. The prevalence and type of pathogenic mutations did not differ between DM and PT patients. The acquisition of a pathogenic mutation in the metastatic focus that was not present in the primary carcinoma was rare (1 case). In summary, FTC presenting with DM compared with PT was more likely to be present in an older age group, to metastasize to bone, and to demonstrate extensive fibrosis possibly representing histologic regression.

Ubiquitin Immunostaining in Thyroid Neoplasms Marks True Intranuclear Cytoplasmic Pseudoinclusions and May Help Differentiate Papillary Carcinoma from NIFTP.

Papillary thyroid carcinoma (PTC) is defined by an invasive growth pattern and classic nuclear features: enlarged, grooved, overlapping nuclei with chromatin clearing and intranuclear cytoplasmic pseudoinclusions (INCP). True INCPs are characteristic of PTC, but may infrequently be seen in noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Nuclear abnormalities that mimic INCP ("pseudo-pseudoinclusions") are common in a variety of thyroid lesions. H&E and ubiquitin-stained whole tissue sections of classic PTC (n = 25) and NIFTP (n = 35) were evaluated. On H&E, true INCPs were present in all (100%) PTCs and absent in all NIFTPs (0%). Pseudo-pseudoinclusions were present in 13 (37%) NIFTPs. In 24 (96%) PTCs, ubiquitin was strongly expressed within INCPs. In NIFTPs, optically clear nuclei or pseudo-pseudoinclusions did not express ubiquitin (0/35). Occasionally, nuclear vacuoles in NIFTP demonstrated a marginated staining pattern, in which strong ubiquitin expression was seen at the periphery of the nucleus, but the central pale area was negative. In addition, 2 NIFTPs demonstrated intrafollicular psammomatoid calcifications which were strongly ubiquitin-positive. Psammoma bodies in PTC were ubiquitin-negative in the majority of cases. We report a previously undescribed finding: strong ubiquitin expression in true INCPs in PTC, absence of true INCPs in NIFTP, and absence of ubiquitin expression in pseudo-pseudoinclusions in NIFTP. This finding supports the difference between true INCPs (found only in PTC) and pseudo-pseudoinclusions (found in NIFTP). Using strict histologic criteria and ubiquitin immunostaining, the presence of true pseudoinclusions may exclude a diagnosis of NIFTP. Caution should be exercised when interpreting nuclear vacuoles or pseudo-pseudoinclusions.

A Herald of Plasma Cell Myeloma: A Report of Malignant Plasma Cells Identified in Parathyroid Adenoma and a Review of Non-parathyroid Malignancies in Parathyroid Glands.

Involvement of the parathyroid glands by non-parathyroid neoplasia is an infrequent event. Rare cases of metastases to the parathyroid gland have been reported in parathyroidectomies and autopsies of patients with known solid or hematopoietic malignancies. Here, we present a case of atypical clonal plasma cells incidentally identified within a parathyroid adenoma resected for hyperparathyroidism and hypercalcemia, which served as the sentinel event for a subsequent diagnosis of plasma cell myeloma. To our knowledge, this is the only reported case of a hematopoietic malignancy involving a parathyroid adenoma and the only reported case of malignant hematopoietic cells initially detected in parathyroidectomy.

Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas with Unique Molecular Signatures.

Despite the relatively high prevalence of thyroid cancer, the occurrence of multiple synchronous, distinct subtypes of primary thyroid carcinoma is uncommon. The incidental finding of papillary thyroid microcarcinoma in a gland with a biologically relevant follicular or medullary carcinoma is more frequent than the synchronous occurrence of multiple clinically significant carcinomas. We report a case of synchronous papillary and follicular thyroid carcinomas metastatic to lymph node and bone, respectively. Next generation sequencing showed BRAF V600E mutation in the primary papillary carcinoma and NRAS Q61R mutation in the primary follicular carcinoma and bony metastasis. To our knowledge, this is the first reported case of synchronous and metastatic primary papillary and follicular carcinomas, and the first report of synchronous BRAF V600E mutated papillary and NRAS mutated follicular carcinoma.