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.

Sinonasal (Schneiderian) Tumors in the Temporal Bone: Case Series and Systematic Review.

BACKGROUND: Neoplasms derived from the sinonasal epithelium are a rare finding in the temporal bone, and their origins are controversial. PURPOSE: To review the characteristics of sinonasal epithelial (previously known as Schneiderian) tumors occurring in the temporal bone. DATA SOURCE: This was a 2-center case series and systematic review of MEDLINE, EMBASE, and the Web of Science through May 2021. STUDY SELECTION: Patients with clinicopathologic evidence of temporal bone involvement by neoplasms of sinonasal epithelial origin were selected, with or without a history of prior primary sinonasal epithelial tumors. DATA ANALYSIS: Clinical, radiologic, and pathologic data were extracted. DATA SYNTHESIS: The systematic review included 56 studies and our 8 unpublished cases, totaling 76 cases of papillomas or squamous cell carcinomas in the temporal bone. Of these, 51% occurred secondary to sinonasal tumors, and 49% occurred primarily. Secondary tumors were usually metachronous (77%), with a median delay of 1 year from sinonasal-to-temporal bone tumor diagnosis. Most cases were unilateral (90%); bilateral temporal bone involvement occurred only as secondary ("trilateral") tumors. Unilateral secondary tumors had ipsilateral (81%) or bilateral (19%) sinonasal counterparts. Secondary tumors were more likely to be malignant (OR, 6.7, P < .001). LIMITATIONS: The review was based on case reports and small case series, which are subject to reporting bias. CONCLUSIONS: The observed tumor patterns support the hypothesis that the Eustachian tube facilitates the spread of sinonasal epithelium-derived neoplasms from the sinonasal cavity to the temporal bone. Transtubal spread of sinonasal epithelium-derived neoplasms should be considered among the rare causes of middle ear masses.

Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma: A Review and Multidisciplinary 2023 Update.

Importance: Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was categorized as a follicular thyroid carcinoma, and its management was standardized with that of other differentiated thyroid carcinomas. In 2022, given an improved understanding of the unique molecular profile and clinical behavior of oncocytic thyroid carcinoma, the World Health Organization reclassified oncocytic thyroid carcinoma as distinct from follicular thyroid carcinoma. The International Thyroid Oncology Group and the American Head and Neck Society then collaborated to review the existing evidence on oncocytic thyroid carcinoma, from diagnosis through clinical management and follow-up surveillance. Observations: Given that oncocytic thyroid carcinoma was previously classified as a subtype of follicular thyroid carcinoma, it was clinically studied in that context. However, due to its low prevalence and previous classification schema, there are few studies that have specifically evaluated oncocytic thyroid carcinoma. Recent data indicate that oncocytic thyroid carcinoma is a distinct class of malignant thyroid tumor with a group of distinct genetic alterations and clinicopathologic features. Oncocytic thyroid carcinoma displays higher rates of somatic gene variants and genomic chromosomal loss of heterozygosity than do other thyroid cancers, and it harbors unique mitochondrial DNA variations. Clinically, oncocytic thyroid carcinoma is more likely to have locoregional (lymph node) metastases than is follicular thyroid carcinoma-with which it was formerly classified-and it develops distant metastases more frequently than papillary thyroid carcinoma. In addition, oncocytic thyroid carcinoma rarely absorbs radioiodine. Conclusions and Relevance: The findings of this review suggest that the distinct clinical presentation of oncocytic thyroid carcinoma, including its metastatic behavior and its reduced avidity to radioiodine therapy, warrants a tailored disease management approach. The reclassification of oncocytic thyroid carcinoma by the World Health Organization is an important milestone toward developing a specific and comprehensive clinical management for oncocytic thyroid carcinoma that considers its distinct characteristics.

Genomic analysis of spermatocytic tumors demonstrates recurrent molecular alterations in cases with malignant clinical behavior.

Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Fluorescence lifetime of injected indocyanine green as a universal marker of solid tumours in patients.

The surgical resection of solid tumours can be enhanced by fluorescence-guided imaging. However, variable tumour uptake and incomplete clearance of fluorescent dyes reduces the accuracy of distinguishing tumour from normal tissue via conventional fluorescence intensity-based imaging. Here we show that, after systemic injection of the near-infrared dye indocyanine green in patients with various types of solid tumour, the fluorescence lifetime (FLT) of tumour tissue is longer than the FLT of non-cancerous tissue. This tumour-specific shift in FLT can be used to distinguish tumours from normal tissue with an accuracy of over 97% across tumour types, and can be visualized at the cellular level using microscopy and in larger specimens through wide-field imaging. Unlike fluorescence intensity, which depends on imaging-system parameters, tissue depth and the amount of dye taken up by tumours, FLT is a photophysical property that is largely independent of these factors. FLT imaging with indocyanine green may improve the accuracy of cancer surgeries.

CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.

Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.

PEComa of the Adrenal Gland: A Clinicopathologic Series of 7 Cases.

PEComas are a family of mesenchymal neoplasms composed of histologically distinctive perivascular epithelioid cells which demonstrate myomelanocytic differentiation. PEComas of the adrenal gland are very rare and can represent a considerable diagnostic challenge given their morphologic overlap with more common adrenal cortical neoplasms. We present the clinicopathologic features of 7 primary adrenal PEComas. The cohort comprised 5 male and 2 female patients with a median age of 63 years (range: 31 to 71 y). One patient had Birt-Hogg-Dubé syndrome and another had Lynch syndrome; however, none had a history of tuberous sclerosis complex. Histologically, tumors showed nested and/or sheet-like growth and epithelioid cytomorphology with pale-to-eosinophilic granular cytoplasm. Two tumors had an admixed spindle cell component. There was a median of 4 mitoses per 10 HPFs (range: 0 to 8). Necrosis was present in 4 tumors and lymphovascular invasion in 1. Four tumors were classified as malignant. By immunohistochemistry, tumors were positive for HMB-45 (3/7), MITF (3/3), Melan-A (3/7), smooth muscle actin (5/7), desmin (5/7), and caldesmon (1/1). Two tumors were positive for TFE3 (2/4). Inhibin and SF1 were negative in all tumors assessed (0/6). Of 3 patients with available clinical follow-up information, 1 patient developed locally recurrent and metastatic disease (at 18 mo) and was alive with persistent disease at the last follow-up. Two patients had no recurrent or metastatic disease at the last follow-up (60 and 25 mo). Although PEComas of the adrenal gland are rare, pathologists need to be alert to this entity in the differential diagnosis of primary adrenocortical neoplasms. In suspected cases, the judicious use of melanocytic and smooth muscle markers, in addition to TFE3 and markers of adrenocortical differentiation (such as SF1 and inhibin) can assist in diagnosis. As in PEComas arising at other visceral sites, an association with tuberous sclerosis complex seems to be uncommon.

Update on Molecular Diagnostics in Thyroid Pathology: A Review.

Thyroid nodules are quite common, and the determination of a nodule of concern is complex, involving serum testing, radiology and, in some cases, pathological evaluation. For those nodules that raise clinical concern of neoplasia, fine needle aspiration biopsy is the gold standard for evaluation; however, in up to 30% of cases, results are indeterminate for malignancy, and further testing is needed. Advances in molecular testing have shown it to be of benefit for both diagnostic and prognostic purposes, and its use has become an integral part of thyroid cancer management in the United States and in several global nations. After The Cancer Genome Atlas (TCGA) consortium published its molecular landscape of papillary thyroid carcinoma (PTC) and reduced the "black matter" in PTC from 25% to 3.5%, further work ensued to clarify the remaining fraction not neatly attributed to the BRAFV600E-like or RAS-like phenotypes of the TCGA. Over the past decade, commercial molecular platforms have been refined as data accrues, and they increasingly cover most genetic variants of thyroid carcinomas. Molecular reporting focuses on the nodule tested, including related clinical information for that nodule (size of nodule, Bethesda category, etc.). This results in a comprehensive report to physicians that may also include patient-directed, clear language that facilitates conversations about nodule management. In cases of advanced or recurrent disease, molecular testing may become essential for devising an individual therapeutic plan. In this review, we focus on the evolution of integrated molecular testing in thyroid nodules, and how our understanding of tumor genetics, combined with histopathology, is driving the next generation of rational patient management, particularly in the context of emerging small, targetable therapeutics.

Diagnosis and Management of Tropomyosin Receptor Kinase Fusion-Positive Thyroid Carcinomas: A Review.

Importance: Thyroid epithelial malignant neoplasms include differentiated thyroid carcinomas (papillary, follicular, and oncocytic), follicular-derived high-grade thyroid carcinomas, and anaplastic and medullary thyroid carcinomas, with additional rarer subtypes. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has fostered developments in precision oncology, with the approval of tropomyosin receptor kinase inhibitors (larotrectinib and entrectinib) for patients with solid tumors, including advanced thyroid carcinomas, harboring NTRK gene fusions. Observations: The relative rarity and diagnostic complexity of NTRK gene fusion events in thyroid carcinoma present several challenges for clinicians, including variable access to robust methodologies for comprehensive NTRK fusion testing and poorly defined algorithms of when to test for such molecular alterations. To address these issues in thyroid carcinoma, 3 consensus meetings of expert oncologists and pathologists were convened to discuss diagnostic challenges and propose a rational diagnostic algorithm. Per the proposed diagnostic algorithm, NTRK gene fusion testing should be considered as part of the initial workup for patients with unresectable, advanced, or high-risk disease as well as following the development of radioiodine-refractory or metastatic disease; testing by DNA or RNA next-generation sequencing is recommended. Detecting the presence of NTRK gene fusions is important to identify patients eligible to receive tropomyosin receptor kinase inhibitor therapy. Conclusions and Relevance: This review provides practical guidance for optimal integration of gene fusion testing, including NTRK gene fusion testing, to inform the clinical management in patients with thyroid carcinoma.

Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma.

Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity. SIGNIFICANCE: HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR-Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC. See related article by Frank et al., p. 1884. This article is highlighted in the In This Issue feature, p. 1749.

The Tyrosine Kinase Inhibitor Lenvatinib Inhibits Anaplastic Thyroid Carcinoma Growth by Targeting Pericytes in the Tumor Microenvironment.

Background: Anaplastic thyroid carcinoma (ATC) is a rapidly fatal cancer with a median survival of a few months. Enhanced therapeutic options for durable management of ATC will rely on an understanding of genetics and the role of the tumor microenvironment. The prognosis for patients with ATC has not improved despite more detailed scrutiny of underlying tumor genetics. Pericytes in the microenvironment play a key evasive role for thyroid carcinoma (TC) cells. Lenvatinib improves outcomes in patients with radioiodine-refractory well-differentiated TC. In addition to the unclear role of pericytes in ATC, the effect and mechanism of lenvatinib efficacy on ATC have not been sufficiently elucidated. Design: We assessed pericyte enrichment in ATC. We determined the effect of lenvatinib on ATC cell growth cocultured with pericytes and in a xenograft mouse model from human BRAFWT/V600E-ATC-derived cells coimplanted with pericytes. Results: ATC samples were significantly enriched in pericytes compared with normal thyroid samples. BRAFWT/V600E-ATC-derived cells were resistant to lenvatinib treatment shown by a lack of suppression of MAPK and Akt pathways. Moreover, lenvatinib increased CD47 protein (thrombospondin-1 [TSP-1] receptor) levels over time vs. vehicle. TSP-1 levels were downregulated upon lenvatinib at late vs. early time points. Critically, ATC cells, when cocultured with pericytes, showed increased sensitivity to this therapy and ultimately decreased number of cells. The coimplantation in vivo of ATC cells with pericytes increased ATC growth and did not downregulate TSP-1 in the microenvironment in vivo. Conclusions and Implications: Pericytes are enriched in ATC samples. Lenvatinib showed inhibitory effects on BRAFWT/V600E-ATC cells in the presence of pericytes. The presence of pericytes could be crucial for effective lenvatinib treatment in patients with ATC. Degree of pericyte abundance may be an attractive prognostic marker in assessing pharmacotherapeutic options. Effective durable management of ATC will rely on an understanding not only of genetics but also on the role of the tumor microenvironment.

Correlation of Intraoperative Ultrasonographic Oral Tongue Shape and Border and Risk of Close Margins.

Intraoperative ultrasound (IOUS) is a potentially useful adjunct to the resection of oral tongue cancers (OTC). IOUS images of the tumor-normal tissue interface show different patterns of invasion. In this retrospective series of 29 patients treated for OTC, we evaluated if there was a correlation between IOUS findings of patterns of invasion and final histology and assessed if there was any associated risk of increased incidence of positive or close margins with different patterns of invasion as seen on ultrasound. Although we found no significant correlation between ultrasound patterns of invasion and histological evaluation, we did find that an infiltrative pattern of invasion on IOUS did result in a significant risk of a close margin. Further exploration of these findings in a larger prospective study could provide definitive information on the efficacy of this modality in OTC resections.

A Comprehensive Study on the Diagnosis and Management of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features.

Background: Since the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) was introduced in 2016, most retrospective studies have included cases diagnosed as encapsulated follicular variant of papillary thyroid carcinoma. We investigate a cohort diagnosed with NIFTP at resection. Methods: Retrospective institutional cohort of NIFTP from 2016 to 2022, including clinical, cytological, and molecular data for 319 cases (6.6% of thyroid surgeries, 183 cases as NIFTP-only). Results: The patient cohort had unifocal or multifocal thyroid nodules. Female:male ratio was 2.7:1, mean age was 52 years and median NIFTP size was 2.1 cm. NIFTP was associated with multiple nodules in 23% patients (n = 73) and 12% of NIFTP were multifocal (n = 39). Fine needle aspiration (FNA) of NIFTP (n = 255) were designated as nondiagnostic = 5%, benign = 13%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) = 49%, follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) = 17%, suspicious for malignancy = 12%, or malignant = 4%. Molecular alterations were identified in 93% (n = 114), RAS or RAS-like. Thyroid Imaging Reporting and Data System (TI-RADS) score 4 was recorded in 50% of NIFTP, followed by scores 3 and 5 (26% and 20%, respectively). We also investigated the factors associated with extent of surgery. In our NIFTP-only group (n = 183), 66% were identified after hemithyroidectomy (HT) and 34% after total thyroidectomy (TT). On univariate analysis, TT patients demonstrated higher Bethesda category by FNA, more often had aberrant preoperative thyroid function, and/or underwent an FNA of additional nodule(s). With multivariable regression, Bethesda V NIFTP, in the presence of other nodules being evaluated by FNA and aberrant preoperative thyroid function, independently predicts TT. Bethesda II NIFTP correlated significantly with HT. Fifty-two patients (28%) with NIFTP-only had at least one postoperative surveillance ultrasound. In the NIFTP-only cohort, no HT patients had completion thyroidectomy or received postoperative radioactive iodine. No recurrence or metastases were recorded with median follow-up of 35 months (6-76 months; n = 120). Conclusions: Given this large cohort of NIFTP, including a large subset of isolated NIFTP-only, some with >6 years of follow-up and no tumor recurrences, consensus practical guidelines are needed for adequate postoperative management. Given the American Thyroid Association (ATA) provides guidelines for management of low-risk malignancies, guidance regarding that for borderline/biologically uncertain tumors, including NIFTP, is a reasonable next step.

Preoperative, Intraoperative, and Postoperative Parathyroid Pathology: Clinical Pathologic Collaboration for Optimal Patient Management.

Parathyroid disease typically presents with parathyroid hyperfunction as result of neoplasia or a consequence of non-neoplastic systemic disease. Given the parathyroid gland is a hormonally active organ with broad physiologic implications and serologically accessible markers for monitoring, the diagnosis of parathyroid disease is predominantly a clinical pathologic correlation. We provide the current pathological correlates of parathyroid disease and discuss preoperative, intraoperative, and postoperative pathology consultative practice for optimal patient care.