Executive Summary of the American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

OBJECTIVE: The aim of this study was to develop evidence-based recommendations for safe, effective and appropriate thyroidectomy. BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the United States. METHODS: The medical literature from January 1, 1985 to November 9, 2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches Laryngology Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSION: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

OBJECTIVE: To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy. BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US. METHODS: The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches to Thyroidectomy, Laryngology, Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSIONS: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

A case of tumor-to-tumor metastasis of cutaneous malignant melanoma.

We report a case of tumor-to-tumor metastasis of a cutaneous malignant melanoma to a synchronous thyroid Hurthle cell carcinoma. A 42-year-old male underwent a biopsy of right inguinal lymphadenopathy which showed metastatic melanoma. The primary lesion was identified on his right posterior leg, and staging workup discovered a synchronous left thyroid lobe nodule concerning for a follicular neoplasm. He underwent excision of the primary melanoma, right inguinal lymphadenectomy, and total thyroidectomy. The resected thyroid contained a 6.6-cm, well-encapsulated left-sided nodule, red-brown in color and homogenous in consistency, with areas of focal hemorrhage and no grossly identifiable calcification. Microscopically, large tumor cells with distinct cell borders were present, with deeply eosinophilic and granular cytoplasm, large nuclei with prominent nucleoli, and loss of polarity consistent with oncocytes. A microscopic single focus of vascular invasion was identified, and a diagnosis of angioinvasive Hurthle cell carcinoma was made. Within the Hurthle cell carcinoma, multiple deposits of metastatic melanoma were seen. These findings were indicative of tumor-to-tumor metastasis of the cutaneous melanoma to the angioinvasive Hurthle cell carcinoma. Our findings show the ability of melanoma to metastasize to a pre-existing neoplasm.

The utility of the Milan System as a risk stratification tool for salivary gland fine needle aspiration cytology specimens.

OBJECTIVE: To perform a retrospective investigation of our institutional experience with salivary gland fine needle aspirations (FNA) through the framework of The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) and assess the risks of neoplasm and malignancy for each diagnostic category. METHODS: All salivary gland FNAs performed from January 2009 to December 2016 were retrospectively categorised according to the MSRSGC. When available, pre-operative cytological results were correlated with subsequent histological follow-up. RESULTS: In total, 893 FNAs were reviewed. The specimens were retrospectively classified as nondiagnostic (ND: 13.5%), non-neoplastic (NN: 16.1%), atypia of undetermined significance (AUS: 10.8%), benign neoplasm (BN: 34.9%), salivary gland neoplasm of uncertain malignant potential (SUMP: 8.2%), suspicious for malignancy (SM: 2.7%) and malignant (M: 13.8%). Histological follow-up was available for 429 cases (48%); the majority (68.1%) were benign. The risks of neoplasm and malignancy for each category were as follows: ND: 64.5%, 16.1%; NN: 42.9%, 17.9%; AUS: 79.6%, 30.6%; BN: 100%, 2.2%; SUMP: 100%, 46.6%; SM: 94.7%, 78.9%; and M: 100%, 98.5%. CONCLUSIONS: The MSRSGC is a useful classification scheme for stratifying salivary gland lesions according to their associated risk of malignancy and guiding clinicians toward appropriate management. Diagnostic pitfalls are seen in a small proportion of cases and a multidisciplinary approach for assessing salivary gland pathology is essential in their evaluation.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a review for pathologists.

The rising incidence of papillary thyroid carcinoma is linked in part to inclusion of noninvasive follicular variant of papillary thyroid carcinoma. Despite its designation as carcinoma, noninvasive follicular variant of papillary thyroid carcinoma appears to be exceptionally indolent, often over treated by current treatment practices. Additionally, criteria for diagnosis have historically been subjective and challenging. Recently, an international multidisciplinary collaborative group performed a clinicopathologic survey of such cases with extended follow-up and concluded based on the outcome data that a revision in nomenclature was warranted, proposing 'Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).' This monograph is a synopsis and guide for pathologists on NIFTP and focuses on histologic features, including inclusion and exclusion criteria used to define NIFTP, as well as grossing guidelines, reporting practices, and potential diagnostic limitations.

Special types of thyroid carcinoma.

This article reviews the small percentage of thyroid tumours that are not classified as classic papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma. It includes subtypes of papillary thyroid carcinoma, including, tall-cell, hobnail/micropapillary, columnar cell, diffuse sclerosing and solid variants. Poorly differentiated carcinoma, high-grade carcinoma and anaplastic thyroid carcinoma are reviewed. Also discussed are entities that are unusual but need to be recognized as primary thyroid neoplasms, i.e. mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, and mammary analogue secretory carcinoma/secretory carcinoma. The pathological features and prognostic factors are described; a brief review of molecular correlates of these neoplasms is included.

Activating KRAS mutations are characteristic of oncocytic sinonasal papilloma and associated sinonasal squamous cell carcinoma.

Oncocytic sinonasal papillomas (OSPs) are benign tumours of the sinonasal tract, a subset of which are associated with synchronous or metachronous sinonasal squamous cell carcinoma (SNSCC). Activating EGFR mutations were recently identified in nearly 90% of inverted sinonasal papillomas (ISPs) - a related tumour with distinct morphology. EGFR mutations were, however, not found in OSP, suggesting that different molecular alterations drive the oncogenesis of these tumours. In this study, tissue from 51 cases of OSP and five cases of OSP-associated SNSCC was obtained retrospectively from six institutions. Tissue was also obtained from 50 cases of ISP, 22 cases of ISP-associated SNSCC, ten cases of exophytic sinonasal papilloma (ESP), and 19 cases of SNSCC with no known papilloma association. Using targeted next-generation and conventional Sanger sequencing, we identified KRAS mutations in 51/51 (100%) OSPs and 5/5 (100%) OSP-associated SNSCCs. The somatic nature of KRAS mutations was confirmed in a subset of cases with matched germline DNA, and four matched pairs of OSP and concurrent associated SNSCC had concordant KRAS genotypes. In contrast, KRAS mutations were present in only one (5%) SNSCC with no known papilloma association and none of the ISPs, ISP-associated SNSCCs, or ESPs. This is the first report of somatic KRAS mutations in OSP and OSP-associated SNSCC. The presence of identical mutations in OSP and concurrent associated SNSCC supports the putative role of OSP as a precursor to SNSCC, and the high frequency and specificity of KRAS mutations suggest that OSP and OSP-associated SNSCC are biologically distinct from other similar sinonasal tumours. The identification of KRAS mutations in all studied OSP cases represents an important development in our understanding of the pathogenesis of this disease and may have implications for diagnosis and therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Preoperative diagnosis of benign thyroid nodules with indeterminate cytology.

BACKGROUND: Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. METHODS: We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed. RESULTS: Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for "atypia (or follicular lesion) of undetermined clinical significance," "follicular neoplasm or lesion suspicious for follicular neoplasm," or "suspicious cytologic findings" were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. CONCLUSIONS: These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.).

Oncocytic lesions of the neuroendocrine system.

This paper reviews the pathologic features of lesions which are oncocytic and involve classic endocrine organs. The history of the oncocytic cell, its morphologic and ultrastructural features, and important immunohistochemical findings are reviewed. Oncocytic proliferations including non-neoplastic and neoplastic of the thyroid, parathyroid, adrenal (both cortex and medulla), and pituitary are described. Their clinical relevance, functional capacity and capability, and where appropriate, prognostic implications are discussed. Important and relevant molecular biological information is included where appropriate.

A prospective assessment defining the limitations of thyroid nodule pathologic evaluation.

BACKGROUND: Clinical management of thyroid neoplasms is based on light microscopic diagnosis, but its accuracy and precision are poorly defined. OBJECTIVE: To assess inter- and intraobserver variability of preoperative cytopathologic and postoperative histopathologic thyroid diagnoses. DESIGN: Samples were collected in a prospective, multicenter trial validating a gene expression classifier between June 2009 and December 2010. SETTING: 14 academic and 35 community clinical sites. PATIENTS: 653 patients with 776 surgically resected thyroid nodules of 1 cm or greater. MEASUREMENTS: Intraobserver concordance among 2 or more central histopathologists who independently read histopathology slides was calculated. Interobserver concordance between the diagnoses made by the central histopathologists and those made by local pathologists were calculated. Intra- and interobserver concordance for cytopathology was similarly calculated by comparing diagnoses made by local pathologists with those made by a central panel of 3 cytopathologists. RESULTS: Concordance on the histopathologic distinction between benign and malignant diagnoses was 91% comparing local with central histopathologists and 90% comparing 2 central histopathologists. Using the 6-category Bethesda System, 64.0% of diagnoses made by local and central cytopathologists and 74.7% of intraobserver diagnoses were concordant. Central cytopathologists made fewer indeterminate diagnoses than local pathologists (41.2% vs. 55.0%). LIMITATIONS: Many local pathologists did not use the Bethesda System, so their reports were translated to allow comparison. The study required histopathology, and the study population and specimens did not encompass all newly evaluated patients with a thyroid nodule. CONCLUSION: Substantial inter- and intraobserver variability exists in the cytopathologic and histopathologic evaluation of thyroid nodules, confirming an inherent limitation of visual microscopic diagnosis. PRIMARY FUNDING SOURCE: Veracyte.

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.

Performance of a multigene genomic classifier and clinical parameters in predicting malignancy in a Southeast Asian cohort of patients with cytologically indeterminate thyroid nodules.

BACKGROUND: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy. METHODS: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed. RESULTS: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria. CONCLUSIONS: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters.

Malignant potential of small oncocytic follicular carcinoma/Hürthle cell carcinoma: an institutional experience.

AIMS: Oncocytic follicular carcinoma/Hürthle cell carcinoma (OFCA/HCCA) is a rare tumour of the thyroid gland that can be associated with an aggressive clinical course. Most OFCA/HCCAs are large; however, tumours ≤20 mm can occur. The aim of this study was to report our experience with OFCA/HCCA diagnosed at our institution. METHODS AND RESULTS: One hundred and nineteen cases of OFCA/HCCA were included in this study. Data points included age, sex, size of tumour, method of diagnosis, lymph node (LN) status, and clinical follow-up. The cohort included 37 males and 82 females (average age: 55 years). Preoperative fine-needle aspiration (FNA) was performed in 73 (61%) cases. Twenty-five (21%) tumours measured ≤20 mm and 94 (79%) measured >20 mm. Angioinvasion (AI) was present in 48 (40%) cases, and LN metastases (LNMs) in seven (6%) cases; of these, eight (17%) with AI and 1 (2%) with LNMs measured ≤20 mm. Clinical follow-up was available in 74 (62%) cases (range 12-144 months); 13 (17.5%) developed LNMs and six (8%) regional recurrence. Distant metastases (DMs) were seen in 12 (16%) cases. Two cases with DMs and two with LN recurrence measured ≤20 mm. CONCLUSIONS: Oncocytic follicular carcinoma/Hürthle cell carcinoma (OFCA/HCCA) can present as small (≤20 mm) tumours, and can be associated with AI, LNM, and DM.

Metastatic cholangiocarcinoma to the ovary: a case series.

Metastases to the ovary can be a challenging diagnostic dilemma as they often present similarly to a primary ovarian cancer, and there are many potential sites of origin. We present a case series of 5 patients with known cholangiocarcinoma recurrent in the ovary after completion of initial multimodality therapy including surgical resection of the primary tumor followed by adjuvant chemotherapy.

Pathology of the parathyroid glands in hyperparathyroidism.

This paper reviews the embryology, histology and pathology of the human parathyroid glands. It emphasizes those pathologic lesions which are found in the setting of clinical hyperparathyroidism. Also discussed are certain molecular features of hyperfunctioning parathyroid glands. The difficulties encountered in parathyroid FNA are reviewed and illustrated.

Insights Obtained from the Nontumorous Glandular Tissue in Patients with Endocrine Tumors.

The pathology of neoplasia tends to focus on the tumor that requires characterization, grading, and staging. However, nontumorous tissue surrounding the lesion can also provide information, particularly about pathogenetic mechanisms. In endocrine tissues, this takes the form of precursor lesions that characterize several genetic predisposition syndromes. In addition, because of the unique functional aspects of endocrine neoplasia, the nontumorous tissue provides evidence of hormone excess, with hyperplasia and/or atrophy and other involutional changes allowing the pathologist to confirm both hormone function by the tumor and the effects of medical therapies. In this article, we review the various clinically relevant features that should be assessed and reported to enhance clinical management of patients with endocrine neoplasms. For example, in thyroid there may be inflammatory thyroiditis or goiter of various etiologies; there may be C-cell hyperplasia either as a preneoplastic lesion in patients with genetic predisposition to medullary thyroid carcinoma or as a reactive phenomenon. Drug-induced changes can be seen in thyroid and adrenal cortex. In neuroendocrine tissues, the nontumorous tissues may show precursor lesions such as endocrine cell hyperplasia/dysplasia; there may be related or unrelated hyperplastic or neoplastic lesions. Some tissues, such as pituitary corticotrophs and adrenal cortex, develop changes that reflect feedback suppression by hormone excess that can serve as biomarkers of tumor functionality and provide enhanced clinicopathologic correlates.

The Thyroid Pathologist Meets Therapeutic Pharmacology.

The effects of many pharmacological agents on thyroid function are well known. Direct influences on measurements of thyroid function tests are also described. However, certain classes of drugs produce morphological changes in the gland. This review focuses on the significance of the following drug classes for the thyroid pathologist: iodine, antithyroid drugs, psychotropic drugs, antibiotics, cardiotropic drugs, antidiabetic drugs, and immunomodulatory agents. Radioactive iodine initially induces mild histologic changes; however, the long-term effects include marked follicular atrophy, fibrosis, and nuclear atypia-changes that vary depending on the pre-therapy condition of the gland. Some psychotropic drugs have been associated with a spectrum of inflammatory changes throughout the gland. The tetracycline class of antibiotics, namely minocycline, can lead to a grossly black thyroid gland with pigment seen in both colloid and follicular epithelial cells while variably present within thyroid nodules. The surgical pathologist most commonly sees an amiodarone-affected gland removed for hyperthyroidism, and the histologic findings again depend on the pre-therapy condition of the gland. While GLP-1 receptor agonists carry an FDA black box warning for patients with a personal or family history of multiple endocrine neoplasia or medullary thyroid carcinoma, the C cell hyperplasia originally noted in rats has not borne out in human studies. Finally, thyroiditis and hypothyroidism are well known complications of checkpoint inhibitor therapy, and rare cases of severe thyroiditis requiring urgent thyroidectomy have been reported with unique histologic findings. In this review, we describe the histologic findings for these drugs and more, in many cases including their functional consequences.

Neoplasms in Struma Ovarii: A Review.

Struma ovarii is a well-known ovarian teratoma made up of benign thyroid tissue. These lesions demonstrate variable, normal architecture and normal thyroid immunohistochemical staining with positivity for TTF1, PAX8, and thyroglobulin. Though most are benign, some of these lesions can also present with a malignant component. Within this article, we review the most common diagnostic malignancies including papillary thyroid carcinoma, strumal carcinoid, highly differentiated follicular thyroid carcinoma, and other thyroid carcinomas. We additionally review the use of TTF1 staining to assist in differentiating these lesions from surrounding gynecologic epithelium, which is imperative in making such diagnoses. In highlighting these entities, we hope to provide practicing pathologists with an effective and concise review of these lesions to assist in more challenging cases of struma ovarii.

The Cooperative Human Tissue Network of the National Cancer Institute: Supporting Cancer Research for 35 Years.

The Cooperative Human Tissue Network was created by the NCI in 1987 to support a coordinated national effort to collect and distribute high quality, pathologist-validated human tissues for cancer research. Since then, the network has expanded to provide different types of tissue samples, blood and body fluid samples, immunohistologic and molecular sample preparations, tissue microarrays, and clinical datasets inclusive of biomarkers and molecular testing. From inception through the end of 2021, the network has distributed 1,375,041 biospecimens. It served 889 active investigators in 2021. The network has also taken steps to begin to optimize the representation of diverse communities among the distributed biospecimens. In this article, the authors review the 35-year history of this network, describe changes to the program over the last 15 years, and provide operational and scientific highlights from each of the divisions. Readers will learn how to engage with the network and about the continued evolution of the program for the future.