A comparison of the histopathologic features of thyroid carcinomas with NTRK fusions to those with other malignant fusions.

BACKGROUND: Chromosomal rearrangements involving one of the NTRK genes result in oncogenic driver mutations in thyroid carcinoma (TC) and serve as a target for therapy. We compared the clinicopathologic features of thyroid carcinomas with NTRK fusions vs. thyroid neoplasms with other malignancy associated gene fusions within our institution. MATERIALS AND METHODS: Our pathology archives were searched from 2013 to 2023 for thyroid neoplasms with gene fusions, excluding THADA fusions and medullary thyroid carcinomas. RESULTS: 55 thyroid lesions were identified: 22 with NTRK fusions (NTRK cohort) and 33 with other fusions (non-NTRK cohort). On fine needle aspiration (FNA), 54% of the NTRK cohort were classified as Category V as per Bethesda System for Reporting Thyroid Cytology (TBSRTC) and 51.5% of non-NTRK cohort as TBSRTC Category III. In the NTRK cohort, the most common reported fusion was ETV6::NTRK3 and the most common reported fusion in the non-NTRK cohort was PAX8::PPAR-gamma. On histologic examination both cohorts were most commonly diagnosed as PTC follicular variant. Invasive features were more common in the NTRK cohort in comparison to the non-NTRK cohort. Locoregional recurrence occurred in 2/22 NTRK cases and 2/33 non-NTRK cases, with average time from surgery to recurrence being 5.5 months and 21 months, respectively. The majority of patients in both groups are alive with no evidence of disease. CONCLUSIONS: Thyroid neoplasms with a malignancy associated gene fusion are likely to be diagnosed as subtype/variant of PTC. Patients whose thyroid lesions harbor NTRK fusions present with a PTC-FV that on presentation has more aggressive clinicopathologic findings and are likely to have earlier disease recurrence.

Differentiated high grade thyroid carcinomas: Diagnostic consideration and clinical features.

BACKGROUND: Differentiated high-grade thyroid carcinomas (DHGTCs) are a new diagnostic entity most recently defined in the 2022 World Health Organization's (WHO) Classification of Endocrine and Neuroendocrine Tumors. This new entity has been minimally described in the literature, and additional cases classified as such are missing. MATERIALS AND METHODS: Cases of DHGTCs diagnosed at our institution from 2012 to 2022 were identified, and the following were reviewed: cytologic and histologic diagnoses, ancillary testing, immunohistochemical staining, treatments, and patient outcomes. Immunohistochemical staining for Ki67 was performed on selected cases lacking this immunostain. A systematic literature review of the English literature on DHGTCs from 2013 to 2023 was performed using PubMed and Embase. RESULTS: Case cohort included 32 cases of DHGTCs, with an average age of 52.6 years (range 17-84 years) and a male:female ratio of 1.3:1. All cases underwent fine needle aspiration (FNA) and were categorized by The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as follows: 14 cases as malignant (43.8 %), 10 as follicular neoplasm (31.3 %), 5 as atypia of undetermined significance (15.6 %), 2 as suspicious for malignancy (6.2 %), and 1 as non-diagnostic (3.1 %). The average tumor size was 5.15 cm, and most were papillary thyroid carcinoma (28, 87.5 %), with classic subtype being the most common. Twenty-one cases revealed tumor necrosis and the mitotic activity in lesions without necrosis averaged to 5.5 mitoses per 2 mm2 (range 0-7). The average Ki67 proliferative index was 5.6 %. Extrathyroidal extension was seen in 17, angioinvasion in 21, lymphatic invasion in 7, and perineural invasion in 1 case. Foci of solid or trabecular growth were identified in five cases. Lymph node metastases at the time of diagnosis were noted in 10 cases and 7 demonstrated distant metastases or locoregional recurrence. To date, 25 patients are alive, and one has died from disease. CONCLUSIONS: Our institutional experience demonstrates that DHGTC is a rare, but aggressive thyroid tumor subtype that requires consideration in the setting of a well-differentiated thyroid neoplasm to appropriately assess for possible disease recurrence and determination of patient prognosis.

An investigation into noninvasive follicular thyroid neoplasms with papillary-like nuclear features: does the initial proposal on noninvasive follicular thyroid neoplasms with papillary-like nuclear features behavior hold true?

Current management of patients with noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) is lobectomy with close clinical follow-up. Because this entity is still young, we present our 5-year institutional experience with NIFTP since that time. Cases of NIFTP diagnosed from 2017 to 2022 were identified. Data points including patient demographics, radiology, cytologic and pathologic diagnoses, molecular profiles, and clinical follow-up were documented. A literature review of NIFTP case series was performed. A total of 379 cases were included (mean age: 52 years, female:male ratio 3.3:1). Ultrasound findings were available for 260 patients, and 247 underwent fine-needle aspiration (FNA). The FNA diagnoses per the Bethesda System for Reporting Thyroid Cytology were nondiagnostic (n = 2), benign (n = 16), atypia of undetermined significance/follicular lesion of undetermined significance (n = 119), follicular neoplasm/suspicious for follicular neoplasm (n = 68), suspicious for malignancy (n = 31), and malignant (n = 11). Molecular testing was performed in 179 cases. Lobectomy was performed for 183, total thyroidectomy for 192, and nodulectomy for 4 cases. The average size of NIFTP was 2.3 cm, and 232 cases had additional nodules (including benign and malignant neoplasms). Multifocal NIFTP occurred in 32 patients. Lymph nodes were evaluated in 196 cases with metastatic carcinoma in 29 cases (all with concurrent diagnoses of carcinoma). Most patients were alive at follow-up, 100 were lost to follow-up, and three died from other causes. Literature review revealed 2870 NIFTP cases with similar patient demographics and pathologic findings. We confirm that NIFTP is a low-risk neoplasm with indolent clinical behavior, which can be managed conservatively.

Impact on clinical follow-up of the Milan System for salivary gland cytology: A comparison with a traditional diagnostic classification.

INTRODUCTION: No universally accepted classification exists for salivary gland FNA. The proposed Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) offers a uniform classification with management recommendations. We compared FNA diagnoses from a prior study with specific diagnoses with corresponding MSRSGC diagnoses. METHODS: One-hundred and sixty-four cases from a prior cytological study with histological follow-up were re-reviewed by one of the authors and assigned to one of the MSRSGC categories. The original and MSRSCG diagnoses were compared, as were follow-up recommendations. RESULTS: The MSRSGC system classified 29 specimens as non-diagnostic (seven histologically shown to be benign salivary gland, two non-mucinous cysts, 14 sialadenitis, one pleomorphic adenoma, one haemangioma, one lymphoma, one adenoid cystic carcinoma, one squamous carcinoma and one benign lymphoid proliferation). The original study diagnosed these lesions as: seven benign cysts, 15 benign salivary gland tissue, one benign neoplasm and two insufficient for diagnosis. In seven cases, MSRSGC disagreed with original diagnoses and surgical resection showed lesions where optimal follow-up was more consistent with original cytological diagnosis. In 10 cases with disagreement, the MSRSGC was associated with a more appropriate follow-up based on the surgical diagnosis. Malignancy risks for the Milan categories were: non-diagnostic (12%), non-neoplastic (5%), atypia of undetermined significance (19%), neoplasm, benign (5%), neoplasm (40%), suspicious for malignancy (60%) and malignant (93%). CONCLUSION: MSRSGC was comparable with the original reported diagnoses in the majority of cases. Both systems had high accuracy for distinguishing benign from malignant lesions and both were associated with appropriate follow-up in most cases.

Increasing the sensitivity of endocervical curettings by performing ThinPrep® Pap on transport container fluid: is diagnostic material going down the drain?

OBJECTIVE: The sensitivity of endocervical curettage (ECC) can be suboptimal because of limited epithelial tissue. The false-negative rate for ECC in patients with cervical intraepithelial neoplasia involving the endocervical canal has been reported to be 45%. ECC samples are transported to pathology in formalin- or saline-filled containers; this fluid is discarded after the specimen has been submitted. We evaluated the utility of performing liquid-based cytological preparations from ECC transport container fluid as a way to increase the sensitivity of ECC specimens. METHODS: Consecutive ECC specimens received at one of the two participating institutions were selected prospectively. A surgical pathology mesh bag was placed over a ThinPrep(®) CytoLyt(®) solution container, and the specimen was filtered through the bag, collecting the transport fluid in the container. The CytoLyt(®) was processed to obtain a container fluid ThinPrep(®) (CF-TP) liquid-based Papanicolaou (Pap) slide. The CF-TP slides were reviewed and the findings were compared with those from the ECC and follow-up specimens. RESULTS: The cohort included 53 patients. Discrepancies between CF-TP and ECC were seen in 14 of the 53 patients (26%); a more significant lesion was identified in CF-TP relative to ECC in 13 of these cases. CF-TP diagnosis was confirmed in eight of 11 cases with histological follow-up. A positive CF-TP result was confirmed by histology in six of nine cases with negative ECC. CONCLUSIONS: Combining the pathological evaluation of ECC specimens with liquid-based cytology performed on the transport container fluid can increase the diagnostic sensitivity of the ECC procedure for the detection of cervical lesions.

The role of MR imaging in detecting nodal disease in thyroidectomy patients with rising thyroglobulin levels.

BACKGROUND AND PURPOSE: One of the dilemmas facing clinicians treating patients with thyroid cancer is the evaluation of postthyroidectomy patients with rising serum thyroglobulin levels and indeterminate or normal findings on neck sonography. In this study, we examine the role of MR imaging in this subgroup of patients. MATERIALS AND METHODS: We retrospectively reviewed MR images of patients with thyroid cancer with abnormal lymph nodes in the retropharyngeal and parapharyngeal spaces and determined the size and signal-intensity characteristics of these nodes. We reviewed patient charts for the following history: 1) thyroidectomy, 2) rising thyroglobulin levels, 3) iodine-131 radiation therapy, 4) neck dissection, and 5) pathology on neck sonography and chest CT. We reviewed pathology findings to determine if thyroid cancer metastases were present in these lymph nodes. RESULTS: Eight patients had abnormal retropharyngeal space nodes, and 1 patient had a parapharyngeal space mass. Lymph nodes ranged from 7 to 25 mm. On MR imaging, 1 patient had a cystic node, 2 had complex nodes, and 6 had solid nodes. Eight patients had rising serum thyroglobulin levels and a history of thyroidectomy, radioiodine therapy, and neck dissection. Two of these patients had no pathologic nodes on sonography and normal findings on chest CT. Six patients had tissue sampling of their skull base node, and metastatic thyroid cancer was present in 5. CONCLUSIONS: MR imaging of the neck should be considered in thyroidectomy patients with rising serum thyroglobulin levels and a history of radioiodine therapy and neck dissection. Radiologists should carefully examine the retropharyngeal and parapharyngeal spaces in these patients because nodal metastases may occur there more commonly than realized.

Diagnostic value of differential expression of CK19, Galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis.

BACKGROUND: Several immunohistochemical markers have been used to aid in the diagnosis of follicular-derived lesions of the thyroid (FDLT). In this study we analyze the diagnostic efficacy of an immunopanel of antibodies to cytokeratin-19 (CK19), galectin-3 (GAL-3), HBME-1, anti-MAP kinase (ERK), ret-oncoprotein (RET), and p16 using a tissue microarray consisting of both benign and malignant FDLT. DESIGN: The study cohort consisted of 90 cases of FDLT (53 benign, 37 malignant) embedded in a microarray and immunostained with antibodies to CK19, Gal-3, HMBE-1, ERK, RET, and p16. Staining was scored as positive when >25% of the lesional cells showed positive immunostaining. RESULTS: HMBE-1 was expressed in 70% of malignant and 10% of benign FDLT (p value: <0.0001). CK19 and GAL-3 were positive in 70% and 73% of malignant lesions, respectively, and 34% of benign FDLT (p value 0.0005 and 0.0015, respectively). ERK was positive in 4% of the benign and 32% of the malignant cases (p value 0.0002). p16 was expressed in 2% and 46% of the benign and malignant lesions, respectively (p value 0.0001). RET positivity was identified in 15% of the benign lesions and 27% of the malignant cases (p value 0.0016). CONCLUSIONS: HBME-1, ERK, and p16 were more specific for malignancy, whereas CK19 and GAL-3 stained benign lesions with a higher frequency and were not specific for malignant FDLT. RET-oncoprotein showed poor sensitivity and specificity.

Aspiration cytology of pediatric solitary papillary hyperplastic thyroid nodule.

CONTEXT: Solitary papillary hyperplastic thyroid nodules (SPHTNs) are frequently encountered in children and teenagers. Although the histologic features are well described, to the best of our knowledge, cytologic findings have not been reported. OBJECTIVES: To review the cytologic features of histologically proven SPHTNs and to identify the potential diagnostic pitfalls in cytologic diagnosis. MATERIALS AND METHODS: Fine-needle aspiration cytology of 3 histologically proven SPHTNs was reviewed. RESULTS: Two girls and 1 boy (ages 11, 12, and 15 years) were affected. The cytologic diagnosis in all 3 cases was suspicious for papillary thyroid carcinoma (PTC). The spectrum of cytologic findings included broad flat sheets and 3-dimensional clusters with fire flares. There was mild to moderate nuclear pleomorphism and nuclear atypia. Short nonbranching papillae with transgressing vessels shown to represent hyperplastic papillae on histologic sections were identified in all cases. The background contained giant cells, histiocytes, and watery and inspissated colloid. Although nuclear grooves were identified in occasional cells, intranuclear inclusions were absent. A cell block section (1 case) and histologic sections of SPHTNs (2 cases) were immunohistochemically negative for cytokeratin 19. CONCLUSIONS: Fine-needle aspiration of SPHTNs may be difficult to interpret accurately and can result in false-positive diagnosis of PTC. Although it shares several cytologic features with PTC, the presence of fire flares and short nonbranching papillae, as well as lack of intranuclear inclusions and watery and inspissated colloid in SPHTN appear to be useful features that are helpful in distinguishing SPHTN from PTC. Negative immunohistochemical staining for cytokeratin 19 is useful in excluding a diagnosis of PTC.

Processing liquid-based gynecologic specimens: comparison of the available techniques.

OBJECTIVE: To develop a cytopreparation protocol suitable for satisfactory processing by the AutoCyte PREP System with the gynecologic specimens collected in PreservCyt fluid for the ThinPrep machine. STUDY DESIGN: The residue of a number of gynecologic specimens collected in PreservCyt and processed by ThinPrep were processed by AutoCyte PREP. Some modifications were made in the cytopreparatory protocol in order to obtain satisfactory specimens. RESULTS: The ThinPrep and AutoCyte PREP specimens were examined independently. The results were comparable, with a high degree of concordance between the two techniques. CONCLUSION: Gynecologic specimens collected in PreservCyt and following the ThinPrep specimen collection protocol can be processed using the AutoCyte PREP System. Minor protocol modifications provided comparable diagnostic material. Additional studies are needed to explore the feasibility of this approach and fulfill the various U.S. regulatory agency requirements for the liquid-based Pap test.

Parathyromatosis as cause of recurrent secondary hyperparathyroidism: a cytologic diagnosis.

Parathyromatosis is a rare cause of hyperparathyroidism. It can be divided into two types: primary and secondary. The pathologic lesion consists of multiple small nodules of hypercellular parathyroid tissue strewn in soft tissue (fat, skeletal muscle, fibrous tissue) of the neck. We present a case of parathyromatosis occurring in a patient with recurrent secondary hyperparathyroidism 4 yr after parathyroidectomy. The diagnosis was confirmed preoperatively by fine-needle aspiration of one of several neck masses.

Interinstitutional review of thyroid fine-needle aspirations: impact on clinical management of thyroid nodules.

Routine interinstitution pathology consultation can result in change in pathologic diagnosis in up to 10% of patients. In this study, we compared the outside cytopathologic diagnosis of thyroid fine-needle aspiration (FNA) specimens with the in-house diagnosis at the University of Pennsylvania Medical Center over an 18-mo period and its effect on patient management. One hundred ten (60%) diagnostic disagreements were identified among 183 patients. In 16 cases, the diagnosis was changed from benign to malignant, and in 12, the diagnosis was reversed from neoplastic/malignant to benign. Histologic follow-up was available in 109 cases; the overall accuracy of outside diagnosis was 73%, and that of inside diagnosis was 85%. In conclusion, we strongly recommend interinstitution cytology consultation on referred thyroid FNA cases, since our data showed a significant change in diagnosis, thus affecting patient management.

Prognostic factors in well-differentiated follicular-derived carcinoma and medullary thyroid carcinoma.

This paper reviews both clinicopathologic and biological factors in differentiated thyroid carcinoma of follicular and C-cell derivation. The value of specific histological parameters including tumor subtypes, vascular invasion as predictors of prognosis in these tumors is discussed and the pertinent literature reviewed. The utility of ploidy analysis and immunohistochemical assessment of hormonal and tumor markers are described. Current information on biological and molecular markers that may be helpful in predicting behavior is discussed. The commonly used staging systems for thyroid cancer are briefly described.

Clinical implications and value of immunohistochemical staining in the evaluation of lymph node infarction after fine-needle aspiration.

We report on a series of 3 patients who underwent fine-needle aspiration (FNA) for clinically apparent lymphadenopathy. In all 3 cases, a diagnosis of malignancy was rendered based on cytologic findings (two metastatic squamous-cell carcinomas and one melanoma). However, initial follow-up surgical pathology reported only "extensive coagulative necrosis, no viable tumor seen." Subsequent immunohistochemical stains (cytokeratins (AE1/AE3), HMB45, S100, and Melan A) demonstrated the presence of metastatic tumor in the area of infarction in each case, thus establishing the presence of metastatic tumor and correct interpretation of the initial FNA. We conclude, based on our own experience and a few previously reported cases, that total infarction of the lymph nodes following FNA can occur, and immunohistochemistry can be helpful in clinical management.

Thyroid papillary microcarcinoma. Is it really a pitfall of fine needle aspiration cytology?

OBJECTIVE: To assess the role of fine needle aspiration (FNA) of the thyroid in the diagnosis of papillary microcarcinoma. STUDY DESIGN: Eight cases of papillary microcarcinoma were diagnosed by fine needle aspiration. On histologic examination they were found to be adjacent to larger nodules of interest. The microcarcinomas were inadvertently sampled when sampling the larger, dominant nodules. RESULTS: None of the eight dominant nodules were papillary carcinoma; seven were benign lesions, and one was an angioinvasive Hürthle cell carcinoma. In three cases the microcarcinomas were situated within the capsule of a hyperplastic nodule. On histologic examination, five cases had multifocal microcarcinomas, with one case having multiple lymph node metastases. Based on the clinical findings and morphologic features, there were no definitive cytologic findings that could distinguish between "incidental" microcarcinoma and clinically significant papillary carcinoma. CONCLUSION: The detection of microcarcinoma by FNA should not be considered a false positive finding since the exact nature of the lesion cannot be determined until complete histologic evaluation reveals it to be truly incidental and clinically insignificant.

Cytoplasmic accumulation of alpha-catenin in thyroid neoplasms.

BACKGROUND: Alpha-catenin (alpha-cat) is one of the anchoring proteins of E-cadherin. It has been shown that deviation in its function may alter the cadherin-catenin complex leading to disturbed cell-cell adhesion. Immunohistochemical studies have shown that cytoplasmic localization of alpha-cat in tumors is associated with aggressive behavior. In this study, we evaluated the expression of alpha-cat in various thyroid tumors by immunohistochemical analysis. METHODS: Fifty cases were selected:18 papillary carcinoma classic type (PTC), 9 follicular variant of PTC (FVPTC), 6 follicular carcinoma (FCA), 4 anaplastic carcinoma (ACA), 8 follicular adenoma (FA), 3 nodular goiter (NG), and 2 lymphocytic thyroiditis (LT). The staining reaction was classified as membranous, cytoplasmic, or both. The intensity of the staining was graded as negative (0), weak (+), moderate (++), and strong (+++). RESULTS: Staining along the cell membrane was observed in 36 (72%) and cytoplasmic expression was present in 28 (57%) cases. The cytoplasmic staining was more commonly seen in malignant lesions; it was more common in PTC (78% of all PTC) than follicular patterned lesions (FVPTC, FCA). All cases of ACA (4 of 4) showed only cytoplasmic expression. No correlation was found between lymph node involvement and alpha-cat staining patterns. CONCLUSIONS: Cytoplasmic expression of alpha-cat is more common in (1) malignant lesions of thyroid and (2) PTC than FVPTC and FCA. The lack of membrane and presence of cytoplasmic expression suggest a role of alpha-catenin in the aggressive biology of ACA.

Role of ultrafast Papanicolaou-stained scrape preparations as an adjunct to frozen sections in the surgical management of thyroid lesions.

OBJECTIVE: To assess the value of intraoperative cytology on scrape preparations of thyroid lesions. METHODS: We conducted a retrospective review of 73 cases of various thyroid lesions in which ultrafast Papanicolaou-stained scrape preparations were performed. Frozen sections were performed in 19 cases (26%). Fine-needle aspiration diagnosis was available in 65 cases. The correlation between the scrape diagnosis and the final diagnosis was analyzed. RESULTS: The agreement rate between the scrape diagnosis and the final diagnosis was 89%. All cases diagnosed as suspicious for papillary thyroid carcinoma on fine-needle aspiration were definite for malignant papillary carcinoma on scrape preparations. Three cases from this category were diagnosed as papillary carcinoma on both frozen section and scrape preparations, leading to total thyroidectomy. CONCLUSION: We conclude that intraoperative consultation is useful for thyroid lesions diagnosed as suspicious for papillary thyroid carcinoma on fine-needle aspiration and that ultrafast Papanicolaou-stained scrape preparations can increase the efficacy of thyroid frozen sections and obviate a second procedure for completion thyroidectomy.

Combined tall cell carcinoma and Hürthle cell carcinoma (collision tumor) of the thyroid.

Tall cell carcinoma and Hürthle cell carcinoma are 2 aggressive forms of differentiated follicular-derived thyroid carcinomas. We present a case where these malignant tumors of thyroid coexisted. The tumor originated in the thyroid as a mixed tumor and metastasized as a tall cell tumor to the lymph nodes and as a Hürthle cell carcinoma to lungs. The coexistence of these tumor types is rare and sheds light on the histogenesis of Hürthle cell tumors and the metastatic behavior of combined tumors.