Mixed medullary-follicular carcinoma of the thyroid: diagnostic dilemmas in fine-needle aspiration cytology

Mixed medullary-follicular carcinoma (MMFC) of thyroid is an extremely rare tumor, characterized by coexistence of morphological and immunohistochemical features of both medullary carcinoma and follicular (or papillary) carcinoma. We herein present fine needle aspiration (FNA) findings of a histology-confirmed MMFC along with a review of literature. The patient was a 64-year-old woman who had a history of Hashimoto's thyroiditis and presented with enlargement of preexisting right thyroid nodule. An US-guided FNA of the thyroid nodule was performed and conventional smears were prepared. A cytologic diagnosis of "positive for malignancy, consistent with medullary thyroid carcinoma (MTC)" was rendered based on the presence of features characteristic for MTC, and the absence of components of follicular neoplasm (adenoma and carcinoma) or papillary carcinoma. However, microscopic examination of the follow-up total thyroidectomy specimen with the aid of immunocytochemical study detected minor portion of follicular carcinoma in addition to MTC. A histologic diagnosis of MMFC was then established. While specific identification of MMFC by FNA may be difficult, it should be emphasized that adequate sampling in conjunction with the proper immunostaining panel could have highlighted the different aspects of the mixed tumor.     

Serum calcitonin negative mixed medullary‐follicular carcinoma initially diagnosed as medullary thyroid carcinoma by fine‐needle aspiration cytology: A case report and review of the literatures

Medullary thyroid carcinoma (MTC) is potentially lethal. A prompt and accurate diagnosis is the prerequisite for the treatment of MTC. Fine‐needle aspiration (FNA) is a reliable diagnostic tool in the assessment of thyroid nodules. However, cytologic assessment of MTC based on FNA has several drawbacks due to morphological variants. We present a case of MTC diagnosed through FNA cytology, which was eventually histologically confirmed as a mixed medullary‐follicular carcinoma with negative serum calcitonin expression. Hence, diagnosis of MTC based on FNA should be applied with caution. Ultrasound characteristics of suspicious thyroid nodules are recommended to be evaluated by FNA. However, calcitonin levels should be measured in both the FNA washout fluid and serum when features of MTC are presented or cytology result is inconclusive. If adequate FNA sample is available, a supplementary immunocytochemical staining of markers such as calcitonin, chromogranin, carcinoembryonic antigen, and thyroglobulin is helpful for a correct diagnosis of MTC.     

Thyroid nodules with FNA cytology suspicious for follicular variant of papillary thyroid carcinoma: follow-up and management

Thyroid nodules diagnosed as follicular neoplasm on fine-needle aspiration biopsy (FNAB) may represent hyperplastic/adenomatous nodules, follicular adenoma or carcinoma, and follicular variants of papillary thyroid carcinoma (FVPTC) on histologic follow-up. In our laboratory, we attempted to identify a subset of cases which showed cellular specimens with focal features (nuclear chromatin clearing, membrane thickening, and rare grooves) suspicious for the follicular variant of papillary thyroid carcinoma. These cases are reported as follicular-derived neoplasms with nuclear features suspicious for FVPTC to distinguish them from those diagnosed as follicular neoplasm. This study documents our experience with 52 cases so diagnosed and followed prospectively with histologic follow-up. A neoplastic nodule was confirmed in 45/52 cases (86%), of which 40 were malignant (77%). FVPTC was identified in 35/52 cases (67%). Four cases were usual papillary carcinoma, 3 were follicular adenoma, 2 were Hürthle-cell adenoma, and 1 was insular carcinoma. In 7 cases, the subsequent histologic findings were nonneoplastic (5 hyperplastic nodules and 2 colloid nodules). Our prospective study shows that in cellular smears from thyroid nodules, a careful search for the nuclear features of papillary carcinoma should be performed, and it is appropriate to diagnose cases as suspicious for FVPTC if the nuclear features of papillary carcinoma are focal. The surgical management of this group may include an intraoperative confirmation of cytologic diagnosis by scrape preparation and/or frozen section in order to avoid a second surgical intervention for completion thyroidectomy.     

Immunohistochemical characteristics of diffuse sclerosing variant of papillary carcinoma: comparison with conventional papillary carcinoma

Koo JS, Shin E, Hong SW. Immunohistochemical characteristics of diffuse sclerosing variant of papillary carcinoma: comparison with conventional papillary carcinoma. APMIS 2010; 118: 744–52. Diffuse sclerosing variant of papillary carcinoma (DSVPC) is a rare variant of papillary thyroid carcinoma (PTC). It shows different clinicopathologic features to the conventional PTC, but the immunohistochemical characteristics of DSVPC are yet to be more clearly defined. The purpose of this study was to investigate the immunohistochemical features of DSVPC, which are different from those of PTC. Tissue microarray was constructed from the paraffin‐embedded tissue of 49 DSVPC and 50 conventional PTC samples. Immunohistochemical stains for p63, p53, galectin‐3, cytokeratin 19, β‐catenin, Bcl‐2, EMA, E‐cadherin, CD15, and CD56 were performed on each tissue microarray. Immunohistochemical stain for p63 was negative in all conventional PTCs, but 14 (28.6%) cases of DSVPC showed p63 expression (p = 0.000). p53 was expressed in 38 (76.0%) cases of conventional PTC and 21 (42.9%) cases of DSVPC (p = 0.001). Galectin‐3 was expressed in all 50 cases of conventional PTC, but eight (16.3%) cases of DSVPC did not express galectin‐3 (p = 0.003). EMA was expressed more in DSVPC (40.8%) than in conventional PTC (20.0%, p = 0.024). In univariate analyses, Bcl‐2 positivity (p = 0.016) and EMA negativity (p = 0.036) in DSVPC were associated with shorter time interval to tumor recurrence, but there was no significance for the two in multivariate analyses. DSVPC, a rare variant of PTC, has different immunohistochemical features from the conventional PTC, showing higher expression rate of p63 and lower expression rate of p53. It also shows galectin‐3 negativity and EMA positivity.     

Cytopathology of follicular lesions of the thyroid gland

Fine needle biopsy is generally considered unreliable in the differential diagnosis of follicular lesions of the thyroid gland. To test this hypothesis, we correlated fine needle biopsy diagnoses with surgical diagnoses in 379 follicular lesions. From nuclear characteristics (especially size) and the architectural pattern of tissue fragments, the following observations were made. Differentiation of goiters (including hyperplastic ones) from neoplastic thyroid disease is quite accurate and no more than 1 to 2% of cancers should be missed. The specific cytologic diagnosis of follicular carcinoma is 75% accurate, and that of follicular variant of papillary carcinoma is over 95% accurate. Of histologically proved follicular carcinomas, almost three-quarters should be diagnosed as such or strongly suspected by fine needle biopsy. The remainder will be identified as cellular follicular adenomas, reaffirming the overlap of cytologic features of benign and malignant neoplastic disease. From cytologic and surgical pathologic data for each fine needle biopsy diagnosis of follicular lesion, a probability of cancer can be stated that is useful in management decisions.     

Follicular lesions of the thyroid: a retrospective study of 1,348 fine needle aspiration biopsies

Fine needle aspiration (FNA) has proven to be an effective tool in management of patients with thyroid nodules. However, the diagnosis of follicular patterned lesions can be challenging. The surgical and cytopathology computer database at a large referral medical center was searched for cases that had both cytologic and histologic thyroid accessions from January 2004 to November 2008. A total of 1,255 histologic thyroid specimens and 2,776 thyroid FNA biopsies were retrieved for review. Histologically, 272 overt malignancies were identified; 20 (7.4%) were follicular carcinomas. Cytologically, 1,348 cases were follicular-patterned lesions, comprising 1,044 cases of "benign follicular nodules" (BFN), 137 cases of "follicular lesions of undetermined significance" (FLUS), and 167 cases of "suspicious for follicular neoplasm" (SFN). Seventy-nine (7.5%) of BFN, 23 (16.8%) of FLUS, and 65 (38.9%) of SFN cases had histologic follow-up. Overt malignancy, a cystic papillary carcinoma, was identified histologically in only one case of BFN, for a negative predictive value of 98.7%. Overt malignancy was identified histologically in two cases of FLUS, both follicular variant of papillary carcinoma, for a positive predictive value of 8.7%. Overt malignancy was identified histologically in 14 cases of SFN, for a positive predictive value of 21.5%. Five follicular carcinomas were identified histologically in the SFN category, all minimally invasive. Incidental ("occult") papillary microcarcinoma were identified histologically in all three categories. In this study, the risk of overt malignancy increases from 1.3%, to 8.7%, to 21.5% for BFN, FLUS, and SFN, respectively. All follicular carcinomas identified histologically occurred in the SFN category and all were minimally invasive. Papillary microcarcinomas can occur in any of the three diagnostic categories.     

The triage efficacy of fine needle aspiration biopsy for follicular variant of papillary thyroid carcinoma using the Bethesda reporting guidelines

Diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) by ultrasound-guided fine-needle aspiration (FNA) is challenging. In this retrospective review, we evaluated triage efficacy (i.e., potential for triggering surgical intervention) in 44 archived FNA biopsies of surgically confirmed FVPTC obtained between December 2006 and December 2008. We compared the original FNA diagnoses with reclassified diagnoses based on 2007 National Cancer Institute (NCI)/Bethesda recommendations, and reviewed FNA cytologic features. Original FNA diagnoses included colloid nodule (7%, 3/44), atypical follicular cells (5%, 2/44), follicular lesion (11%, 5/44), follicular neoplasm (16%, 7/44), suspicious for malignancy/PTC (27%, 12/44), and papillary thyroid carcinoma (34%, 15/44). Reclassified diagnoses included indeterminate (5%, 2/44), colloid nodule (7%, 3/44), atypical cells of undetermined significance [ACUS] (7%, 3/44), Hurthle cell neoplasm (2%, 1/44), follicular neoplasm (7%, 3/44), suspicious for malignancy/PTC (25%, 11/44), and PTC (48%, 21/44). Triage efficacy was 77% (34/44) for original diagnoses versus 82% (36/44) for reclassified FNA diagnoses. We frequently observed cytologic features of PTC, such as nuclear grooves and fine chromatin; conversely, intranuclear inclusions, though present in 77% cases, were scant. Our review findings suggest that lack of characteristic cytologic features of PTC,coexistence with other thyroid lesions, and small tumor size arethe major obstacles to FNA diagnosis of FVPTC. Reclassification of thyroid FNA diagnoses does not significantly improve triage efficacy. Furthermore, FNA diagnoses of follicular neoplasm and suspicious for malignancy are valuable in patients with FVPTC because they trigger triage toward surgical intervention.     

Sensitive cytologic criteria for the identification of follicular variant of papillary thyroid carcinoma in fine-needle aspiration biopsy

The cytologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) can be extremely challenging and may be associated with false negative diagnoses. The purpose of this study was to determine the minimal cytologic criteria needed to identify FVPTC. We examined sixty-nine fine-needle aspiration (FNA) cases, processed with Diff-Quik and Papanicolaou stains, that were either diagnostic or suspicious of FVPTC. All cases had histologic confirmation. These cases included 29 FVPTC, 18 classic papillary thyroid carcinoma (PTC), 17 follicular neoplasm (6 adenomas, 10 carcinomas, 1 neoplasm NOS), 2 lymphocytic thyroiditis and 3 nodular goiter. Seven of the most commonly cited cytomorphologic features, including flat syncytial sheets, nuclear enlargement, fine chromatin, nuclear grooves, nuclear pseudoinclusions, and amount of colloid and cytoplasm, were evaluated. A diffuse distribution of fine chromatin, nuclear grooves, and colloid was seen more often in FVPTC than in follicular neoplasm (p<0.01). The combination of flat/syncytial sheets, nuclear enlargement, and fine chromatin was observed in all our cases of FVPTC, and is therefore considered a sensitive marker in detecting FVPTC. Logistic regression analysis revealed colloid to be the only positive predictor in favor of FVPTC over classic PTC.     

Poorly differentiated oxyphilic (Hürthle cell) carcinoma arising in lingual thyroid: a case report and review of the literature

Clinically significant lingual thyroid is an unusual developmental anomaly, and carcinoma arising in lingual thyroid, an extremely rare entity. Here we describe the cytologic, histologic, immunohistochemical, and ultrastructural findings of the first poorly differentiated oxyphilic (Hürthle cell) carcinoma described in lingual thyroid along with a review of the literature. Carcinoma arising in lingual thyroid was reported in 12 males and 21 females age 12 to 86 yr (mean age: 40). Because in nonneoplastic lingual thyroid there exists an intimate and irregular relationship of normal follicles with the surrounding skeletal muscle fibers, unequivocal infiltration, with desmoplastic response, and/or vascular invasion should be demonstrated before making a diagnosis of carcinoma. Immunostain for thyroglobulin is the most useful marker for the differential diagnosis. Although, in some older cases, the precise histologic type is difficult to determine, follicular carcinoma seems to be prevalent. This contrasts with the predominance of the papillary type in thyroglossal duct-associated carcinoma. This fact is probably related to the history of hypothyroidism and compensatory hyperplasia secondary to the absence of the orthotopic gland, like that occurring in areas of endemic goiter.     

Correlation of thyroid nodule fine-needle aspiration cytology with corresponding histology at Mayo Clinic, 2001-2007: an institutional experience of 1,945 cases

Following the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference, the thyroid fine‐needle aspiration biopsy (FNAB) practice at Mayo Clinic, Rochester, Minnesota, conducted retrospective analyses correlating cytologic and histologic evaluations of thyroid nodules. Cytologic and histologic reports were retrieved for patients with thyroid nodules who underwent thyroid FNAB between January 2001 and December 2007, with subsequent surgical thyroid resection. Cases were classified by major cytologic and histologic diagnosis and specific diagnostic subcategories. Of 1,945 FNAB cytologic results, 180 (9.3%) were nondiagnostic; 512 (26.3%) were negative for malignancy; 27 (1.4%) were atypical; 729 (37.5%) were suspicious for malignancy; and 497 (25.6%) were positive for malignancy. Histology was benign in 1,179 (60.6%) and malignant in 766 (39.4%). For thyroid malignancy as the disease outcome, at cytologic thresholds of atypical, suspicious, and positive, overall sensitivity of thyroid FNAB was 94.5%, 94.1%, and 65.0%, respectively, and specificity was 46.0%, 48.3%, and 98.5%, respectively. Positive predictive value for all malignancies was 97.0%, and negative predictive value was 92.0%. When separated by specific malignant outcomes, diagnoses of papillary carcinoma, medullary carcinoma, and lymphoma had specificity of suspicious FNAB diagnoses ranging from 90.5% to 99.6%; positive predictive value ranged from 87.5% to 91.4%. For follicular or Hürthle carcinoma, suspicious FNAB diagnoses had a specificity of 52.5% and a positive predictive value of 5.9%. Sensitivity of indeterminate FNAB diagnoses ranged from 72.7% to 95.3%. For follicular or Hürthle pattern malignancies, indeterminate cytologic diagnoses should be interpreted with caution by the clinician considering surgical management. Diagn. Cytopathol. 2012;40:E27–E32. © 2010 Wiley Periodicals, Inc.     

Cytology of thyroglossal cyst papillary carcinoma

The cytologic and histologic features of two cases of carcinoma arising in thyroglossal cyst are reported. The carcinoma in both cases was papillary thyroid carcinoma. The aspirated cyst fluid in one case revealed only macrophages and benign squamous epithelial cells, while in the other case the cyst fluid showed cytologic features of papillary carcinoma including psammoma bodies and epithelial cells with papillary clustering, intranuclear cytoplasmic inclusions, and positive immunohistochemical reaction to thyroglobulin.     

Cytologic features of insular carcinoma of the thyroid: a case report

Fine-needle aspiration of the thyroid has been accepted as one of the initial diagnostic tools in the evaluation of thyroid nodules. As its use becomes more widespread, the demand for more precise diagnosis has increased. The histopathology of insular carcinoma of the thyroid is now well recognized. However, the cytologic diagnostic criteria are not well established. The reported series have been small (4-6 cases), which is not surprising because of the rarity of this tumor. They consist of retrospective reviews of the aspirates (after the histologic diagnosis had been made from the thyroidectomy specimens). Also, the case reports do not provide uniform cytologic criteria; this could be due to limited sampling of these tumors (which are usually large). A cytologic diagnosis of insular carcinoma can be suggested if multiple samples of a thyroidal mass are markedly cellular, with a cytologic pattern reminiscent of a follicular variant of papillary carcinoma. However, the follicular cells are arranged predominantly in rosettes, their nuclei appear more monotonous, some "intranuclear cytoplasmic pseudoinclusions" are seen, and there is an occasional large cell with a pleomorphic nucleus.     

Three-dimensional reconstruction of vessel distribution in benign and malignant lesions of thyroid

In order to better understand the spatial distribution of thyroid vessels, a series of benign and malignant thyroid lesions were studied with three-dimensional (3D) histological stereomicroscopic reconstruction. Cases consisted of normal autoptic thyroids (n=6), colloid goitres (n=6), Basedows disease (n=2), follicular adenoma (FA) (n=4) one of which with Hurthle cells (HC), minimally invasive, well-differentiated follicular carcinoma (FTC) (n=1), well-differentiated FTC with HC (n=1), poorly differentiated FTC (n=13) with extensive angioinvasion, papillary carcinoma (PTC) (n=8) and medullary carcinoma (MTC) (n=1). From each selected nodule, parallel sections were obtained for 3D reconstruction and for histological and immunohistochemical studies. In normal thyroid, large vessels were located at the periphery of the gland with smaller branches present within the thyroid parenchyma that encircled follicles. The same pattern of vascularisation is maintained in lesions showing a follicular architecture as colloid goitre, Basedows disease, FA, well-differentiated FTC and the follicular variant of PTC. Neoplastic lesions, at variance with non-neoplastic lesions, contained rare anastomoses. Poorly differentiated FTC and MTC contained large intratumoural vessels surrounding avascular areas corresponding to solid neoplastic cellular sheets with necrosis. PTC were more vascularised and contained numerous vascular anastomoses. In conclusion, the present data indicate that the vascular distribution is related to the follicular, papillary or solid type of growth. Vascular anastomoses and intratumoural vessels surrounding solid avascular areas are signs of malignancy.     

Macrofollicular variant of papillary carcinoma: a potential thyroid FNA pitfall

Macrofollicular variant of papillary carcinoma (MFPC) is a rare variant of papillary carcinoma in which over 50% of the follicles are represented by macrofollicles. The cytologic features from 7 cases of histologically confirmed MFPC were evaluated. The cytology specimens were evaluated for the following criteria: cellularity, cluster arrangement (micro and macrofollicular), chromatin pattern, nuclear grooves, pseudonuclear inclusions, nuclear shape, nuclear overlap, nucleoli, presence of lymphocytes, macrophages and Hurthle cell, amount and characteristics of background colloid. Most cases were moderately to highly cellular with presence of both microfollicles as well as macrofollicles, but nuclear features of papillary thyroid carcinoma were absent or focal in all cases. MFPC is a variant of papillary carcinoma that can be extremely difficult to diagnose cytologically. The presence of abundant colloid, macrophages, macrofollicular follicular cell arrangement and/or absence of widespread cytologic features associated with papillary carcinoma can lead to an erroneous diagnosis of goiter.     

Follicular variant of papillary carcinoma of the thyroid: Fine-needle aspirates with histologic correlation

Crile and Hazard reported in 1953 a follicular pattern of papillary thyroid carcinoma. Little has been said about this pattern in the cytologic literature. From more than 8,000 thyroid aspirates in our files, we reviewed all those diagnosed as “follicular variant of papillary carcinoma,” “suspect follicular variant of papillary carcinoma,” and “follicular neoplasm vs. follicular variant of papillary carcinoma.” Also, we reviewed all aspirates in which a diagnosis of follicular variant of papillary carcinoma had been made on surgically excised glands, regardless of the cytologic diagnosis; 63 aspirates from 45 patients were collected. All smears were air-dried and stained with Diff-Quik. Most smears were very cellular (“tumor cellularity”), and the neoplastic follicular cells formed empty follicles, rosettes, tubules, and papillary structures. Nuclei were twice the size of red blood cells, had smooth contours, were hyperchromatic, and varied in shape but not much in size. Nuclear overlapping was common. Some nuclei had one small and almost pointed end, thereby resembling arrowheads. Intranuclear inclusions, multinucleated histiocytes, and psammoma bodies were uncommon. Pink-stained colloid was frequent. Diagn. Cytopathol. 16:207–213, 1997. © 1997 Wiley-Liss, Inc.     

Cytologic diagnosis of “CASTLE” of thyroid gland: Report of a case with histologic correlation

We report on the cytologic and histologic features of a rare form of lymphoepithelioma-like carcinoma of the thyroid, i.e., carcinoma showing thymus-like element (CASTLE). Sixteen cases of cervical lymph node aspirates with metastatic nasopharyngeal carcinoma are also reviewed. While it is important to recognize CASTLE of the thyroid because of its distinctly good prognosis, its cytologic features closely resemble those in metastatic nasopharyngeal carcinoma. Diagn Cytopathol 1996;15:224–227. © 1996 Wiley-Liss, Inc.     

The many faces and mimics of papillary thyroid carcinoma

This article provides an overview of the 15 histologic variants of papillary thyroid carcinoma listed by the 2004 World Health Organization (WHO) monograph on endocrine tumors. The histologic features, differential diagnosis, and clinical course of each variant are discussed in some detail. The follicular variants (conventional and macrofollicular) constitute a morphologic challenge because the majority of these tumors are encapsulated and, also, because, in many tumors, not all neoplastic cells show the nuclear features considered to be diagnostic of papillary carcinoma. As a result, most of these tumors are missed even by experienced pathologists. Moreover, hyperplastic thyroid lesions, follicular adenomas, and Hashimoto’s thyroiditis may contain cells with clear nuclei resembling those of papillary carcinoma. Papillary carcinomas composed entirely of hyperchromatic cells have been overlooked. The WHO monograph defines papillary carcinoma with focal spindle and giant cell carcinoma components but its clinical behavior is unknown. Papillary carcinoma with an insular pattern that does not show the artifactual separation of the cell nests has been misinterpreted as the solid variant of papillary carcinoma. Papillary microcarcinomas include not only the conventional type and the follicular variants but also the tall cell and columnar cell variants.