Multiple brain metastases from a diffuse sclerosing variant of papillary carcinoma of the thyroid

We report a 53-yr-old man who presented with multiple brain metastases from a diffuse sclerosing papillary carcinoma of the thyroid. The presenting clinical features were those of an intracranial space-occupying lesion. Three brain tumors, confirmed pathologically to be metastatic thyroid papillary carcinomas, were removed. Two weeks after craniotomy, total thyroidectomy with cervical lymph node dissection was performed. Both lobes of the thyroid were diffusely enlarged and firm with a dominant mass. Histologically, the tumor was characterized by a combination of bilateral diffuse involvement of the gland, marked fibrosis, squamous metaplasia, abundant psammoma bodies, lymphocytic infiltration, frequent lymphatic and blood vessel permeation of the tumor, and typical elements of a conventional papillary carcinoma. In addition to these histologic findings, elements of other papillary carcinoma variants such as follicular and tall cell variants were also found focally. Twenty-three of twenty-four resected bilateral lymph nodes showed metastases of papillary carcinoma. Although the diffuse sclerosing variant of papillary carcinoma of the thyroid seems to be recognized as an aggressive variant of papillary carcinoma, there is no previous report of brain metastasis from this variant.     

Diffuse sclerosing variant of papillary carcinoma of the thyroid: a histological and immunohistochemical study of three cases

Three cases of an unusual diffuse sclerosing variant of papillary carcinoma of the thyroid occurring in young adults are reported. The tumour is characterized by diffuse involvement of one or both lobes of the thyroid, marked squamous metaplasia, numerous psammoma bodies, extensive interstitial fibrosis and heavy lymphocytic infiltration with formation of germinal centres. Lymphatic and vascular permeation was found in all three cases. An interesting finding was the presence of irregularly disposed thin bundles of smooth muscle within the fibrous stroma, presumably a result of splaying of the smooth muscle of vessel walls by the sclerotic process. The papillary areas of the tumour stained for thyroglobulin and cytokeratin, while the squamous areas stained strongly for cytokeratin but not for thyroglobulin. The tumours were negative for calcitonin and carcinosmbryonic antigen, but showed weak staining for S-100 protein. Numerous S-100 positive Langerhans/interdigitating reticulum cells were scattered within the tumour islands and the lymphoid infiltrate, suggesting an immunological reaction mediated by these antigen-presenting cells.     

Morules in cribriform-morular variant of papillary thyroid carcinoma: Immunohistochemical characteristics and distinction from squamous metaplasia

Morules are a diagnostic clue to the cribriform-morular variant (C-MV) of papillary thyroid carcinoma, and are superficially similar to squamous metaplasia. In order to clarify the histogenesis of morules and differentiate them from squamous metaplasia, we immunohistochemically compared the morules in five cases of C-MV with squamous metaplasia in six cases of diffuse sclerosing variant (DSV) of papillary thyroid carcinoma. The squamous metaplastic cells were immunopositive for low- and high-molecular-weight cytokeratin, whereas the morular cells were negative or focally positive. Vimentin-positive cells were observed focally in the morules and squamous metaplasia, except for one case of CMV that showed intense positivity. The morular cells showed weak cytoplasmic positivity for beta-catenin, and the cell membrane was not highlighted. Some nuclei of the morular cells were also positive for this antibody. Beta-catenin was intensively positive along the cell membrane of the metaplastic cells, and did not react against the nuclei or cytoplasm. Bcl-2 was positive in the morular cells, but negative in the metaplastic cells. S-100 protein-positive dendritic cells were observed in the metaplastic nests, but not in the morules. We argue that morules appear in connection with nuclear and cytoplasmic aberrant localization of beta-catenin, and are not an early form of squamous metaplasia.     

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.     

Fine‐needle aspiration of the diffuse sclerosing variant of papillary thyroid carcinoma masked by florid lymphocytic thyroiditis; A potential pitfall: A case report and review of the literature

The diffuse sclerosing variant of papillary thyroid carcinoma (DSV–PTC) is a rare tumor with aggressive behavior that requires aggressive treatment. Despite characteristic clinical and histological features that easily permit diagnosis, pre‐operative fine‐needle aspiration cytology (FNAC) diagnosis is often challenging and thus delays diagnosis. We describe the cytological features of a case of DSV–PTC diagnosed by FNAC in a 30‐year‐old woman presenting with an ill‐defined mass in her neck lasting for 2 months. Ultrasonograpy revealed a heterogeneous enlargement of both thyroid lobes suspicious for a lymphoproliferative syndrome. Flow cytometry showed a suspect B‐lymphocyte population. FNAC showed in five out of six slides an overwhelming presence of slightly atypical monomorphic small lymphocytes. The remaining slide showed syncytial tissue fragments of follicular cells with nuclear enlargement and pleomorphism, irregular nuclear membrane, grooves with scattered intranuclear inclusions, squamous metaplastic epithelium, and abundant psammoma bodies. A diagnosis of DSV–PTC was rendered and confirmed by total thyroidectomy and lymph node dissection. Our report supports the possibility of obtaining a preoperative diagnosis of DSV–PTC by FNAC. In the case of diffuse thyroid enlargement, adequate sampling of the thyroid and the presence of the combination of features described in our case permitted the diagnosis of this PTC variant. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Abnormalities of the E-cadherin/catenin adhesion complex in classical papillary thyroid carcinoma and in its diffuse sclerosing variant.

The cadherin/catenin complex regulates cellular adhesion and motility and is believed to function as an invasion suppressor system. Several studies have identified alterations in the expression profiles of those molecules in different histotypes of thyroid carcinoma. The diffuse sclerosing variant (DSV) of papillary thyroid carcinoma (PTC) is a rare, highly invasive variant of PTC in which an impairment of cell-cell adhesion may play a major role. In an attempt to progress in the understanding of the clinicopathological features of DSV, this study examined eight cases of DSV, 18 cases of classical PTC and a control group of normal thyroid by immunohistochemistry (E-, P- and N-cadherins and beta-, gamma- and alpha-catenins). The E-cadherin gene was also studied by polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) and methylation-specific PCR (MSP). In contrast to classical PTC, which showed heterogeneous loss of E-cadherin expression, in almost every case of DSV a pronounced reduction was observed in its membranous expression, accompanied by a relocation to the cytoplasm. Inactivation of the E-cadherin/catenin complex appears to occur in DSV via two different pathways: E-cadherin alteration either through mutation (one out of the eight cases) or through methylation of the E-cadherin gene promoter (three out of five cases); and beta- and/or gamma-catenin alterations (three of the eight cases). Methylation of the E-cadherin gene promoter, abnormalities of E-cadherin expression and alterations of gamma-catenin were also detected in classical PTC. In DSV, as in classical PTC, there is neo-expression of P-cadherin in areas of squamous metaplasia and no N-cadherin expression. In conclusion, abnormalities of the E-cadherin/catenin complex appear to be more pronounced in DSV than in classical PTC. It remains to be shown whether or not such differences are associated with the more aggressive behaviour of DSV compared with classical PTC.     

Macrofollicular variant of papillary thyroid carcinoma

A rare case of a macrofollicular variant of papillary thyroid carcinoma occurring in an 18-years-old male is described. The extirpated tumor, 5.5 × 5.5 × 3.5 cm In size, was well demarcated and multinodular, and histopathologically showed a predominantly macrofolllcular structure reminiscent of adenomatous goiter or macrofollicular adenoma. In the tumor tissue, however, there were several small foci of microfollicular or paplllary structure with the nuclei charae teristic of papillary carcinoma. Parts of the macrofollicular areas also showed similar nuclear characteristics with a transition to microfollicular or papillary areas. Incomplete capsular invasion and minimal vascular invasion were also present. Additional resected specimens contained small metastatic nodules in the residual left lobe and lymph nodes. Immunohistochemistry showed a small number of p53-positive tumor cells in the microfollicular or papillary areas. It is suggested that this tumor is a well-differentiated variant which should be distinguished from benign thyroid lesions, although there have been some cases of metastases which appear related to capsular and/or vascular invasion.     

筛状-桑椹状型甲状腺乳头状癌1例报道及文献复习

目的 探讨筛状-桑椹状型甲状腺乳头状癌的病理特征。方法 复查1例女性患者的临床资料及病理切片行免疫组化标记,选用的一抗有CKpan、CK19、EMA、TG、TTF1、CD99、CT、SYN和CgA,并复习文献。结果 肿瘤位于甲状腺右叶。大体为淡白色卵圆形孤立实性肿块。组织学表现为乳头状、筛状、桑椹状、滤泡状、小梁状、肉瘤样、实性的结构伴囊性变和组织细胞反应,未见砂粒体。免疫组化显示肿瘤性的乳头状上皮、筛状和肉瘤梭形细胞表达CKpan和CK19。结论 甲状腺乳头状癌中的乳头状、筛状-桑椹状肿瘤细胞和肉瘤样的梭形细胞具有表达上皮性细胞的特征,该肿瘤是乳头状癌的一种罕见的变型。     

Diffuse sclerosing variant of papillary thyroid carcinoma. A clinicopathologic study of 10 cases

The clinico-pathologic features of ten cases of the diffuse sclerosing variant (DSV) of papillary carcinoma of the thyroid (PCT) are presented and compared with those of 259 common PCT diagnosed during the same period at the Instituto Português de Oncologia (Centro de Lisboa). The primary therapeutic approach was basically the same in every case and follow-up information was obtained in every patient. DSV comprises 3.4% of our series of PCT. Patients with DSV are suggestively younger (34.7 +/- 19.9), than those with common PCT (42.3 +/- 16.1) regional lymph node metastases and distant metastases are significantly greater in DSV (100.0% and 50.0%, respectively) than in common PCT (38.6% and 14.3%, respectively). No significant differences were found between the two groups with regard to sex-ratio, extrathyroid invasion and mortality rate. No differences were either found regarding the immunohistochemical results: neoplastic cells of both groups showed immunoreactivity with antisera for thyroglobulin, epidermal keratins, S-100 protein and NSE. Some foci of three DSV cases displayed histological and histochemical features resembling those of the so-called mucoepidermoid carcinoma. It is concluded that a) DSV is an exceptional example of PCT in which most of the usual morphologic features of this type of carcinoma are overexpressed; b) DSV is not exclusively found in young patients and, in older patients, merges with other variants of PCT; c) DSV is indeed a more aggressive tumor than common PCT and should therefore be treated accordingly regardless of the age of the patients.     

Distinguishing tall cell variant of papillary thyroid carcinoma from usual variant of papillary thyroid carcinoma in cytologic specimens

Tall cell variant (TCV) is an aggressive form of papillary thyroid carcinoma (PTC), usually associated with higher local recurrence and distant metastasis. Some authors have suggested that TCV can be effectively diagnosed on thyroid fine-needle aspiration (FNA); this diagnosis may help clinicians plan a more effective treatment regimen. The objective of this study was to compare the FNA specimens of TCV with those of usual variant of PTC (UV-PTC) and to define a set of distinguishing cytologic features. Thirty FNA specimens of histologically proven TCV were compared with 32 FNA specimens of histologically proven UV-PTC. All specimens were evaluated for the following features: papillary groups (PG), elongated/tall cells (EL/TC), oncocytic cytoplasm (OC), distinct cell borders (DCB), prominent central nucleoli (PCN), intranuclear grooves (NG), and intranuclear inclusions (NI). These features were semiquantitatively measured on a sliding scale of 0-4 in both air-dried Diff-Quik-stained and ethanol-fixed Papanicolaou-stained preparations. TCV showed distinctive cytologic features, which can distinguish them from UV-PTC. These included EL/TC, OC, and DCB and were also found to be statistically significant (P < 0.0001). No significant differences were noted for PG and NG. The NIs in TCV cases were qualitatively different than those in UV-PTC. In TCV there were multiple inclusions within the same nucleus imparting a "soap bubble appearance" to the nucleus. This feature was seen in almost all cases of TCV and was rarely seen in usual PTC. On the basis of the above-mentioned cytologic features, TCV can be distinguished from usual PTC in FNA specimens.     

The fine-needle aspiration appearance of the follicular variant of thyroid papillary carcinoma: A report of three cases

The follicular variant of thyroid papillary carcinoma (FVTPC) is an uncommon neoplasm with the architectural features of a follicular lesion and the nuclear characteristics of a papillary carcinoma. The fine-needle aspiration (FNA) appearance is underreported in the literature. Three cases of histologically confirmed FVTPC that were aspirated prior to surgery are presented. Although the cytological features were suspicious or confirmatory of a low-grade thyroid carcinoma, they did not convey a specific diagnosis of the FVTPC. We suggest that this variant is recognizable as a neoplasm requiring surgical excision on FNA, but that the cytological appearance does not allow its specific diagnosis.     

Cytopathology of high‐grade papillary thyroid carcinomas: Tall‐cell variant,diffuse sclerosing variant,and poorly differentiated papillary carcinoma

Cytologic reports of the aggressive tall‐cell and diffuse sclerosing variants of papillary carcinoma have emphasized features such as tall and large cells, increased nuclear size, nuclear pleomorphism, intranuclear pseudoinclusions, three‐dimensional tissue fragments, squamous‐like cells, and dense inflammatory background as characteristic features. However, the specificity of these features in identifying the particular variants and distinguishing them from other poorly differentiated papillary carcinomas and typical low‐grade forms of papillary carcinoma has not been established. The objective of this study was to assess the predictive value of these reported cytologic features. Fourteen cases of high‐grade papillary carcinoma consisting of the aggressive variants (tall‐cell variant (tcv) and diffuse sclerosing variant (dsv)) and poorly differentiated papillary carcinomas (pdpc) were compared to 18 cases of low‐grade papillary carcinoma. Seven cytologic features consisting of the presence of tall and large cells, architectural disorganization, nuclear enlargement, prominent intranuclear pseudoinclusions, nuclear pleomorphism, lymphocytic infiltrate, and squamoid appearance of the neoplastic cells were evaluated. Cytology samples from tcv, dsv, and pdpc consistently demonstrated 3 of the 7 cytologic features (architectural disorganization, nuclear enlargement, and pleomorphism). In contrast, only two of the samples from low‐grade cases demonstrated these 3 features. The recognition of these 3 cytologic features had a positive predictive value of 88% and a negative predictive value of 100% for identifying tcv, dsv, and pdpc. The remaining cytologic features were not a consistent feature in the variants, and by cytology alone, distinction between the aggressive variants (dsv and tcv) and pdpc could not be made. Diagn. Cytopathol. 1999;20:19–23. © 1999 Wiley‐Liss, Inc.     

Immunohistochemical separation of follicular variant of papillary thyroid carcinoma from follicular adenoma

The accurate diagnosis of differentiated thyroid tumors is very important for clinical management of patients. The histopathological distinction between some types of differentiated thyroid tumors can be very difficult even for experienced pathologists. We used immunohistochemical markers from published data obtained from DNA expression profiling, tissue microarray analysis, and immunohistochemistry to analyze a series of 157 thyroid tumors and 5 normal thyroids. These analyses showed that several antibodies were useful in distinguishing follicular adenomas from follicular variant of papillary thyroid carcinomas including HBME-1, CITED 1, galectin-3, cytokeratin 19, and S100A4 (p<0.0001). A combination of markers consisting of a panel of HBME-1, galectin-3, and CK19 or a panel of HBME-1, CITED1, and galectin-3 was usually most effective in distinguishing follicular adenoma from follicular variant of papillary thyroid carcinoma. Because individual tumors may not express some of these markers, the use of a panel of antibodies is recommended. These results indicate that some individual antibodies or a panel of antibodies combined with histopathological analysis can be useful in separating follicular adenoma (FA) from follicular variant of papillary thyroid carcinoma (FVPTC).     

Diffuse sclerosing papillary carcinoma of the thyroid gland: immunohistochemical analysis of the local host immune response

Surgical specimens from four patients with diffuse sclerosing papillary carcinoma of thyroid were examined by electronmicroscopy. In addition, immunohistochemical examination using a panel of monoclonal and polyclonal antibodies was carried out in order to investigate the expression of HLA-DR antigen, the presence of Langerhans' cells and the phenotypic characteristics of the inflammatory infiltrate. The ultrastructural study showed that the intraglandular dissemination, typical of this tumour, was due to massive lymphatic invasion. Many Langerhans' cells were observed among tumour cells and in the lymphoid infiltrates in proximity to tumour foci. HLA-DR expression was seen on macrophages, Langerhans' cells, endothelial cells, lymphoid cells, many tumour cells and in some non-neoplastic follicles close to tumour clusters and lymphoid infiltrates. The immunohistochemical analysis of the inflammatory infiltrates showed a high proportion of B- and T-cells, and moderate numbers of plasma cells. Our results suggest that the tumour-specific immune response can give rise to an autoimmune reaction involving non-neoplastic follicles. It is suggested that this could be one of the mechanisms responsible for immunofacilitation of tumour growth.     

Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer

Papillary thyroid carcinoma (PTC) has long been diagnosed based on its unique nuclear features (PTC-N); however, significant observer discrepancies have been reported in the diagnosis of encapsulated follicular patterned lesions (EnFPLs), because the threshold of PTC-N is subjective. An equivocal PTC-N may often occur in non-invasive EnFPLs and benign/malignant disagreements often create serious problems for patients' treatment. This review collects recent publications focusing on the so-called encapsulated follicular variant of papillary thyroid carcinoma (EnFVPTC) and tries to emphasize problems in the histopathological diagnosis of this spectrum of tumors, which covers encapsulated common-type PTC (EncPTC), EnFVPTC, well-differentiated tumor of uncertain malignant potential (WDT-UMP), follicular adenoma (FA) with equivocal PTC-N and minimally invasive follicular carcinoma (mFTC). We propose that EnFVPTC and other EnFPLs with equivocal PTC-N should be classified into a unified category of borderline malignancy, such as well-differentiated tumor of uncertain behavior (WDT-UB), based on their homogeneous excellent outcome. It is suggested that the unified nomenclature of these lesions may be helpful to reduce significant observer disagreements in diagnosis, because complete agreement in the diagnosis of an EncPTC, EnFVPTC or FA by all pathologists may be not possible for this problematic group of tumors. In conclusion, a malignant diagnosis of EnFVPTC should not be used to cover this spectrum of tumors until uncertainty about the nature of this lesion is settled, whether it is benign, precancerous or malignant.     

Hobnail variant of papillary thyroid carcinoma: A case with an unusual presentation

Variants of papillary thyroid carcinoma (PTC) account for up to 25% of the cases, some of which are proven to be associated with aggressive clinical behavior such as tall cell and columnar cell variants. Hobnail variant of PTC (HVPTC) is recently described as a rare and aggressive variant of PTC. Herein, we are reporting a case of HVPTC in a patient who presented with hemoptysis and an intratracheal blood clot that was aspirated and submitted for cytopathological examination. Cytomorphology displayed neoplastic cells with profound micropapillary architecture, elongated nuclei, and prominent hobnail configuration. Nuclear features of PTC such as pseudoinclusions, nuclear overlapping, crowding, and grooves were readily identified. Subsequent total thyroidectomy revealed a 1.4 cm PTC with columnar and hobnail components. HVPTC is a rare locally aggressive subtype, which may present with metastasis from an occult thyroid primary. HVPTC needs to be included in the differential diagnosis of metastatic carcinoma with micropapillary architecture on fine needle aspiration, particularly in head and neck area. Diagn. Cytopathol. 2017;45:754–756. © 2017 Wiley Periodicals, Inc.     

Tall cell variant of papillary thyroid carcinoma: Its characteristic features demonstrated by fine‐needle aspiration cytology and immunohistochemical study

Tall cell variant (TCV) of papillary thyroid carcinoma is a rare tumor, which is usually associated with poor outcome, and pathologists often face the dilemma of proper diagnosis of TCV, not only by cytology but also histology. To allow surgeons to determine aggressiveness of the tumor before operation, it is important for pathologists to detect tall cell features correctly by fine‐needle aspiration cytology (FNAC). However, the current criteria and definition of TCV are still controversial and confounded by another problem, the differential diagnosis from poorly differentiated thyroid carcinoma (PDC). In this report, we describe two cases of TCV and present characteristic FNAC findings. The tumor cells had a peculiar shape, which included tall, columnar, and oxyphilic cytoplasm with “eccentric,” basally located nuclei. We propose new terms for these cells, such as “tail‐like cells” or “tadpole cells.” In the surgically‐resected specimens, both cases exhibited remarkable extrathyroidal invasion accompanying prominent vascular invasions. They showed high Ki‐67 (MIB‐1) labeling index by immunohistochemistry, which indicated a higher proliferation activity of TCV than conventional form of papillary thyroid carcinoma. Furthermore, we discuss in this report the problematic issue of differential diagnosis of TCV from PDC and oxyphilic papillary thyroid carcinoma. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.