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Some pediatric papillary thyroid carcinoma (PPTC) cohorts have suggested a preliminary correlation with respect to DICER1 mutation status and histomorphology in both benign and malignant follicular cell-derived nodules; however, the data regarding correlates of DICER1-related sporadic PPTCs subtyped based on the 2022 WHO classification criteria are largely unavailable. The current study investigated the status of hotspot DICER1 mutations with clinical, histological and outcome features in a series of 56 patients with PPTCs with no clinical or family history of DICER1-related syndromic manifestation. Fifteen (27%) PPTCs harbored BRAF p.V600E. Eight (14%) cases of PPTCs harbored DICER1 mutations with no associated BRAF p.V600E. DICER1 mutations were identified in exons 26 and 27. A novel D1810del (c.5428_5430delGAT) mutation was also detected. We also confirmed the absence of hotspot DICER1 mutations in the matched non-tumor tissue DNA in all 8 DICER1-related PPTCs. The mean age of DICER1-harboring PPTCs was 15.1 (range: 9-18) years whereas the rest of this cohort had a mean age of 14.8 (range 6-18) years. With the exception of one PPTC, all DICER1-related PPTCs were seen in females (female-to-male ratio: 7). The female to male ratio was 3.8 in 48 DICER1-wild type PPTCs. In terms of histological correlates, 5 of 8 (63%) DICER1-mutant PPTCs were invasive encapsulated follicular variant papillary thyroid carcinomas (FVPTCs) including 4 minimally invasive FVPTCs and 1 encapsulated angioinvasive FVPTC, whereas the remaining 3 PPTCs were infiltrative classic papillary thyroid carcinomas (p 0.05). The incidence of DICER1 mutations was 19.5% in BRAF p.V600E-wild type PPTCs. Sixty-three percent of DICER1 hotspot mutations occurred in invasive encapsulated FVPTCs, and this figure represents 38% of invasive encapsulated FVPTCs. Only one (12%) patient with DICER1-related disease showed a single lymph node with micro-metastasis. Unlike DICER1-wild type patients, no distant metastasis is identified in patients with DICER1-related PPTCs. The current series expands on the surgical epidemiology of somatic DICER1-related PPTCs by correlating the mutation status with the clinicopathological variables. Our findings underscore that female gender predilection and enrichment in low-risk follicular-patterned PTCs are characteristics of DICER1-related PPTCs.

Technetium-99 m sestamibi parathyroid scintigraphy (MIBI scan) has been used to localize abnormal glands in patients with primary hyperparathyroidism to guide parathyroidectomy. This series aimed to identify the biochemical and histopathological correlates of MIBI scan findings in patients with parathyroid adenoma. A total of 378 patients with histologically and biochemically proven parathyroid adenoma were included. The results of MIBI scan, histopathological (gland volume and weight, oxyphil cell ratio), biochemical (blood and 24 h urine calcium, creatinine, glomerular filtration rate, parathormone, alkaline phosphate, and vitamin D3) variables were recorded. A positive uptake on the MIBI scan referred to a localized adenoma. Among histological variables, a cutoff of 30% was applied to define parathyroid adenomas with low (≤ 30%) and high (> 30%) oxyphil cell content. Statistical analyses were performed to assess the relationship among variables. MIBI scan localized the adenoma in 306 patients. Parathyroid gland volume and weight, and oxyphil ratio were significantly higher in the MIBI scan-positive group. Among the biochemical variables, only PTH was found to be significantly increased in the MIBI scan-positive group. Binary logistic regression models identified statistically significant cutoffs for the gland volume (1700 mm3), gland weight (1.3 g) and PTH levels (170 pg/mL) that can be used to predict the MIBI scan positivity. In addition to PTH levels, this series underscored the impact of cellular composition along with the parathyroid gland volume and weight, both of which correlate with sestamibi positivity in patients with benign uniglandular parathyroid disease.

This morphological and immunohistochemical study demonstrates that tumors currently known as "middle ear adenomas" are truly well-differentiated epithelial neuroendocrine tumors (NETs) composed of cells comparable to normal intestinal L cells, and therefore, these tumors resemble hindgut NETs. These tumors show consistent expression of glucagon, pancreatic polypeptide, PYY, and the transcription factor SATB2, as well as generic neuroendocrine markers and keratins. The same L cell markers are expressed by cells within the normal middle ear epithelium. These markers define a valuable immunohistochemical profile that can be used for differential diagnosis of middle ear neoplasms, particularly in distinguishing epithelial NETs from paragangliomas. The discovery of neuroendocrine cells expressing the same markers in non-neoplastic middle ear mucosa opens new areas of investigation into the physiology of the normal middle ear and the pathophysiology of middle ear disorders.

Approximately one-tenth of the general population exhibit adrenal cortical nodules, and the incidence has increased. Afflicted patients display a multifaceted symptomatology-sometimes with rather spectacular features. Given the general infrequency as well as the specific clinical, histological, and molecular considerations characterizing these lesions, adrenal cortical tumors should be investigated by endocrine pathologists in high-volume tertiary centers. Even so, to distinguish specific forms of benign adrenal cortical lesions as well as to pinpoint malignant cases with the highest risk of poor outcome is often challenging using conventional histology alone, and molecular genetics and translational biomarkers are therefore gaining increased attention as a possible discriminator in this context. In general, our understanding of adrenal cortical tumorigenesis has increased tremendously the last decade, not least due to the development of next-generation sequencing techniques. Comprehensive analyses have helped establish the link between benign aldosterone-producing adrenal cortical proliferations and ion channel mutations, as well as mutations in the protein kinase A (PKA) signaling pathway coupled to cortisol-producing adrenal cortical lesions. Moreover, molecular classifications of adrenal cortical tumors have facilitated the distinction of benign from malignant forms, as well as the prognostication of the individual patients with verified adrenal cortical carcinoma, enabling high-resolution diagnostics that is not entirely possible by histology alone. Therefore, combinations of histology, immunohistochemistry, and next-generation multi-omic analyses are all needed in an integrated fashion to properly distinguish malignancy in some cases. Despite significant progress made in the field, current clinical and pathological challenges include the preoperative distinction of non-metastatic low-grade adrenal cortical carcinoma confined to the adrenal gland, adoption of individualized therapeutic algorithms aligned with molecular and histopathologic risk stratification tools, and histological confirmation of functional adrenal cortical disease in the context of multifocal adrenal cortical proliferations. We herein review the histological, genetic, and epigenetic landscapes of benign and malignant adrenal cortical neoplasia from a modern surgical endocrine pathology perspective and highlight key mechanisms of value for diagnostic and prognostic purposes.

Molecular pathology has advanced our understanding of many tumors and offers opportunities to identify novel therapies. In the pituitary, the field has uncovered several genetic mutations that predispose to pituitary neuroendocrine tumor (PitNET) development, including MEN1, CDKN1B, PRKRIα, AIP, GPR101, and other more rare events; however, these genes are only rarely mutated in sporadic PitNETs. Recurrent genetic events in sporadic PitNETs include GNAS mutations in a subset of somatotroph tumors and ubiquitin-specific peptidase mutations (e.g., USP8, USP48) in some corticotroph tumors; to date, neither of these has resulted in altered management, and instead, the prognosis and management of PitNETs still rely more on cell type and subtype as well as local growth that determines surgical resectability. In contrast, craniopharyngiomas have either CTNNB1 or BRAFV600E mutations that correlate with adamantinomatous or papillary morphology, respectively; the latter offers the opportunity for targeted therapy. DICER1 mutations are found in patients with pituitary blastoma. Epigenetic changes are implicated in the pathogenesis of the more common sporadic pituitary neoplasms including the majority of PitNETs and tumors of pituicytes.

Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant is identified in 95–100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, liver) revealed a VHL c.593 T > C (p.Leu198Pro) variant at varying allele fractions (range: 10–55%) in all tissues. Re-examination of the peripheral blood sequencing data identified this variant at 6% allele fraction. Tumor analysis revealed characteristic cytomorphological, immunohistochemical reactivity for alpha-inhibin, and CAIX, and reduced pVHL reactivity supported VHL-related pseudohypoxia. This report of a rare case of VHL mosaicism highlights the value of tissue testing in VHL variant negative cases.

Neuroendocrine neoplasms (NENs) have been primarily associated with germline pathogenic variants in genes involved in chromatin remodeling (MEN1), cell cycle control (CDKN1B), PI3K/mTOR signaling (TSC1/2, PTEN) as well as pseudohypoxia (VHL, SDHx). Recent work has implicated various genes involved in DNA repair pathways in the pathophysiology of a subset of pancreatic neuroendocrine neoplasms, including BRCA2, via the homologous recombination pathway (HRD). To date, germline variants in other HRD pathway genes have not been described to contribute to NEN. PALB2, RAD51C, and BARD1 are additional tumor suppressor genes which also mediate repair of double stranded DNA breaks through the HRD pathway and are implicated in hereditary breast (PALB2; BARD1) and ovarian (RAD51C) cancer. Here we report three cases of NEN associated with germline pathogenic variants in PALB2 (pancreatic NEN), RAD51C (thymic NEN), and BARD1 (pancreaticoduodenal NEN) respectively, further linking the DNA repair pathway to NENs.

Hyperparathyroidism, commonly observed in asymptomatic middle-aged women, with mild hypercalcemia, is usually caused by a benign adenoma. Some cases present with more severe manifestation and greater hypercalcemia. Within this spectrum, several familial/genetic associations have been discovered. While the majority are caused by benign disease, adenomas, or hyperplasia, a small proportion (

Solid cell nests (SCNs) are usually distinguished on conventional HE-stained sections; however, the morphological heterogeneity in SCNs and hyperplasia of these ultimobranchial body remnants can mimic other diagnostic entities including but not limited to papillary microcarcinoma. In order to confirm the thyroid follicular epithelial origin and exclude the possibility of SCNs, most diagnosticians use immunohistochemical biomarkers of thyroid follicular epithelial cells and/or those of SCNs. While the expression profile of monoclonal PAX8 has not been reported previously in SCNs, the status of TTF-1 expression using the 8G7G3/1 clone has been inconsistent among several studies. Given the potential diagnostic pitfalls, this series investigated the expression profile of GATA3, monoclonal PAX8, and TTF-1 (SPT24), along with p63, p40, monoclonal calcitonin, monoclonal CEA, and HBME-1 in a tissue microarray (TMA) of 56 SCNs. SCNs were all diffusely and strongly positive for TTF-1 (SPT24), p63, and p40, and were negative for monoclonal PAX8 and calcitonin. Positivity for GATA3 and monoclonal CEA was identified in 41 (73.2%) and 36 (64.3%) of SCNs. In addition, 18 (32.1%) SCNs displayed HBME-1 reactivity. These findings expand the immunohistochemical correlates of SCNs by demonstrating positivity for GATA3 and TTF-1 (SPT24), and negativity for monoclonal PAX8. The identification of monoclonal CEA expression and HBME-1 in SCNs also underscores the limitations of these select biomarkers in the distinction of C cell proliferations and papillary microcarcinoma, respectively. The findings of this series also suggest that positivity for TTF-1 (SPT24) alone should not be used to confirm the thyroid follicular epithelial origin. Therefore, the combined use of TTF-1 (SPT24) and monoclonal PAX8 in association with p63 or p40 provides an accurate distinction of SCNs.

Renaming encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently suggested to prevent the overtreatment, cost and stigma associated with this low-risk entity. The purpose of this study is to document the incidence and further assess the clinical outcomes of reclassifying EFVPTC to NIFTP. We searched synoptic pathologic reports from a high-volume academic endocrine surgery hospital from 2004 to 2013. The standard of surgical pathology practice was based on complete submission of malignant thyroid nodules along with the nontumorous thyroid parenchyma. Rigid morphological criteria were used for the diagnosis of noninvasive EFVPTC, currently known as NIFTP. A retrospective chart review was conducted looking for evidence of malignant behavior. One hundred and two patients met the strict inclusion criteria of NIFTP. The incidence of NIFTP in our cohort was 2.1% of papillary thyroid cancer cases during the studied time period. Mean follow-up was 5.7 years (range 0–11). Five patients were identified with nodal metastasis and one patient with distant metastasis. Overall, six patients showed evidence of malignant behavior representing 6% of patients with NIFTP. Our study demonstrates that the incidence of NIFTP is significantly lower than previously thought. Furthermore, evidence of malignant behavior was seen in a significant number of NIFTP patients. Although the authors fully support the de-escalation of aggressive treatment for low-risk thyroid cancers, NIFTP behaves as a low-risk thyroid cancer rather than a benign entity and ongoing surveillance is warranted.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous condition that predisposes to numerous proliferative lesions, including perivascular epithelioid cell tumors (PEComas), such as lymphangioleiomyomatosis (LAM) and angiomyolipomas, and rare neuroendocrine neoplasms. We describe herein a TSC2-harboring tuberous sclerosis patient manifesting with a synchronous well-differentiated L-cell rectal neuroendocrine tumor and leiomyomatosis-like LAM of the rectum. The background large bowel wall was thickened by confluent nodular areas comprising vessels and spindle-to-epithelioid cells, which are immunoreactive for myoid (smooth muscle actin, muscle specific actin, and desmin) and melanocytic markers (HMB45, Melan-A, microphthalmia transcription factor, and CD117). With the exception of TSC-related pancreatic neuroendocrine tumors, the association between tuberous sclerosis and neuroendocrine neoplasms remains largely unknown in the gastrointestinal tract. Neuroendocrine tumorigenesis in tuberous sclerosis is often linked to inactivating mutations of TSC2 leading to aberrant activation of mammalian target of rapamycin (mTOR) pathway. In this report, we document, for the first time, two foci of L-cell rectal neuroendocrine tumor arising in the setting of tuberous sclerosis, thus broadening the spectrum of TSC-associated endocrine disorders. Moreover, to our knowledge, this is only the second documented case of gastrointestinal leiomyomatosis-like LAM in a patient with tuberous sclerosis. The current case provides further evidence that, similar to pancreatic neuroendocrine tumors, neuroendocrine tumors of the luminal gastrointestinal tract may also be a feature of tuberous sclerosis and can be seen in association with PEComas.

Xanthomatous hypophysitis is a rare inflammatory disease of the pituitary gland that can mimic a neoplastic lesion clinically and radiologically. Its pathogenesis remains largely unknown, although recent evidence suggests that pituitary inflammation may occur as a secondary reaction to mucous content released from a ruptured cyst. In a series of 1221 pituitary specimens, we identified seven cases of xanthomatous hypophysitis. Six patients had complete radiological and biochemical workup preoperatively: a cystic-appearing pituitary mass was identified in all six patients (100%) with a mean size of 2.0 cm (range 1.4-2.5 cm) on imaging, and pituitary endocrine dysfunction was noted in five patients (83.3%). In all cases, the pituitary mass was resected through an endoscopic transsphenoidal approach. Pathological examination revealed the presence of foamy macrophages admixed with variable amounts of giant cells and chronic inflammatory cells, confirming the diagnosis of xanthomatous hypophysitis. Additionally, all cases presented with concurrent findings of ruptured Rathke's cleft cyst, with the exception of one patient who had previous surgery for a Rathke's cleft cyst, followed by recurrence and diagnosis of xanthomatous hypophysitis. While accurate distinction of hypophysitis from a pituitary neoplasm can be problematic in the preoperative setting, the identification of a cystic lesion in the sella turcica should raise the possibility of such an entity in the clinical and radiological differential diagnosis. The current series provides further evidence that xanthomatous hypophysitis predominantly occurs as a secondary reaction to a ruptured Rathke's cleft cyst; thus, it is best classified as a secondary (reactive) hypophysitis.

This study compared the expression profile of HBME-1 and claudin-1 in 90 papillary thyroid carcinomas (PTCs) with respect to the tumor architecture and invasive growth as reflected in 46 BRAF-like, 31 non-invasive RAS, and 13 invasive RAS-like phenotypes. Individual tumors were given an expression score (max 300) by multiplying the percent positive tumor cells by the intensity score (range 0-3). The higher expression of HBME-1 and claudin-1 distinguished BRAF-like phenotype from RAS-like phenotype. The same correlation was also retained for both markers when comparing BRAF-like phenotype with non-invasive and invasive RAS-like phenotypes. The expression scores and positivity rates for both markers did not yield any statistical difference among BRAF-like PTCs. Except the higher positivity rate of HBME-1, invasive RAS-like tumors were not statistically different than their non-invasive counterparts with respect to the positivity rate of claudin-1 and the expression scores of both markers. A central lymph node dissection or selective lymph node sampling was available in 20 specimens. The absence of claudin-1 expression has not been a feature of lymph node metastasis in this series. Despite the limited number of nodal sampling, BRAF-like phenotype and claudin-1 positivity status have been considered the best determinants of positive predictive value and negative predictive value in the prediction of lymph node metastasis among variables, respectively. Adoption of the simplified architectural classification approach to PTCs showed distinct biomarker expression profile in this series; however, immunohistochemistry for HBME-1 and claudin-1 does not seem to be useful in the distinction of invasive RAS-like PTCs from their non-invasive counterparts. Given the overlapping molecular signatures within the RAS-like phenotype, further studies with additional biomarkers are still needed to identify distinct protein expression signatures of non-invasive RAS-like phenotype as this diagnostic category still remains a surgical diagnosis at this time.

The authors present clinicopathological features of parathyroid lipoadenoma in a 48-year-old woman who presented with symptomatic primary hyperparathyroidism manifesting with pathological fractures and osteoporosis. Preoperative sestamibi scan failed to localize the source of her disease. Exploratory surgery identified an enlarged parathyroid gland with abundant fat tissue. The significant drop of intraoperative serum parathyroid hormone after the removal of this gland and postoperative biochemical cure justified the presence of a single gland disease presenting as parathyroid lipoadenoma. From an educational perspective, the presented case emphasizes why the historical approach to parathyroid proliferations by assessing alone the ratio of parenchymal cells to adipocytes is not a reliable method in the diagnostic evaluation of parathyroid disease. While the accurate size and weight of a parathyroid gland are defining parameters of an abnormal gland, intraoperative and postoperative biochemical workup distinguishes uniglandular disease (adenoma) from multiglandular disease (hyperplasia). The authors also provide a brief review of the previously published cases of parathyroid lipoadenomas to highlight their clinicopathological characteristics of relevance to surgical pathologists.

Thyrotropin (TSH)-secreting pituitary adenomas are exceedingly rare at the pediatric age and no cases of co-secretion with other pituitary hormones in these tumors have been described in this age range. We present a case of a monomorphous plurihormonal pituitary adenoma that co-secreted TSH and GH in a pediatric patient. A 13-year-old male presented with increasing height velocity (17.75 cm/year, 9.55SD), weight loss, and visual impairment. Initial biochemical evaluations revealed secondary hyperthyroidism. A giant pituitary tumor compressing the surrounding structures was detected by magnetic resonance, and a transsphenoidal surgery was initially performed. Pathological examinations revealed an atypical, monomorphous plurihormonal Pit-1 lineage tumor with mixed features of silent subtype 3 adenoma and acidophil stem cell adenoma. In the postoperative period, secondary hyperthyroidism recurred with high levels of both GH and IGF1. In addition, due to tumor re-growth, a multimodality treatment plan was undertaken including surgery, somatostatin analogs, and radiotherapy. We report the first pediatric case of a plurihormonal TSH- and GH-secreting pituitary adenoma, further expanding the clinical manifestations of pediatric pituitary tumors. Comprehensive pathological evaluation and close follow-up surveillance are crucial to the prompt delivery of the best therapeutic options in the context of this particularly aggressive pituitary tumor.

Xanthogranulomatous inflammation (XGI) is an uncommon destructive chronic inflammatory process mainly occurring in the kidney and gallbladder, characterized by the accumulation of foamy histiocytes, multinucleated giant cells (Touton type), cholesterol clefts and chronic inflammatory cells. The head and neck region is an uncommon site for XGI. This type of inflammatory reaction has been defined in branchial cleft cyst, salivary gland tumors following fine-needle aspiration biopsies, Rathke’s cleft cyst in the pituitary gland, and colloid cyst in the 3rd ventricle. We present herein a unique case of ruptured thyroglossal duct cyst leading to XGI, characterized by an infiltrative subcutaneous central neck lesion, clinically mimicking a thyroid carcinoma. In addition, we also summarize current insights into the pathogenesis of XGI in the head and neck region.

Germline mutations in Von Hippel-Lindau (VHL), succinate dehydrogenase subunit B (SDHB), SDHC, and SDHD have been detected in individuals with synchronous or metachronous pheochromocytoma/paraganglioma (PHEO/PGL) and renal cell carcinoma (RCC). Most recently, FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial RCC. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC driven by a novel germline mutation in the TMEM127 gene. Morphologically, both the PHEOs and multilocular RCC were indistinguishable from those associated with VHL disease. However, at the biochemical level, the predominant adrenergic catecholamine profile distinguishes this presentation from SDH- and VHL-related PHEOs. This case justifies the prioritization of genetic testing for germline TMEM127 in individuals with RCC and PHEO with a predominantly adrenergic phenotype.

Paragangliomas are catecholamine-secreting tumors external to the adrenal glands, most commonly arising in the head and neck, followed by the abdominal and thoracic cavities. The heart is a rare location for paragangliomas to originate from, with fewer than 50 cases as described in the literature. Functional paragangliomas of the right atrium are even more unusual, with only five cases reported to date. The investigations and therapies of a 41-year-old male presenting with a clinically functional cardiac paraganglioma are discussed. We performed a detailed pathology review of the primary cardiac tumor and a lung nodule to examine morphologic changes, along with an immunohistochemical profile (chromogranin A, tyrosine hydroxylase, MIB-1, and succinate dehydrogenase subunit B (SDHB)) of both tumors. Genetic testing of germline mutations in SDH genes was also completed. Both the 9.5-cm cardiac mass and 0.5-cm lung nodule were positive for chromogranin A and tyrosine hydroxylase and showed a global loss of SDHB expression. The MIB-1 labeling index of the smaller lesion and the bulk of the larger lesion was5 %, but there were cellular foci of the larger lesion that had a labeling index of 10%. Genetic testing yielded an intronic frameshift mutation in the SDHC gene, c.IVS 5 + 1, G A. We report the first case of a functional cardiac paraganglioma associated with an intronic frameshift SDHC gene mutation.

The history of pituitary pathology is a long one that dates back to biblical times, but the last 25 years have represented an era of "coming of age." The role of the pituitary in health and disease was the subject of many studies over the last century. With the development of electron microscopy, immunoassays, and immunohistochemistry, the functional alterations associated with pituitary disease have been clarified. The additional information provided by molecular genetic studies has allowed progress in understanding the pathogenesis of pituitary disorders. Nevertheless, many questions remain to be answered. For example, pathologists cannot morphologically distinguish locally aggressive adenomas from carcinomas when tumor is confined to the sella. Sadly, basal cell carcinoma, the most common carcinoma of skin, usually causes less morbidity than pituitary adenomas, which occur in almost 20 % of the general population, can cause significant illness and even death, and yet are still classified as benign. The opportunity to increase awareness of the impact of these common lesions on quality of life is the current challenge for physicians and patients. We anticipate that ongoing multidisciplinary approaches to pituitary disease research will offer new insights into diseases arising from this fascinating organ.

Silent corticotroph adenomas (SCAs) represent a distinct subset of clinically non-functioning pituitary adenomas. There are two variants of SCA; type I are densely granulated basophilic tumors and type II are sparsely granulated and chromophobic tumors. SCAs are known to be aggressive than the more common non-functioning gonadotroph adenomas (NFGAs). Cell-matrix interactions play an important role in the pathogenesis of pituitary adenomas. In this study, we compared 19 SCAs and 50 NFGAs with known fibroblast growth factor receptor-4 (FGFR4) status using semi-quantitative immunohistochemistry to localize β1-integrin, osteopontin, and matrix metalloproteinase-1 (MMP-1) as cytoplasmic, membranous, or mixed cytoplasmic-membranous staining to achieve scores of 1-4. Staining for β1-integrin was significantly higher in SCAs (100 %, score 3.3) than in NFGAs (96 %; score 2.6) (p = 0.0482); there was no statistical difference within subgroups of SCA (type II score 3.4; type I score 2.8) (p = 0.2663). Osteopontin immunoreactivity was also higher in SCAs (100 %, score 3.7) than in NFGAs (42 %, score 0.8) (p = 0.0001); there was no statistical difference within subgroups of SCA (type II score 3.6; type I score 3.9) (p = 0.2787). In contrast, MMP-1 immunoreactivity was lower in SCAs (89 %; score 2.5) than in NFGAs (98 %; score 3.6) (p = 0.0005); there was no statistical difference within subgroups of SCA (type II score 2.7; type I score 2.0) (p = 0.30704). The MMP-1 results correlated with FGFR4 expression (NFGA 96 %, type II SCA 71 %, type I SCA 40 %). Our data indicate that the biological aggressivity of SCAs compared with NFGA may be due to high osteopontin expression; in contrast, high MMP-1 is characteristic of NFGAs that also express more FGFR4. Further investigations are warranted to clarify the underlying regulatory mechanisms of these markers. The high osteopontin or FGFR4/MMP-1 expression levels in SCAs and NFGAs, respectively, indicate the potential for therapeutic strategies targeting osteopontin or FGFR4/MMP-1 for inoperable tumors of these types.

This report describes a case of pituitary adenoma with interspersed adrenal cortical cells. The pituitary cells were confirmed to be corticotrophs with Tpit and adrenocorticotropic hormone immunohistochemistry, whereas the adrenal cortical cells were verified to be such with steroidogenic factor-1 (SF-1), inhibin, calretinin, and Melan A staining. The presence of normal adrenal cortical cells in the heterotopic location of the sella fulfills the definition of choristoma. The origin of adrenal cortical cells within a pituitary adenoma remains unexplained. The important role of SF-1 in both pituitary and adrenal cortex may explain a relationship that supports the possibility of an abnormal proliferation and differentiation of uncommitted mesenchymal stem cells within the sella. However, it remains possible that misplaced adrenal cortical cells derived during embryogenesis give rise to this rare but distinct morphological entity that can pose a difficult diagnostic dilemma. The approach to differential diagnosis is discussed.

In chronic lymphocytic thyroiditis (CLT), the follicular epithelial cells display cytological atypia resembling papillary thyroid carcinoma (PTC), and epidemiological studies have suggested an increased risk of PTC in patients with this condition. While reactive atypia is observed diffusely in CLT-affected thyroid parenchyma, it is not unusual to find microscopic foci morphologically distinct from the surrounding parenchyma, exhibiting more pronounced cytological and architectural atypia. These small atypical lesions, which we term "follicular epithelial dysplasia" (FED), are particularly prominent in cases of severe CLT, yet lack invasive growth, papillary architecture, or intranuclear pseudoinclusions. To gain further insight into their biological significance, we constructed a tissue microarray of 70 cases of CLT, comprised of morphologically normal thyroid, thyroid with reactive atypia, FED, follicular nodular disease (nodular hyperplasia or follicular adenoma), and PTC. Immunohistochemical staining was performed for a marker panel including PTC (HBME-1, cytokeratin 19, galectin-3, and cyclin-D1) as well as TTF-1, thyroglobulin, and p63. Slides were digitally scanned and immunohistochemical staining evaluated using automated image analysis software. FED lesions were positive for TTF-1 and thyroglobulin (50/50, 100 %), though some (13/50, 26 %) also expressed p63. Similar to PTC, strong diffuse staining was observed for HBME-1 (43/50, 86 %), cytokeratin 19 (48/50, 96 %), galectin-3 (20/50, 40 %) and cyclin-D1 (38/50, 76 %). In contrast, normal thyroid, reactive atypia, and follicular nodular disease were negative, or at most, exhibited focal weak staining for HBME-1, cytokeratin 19, and galectin-3. The results of this study demonstrate the presence of atypical microscopic lesions in CLT with an immunohistochemical profile similar to PTC, supporting the concept of a premalignant lesion preceding PTC, arising in the context of severe chronic inflammation.

Unlike papillary thyroid carcinoma, medullary thyroid carcinoma is insensitive to adjuvant treatment with radioactive iodine. The clinical management of patients with advanced or metastatic disease remains challenging since no effective systemic adjuvant therapy is available. We aimed to identify markers of aggressive disease and novel drugable protein targets that would provide systemic adjuvant treatment for patients with advanced medullary thyroid carcinoma. We therefore examined morphologic features of aggressive behavior and the expression of 41 proteins involved in apoptosis, cell cycle, angiogenesis, inflammation, cell adhesion, tumor-specific markers, and WNT, SHH, and AKT pathways using tissue microarray from 23 patients with medullary thyroid carcinoma. Protein expression was determined using computerized image analysis software. Statistical analysis was carried out to correlate clinical data with the average score for each marker. Angioinvasion proved to be the most reliable predictor of disease recurrence and death. The rate of angioinvasion was 43 %. All angioinvasive medullary thyroid carcinomas had locoregional and/or distant metastasis; 60 % of angioinvasive medullary thyroid carcinomas developed distant metastasis. We identified expression of several potentially important protein targets such as COX-1/2, Bcl-2a, Gst-π, Gli-1, Gli-2, Gli-3, and Bmi-1 that may be therapeutically targeted in medullary thyroid carcinoma. More importantly, the immunohistochemical profile of SSTRs in medullary thyroid carcinoma may also have clinical relevance for the administration of peptide receptor radionuclide treatment. Successful outcome of clinical trials directed against these novel targets would provide much needed systemic adjuvant treatment for patients with advanced medullary thyroid carcinoma, and our data suggest the possibility of stratifying patients who are likely to require adjuvant therapy before their burden of disease precludes successful therapeutic effect.

Marfan syndrome (MFS) is an autosomal dominant hereditary disorder of connective tissue associated with perturbations in transforming growth factor β (TGF-β) biology, most often due to mutations in FBN1 gene that encodes fibrillin-1. To our knowledge, there is no known association of MFS with thyroid carcinoma. We report a 46-year-old man with known history of MFS who developed an unusual histological variant of papillary thyroid carcinoma. The tumor exhibited a widely invasive florid papillary growth pattern with prominent long villous fronds. Immunohistochemical and molecular analysis revealed a BRAF(V600E) mutation, evidence of aggressive biomarker expression (positivity for HBME-1, cytokeratin 19, galectin-3 and cyclin D1, and loss of p27), and changes associated with TGF-β-related epithelial-to-mesenchymal transition with active phospho-SMAD signaling. We introduce a unique histological pattern of papillary thyroid carcinoma that is associated with MFS. The combination of BRAF(V600E) mutation in the setting of altered TGF-β signaling and weak connective tissue integrity associated with MFS may cooperate and possibly be responsible to form this unique villous morphology with epithelial-to-mesenchymal transition and invasive growth.

Silent corticotrph adenomas represent a distinct pathological subtype of non-functioning pituitary adenomas that are traditionally believed to carry a more aggressive biological behavior and higher potential for recurrence.We conducted a retrospective review of all silent corticotroph adenomas treated and followed at our institution over the last 10 years. We reviewed clinical, radiological and pathological features. The series was compared to a matched cohort of ACTH-negative, non-functioning adenomas to compare clinical, radiological and pathological features. Our results were compared to the literature.Twenty patients met our inclusion criteria. Fifty-six percent of the patients were females. Mean age was 51 years (range 24-78 years). Visual dysfunction was the most common clinical presentation (38 %). Thirteen percent of the cases presented with acromegaly secondary to double adenoma (silent corticotroph adenoma and growth hormone adenoma) and 13 % presented with pituitary tumor apoplexy. All the tumors were macroadenomas. Frank cavernous sinus invasion occurred in 31 % of the cases. The patients who presented with acromegaly did not achieve remission postoperatively. In the remaining patients, recurrence occurred in 14 % of the cases over a mean follow-up period of 41 months. Compared to non-functioning adenomas, silent corticotroph adenomas were more likely to bleed (p value 0.014) and have double adenoma (p value 0.047). There was no difference in recurrence rates between silent corticotroph adenomas and non-functioning adenomas (p value 0.647).These results suggest that silent corticotroph adenomas have some unique features compared to non-functioning adenomas. Within the limits of our follow-up duration and sample size and our review of the literature, we would recommend that the traditional view to manage all silent corticotroph adenomas with adjuvant radiation should be reconsidered. We suggest adopting an initially more conservative follow-up surveillance and delay of upfront radiation until there is clear evidence of tumor recurrence.

Ovarian thecal metaplasia is a rare tumor-like mesenchymal lesion of the adrenal gland that has been reported mainly in postmenopausal women and rarely in men. It was originally described as a wedge-shaped lesion composed of ovarian-like stroma resembling theca that shows continuity with the capsule of the adrenal gland. We report three cases and identify that these lesions can resemble a radial scar. While a single case has been reported to contain true ovarian stromal elements, there was no evidence of steroidogenic differentiation in our cases. These findings justify the need for a better terminology since the entity falls within the spectrum of fibroblastic-myofibroblastic proliferations. We propose the terminology of "radial scar-like spindle cell myofibroblastic nodule of the adrenal gland" as a more accurate nomenclature to designate these lesions. Although rare, calcifying fibrous tumor of the adrenal gland, hypertrophic nerve bundles, and peripheral nerve sheath tumors may mimic these lesions.

In the evaluation of retroperitoneal masses, the practicing pathologist faces a dilemma when making a diagnosis based on histology given the often overlapping morphologic appearances of the adrenocortical carcinoma, renal cell carcinoma (RCC), and hepatocellular carcinoma (HCC). CD10 is expressed in a membranous fashion in the vast majority of clear cell RCCs; therefore, it is widely used for distinction from its mimics. However, its expression is not well-investigated in adrenal cortical tumors. We examined CD10 expression in 47 surgically resected adrenocortical tumors (26 adenomas and 21 carcinomas) and compared with 20 clear cell RCCs and 25 HCCs. Twenty HCCs (80%), 18 RCCs (90%), 11 adrenocortical carcinomas (52%), and 18 adrenocortical adenomas (69%) were positive for CD10. HCCs were characterized by a canalicular staining, and clear cell RCCs exhibited membranous or mixed membranous-cytoplasmic staining. Adrenocortical tumors displayed mainly cytoplasmic staining. Four adrenocortical carcinomas and one adenoma also displayed the membranous staining pattern. Despite the relatively small number of samples, our preliminary results revealed that adrenocortical tumors may express CD10 (Clone: 56C6). The most important point from this paper is the fact that anti-CD10 expression has not been previously reported in adrenocortical carcinomas. This suggests that CD10 does not seem to be a useful marker for discriminating clear cell RCCs from adrenocortical tumors since CD10 expression does not rule out the possibility of adrenocortical tumors. This feature should be kept in mind when constructing an antibody panel for an epithelial tumor that involves the adrenal gland and kidney, especially in small biopsy specimens.

We report an interesting morphological alteration in the adrenal of a 72-year-old woman suffering from severe hypertension due to primary hyperaldosteronism. The laparoscopic left adrenalectomy specimen revealed an adrenal cortical adenoma composed of varying proportions of oncocytic and clear cells, predominantly showing central oncocytic change. Oncocytes also exhibited numerous eosinophilic intracytoplasmic globular inclusions, which are not commonly observed in aldosterone-producing adrenal cortical adenomas. Ultrastructural study revealed that the inclusions originated in degenerating mitochondria, explaining their association with the oncocytic phenotype of the tumor.

Among the epithelial renal tumours with eosinophilic cytoplasm, the main differential diagnostic problem arises between renal oncocytomas (ROs) and eosinophilic variants of chromophobe renal cell carcinomas (RCCs). We investigated the possible role of anti-mitochondrial (AMA), anti-caveolin 1 (CAV1), anti-CD63 (CD63) and anti-cytokeratin 14 (CK14) antibodies in the differential diagnosis of eosinophilic epithelial tumours and applied the Muller and Mowry modification of Hale's colloidal iron stain (HCI). Thirty-five ROs and 77 eosinophilic RCCs (27 chromophobe, 28 clear cell and 22 papillary RCCs) were included in this study. Apical and/or polar CD63 immunostaining (94%) and diffuse AMA (91%) and CAV1 (88%) immunostainings were the characteristics of ROs, whereas diffuse CD63 immunostaining (96%) and diffuse-peripheral AMA (96%) and CAV1 (92%) immunostainings were characteristic immunohistochemical features of eosinophilic chromophobe RCCs. We showed CK14 antibody not to be useful in the differential diagnosis of the eosinophilic epithelial renal tumours. The staining localisations with AMA, CAV1 and CD63 antibodies were significantly different between tumour groups. AMA had 96% sensitivity and 94% specificity, whereas CAV1 had 92% sensitivity and 97% specificity in diagnosing chromophobe RCCs. With HCI staining, ROs, showing apical and/or polar staining, could be differentiated from chromophobe RCCs, showing diffuse cytoplasmic staining. HCI had fairly low (69%) sensitivity and 100% specificity, whereas CD63 had 95% sensitivity and 100% specificity to diagnose ROs. We recommend using CD63 as the best marker of choice for distinguishing ROs from eosinophilic chromophobe RCCs when standard diagnostic criteria are not helpful.

Synovial sarcoma is a soft tissue sarcoma of unknown histogenesis and occurs predominantly in the lower extremities of young adults. The head and neck is a relative rare location. There are about 10 cases with laryngeal localization in the literature. We present a 24 year-old male with an endolaryngeal mass. Incisional biopsy and the hemilaryngectomy material revealed a biphasic synovial sarcoma. One year later a local recurrence occurred. Tumor excision and neck dissection were performed. Radiotherapy was added. Six months later lung metastases was discovered on thoracic CT. The patient received chemotherapy for 6 courses. The metastases responded well to chemotherapy and the patient is now alive without tumor on radiological and clinical examination after 3.5 years of follow-up.