Paired box 8 (PAX8) mutations are an established genetic cause of congenital hypothyroidism (CH). The majority of these mutations are found in the protein-coding exons of the gene. The proband, a 3-yr-old girl, had tetralogy of Fallot and polydactyly soon after birth. She was diagnosed with CH in the newborn screening for CH. She had a high serum TSH level (239 mU/L) and low free T4 level (0.7 ng/dL). Ultrasonography revealed thyroid hypoplasia. We performed array comparative genomic hybridization because the patient exhibited a variety of symptoms across multiple organ systems. The analysis revealed a novel heterozygous deletion that spanned a 15.2 Mb region in 2q12.3q14.3 (GRCh37; chr2:109,568,260-124,779,449). There were 71 protein-coding genes in this region, including two genes (PAX8 and GLI2) associated with congenital endocrine disorders. The common clinical features of the two previously reported patients with a total PAX8 deletion and our case were CH, short stature and intellectual disability, but the severity of hypothyroidism and other clinical features were variable. In conclusion, we describe a syndromic CH patient with a novel 2q12.3q14.3 deletion involving PAX8. Patients with CH, whose unifying diagnosis is not obvious, could have a genomic deletion involving PAX8.

Granular cell tumors of the pituitary belong to a rare family of neoplasms, arising from the posterior pituitary gland. Although considered benign, they may cause significant morbidity and residual disease after resection can lead to poor clinical outcomes. Currently, there is no known medical therapy for any posterior pituitary gland tumor, in part due to sparse molecular characterization of these lesions. We report data from whole exome sequencing of a case of granular cell tumor of the pituitary, performed under an institutional review board approved protocol. A 77 year-old female underwent resection of an incidentally diagnosed pituitary mass that was causing radiographic compression of the optic nerves with a subclinical temporal field defect and central hypothyroidism. The pathology of the resected specimen demonstrated a granular cell tumor of the posterior pituitary gland. Whole-exome sequencing revealed mutations predicted to be deleterious in key oncogenes, SETD2 and PAX8, both of which have been described in other cancers and could potentially be amenable to targeted therapies with existing approved drugs, including immune checkpoint inhibitors and histone deacetylase inhibitors, respectively. To our knowledge, this is the first comprehensive genomic characterization of granular cell tumor of the posterior pituitary gland. We report mutations in oncogenes predicted to be deleterious and reported in other cancers with potential for therapeutic targeting with existing pharmacologic agents. These data provide new insights into the molecular pathogenesis of GCT of the pituitary and may warrant further investigation.

A 20-year-old male presented to the emergency department with lower abdominal pain, urinary retention, and constipation. Computed tomography (CT) revealed a large cyst on the posterior aspect of the prostate gland; he was ultimately diagnosed with a Müllerian duct cyst (MDC). Although much has been written on the radiologic diagnosis of such cysts, there is a paucity of recent literature concerning the pathological diagnosis. While older studies debated the Müllerian origin of a midline cyst abutting the poster prostate, we believe that with the advent of monoclonal PAX8 (which was positive in this lesion) and monoclonal PAX2 (which was negative), we have strong evidence that the present cyst is indeed of Müllerian origin. Further, there is debate in the literature as to whether MDC is synonymous or distinct from prostatic utricle cyst. We present an interdisciplinary analysis as to the merits and weaknesses of both sides of the debate and how data gathered from the current case could be used in a future, larger study to arrive at a more definitive conclusion.

Primary squamous cell carcinoma (SCC) in the thyroid is extremely rare and has been reported in < 1% of all thyroid cancer cases. Primary SCC in the thyroid was thought to be a transitional form derived from adenocarcinomas; therefore, the majority of reported cases have focused on the conjunction with other histological adenocarcinomas. A 73-year-old male presented to our hospital with bilateral vocal fold palsy and an anterior neck mass. Ultrasound sonography revealed a bulky tumor in the thyroid and bilateral cervical lymphadenopathy. We performed fine-needle aspiration cytology from the thyroid tumor, which revealed SCC. Positron emission tomography/computed tomography showed distant metastases in the lungs, mediastinal lymph nodes, and vertebra. We diagnosed the patient as having stage IVC SCC in the thyroid and administered weekly paclitaxel. Four and a half months after treatment initiation, the tumor progression resulted in aspiration pneumonia, which proved fatal. We performed an autopsy in accordance with the patient\'s wishes. Pathological findings revealed that all carcinomas in the thyroid, cervical lymph nodes, and lungs were pure SCCs. Immunohistochemical examinations for PAX8, thyroglobulin, and TTF-1 were all negative. Differentiated thyroid carcinomas have 3 major positive markers - PAX8, thyroglobulin, and TTF-1 -, and PAX8 is also sometimes positive for SCC in the thyroid. PAX8 positivity of SCC in the thyroid might, however, be associated with conjunction with other histological adenocarcinomas such as papillary or follicular thyroid carcinoma; therefore, pure SCC in the thyroid might be negative for PAX8.

OBJECTIVE: Intramucosal gastric adenocarcinoma of the well-moderately differentiated type only exhibits lymph node metastasis in extremely rare cases. We encountered such case and investigated both the lymphangiogenic properties and somatic mutations in the cancer to understand the prometastatic features of early-stage gastric cancer.
METHODS: We quantitatively measured the density of lymphatic vessels and identified mutations in 412 cancer-associated genes through next-generation target resequencing of DNA extracted from tumor cells in a formalin-fixed and paraffin-embedded tissue. Functional consequence of the identified mutation was examined in vitro by means of gene transfection, immunoblot, and the quantitative real-time polymerase chain reaction assay.
RESULTS: The intramucosal carcinoma was accompanied by abundant lymphatic vessels. The metastatic tumor harbored somatic mutations in NBN, p.P6S, and PAX8, p.R49H. The PAX8R49H showed significantly higher transactivation activity toward E2F1 than the wild-type PAX8 (P< 0.001).
CONCLUSIONS: Our data suggest that increased lymphangiogenesis and somatic mutations of NBN and/or PAX8 could facilitate lymph node metastasis from an intramucosal gastric carcinoma. These findings may potentially inform evaluations of the risk of developing lymph node metastasis in patients with intramucosal gastric cancer.

Nephroblastomas are uncommon embryonal tumors in dogs. We report herein a blastema-predominant nephroblastoma with gingival metastasis in an 8-y-old Miniature Pinscher dog. Histologically, the mass was composed mainly of blastemal elements with minor epithelial and mesenchymal differentiation. Metastatic masses in the gingiva had histologic and immunohistochemical features similar to those of the primary renal nephroblastoma. Neoplastic cells were extensively positive for both vimentin and PAX8, and scattered positive for cytokeratin. Using the clinical staging of human Wilms tumor, we staged our case as stage IV with <4 mo of survival time. We summarized previous studies of canine renal and spinal nephroblastomas, and analyzed the correlations among clinical staging, histologic classification, and mean survival time of dogs with renal nephroblastomas. Clinical staging was significantly correlated with survival time, as shown in humans. In dogs, however, additional factors can potentially influence the outcome of treatment and disease development.

Diagnosis of cystic papillary thyroid carcinoma (PTC) lymph node metastasis at head neck region can be a challenge in the absence of known PTC history. The congenital cystic lesions of head neck, especially thyroglossal duct cyst (TGDC) and branchial cleft cyst (BCC), are major differential diagnoses in this clinicopathological scenario. The location of cyst and morphology of lining epithelium are critical clues for reaching correct diagnosis. However it is not uncommon that the flattened bland epithelial lining can be seen in both cystic metastases and congenital cystic lesions. Given that Pax8 and TTF-1 are common markers in thyroid follicular epithelium; we applied immunohistochemical stains of those two markers on aforementioned cystic lesions. Here we reported a case of cystic PTC metastasis to lymph node without prior malignancy history and cases of TGDC and BCC. Both Pax8 and TTF-1 stainings highlighted the cyst lining in PTC metastatic lymph node, while they were negative in the lining of TGDC and BCC. Collectively, Pax8 and TTF-1 immunohistochemical studies are very helpful tools for making correct diagnosis of head neck cystic lesions in the challenging clinical cases.

Mesonephric adenocarcinoma is a rare tumor type that is usually found in areas where the Wolffian duct was present during the fetal period. We report a case of mesonephric adenocarcinoma of the uterine corpus in a 66-year-old woman who presented with vaginal bleeding. Pelvic magnetic resonance imaging revealed a 2.7-cm-sized irregular thickening and enhancement of the uterine body. The diagnosis following endometrial curettage biopsy was endometrioid adenocarcinoma, and the patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. The tumor was composed of small tubular and ductal components, and a retiform appearance was also observed in the deeper areas. The tumor cells were immunopositive for cytokeratin, vimentin, CD10 with a luminal staining pattern, PAX2, and PAX8, and immunonegative for estrogen receptor and progesterone receptor, which was consistent with tumor of mesonephric origin. Mesonephric neoplasms reveal relatively low-grade nuclear feature, characteristic immunoprofiles (immunonegative for ER and PR, and immunopositive for CD10, PAX2, PAX8, and GATA3), and unique tumor location (myometrium), whereas Müllerian neoplasms such as endometrial adenocarcinoma show various morphology, immunopositivity for ER and PR, and primarily endometrial location. As described above, an integration of the clinical features, morphologic characteristics, and immunohistochemical profiles is needed to make a diagnosis.

Anaplastic thyroid carcinoma (ATC) is a rare but aggressive form of undifferentiated thyroid carcinoma which arises from previously well-differentiated thyroid carcinomas, such as papillary carcinoma or follicular carcinoma. We report on an interesting case of ATC found in an enlarging neck mass with metastatic papillary carcinoma found in mediastinal lymph nodes sampled by endoscopic bronchial-ultrasound guided- fine-needle aspiration, due to the incidental finding of a lung mass by CT scan. Divergent morphologies on cytology preparations were resolved by immunohistochemistry, which aided in the identification of both sites of malignancy and the common thread between them. The eventual palliative resection demonstrated the various components including undifferentiated thyroid carcinoma, papillary carcinoma, and background lymphocytic thyroiditis.