BACKGROUND

Adrenal rest (AR) is the presence of ectopic adrenal cortical tissue, often identified incidentally during autopsy (20% of postmortem examination). In the kidney, AR can be found in 6% of the general population. Ectopic adrenal tissue is of no functional significance but may in some cases, pose a diagnostic challenge for the pathologist, especially in the context of renal clear cell renal cell carcinoma (RCC) and small needle biopsies.

OBJECTIVE

To investigate the utility of immunohistochemical stains in distinguishing AR from RCC.

METHODS

Archival cases of AR, in our institution, were reviewed and compared with a cohort of RCC cases using a panel of immunohistochemical stains, including PAX2, PAX8, calretinin, and inhibin.

RESULTS

Nine of 10 (90%) cases of AR showed positive staining for inhibin and negative staining for calretinin, PAX2 and PAX8. One AR case was positive for PAX2 and PAX8 in addition to inhibin. All (100%) RCC cases were positive for PAX2 and PAX8, but negative for inhibin and calretinin.

CONCLUSIONS

A panel of PAX2, PAX8 and inhibin may be useful markers for distinguishing AR from RCC. Calretinin was noncontributory in our study.

PAX8 is a transcription factor involved in the regulation of organogenesis of the thyroid gland, kidney, and Müllerian system. It is commonly expressed in epithelial tumors of thyroid and parathyroid glands, kidney, thymus, and female genital tract. PAX8 is increasingly used in the establishment of tissue of origin in carcinomas and has recently been identified in a subset of small blue round cell tumors including Ewing sarcomas/PNETs. However, it is unclear if this association in ES/PNETs is due to renal origin or is PNET specific. In this study we investigated the PAX8 staining pattern of primary renal and extra-renal ES/PNETs to explore its potential diagnostic and prognostic role. A tissue microarray (TMA) of 22 cases of extra-renal Ewing/PNETs and two separate cases of primary renal PNET whole slide sections were immunohistochemically stained with rabbit polyclonal PAX8 antibody. PAX8 was positive in 2 of 2 primary renal PNETs and in 14 (64 %) cases of the extra renal PNETs. The association between PAX8 immunoreactivity and Ewing/PNET was identified in both primary renal and extra-renal Ewing/PNETs for the first time. Further studies are warranted to verify these findings and to shed light in the tumorigenesis of Ewing/PNET. However, PAX8 is not useful in establishing a diagnosis of Ewing/PNET due to its presence in different tumors like carcinomas, lymphomas and sarcomas. PAX8 does not seem to have prognostic value.

OBJECTIVE

To determine TERT promoter mutation status as well as the expression of PAX8, GATA3, p63, p40, p53 and uroplakin III in 17 patients with the upper urinary tract sarcomatoid urothelial carcinoma.

RESULTS

TERT C228T mutations were found in six of 17 cases (35%). p53 was expressed in 77% of these tumors. PAX8, GATA3, p40 and uroplakin III are less frequently expressed. Lymph node metastases were present in ten cases (59%). Eight patients (47%), including all three patients with TERT mutation, died of cancer within 2 years after surgery.

CONCLUSIONS

Sarcomatoid carcinoma of the upper urinary tract is an aggressive tumor and the presence of TERT mutation may portend poor prognosis.

PAX2 and PAX8 are transcription factors involved in embryogenesis that have been utilized as immunohistochemical indicators of tumor origin. Specifically, PAX2 is a marker of neoplasms of renal and müllerian origin, while PAX8 is expressed by renal, müllerian, and thyroid tumors. While studies examining these transcription factors in a variety of tumors have been published, data regarding their expression in salivary gland neoplasms are limited. The goal of this study was to assess expression of PAX2 and PAX8 in a large cohort of salivary gland tumors. Utilizing tissue microarrays, samples of normal salivary glands (n = 68) and benign and malignant salivary gland neoplasms (n = 442) were evaluated for nuclear immunoreactivity with PAX2 and PAX8. No expression was observed with either marker in the normal salivary glands, and PAX8 was negative in all neoplasms. Focal expression of PAX2 was observed in one example each of oncocytoma and acinic cell carcinoma. These results indicate that evaluation of PAX2 and/or PAX8 expression would be valuable in differentiating primary salivary gland tumors from metastases known to express PAX2 and/or PAX8.

Differentiated thyroid cancers are the predominant malignancies of the thyroid. Due to advances in the understanding of the activation of the cell proliferation pathway at a molecular level, multiple genetic alterations have been linked to the development of thyroid carcinogenesis. Although the genetic alterations can be categorized into 7 categories, the BRAF mutation, RET/PTC, Pax8/PPARGamma, and dysfunctional Fas pathway have been most commonly described. Each of the gene alterations can ultimately result in cancer development, invasion and/or metastasis. This article provides a detailed review of the altered cell proliferation pathway activations found in thyroid carcinogenesis. The molecular targets that may be disrupted by therapeutic agents during the abnormal proliferation are also summarized.

UNASSIGNED

This study reports a case of primary mucinous carcinoma of the thyroid gland with signet-ring-cell differentiation, and reviews the literature to evaluate its real incidence and the prognosis of these patients.

UNASSIGNED

A 74-year-old Chinese woman, presenting with a mass in the right lobe of thyroid gland, came to the hospital. Computed tomography revealed a mass in the right lobe of the thyroid gland, accompanied with right neck lymphadenectasis and airway deviation caused by tumor compression. Thyroid imaging suggested a thyroid malignant tumor and suspicious lymph node metastasis. Histologically, the tumor was characterized by the tumor cells arranged in small nests or trabeculae with an abundant extracellular mucoid matrix. The tumor cells formed diffuse invasion among thyroid follicles. In the peripheral regions, prominent signet-ring-cells formed a sheet-like structure and extended into the extrathyroidal fat tissue. The tumor cells were diffusely positive for thyroid transcription factor-1 (TTF-1) and PAX8, while they were focally positive for pan-cytokeratin (AE1/AE3) and weakly expressed thyroglobulin.

UNASSIGNED

Based on the histological features and immunohistochemical profile, a diagnosis of primary mucinous carcinoma of the thyroid gland with signet-ring-cell differentiation was rendered.

UNASSIGNED

Using a panel of immunohistochemical markers may be helpful for differential diagnosis and for determining whether the tumor is primary or not.

Lynch syndrome (LS) is an autosomal dominant disease caused by a germline mutation in DNA mismatch repair genes which increases the risk of several cancers such as endometrial and colorectal cancers. However, there are only a few reports of peritoneal malignancies in patients with LS. Herein, we report the first case of a primary peritoneal low-grade serous carcinoma in a woman with LS and provide a literature review of peritoneal malignancies in patients with LS. The patient was a 72-yr-old gravid 2 para 2 Japanese woman with a germline mutation in MLH1. She had a history of colon cancer and endometrial cancer and was treated with total hysterectomy and bilateral salpingo-oophorectomy 14 yr ago. During the follow-up, peritoneal nodules were detected by abdominal computed tomography which were surgically resected. Pathologic examination revealed a low-grade serous carcinoma with cells positive for BerEP4, MOC31, CEA, and WT-1 and negative for BAP1, PAX8, MLH1, and PMS2, by immunohistochemistry. This case report and literature review show that peritoneal low-grade serous carcinoma can occur in patients with LS and that LS-related cancers usually precede primary peritoneal malignancies. The differential diagnosis for peritoneal nodules in patients with LS should, therefore, include peritoneal serous carcinoma and malignant mesothelioma besides metastasis of LS-related cancers. Considering the ambiguous immunophenotypes, a combination of immunohistologic markers would be useful for an accurate diagnosis of such cases.

Papillary cystadenoma is an uncommon epithelial tumor, originating within the head of the epididymis and broad ligament. When the lesion is bilateral, it is associated with von Hippel-Lindau disease. Its resemblance to metastatic clear cell renal cell carcinoma (RCC) has been noted in the literature. Owing to the emergence of additional markers for RCCs, we have evaluated the immunohistochemical staining patterns of a series of 7 papillary cystadenomas using CK7, RCC, PAX8, carbonic anhydrase IX, and AMACR. Six of the cases involved the epididymis, and 1 involved the broad ligament. The patients ranged in age from 20 to 65 years old. All of the tumors were unilateral and not known to be associated with von Hippel-Lindau disease. The lesions were composed of cystic structures, which focally contained papillary fibrovascular cores lined by cuboidal to columnar bland-appearing cells with clear cytoplasm. Another component was the presence of tubules, which focally had elongated profiles. Reverse polarity, wherein the nuclei are oriented toward the luminal surface with subnuclear vacuoles, was present focally in 4 cases and more extensively in a fifth case. Features associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis, were not identified. All lesions were strongly positive for CK7 and negative for RCC. Carbonic anhydrase IX was positive in all tumors (diffusely positive in 6, patchy in 1) with lack of staining in the apical portion of the cytoplasm (ie, cup-shaped staining). PAX8 showed diffuse positivity in 6 of the 7 lesions, with one of the epididymal cases showing negative staining. AMACR staining was negative in 5 of the 7 cases and showed only focal, weak staining in the remaining 2 cases. The current study more specifically demonstrated that papillary cystadenoma does not resemble clear cell RCC. Rather, papillary cystadenomas of the epididymis and broad ligament have identical morphology and immunohistochemical staining to clear cell papillary RCC. The diagnosis of papillary cystadenoma can be established as clear cell papillary RCC to date has not exhibited metastatic behavior.

OBJECTIVE

To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC.

RESULTS

We identified 28 tumours from multiple institutions. They typically showed two cell populations-larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5-100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39-86 years). The median tumour size was 20 mm (range 9-65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low-grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt-Hogg-Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α-methylacyl-CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA-3, WT1, CK5/6, and CK20; CD10 and 34βE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow-up was available for 23 patients (median 24 months, range 1-244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes).

CONCLUSIONS

Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal.

Acquired cystic disease of kidney-associated renal cell carcinoma (ACD-RCC) is a distinct subtype of renal cell carcinoma with unique morphologic and clinicopathologic features. Generally, ACD-RCC is regarded as an indolent tumor; however, prognostic and outcomes data have been conflicted by the limited and relatively low number of cases with patient follow-up or adverse events. In this study, we focused on the histology of metastatic lesions and identifying prognostic factors associated with metastatic progression. From 32 cases in the cohort, 9 patients had metastasis [ACD-RCC (M+)] and 23 patients were without metastasis [ACD-RCC (M-)]. The median age of patients was 52 years; right side, n=10; left side, n=18; bilateral, n=4; median tumor size=2.6 cm; median hemodialysis duration=17 y; and the median duration of follow-up was 50 mo. Immunohistochemistry showed ACD-RCC to be racemase positive and CK7 negative to focally positive within tumor cells, with consistent positivity for renal histogenesis-associated markers (PAX8 and RCC antigen); S100A1 was a less reliable marker at metastatic sites. All metastatic ACD-RCC except 2 cases involved lymph nodes (para-aortic, renal hilar, subclavicular). Overall, 6/9 (67%) had visceral metastasis to sites including lung (n=3), liver (n=3), bone (n=5), stomach (n=1), and brain (n=1). In total, 5/9 (56%) metastatic tumors had distinctive cystic growth pattern at the metastatic site; intriguingly metastatic tumors had intrametastatic oxalate crystal deposition, a pathognomonic feature associated with primary tumors. Four of nine (44%) patients with ACD-RCC (M+) had fatal outcomes due to metastatic disease. Clinically significant adverse prognostic features associated with metastasis [median follow-up 47 mo, ACD-RCC (M+) vs. ACD-RCC (M-), 50 mo] included: duration of hemodialysis (≥20 vs. <20 y, P=0.0085) and tumor necrosis (P=0.049). Because of sufficient overlap between these parameters, the study was not able to identify parameters that would be reliable in further management strategies, in clinical settings. Our data indicate that ACD-RCC is a tumor which has distinct metastatic potential with nodal and visceral tropism and proclivity for cystic morphology at metastatic sites; this is the first report of the presence of oxalate crystals in metastatic tumors. Our data suggest that ACD-RCC patients with prolonged hemodialysis and tumoral coagulative necrosis require additional surveillance in view of the association of these parameters with metastatic progression.

OBJECTIVE

To report a series of 11 ovarian and one endometrial neoplasm in elderly patients with mixed clear cell tumour and germ cell tumour (GCT) components, to compare their immunohistochemical profiles and demonstrate a putative stem cell population.

RESULTS

The clear cell tumours included 11 clear cell carcinomas (CCC) and one borderline clear cell tumour, while the GCT always included glandular yolk sac tumour (YST). In four cases, there were also foci of teratoma with immature neuroepithelial and endodermal tissues and undifferentiated areas showing true embryoids. To distinguish between the clear cell and YST components, the following antibodies were used: HNF1-β, napsin-A, cytokeratin 7 (CK7), PAX8, EMA, AFP, SALL4, villin, glypican-3 (GPC-3), GATA3, HepPar-1, OCT4, CDX2, CD30 and SOX2. HNF1-β, CK7, EMA and GPC-3 were often expressed in both components. Other markers had higher specificity for each cellular lineage; napsin-A and PAX8 were expressed only in CCC, while SALL4, villin, AFP and HepPar-1 were positive in the glandular YST component but negative in the clear cell component. OCT4 expression occurred in six of 10 cases and consistently in teratoma (four of four).

CONCLUSIONS

There is considerable immunophenotypical overlap between the two components in these mixed neoplasms, and a panel of markers should be used to facilitate the distinction. We propose that OCT4-expressing somatic cancer cells differentiate into GCT and represent spontaneously induced pluripotent stem cells, possibly conditioned by age-related epigenetic factors. These neoplasms have features of prepubertal type GCT showing lack of 12p gain, preponderance of YST and coexistence with immature neuroectoderm. However, there may also be undifferentiated stem cell areas with embryoid bodies, of the type seen in postpubertal testicular GCT, but lacking a complete embryonal carcinoma immunophenotype.

GLI-similar 1-3 (GLIS1-3), a subfamily of Krüppel-like zinc finger transcription factors, function as key regulators of several biological processes important to oncogenesis, including control of cell proliferation, differentiation, self-renewal, and epithelial-mesenchymal transition. This review provides a short overview of the critical roles genetic changes in GLIS1-3 play in the development of several malignancies. This includes intrachromosomal translocations involving GLIS2 and ETO2/CBFA2T3 in the development of pediatric non-Down's syndrome (DS), acute megakaryoblastic leukemia (AMKL), a malignancy with poor prognosis, and an association of interchromosomal translocations between GLIS3, GLIS1, and PAX8, and between GLIS3 and CLPTM1L with hyalinizing trabecular tumors (HTTs) and fibrolamellar hepatocellular carcinoma (FHCC), respectively. Targeting upstream signaling pathways that regulate GLIS signaling may offer new therapeutic strategies in the management of cancer.

Background: Large-scale loss-of-function screening database such as Cancer Dependency Map (Depmap) provide abundant resources. Investigation of these potential dependency genes from human cancer cell lines in the real-world patients cohort would evaluate their prognostic value thus facilitate their clinical application and guide drug development.

Methods: A few genes were selected from top clear cell renal cell carcinoma (ccRCC) lineage preferential dependency candidates from Depmap. Their characteristic including expression levels both in normal and tumor tissues and correlations with methylation or copy number, genetic alterations, functional enrichment, immune-associated interactions, prognostic value were evaluated in KIRC cohort from TCGA, GTEx, and multiple other open databases and platforms.

Results: 16 genes were collected from 106 ccRCC preferential candidates and further analyzed including B4GALT4, BCL2L1, CDH2, COPG1, CRB3, FERMT2, GET4, GPX4, HNF1B, ITGAV, MDM2, NFE2L2, PAX8, RUVBL1, TFRC, and TNFSF10. The normalized gene effect scores of these genes varied from different ccRCC cell lines and principal component analysis (PCA) showed their tissue specificity expression profiles. Genetic alteration rates of them were low to moderate (0.7%-13%) in KIRC cohort. CDH2, MDM2, TNFSF10 showed a statistically significant higher level in tumors than normal tissues while PAX8 and FERMT2 were significantly downregulated. Moderate positive or negative correlations were observed in several genes between their expression and relative gene copy number or methylation levels, respectively. Based on the multivariable COX regression model adjusted by critical clinical variables revealed the expression of GET4 (p=0.002, HR=1.023 95%CI 1.009-1.038) and CRB3 (p<0.001, HR=0.969 95%CI 0.960-0.980) were independent predictive factors for overall survival in KIRC cohort.

Conclusions: A dependency gene validated in cell lines didn't directly represent its role in corresponding patients with same histological type and their prognostic value might be determined by multiple factors including dependency driven types, genetic alteration rates and expression levels. GET4 and CRB3 were the independent prognostic factors for ccRCC patients. CRB3 seemed like a potential broad tumor suppressor gene while GET4 might be a ccRCC preferential dependency gene with a ligandable structure.

Keywords: Clear cell renal cell carcinoma; Dependency; Depmap database; Prognostic value; TCGA..

Nephrogenic adenomas are uncommon benign lesions that are typically cytologically bland, but degenerative and reactive changes may make it difficult to distinguish these lesions from malignant entities, such as urothelial carcinoma and prostatic adenocarcinoma. In this study, we explored whether napsin A, a sensitive marker for lung adenocarcinoma, may also have a role in distinguishing nephrogenic adenoma from other genitourinary lesions. Immunohistochemically, napsin A was expressed in all 43 nephrogenic adenomas (bladder 38, prostatic urethra 4, and ureter 1; mean positive tumor cells 72%, median 80%, range 15-100%) and showed regional variability in its expression pattern with a bias towards surface architectures (flat, papillary) compared to stromal architectures (tubular/glandular, microcystic). We also compared napsin A to other markers including PAX8, GATA3, p63 and 34BE12. While napsin A matched PAX8 in terms of its sensitivity for nephrogenic adenoma (100%), napsin A stained a lower percentage of tumor cells than PAX8 (72% vs 99%, p =1.0 x10^-5). P63 was negative in all nephrogenic adenomas whereas GATA3 showed variable staining in 25 cases (58%). All 43 nephrogenic adenomas showed variable 34BE12 staining. Finally, we profiled napsin A expression among 401 genitourinary tumors on tissue microarrays (n=308) and full tissue blocks (N=93), and observed napsin A positivity in 37 tumors (9%) which included urothelial carcinomas with the glandular/microcystic component differentiation (in the glandular/microcystic component in 4/6), bladder adenocarcinomas (primary 4/4 and metastatic 3/3), urinary tract clear cell carcinomas (primary 8/9, 1/1 metastatic uterine primary) and some renal tumors (17/174). All 81 pure urothelial carcinomas and 53 prostatic acinar adenocarcinomas were negative for napsin A. Our study indicates that napsin A is a highly sensitive marker for nephrogenic adenoma and can serve as a useful addition in immunohistochemical panels seeking to distinguish it from pure urothelial carcinoma and prostatic acinar adenocarcinoma but not clear cell carcinoma or urothelial carcinoma with glandular differentiation.

Keywords: Napsin A; clear cell carcinoma; genitourinary tumors; immunohistochemistry; nephrogenic adenoma.

It has been a subject of much debate whether thyroid follicular cells originate from the ultimobranchial body, in addition to median thyroid primordium. Ultimobranchial remnants are detected in normal dogs, rats, mice, cattle, bison and humans and also in mutant mice such as Eya1 homozygotes, Hox3 paralogs homozygotes, Nkx2.1 heterozygotes and FRS2α^2F/2F. Besides C cells, follicular cell lineages immunoreactive for thyroglobulin are located within these ultimobranchial remnants. In dogs, the C cell complexes, i.e., large cell clusters consisting of C cells and undifferentiated cells, are present together with parathyroid IV and thymus IV in or close to the thyroid lobe. In addition, follicular cells in various stages of differentiation, including follicular cell groups and primitive and minute follicles storing colloid, are intermingled with C cells in some complexes. This review elaborates the transcription factors and signaling molecules involved in folliculogenesis and it is supposed why the follicular cells in the ultimobranchial remnants are sustained in immature stages. Pax8, a transcription factor crucial for the development of follicular cells, is expressed in the fourth pharyngeal pouch and the ultimobranchial body in human embryos. Pax8 expression is also detected in the ultimobranchial remnants of Eya1 and Hes1 null mutant mice. To determine whether the C cells and follicular cells in the ultimobranchial remnants consist of dual lineage cells or are derived from the common precursor, the changes of undifferentiated cells in dog C cell complexes are examined after chronically induced hypercalcemia or antithyroid drug treatment.

A subset of thyroid carcinomas contains a t(2;3)(q13;p25) chromosomal translocation that fuses paired box gene 8 (PAX8) with the peroxisome proliferator-activated receptor γ gene (PPARG), resulting in expression of a PAX8-PPARγ fusion protein, PPFP. We previously generated a transgenic mouse model of PPFP thyroid carcinoma and showed that feeding the PPARγ agonist pioglitazone greatly decreased the size of the primary tumor and prevented metastatic disease in vivo The antitumor effect correlates with the fact that pioglitazone turns PPFP into a strongly PPARγ-like molecule, resulting in trans-differentiation of the thyroid cancer cells into adipocyte-like cells that lose malignant character as they become more differentiated. To further study this process, we performed cell culture experiments with thyrocytes from the PPFP mouse thyroid cancers. Our data show that pioglitazone induced cellular lipid accumulation and the expression of adipocyte marker genes in the cultured cells, and shRNA knockdown of PPFP eliminated this pioglitazone effect. In addition, we found that PPFP and thyroid transcription factor 1 (TTF-1) physically interact, and that these transcription factors bind near each other on numerous target genes. TTF-1 knockdown and overexpression studies showed that TTF-1 inhibits PPFP target gene expression and impairs adipogenic trans-differentiation. Surprisingly, pioglitazone repressed TTF-1 expression in PPFP-expressing thyrocytes. Our data indicate that TTF-1 interacts with PPFP to inhibit the pro-adipogenic response to pioglitazone, and that the ability of pioglitazone to decrease TTF-1 expression contributes to its pro-adipogenic action.

Thyroid cancer is the most common malignancy of the endocrine system and includes well-differentiated forms, namely papillary and follicular carcinomas, and the poorly differentiated and undifferentiated forms that result from the transformation of thyroid follicular cells (anaplastic carcinomas). Notably, 5-10% of all thyroid cancers are medullary thyroid cancers that arise from parafollicular cells also known as C cells. The most common genetic mutations in papillary and follicular thyroid cancers are point mutations of the BRAF or RAS genes, while the most common chromosomal alterations are RET/PTC and PAX8/PPARγ rearrangements. The most frequent initial manifestation of thyroid cancer is the appearance of a nodule most of which are benign; indeed, less than 5% are malignant. However, some cases are misdiagnosed, and many patients undergo unnecessary surgery. Therefore, an accurate pre-surgery evaluation is crucial. The most reliable diagnostic test for thyroid nodules is fine needle aspiration (FNA) cytology, which accurately distinguishes between a benign and malignant lesion in most cases. However, cytological discrimination between malignant and benign follicular cancer is often difficult because of poor quality samples. Here we describe rapid methods to create a positive control and identify the PAX8/PPARγ rearrangement in FNA thyroid samples by molecular biology.

OBJECTIVE

Thyroid hemiagenesis is a rare congenital disorder characterized by the absence of a lobe and/or of isthmus. Studies on the association between thyroid hemiagenesis, Graves' disease and differentiated thyroid cancer are rare.

METHODS

We describe the medical and surgical history of a patient in whom a molecular evaluation was performed. A 36-year-old man presented with symptoms and signs of hyperthyroidism of a few months' duration. Hyperthyroidism was confirmed biochemically and anti-TSH-receptor antibodies were positive. Thyroid ultrasonography showed no left lobe and demonstrated a diffused enlargement of the right lobe; an ipoechoic, non-homogenous nodule 15 millimeters in size was identified in the middle part of the lobe. A 99mTc-pertechnetate thyroid scintigraphy (111 MBq) confirmed thyroid hemiagenesis due to the absence of the left lobe. Treatment with methimazole (30 mg/day) was started. As the patient's hyperthyroidism improved, he underwent fine-needle needle aspiration cytology (FNAC) of the right nodule. Cytology was suspicious for malignancy (THY4) and the patient was referred for surgery. Histopathological findings revealed a papillary thyroid carcinoma. The molecular analysis did not show PAX8 or TSHR mutations in the thyroid tissue nor mutations of BRAF, H-RAS, N-RAS or K-RAS genes in the tumor.

CONCLUSIONS

Though thus far studies on the association of thyroid hemiagenesis, Graves' disease and differentiated thyroid cancer are extremely rare, the possibility of the development of thyroid cancer must be taken into account in patients affected by thyroid hemiagenesis and the nodular variant of Graves' disease.

Malignant struma ovarii presenting with follicular carcinoma is extremely rare, and its mechanism of tumorigenesis remains unknown. Here, we present a case of malignant struma ovarii with peritoneal dissemination of follicular carcinoma, for which a molecular analysis for major oncogenic gene alterations in follicular thyroid carcinoma was performed. A 39-year-old nulliparous woman was referred with a diagnosis of highly differentiated follicular carcinoma of ovarian origin. Primary thyroid cancer was not diagnosed, and she had a normal thyroid function. ¹²³I scintigraphy revealed multiple peritoneal dissemination that was surgically resected. Histologically, the tumor consisted of numerous follicles without nuclear features of papillary thyroid carcinoma. Tumor samples were investigated for 50 cancer-related genes, including RAS, BRAF, and p53, and PPARg-PAX8 gene fusion by targeted DNA sequencing and fluorescence in situ hybridization, respectively. No major oncogenic gene alterations were detected. These negative findings suggest a different mechanism of tumorigenesis from that of adult-type follicular thyroid carcinoma.

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.