Identification of Germline FOXE1 and Somatic MAPK Pathway Gene Alterations in Patients with Malignant Struma Ovarii, Cleft Palate and Thyroid Cancer.

Germline variants in the FOXE1 transcription factor have been associated with thyroid ectopy, cleft palate (CP) and thyroid cancer (TC). Here, we aimed to clarify the role of FOXE1 in Portuguese families (F1 and F2) with members diagnosed with malignant struma ovarii (MSO), an ovarian teratoma with ectopic malignant thyroid tissue, papillary TC (PTC) and CP. Two rare germline heterozygous variants in the FOXE1 promoter were identified: F1) c.-522G>C, in the proband (MSO) and her mother (asymptomatic); F2) c.9C>T, in the proband (PTC), her sister and her mother (CP). Functional studies using rat normal thyroid (PCCL3) and human PTC (TPC-1) cells revealed that c.9C>T decreased FOXE1 promoter transcriptional activity in both cell models, while c.-522G>C led to opposing activities in the two models, when compared to the wild type. Immunohistochemistry and RT-qPCR analyses of patients' thyroid tumours revealed lower FOXE1 expression compared to adjacent normal and hyperplastic thyroid tissues. The patient with MSO also harboured a novel germline AXIN1 variant, presenting a loss of heterozygosity in its benign and malignant teratoma tissues and observable ß-catenin cytoplasmic accumulation. The sequencing of the F1 (MSO) and F2 (PTC) probands' tumours unveiled somatic BRAF and HRAS variants, respectively. Germline FOXE1 and AXIN1 variants might have a role in thyroid ectopy and cleft palate, which, together with MAPK pathway activation, may contribute to tumours' malignant transformation.

Synchronous thyroid cancer and malignant struma ovarii: concordant mutations and microRNA profile, discordant loss of heterozygosity loci.

BACKGROUND: Struma ovarii is an unusual ovarian teratoma containing predominantly thyroid tissue. Less than 10% of cases undergo malignant transformation in the thyroid tissue and are considered malignant struma ovarii (MSO). MSO have been reported with concurrent thyroid lesions, but molecular data is lacking. CASE PRESENTATION: A 42-year-old female developed MSO and synchronous multifocal subcentimeter papillary thyroid carcinoma (PTC). The patient underwent a salpingo-oophrectomy, thyroidectomy, and low-dose radioactive iodine ablation. Both the thyroid subcentimeter PTC and MSO were positive for BRAF V600E mutation, and microRNA expression profiles were similar across all tumor deposits. However, only the malignant component demonstrated extensive loss of heterozygosity (LOH) involving multiple tumor suppressor gene (TSG) chromosomal loci. CONCLUSIONS: We present the first reported case of MSO with synchronous multifocal subcentimeter PTC in the thyroid containing concordant BRAF V600E mutations and resulting with discordant LOH findings. This data suggests that loss of expression in tumor suppressor gene(s) may be an important contributor to phenotypic expression of malignancy.

Metabolic Response by 18F-FDG PET/CT in Metastatic Malignant Struma Ovarii Treated With Targeted Therapies.

Malignant struma ovarii (MSO) is a rare malignant ovarian tumor, histologically identical to differentiated thyroid cancers. Given the rarity of this disease, there are no treatment guidelines, and the place of imaging for response assessment remains controversial. We report a metabolic response assessed by F-FDG PET/CT in a 71-year-old woman with radioiodine-refractory metastatic MSO treated by targeted therapies (first line with lenvatinib and second line with pazopanib). This case of exceptional response also highlights the usefulness of F-FDG PET/CT for therapeutic assessment of targeted drugs in such a rare clinical entity of malignant MSO.

The role of immunohistochemical examination in diagnosis of papillary thyroid cancer in struma ovarii.

INTRODUCTION: Struma ovarii (SO) is a monodermal teratoma in which thyroid tissue comprises more than 50% of the tumour. Papillary thyroid cancer (PTC) in SO is a rare finding, as only 5% of SO cases undergo malignant transformation. Malignant SO is usually asymptomatic and infrequently diagnosed preoperatively. Because of its rarity, there is no consensus about diagnosis and management, while treatment and follow-up procedures are not clearly established. MATERIAL AND METHODS: Herewith, we report two cases of PTC in SO. The first patient was a 25-year-old woman diagnosed with bilateral ovarian tumours. The second patient, 19-year-old woman, presented with unilateral ovarian mass. Both patients were qualified for surgical excision of the tumours. Histopathological specimens underwent both conventional histopathological assessment and immunohistochemical staining. RESULTS: In the first patient histopathology revealed SO with two foci of PTC. Immunohistochemically a positive expression of CK7, CK19, p63 and thyroglobulin (Tg) confirmed the diagnosis. She underwent total thyroidectomy in 2016 in order to enable ablative radioiodine therapy and facilitate further thyroglobulin monitoring. Unfortunately, the patient was lost from follow-up. In the second patient, histopathological diagnosis was follicular variant of PTC in SO. Postoperatively, a pelvic CT revealed osteolytic lesion 6 cm in size, being a metastatic change. The patient underwent unilateral ovariectomy, total thyroidectomy and multiple cycles of radioiodine therapy. Currently, 9 years following the diagnosis, the patient achieved disease remission. CONCLUSIONS: PTC in SO still remains a diagnostic and therapeutic challenge. Immunostaining for CK7, CK19, p63 and Tg might be helpful in histopathological diagnosis. The decision on the need of total thyroidectomy and radioiodine therapy should be made individually. However, thyroid remnant ablation increases the sensitivity and specificity of follow-up testing using serum Tg level as a tumour marker.

Malignant Struma Ovarii With a Predominant Component of Anaplastic Carcinoma.

Struma ovarii exhibiting malignant histology are uncommon, and aggressive clinical courses with initial extraovarian spread are even more rare. This report describes a case of malignant struma ovarii with a predominant anaplastic carcinoma component. A 65-yr-old, gravida 2, para 2, female presented with lower abdominal discomfort and pain. She had a 12×10×7.5 cm tumor in the right ovary. Intraoperative diagnosis was high-grade spindle cell tumor. Right salpingo-oophorectomy and hysterectomy were performed. Macroscopically, the tumor invading the right tube was a yellow-white solid mass with focal microcysts containing greenish liquid and focal calcification. The tumor was histologically characterized by a spindle cell and pleomorphic sarcomatous component, and a minor component of benign-looking thyroid tissue with ossification. Immunohistochemically, the sarcomatous component was focally positive for CAM 5.2, EMA, thyroid transcription factor-1, and thyroglobulin, indicating anaplastic carcinoma. The patient was treated with chemotherapy and is alive, yet with tumor, 25 mo after surgery. This is the first case of malignant struma ovarii with a predominant component of anaplastic carcinoma. This type of malignant struma ovarii may lead to diagnostic problems, and sampling and differential diagnosis among sarcomatous ovarian tumors are important for making the correct diagnoses.

Ovarian strumal carcinoid producing peptide YY associated with severe constipation: a case report and review of the literature.

Primary carcinoid tumors are rare neoplasms of the ovary. Of the 4 histologic subtypes, ovarian carcinoid tumors with insular patterns produce carcinoid syndrome in approximately one third of cases, versus strumal and trabecular carcinoids which very rarely cause typical carcinoid syndrome. A unique presentation of ovarian carcinoid tumors with concurrent severe constipation has been reported, which is thought to represent a new carcinoid syndrome. The proposed mechanism is the production of peptide YY by the tumor, a gastrointestinal hormone responsible for decreasing gut motility. We report a case of a 34-yr-old white woman who presented with constipation and weight loss for 1 yr, and was found to have a unilateral ovarian strumal carcinoid, which produced peptide YY as demonstrated by immunohistochemistry. The 13 previous case reports of ovarian carcinoids with constipation are reviewed and the clinicopathologic features are discussed. This report and literature review further solidifies this entity as a new type of carcinoid syndrome.

Coexistence of malignant struma ovarii and cervical papillary thyroid carcinoma.

CONTEXT: Struma ovarii is an uncommon monodermal teratoma in which thyroid tissue is the predominant element. Malignant transformation of struma ovarii is an even rarer occurrence. CASE PRESENTATION: We describe a 42-year-old woman who underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a symptomatic left pelvic mass. Histology revealed malignant struma ovarii with classical papillary thyroid carcinoma expression. Ultrasonography of the cervical neck showed thyroid micronodules and a dominant 1-cm nodule in the left thyroid lobe. As the ovarian tumor was large, the patient underwent a total thyroidectomy with the intention of administering ¹³¹I therapy in an adjuvant setting. Histology of the cervical thyroid gland revealed bilateral multifocal papillary thyroid carcinoma with extrathyroidal extension and perithyroidal lymph node metastasis. METHODS: Morphological (microscopy), immunohistochemical (Hector Battifora mesothelial cell 1, cytokeratin-19, galectin-3), and molecular (BRAF V600E, RAS, RET-PTC) characteristics and clonality analysis of the cervical thyroid and ovarian tumors were explored to distinguish them as separate malignancies. RESULTS: The thyroid-type tumors from the cervical gland and ovary were discordant in terms of tissue histology and level of cytokeratin-19 expression. The clinical features and tumor profile results supported the independent existence of these two embryologically related, although topographically distinct, malignancies. CONCLUSION: Our findings provided support for synchronous, albeit distinct, primary tumors in the ovary and cervical thyroid. "Field cancerization" and early genomic instability may explain multifocality in all thyroid-type tissue. In this regard, patients with malignant struma ovarii should undergo imaging of their thyroid gland for coexisting disease and thyroidectomy recommended for suspected malignancy or in preparation for radioiodine therapy.

Struma ovarii simulating ovarian sertoli cell tumor: a case report with literature review.

Struma ovarii, as a monodermal variant of ovarian teratoma, constitutes about less than 3% of ovarian teratomas. It is difficult to be macroscopically recognized. Multiple appearances under microscope serve as another reason to mislead the accurate pathologic evaluation. Here, we report an unusual case of struma ovarii occurred in a 77 years old woman, which is currently known as the oldest age for this disease. The frozen section morphologically showed sex cord like elements and was suspicious for a sex-cord stromal tumor, probably a Sertoli cell tumor. Final pathological diagnosis was confirmed as struma ovarii based on the typical morphologic thyroid follicles and immunohistochemical staining results.

Case of peptide-YY-producing strumal carcinoid of the ovary: a case report and review.

Ovarian carcinoid is a rare tumor accounting for approximately 0.1% of all ovarian malignancies. We describe a case of peptide-YY-producing strumal carcinoid of the ovary associated with severe constipation. A 48-year-old woman was found to have a pelvic mass on ultrasonography when she visited her primary doctor for a health check-up. She was thus referred to our department. Magnetic resonance imaging revealed a solid right ovarian tumor 60 × 50 mm in size. The patient underwent a right adnexectomy and was histopathologically diagnosed as having strumal carcinoid of the ovary. On immunohistochemical examination, the tumor cells were positive for peptide YY. The patient's constipation resolved rapidly after surgery. Based on her clinical course, her constipation was considered to have been caused by the strumal carcinoid of the ovary. The clinical course of this case supports the previously recognized correlation between peptide-YY-producing ovarian carcinoid and constipation.

Peptide YY producing strumal carcinoid tumor of the ovary.

BACKGROUND: Primary ovarian carcinoid tumor is uncommon and represents less than 0.1% of ovarian malignancies. The strumal carcinoid may be complicated by carcinoid syndrome induced by peptide YY (PYY). CASE REPORT: We describe a 45-year-old woman with a bilateral ovarian tumor diagnosed through periodical gynecological examination. She presented with severe constipation. Right ovarian cyst laparoscopically resected was diagnosed as a strumal carcinoid tumor; the left one was mature cystic teratoma. No metastatic findings were seen macroscopically on the ovarian surface and pelvic peritoneum. Constipation was drastically improved by resecting the tumor. The carcinoid tumor cells were positive for tumor-producing PYY by mRNA analysis. CONCLUSION: It is important to be aware of this entity in the pathological diagnosis of ovarian tumors, in the presence of any clinical indicator of carcinoid tumor/syndrome, as it carries a markedly better prognosis and clinical outcome in comparison with most other malignant ovarian tumors.

Thyroid-type solid cell nests in struma ovarii.

Solid cell nests (SCNs) of the thyroid are single or multiple foci of solid and/or cystic clusters of squamoid cells (main cells) with a minor proportion of C-cells, found in the normal thyroid. The SCNs have also been reported in the heart as an ultimobranchial heterotopia. Here, the authors describe a case of thyroid-type SCNs associated with struma ovarii. Main cells were positive for simple and stratified epithelial-type cytokeratins, carcinoembryonic antigen, carbohydrate antigen 19.9, p63, bcl-2, and galectin-3. The neuroendocrine cell population was positive for chromogranin A and synaptophysin but negative for calcitonin, suggesting a common ancestor cell capable of dual differentiation toward thyroid follicular cells and hindgut-type endocrine cells. The existence of thyroid-type SCNs in struma ovarii could be easily understood by considering the struma ovarii as a teratoma; at the same time, these findings also support the idea of a close histogenetic link between the main cells of SCNs and thyroid tissue.

Primary strumal carcinoid tumor of the ovary with multiple bone and breast metastases.

Although primary carcinoid tumor of the ovary is an extremely rare neoplasm, survival is excellent if the disease is confined to one ovary. Herein, we present a case of primary strumal carcinoid tumor of the ovary, stage IA, borderline malignancy, in a 34-year-old woman. Histological findings of the right ovary indicated higher atypical nuclei, higher mitotic rate and focal necrosis of tumorous cells in some areas, findings that are compatible with atypical carcinoid of the lung. Immunohistochemical staining was positive for synaptophysin, neuron-specific enolase, chromogranin A, Ki-67, topoisomerase IIalpha, peptide YY, and thyroglobulin. Three and a half years postoperatively, multiple bone and breast metastases were found and anticancer chemotherapy was ineffective. The results in the present case indicate that an ovarian carcinoid tumor found to be 'atypical carcinoid' according to pulmonary carcinoid criteria or immunohistochemical staining (i.e. highly positive for topoisomerase IIalpha and Ki-67) may have a poor prognosis.

Cytologic differentiation of struma ovarii from other ovarian neoplasms.

OBJECTIVE: To present the cytologic findings of struma ovarii and value of cytology and immunocytochemistry (ICC) using thyroglobulin (TGB) and thyroid transcription factor-1 (TTF-1) in evaluation of this unusual ovarian neoplasm, together with the diagnostic pitfalls. STUDY DESIGN: Intraoperative cytologic findings of 7 patients with struma ovarii are reviewed. Cytologic material of both cystic and solid components was collected intraoperatively. ICC staining was done, and cell block preparation performed on selected cases. RESULTS: The cases were divided in to 3 groups: group 1--diagnosis of struma ovarii was made by cytology and confirmed by ICC (1 case); group 2--diagnosis was suggestive on cytology or cell block and confirmed by ICC staining (4 cases); group 3--on cytologic diagnosis indistinguishable from other cystic ovarian neoplasms (2 cases). Cytologic findings were typically colloid with mosaic pattern, follicles, follicular cells only, sheets of follicular cells, both colloid and follicular cells, proteinaceous background or degenerated epithelial cells indistinguishable from other cystic ovarian neoplasms. CONCLUSION: Cytologic findings of struma ovarii are distinct enough to be suggested intraoperatively, and ICC for TGB or TTF-1 is a valuable tool for preoperative fine needle aspiration biopsy and intraoperative diagnosis of this benign ovarian neoplasm.

Follicular variant papillary thyroid carcinoma arising in struma ovarii.

Struma ovarii is a rare monodermal ovarian teratoma in which thyroid tissue is the predominant or exclusive element. Malignant transformation is known to occur, usually as classical papillary thyroid carcinoma (PTC). However, the recognition of follicular variant PTC raises the possibility of similar malignancy arising in struma ovarii. We examined 13 cases of struma ovarii to determine if these lesions can exhibit histological, immunohistochemical, and/or molecular features of follicular variant PTC. Ten of these had atypical histology, cytologic features of PTC, and all ten showed diffuse positivity for CK19; eight of these were also positive for HMBE-1. Mutational analysis for BRAF identified no V600E mutations. However, seven of the ten cases with features of follicular variant PTC exhibited a rearranged in transformation (RET)/PTC rearrangement by reverse transcriptase polymerase chain reaction (RT-PCR). The three cases considered to be benign based on histologic and cytologic criteria were negative for CK19 and HBME-1 by immunohistochemistry, and had no evidence of BRAF mutation or ret/PTC-1 and ret/PTC-3 rearrangements. These results indicate that follicular variant PTC can occur in struma ovarii and that such lesions exhibit the same morphologic and immunohistochemical profile as follicular variant PTC in thyroid. The application of molecular testing to verify the diagnosis can be valuable, as these lesions may harbor ret/PTC gene rearrangements.

Expression of thyroid transcription factor 1 (TTF-1) in extra thyroidal sites: papillary thyroid carcinoma of branchial cleft cysts and thyroglossal duct cysts and struma ovarii.

The thyroid-associated transcription factor-1 (TTF-1) is a nuclear tissue specific protein, found only in thyroid and thyroid tumors regardless of histologic type as well as in lung carcinomas. Most ectopic thyroid tissue are found along the thyroglossal duct tract and around the bilateral main lobes of thyroid glands. Ectopic thyroid tissue within a branchial cleft cyst is a rare abnormality and papillary carcinoma arising in this tissue is extremely rare. Thyroid tissue may also be found as one of the many components of teratoma, particularly those located in the ovary. The aim of this study is to evaluate, through immunohistochemistry, the expression of TTF-1 in branchial cleft cysts with ectopic normal thyroid tissue, in primary thyroid papillary carcinomas of branchial cleft cysts and thyroglossal duct cysts and in struma ovarii, in order to evaluate the expression of this antigen in extra thyroidal sites.

Malignant struma ovarii: a case report.

Malignant struma ovarii is a rare form of the ovarian germ cell tumors. Hence, diagnosis and management of malignant struma ovarii have not been clearly defined. We present the case of a 34-year-old woman with papillary carcinoma arising in struma ovarii. The malignant component of this tumor was detected after laparoscopic removal, and a re-staging operation was performed afterwards. There was no evidence of clinical malignancy or metastases. In this paper, clinical features, treatment guidelines, diagnostic features, and immunohistochemical characteristics of this tumor are reviewed.