Endocr Pathol DOI 10.1007/s12022-014-9305-z

Parvovirus B19 Persistence in Abnormal Thyroid Tissue of a Mature Cystic Ovarian Teratoma: A Case Report Laura A. Adamson-Small & Larry J. Fowler & Jacqueline A. Hobbs

# Springer Science+Business Media New York 2014

Abstract Ovarian teratomas represent the most common neoplasm derived from germ cells and can contain mature ectodermal, mesodermal, and endodermal tissues. In rare cases, these teratomas can be composed predominantly or solely of thyroid tissue. These thyroid cells often function similarly to normal thyroid tissues. This laboratory and others have previously shown that parvovirus B19 (B19V) persists in primary and metastatic thyroid tissues. No reports exist on possible B19V persistence in thyroid tissues that may arise de novo outside the thyroid gland proper. In this case report, the detection of B19V (genotype 1) in the thyroid epithelial cells of a mature teratoma is reported. Nested PCR and immunohistochemistry were used to detect viral nucleic acids and proteins, respectively. Viral genomes were amplified in lesion DNA, confirming persistence of B19V. Positive immunohistochemical staining was seen for B19V capsid proteins in the thyroid epithelial cells within the mature teratoma, but not in surrounding ovarian tissue or in the non-thyroidal elements of the mature teratoma. These results demonstrate for the first time that thyroid epithelial cells, derived from non-thyroid L. A. Adamson-Small (*) : J. A. Hobbs Department of Pediatrics, College of Medicine, University of Florida, 1200 Newell Road, R1-136, Gainesville, FL 32610, USA e-mail: [email protected] J. A. Hobbs e-mail: [email protected] L. J. Fowler Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA e-mail: [email protected] J. A. Hobbs Department of Psychiatry, College of Medicine, University of Florida, Gainesville, FL, USA L. J. Fowler P.O. Box 100275, Gainesville, FL 32610, USA

tissue, are capable of supporting B19V infection and persistence. Keywords Parvovirus B19 . Ovary . Cystic teratoma . Thyroid

Introduction Mature cystic teratomas account for approximately 10–20 % of all ovarian tumors [1]. These tumors arise from totipotent germ cells and can occur as a result of failure during meiosis or mitotic division [2]. Malignancies of these tumors are rare and are often diagnosed as squamous cell carcinomas [3]. Multiple histological tissue types can develop from cells in these teratomas including skin, brain, muscle, fat, mucinous, or ciliated epithelium cells [4]. Approximately 15 % of reported cases contain thyroid tissue [5]. While little research has focused on viral infection of ovarian teratomas, studies have examined virus detection and expression in primary thyroid tissue. Multiple viruses have been reported to infect the thyroid, including Epstein-Barr virus, enterovirus, influenza virus, cytomegalovirus, herpes simplex virus, and human foamy virus [6]. Human parvovirus B19 (B19V) has also been shown by this laboratory and others to infect normal, autoimmune, cancerous, and metastatic thyroid tissues [7–9]. B19V is a singlestranded DNA virus that is ubiquitous in the human population. It is the causative agent of a variety of diseases, including erythema infectiosum in healthy children, non-immune hydrops fetalis, and aplastic crisis in individuals with underlying hemolytic disorders [10]. B19V detection has also been associated with several autoimmune disorders, including Hashimoto’s thyroiditis, rheumatoid arthritis, and lupus, and cancers other than thyroid, such as testicular cancer [9, 11–14]. B19V replication occurs preferentially in rapidly

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The patient was a 62-year-old African-American female with a history of adult type II diabetes mellitus and hypertension. She was referred for uterine leiomyomata and a right adnexal complex mass with imaging features suggestive of a dermoid tumor. The patient complained of bilateral lower quadrant pain that increased with physical activity. She denied postmenopausal bleeding. Her review of systems was negative for symptoms of thyroid disease, though no thyroid function tests were reported. Laboratory values other than blood sugar were unremarkable. CA-125 was measured and reported to be minimally elevated 2 months prior to surgery. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The 525-g uterus revealed multiple benign cellular leiomyomatas that were submucosal and intramural, and the right ovary weighing 118.0 g and measuring 10.0×6.0×6.0 cm revealed a mature cystic teratoma with predominant thyroid elements. Histologically, the mature cystic teratoma had characteristic features of a thyroid composed of large colloid spaces surrounded by thyroid epithelial cells. Only 1 out of 14 archived tissue blocks showed mature teratomatous dermal elements. All other blocks showed only thyroidal tissue with intervening fibrosis. Following surgery, tissue was collected, formalin fixed and paraffin embedded, and stored with approval of the University of Florida Institutional Review Board (IRB) for research. IRB approval was obtained prior to tissue analysis for detection of B19V (IRB no. 36-2010). All experiments were performed in compliance with relevant laws and institutional guidelines and

in accordance with the ethical standards of the Declaration of Helsinki. Pathological examination confirmed prior diagnosis. Total genomic DNA was extracted from a tissue block containing predominantly thyroid tissue surrounded by ovarian tissue and from the second which was composed mostly of lesion tissue lacking thyroid morphology as previously described [7]. Nested PCR was employed to detect the presence of viral DNA and to confirm the persistence of B19V. Amplification for B19V genotypes 1–3 and confirmation of positive samples were performed as previously described [7, 15]. Genotype 1 B19V sequences were clearly detected in DNA from this teratoma, demonstrating the presence of B19V in the ovarian teratoma (Fig. 1a). No sequences for genotype 2 or 3 were detected (data not shown). A second set of primers amplifying a region of the B19V capsid sequence was also used to confirm the presence of viral DNA (Fig. 1b). Sequencing of positive bands was performed at the University of Florida Interdisciplinary Center for Biotechnology Research DNA Sequencing Core Facility and confirmed B19V DNA homology. This demonstrates that mature cystic teratomas are capable of B19V infection and persistence. The two tissue blocks from the mature cystic teratoma were stained with hematoxylin and eosin and with a B19V capsid antibody as previously described [7]. One section contained predominately thyroid tissue, while the other contained the mature teratoma and no thyroid features. A representative H&E image showing the predominant thyroid tissue is shown (Fig. 2a). Using a monoclonal antibody against the capsid of B19V, viral protein was strongly detected in thyroid tissue of the teratoma, but not in surrounding ovarian tissue (Fig. 2b). This staining was similar to previously published images of B19V staining in thyroid tissues [7]. Specificity of staining was confirmed by the absence of DAB staining in the IgG control (Fig. 2c). Positive B19V staining localized to the nuclei of the thyroid epithelial cells of the mature cystic teratoma, with weak

Fig. 1 Detection of B19V DNA in an ovarian teratoma. a DNA from the lesion tissue was amplified using B19V genotype 1-specific primers. b Detection of B19V was confirmed using a second set of primers detecting a portion of the B19V capsid sequence. In both gels, lane 1 contains a 100-bp molecular weight ladder, lane 2 contains a nearly full-length

B19V genome-containing plasmid (pYT103C)-positive control, lane 4 contains DNA from the lesion tissue containing thyroid morphology, lane 6 contains DNA from the lesion tissue lacking thyroid morphology, and lane 8 contains the PCR negative. Lanes 3, 5, and 7 are blank wells separating each sample

dividing erythroid precursor cells, but persistence has been reported in a wide range of tissues [12]. Here, we report an ovarian cystic teratoma with predominant thyroid features persistently infected with B19V.

Case Report

Endocr Pathol Fig. 2 B19V capsid protein staining in thyroid tissue within an ovarian teratoma. Hematoxylin and eosin staining in tumor tissue adjacent to ovary (a). B19V capsid staining (brown) can be seen in the thyroid tissue within the teratoma (b), with no staining seen in the IgG control (c). B19V staining was absent in the adjacent ovary tissue (d). Scale bars represent 25 μm

cytoplasmic staining also observed. B19V staining was not observed in the surrounding ovarian tissue or in the lesion tissue section from the same patient lacking thyroid cells and morphology. No cytopathic changes consistent with acute B19V infection were seen within B19V protein-positive cells, suggesting that the detected protein was from persistent, nonacute viral infection. Together, these data demonstrate that similar to primary thyroid tissue, thyroid epithelial cells present in cystic ovarian teratoma tumors can be persistently infected with B19V.

Discussion Viral infections within mature cystic ovarian teratomas have not been extensively investigated. Five case reports have detected HPV DNA and/or proteins in squamous cell carcinomas arising within ovarian teratomas [16–20]. Viral detection was typically localized to carcinoma cells, although viral DNA in normal epithelium samples was also reported. In this report, B19V DNA was detected in blocks containing both non-thyroidal lesion tissue and predominantly thyroid tissue, but viral proteins were only seen in cells with a histological thyroid appearance. B19V, along with other viruses and infectious agents, have been detected in, and associated with, thyroid autoimmune disease and cancer [6, 12]. Similar case reports have detected malignant dermoid cyst and squamous cell carcinoma in cervical teratomas in patients infected with HIV [21, 22]. These infectious agents could potentially induce autoantibodies, contribute to cell lysis and immune recognition, or alter cellular gene expression. How B19V, in particular, persists in tissues and what role it may play in these tumors

are unknown. Without further studies, the role of viral infection in teratomas cannot be determined. Acute B19V infection is typically diagnosed by the presence of virus-specific IgM antibodies. Viral infection and replication lead to cytological changes including enlarged basophilic, amphophilic, or eosinophilic inclusions in the nucleus in erythroid precursor cells [23]. With this case report, serum was not banked alongside the tumor tissue, so serological testing for B19V antibodies could not be performed. Similar studies in primary thyroid tissue matched to serum have shown that B19V DNA and proteins can be detected in tissues where serum is B19V IgM negative but IgG positive [14]. Cytopathic cellular changes are not reported in these tissues, suggesting non-acute infection. Together, these data demonstrate the persistence of B19V proteins in non-erythroid cells. This case report further demonstrates the persistence of B19V capsid proteins within thyroid tissue, despite it being thyroid features within a teratoma. The question is raised as to whether B19V infection is occurring in the original germ cell prior to teratoma formation or in the thyroid tissue that develops within the tumor. There are no other reports of B19V infection of ovarian cells to compare. Multiple groups have detected B19V DNA persisting in testicular germ cell tumors demonstrating the ability of B19V to infect and persist in germ cells [11, 24–26]. Since this is only a case study and the other studies have relied on archived or fixed tissues as well, it is not possible to determine which cells become infected initially. Larger studies of ovarian germ cell tumors for the presence of B19V as well as more basic studies will be very important to determine which cells are the true points of entry for B19V in ovarian teratomas as well as other germ cell tumors.

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Symptoms resembling a thyroid disorder can be associated with ovarian teratomas containing thyroid tissue, but whether B19V contributes through its persistence in the thyroid tissue is unknown [27]. While B19V tropism is classically restricted to erythroid progenitor cells, viral DNA has been shown to persist in a wide variety of organs, including the thyroid [7, 11, 16]. Multiple groups have associated B19V with thyroid disease, especially papillary thyroid carcinomas and autoimmune thyroid disease, particularly Hashimoto’s thyroiditis [7–9, 13, 14, 28]. The prevalence of B19V in a large percentage of these cases examined, as well as detection in normal thyroid cells, suggests that B19V infection alone is not responsible for the increased proliferation of thyroid carcinomas. There is the question of whether B19V infection participates in disease pathogenesis via an inflammation-mediated process. Several studies have reported a link between persistent B19V infection in vivo and an increase in inflammation-related cytokines [9, 29–31]. The samples available for this case report cannot elucidate if that relationship exists here, but a prospective study in similarly diagnosed patients may better determine if there is a role for B19V infection in ovarian teratomas. In conclusion, this case study represents the first report of viral infection, specifically B19V, in the thyroid tissue within a mature cystic ovarian teratoma. It is also the first study to show that B19V infects and persists in non-primary and nonmetastatic thyroid tissues. While it is unlikely that B19V is a causative agent of these types of cancers, further studies are warranted to determine what role B19V may play in cystic teratomas of the ovary.

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Parvovirus b19 persistence in abnormal thyroid tissue of a mature cystic ovarian teratoma: a case report.

Ovarian teratomas represent the most common neoplasm derived from germ cells and can contain mature ectodermal, mesodermal, and endodermal tissues. In...
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