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Coexistence of Graves’ disease, papillary thyroid carcinoma and unilateral benign struma ovarii: Case report and review of the literature
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Metabolism www.metabolismjournal.com
Brief Report
Coexistence of Graves’ disease, papillary thyroid carcinoma and unilateral benign struma ovarii: Case report and review of the literature Athanasios D. Anastasilakis a,⁎, Rosaria-Maddalena Ruggeri b , Stergios A. Polyzos c , Polyzois Makras d , Dimitra Molyva e , Alfredo Campennì f , Athina Gkiomisi g , Christos Balaris a , Panagiotis P. Fotiadis h , Giovanni Tuccari i , Stergios Papachatzopoulos g a
Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece Department of Clinical and Experimental Medicine and Pharmacology, Section of Endocrinology, University of Messina, Messina, Italy c Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration General Hospital, Thessaloniki, Greece d Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece e Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece f Department of Radiological Sciences, Nuclear Medicine Unit, University of Messina, Messina, Italy g Department of Obstetrics and Gynaecology, 424 General Military Hospital, Thessaloniki, Greece h 1st Department of General Surgery, 424 General Military Hospital, Thessaloniki, Greece i Department of Human Pathology, University of Messina, Messina, Italy b
A R T I C LE I N FO Article history: Received 27 March 2013 Accepted 20 May 2013
AB S T R A C T Background. Struma ovarii is a rare cause of hyperthyroidism, while coexistence with Graves’ disease has been scarcely reported. Patient Findings. We report a patient with Graves’ disease and unilateral benign functioning struma ovarii, accompanied by ascites, pleural effusion and elevated cancer antigen-125 (CA-125)
Keywords:
levels. In subsequent thyroidectomy, incidental papillary thyroid carcinoma was also identified.
Hyperthyroidism
The functionality of struma ovarii tissue in our patient was supported by the immuno-
Meigs syndrome
histochemical identification of TSH receptors (TSHR), which may stimulate growth and thyroid
Pleural effusion
hormone production in the presence of circulating TSHR stimulating antibodies (TSHR-Ab).
Thyroid cancer TSH receptor
Review of the literature. A systematic review of reported cases of coexistent Graves’ disease and struma ovarii was performed. Conclusions. The diagnosis of struma ovarii may be masked by Graves’ disease and, therefore, be delayed for several years. Furthermore, ascites, pleural effusion and increased CA-125 may result from a benign struma ovarii. The presence of TSHR in the struma ovarii tissue along with their absence in the surrounding ovarian tissue indirectly suggests that struma ovarii is functional. It is unclear whether TSHR-Ab play a role in the development of thyroid carcinomas in such patients. © 2013 Elsevier Inc. All rights reserved.
Abbreviations: CA-125, cancer antigen-125; CT, computed tomography; TFTs, thyroid function tests; TG-Ab, thyroglobulin autoantibodies; TPO-Ab, thyroid peroxidase autoantibodies; TSH, thyrotropin; TSHR, thyrotropin receptors; TSHR-Ab, thyrotropin receptors autoantibodies; US, ultrasound. ⁎ Corresponding author. Tel.: +30 2310 381 697; fax: + 30 2310 381 010. E-mail address: [email protected] (A.D. Anastasilakis). 0026-0495/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2013.05.013
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1.
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Introduction
Struma ovarii is a rare ovarian teratoma consisting predominantly (more than 50%) of mature thyroid tissue. It usually presents as a pelvic mass, whereas only rarely does it present as hyperthyroidism or pseudo-Meigs syndrome (pleural effusion and ascites in benign ovarian tumors other than fibromas). Malignant transformation is rare (5%–10%) and may be papillary, follicular or mixed type [1]. Graves’ disease represents the most common cause of hyperthyroidism, and may rarely coexist with struma ovarii [2]. In patients with coexistent struma ovarii and hyperthyroidism, the increased thyroid hormone production could result from: 1) hyperfunctioning struma ovarii alone, 2) both hyperfunctioning thyroid gland and struma ovarii or 3) a hyperfunctioning thyroid gland with incidental presence of non-functioning struma ovarii [3]. Thus, it may be difficult to determine the precise cause of hyperthyroidism in such patients. Increased radioiodine uptake by the ovary in whole-body scan [2] and expression of TSHR in the ovarian tissue in presence of TSHR-Ab are indicative of a functioning struma ovarii [4]. Thyroid cancer may occur in patients with Graves’ disease and recent studies confirm higher than expected incidental thyroid cancer rates in patients subjected to thyroidecromy for Graves’ disease [5]. On the other hand, patients with microcarcinomas and Graves' disease were found to have longer survival and excellent prognosis when compared to euthyroid patients with cancer of the same size [6]. Serum CA-125 is a tumor marker derived from tissues originated from the fetal coelomic epithelium (müllerian epithelium, pleura, pericardium, peritoneum). Besides ovarian malignancy, elevated CA-125 levels may also indicate endometriosis, pelvic inflammatory disease or peritoneal damage [7]. Herein, we report a unique case of coexistent Graves’ disease, papillary thyroid carcinoma and unilateral benign functioning struma ovarii, accompanied by ascites, pleural effusion and elevated CA-125 levels.
2.
Case description
A 49-year-old woman, admitted to the Gynaecology Department of 424 General Military Hospital, Thessaloniki, Greece, for a large right pelvic mass, possibly originating from the ovary, was referred to Endocrinology Clinics for preoperative evaluation due to coexistent hyperthyroidism. The mass had been diagnosed two weeks earlier, when the patient presented with a large right pleural effusion (Fig. 1A); thoracentesis showed transudative fluid with no neoplastic cells, while subsequent pelvic US examination revealed a large, right-sided, lobulated mass, a normal uterus, and moderate ascites. CT examination of the abdomen and pelvis showed a 15-cm solid mass with cystic components and microcalcifications, possibly arising from the right ovary (Fig. 1B). CA-125 levels were clearly high (404.7 IU/mL; normal values < 35). Given the combination of large abdominal tumor, ascites, pleural effusion, and elevated CA-125, ovarian malignancy was suspected. Graves’ disease was diagnosed in 2010 and, since then, the patient had been insufficiently treated with propylthiouracil
Fig. 1 – Computed tomography findings in our patient: (A) large right pleural effusion, (B) abdominal mass and moderate ascites, (C) Substernal goiter.
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50 mg three times a day. At clinical examination, the patient was clinically hyperthyroid, with a diffusely enlarged thyroid gland, but without orbital disease. The TFTs were consistent with thyrotoxicosis, while TSHR-Ab, TPO-Ab and TG-Ab were clearly above the upper limit of reference range (TSHR-Ab 3.16 IU/L, normal values < 1.75; antiTPO 854.9 IU/mL, normal values < 5.6; antiTG 157.4 IU/mL, normal values < 4.1). Thyroid US showed a large, substernal goiter with diffusely increased blood flow, which was also evident in the thoracic CT performed during the pleural effusion evaluation (Fig. 1C). Thyroid scan showed diffuse enlargement of the gland with increased technetium-99 m (Tc 99m) uptake (6.4%, normal values 0.3%–3%), despite propylthiouracil treatment. Since the patient was hyperthyroid, we changed her medication to methimazole 20 mg twice a day until surgery. The patient subsequently underwent total abdominal hysterectomy and bilateral oophorectomy. Histology revealed an 18 × 12 × 10-cm monophasic teratoma, consisting exclusively of thyroid tissue with no features of malignancy. Both pleural effusion and ascites resolved rapidly after tumor resection. In postoperative evaluation, CA-125 was within normal range (27.0 IU/mL), while TFTs were still abnormal. Subsequently, methimazole was continued along with oral Lugol’s iodine preparation, until the performance of total thyroidectomy two weeks later. Histology of the thyroid gland confirmed Graves’ disease and revealed a 0.9-cm papillary thyroid carcinoma of the follicular variant in the right lobe, without blood or lymphatic vessel invasion or extrathyroidal extension. Postoperatively, the patient was started on suppression therapy with 150 μg L-thyroxine once daily. We retrospectively performed immunohistochemical analysis to detect the presence of TSHR in tissue samples from the struma ovarii and thyroid tissue (Fig. 2). Normal human thyroid tissue (archival specimen) was used as a positive control (Fig. 2B) with ovarian tissue surrounding struma ovarii as negative control (Fig. 2C). A semiquantitative evaluation was performed, based on the intensity of immunostaining and the percentage of cells positively stained. Most thyroid follicular cells in our samples (the control normal thyroid tissue, the Graves’ disease the papillary carcinoma and the struma ovarii tissue) expressed the TSHR with various degrees of staining intensity in the same tissue sample, but without difference in the intensity of the staining between different tissues. The intensity of the staining was even higher in the papillary carcinoma tissue than in benign (Graves’ disease) or normal thyroid tissue, but it was only cytoplasmic (Fig. 2D). The surrounding ovarian tissue was not stained, indicating absence of TSHR (Fig. 2C).
3.
Literature search
Computerized advanced search for primary evidence was performed in PubMed (Public/Publisher MEDLINE) electronic database in 15 January 2013 by the combination of terminological (MeSH terms) and methodological search filters. Search was not limited by publication time and not restricted to English literature. The original detailed query was: (“struma ovarii”[MeSH Terms] OR (“struma”[All Fields] AND “ovarii”[All Fields]) OR “struma ovarii”[All Fields]) AND
Fig. 2 – The TSH-receptor immunostaining was diffusely appreciable in the cytoplasm of follicular cells revealed in the struma ovarii (A), in a pattern similar to the control normal thyroid epithelium (B), while the adjacent follicular cysts were unstained (C). The follicular variant of papillary carcinoma exhibited a strong para-nuclear immunoreactivity (D).
Table 1 – Cases of coexistent struma ovarii and Graves’ disease. Author, year
Side
Maximum Exophthalmos Pleural Ascites TSHR-Ab TPO-Ab TG-Ab CA-125 Ovarii scan Years after Graves’ diameter (cm) effusion diagnosis
64
No
NA
NA
Yes
NA
NA
NA
NA
NA
NA
NA
18
38
No
Right
7
Yes
No
No
+
NA
NA
NA
+
12
48
No
Left
9
Yes
No
Yes
+
−
−
NA
+
26
40
No
Right
5
No
No
No
+
NA
NA
NA
NA
4
30
NA
Right
7
No
No
No
−
+
NA
NA
+
0
78
No
Bilateral
10
NA
No
Yes
NA
NA
NA
NA
+
4
50
Yes
Left
7
NA
NA
NA
+
NA
NA
−
NA
NA
26
No
Left
16
No
No
No
+
+
−
NA
+
4
53
Yes
Right
1
No
No
No
NA
NA
NA
−
NA
5
42
No
Right
12
Yes
No
Yes
NA
NA
+
+
−
1
54
No
Left
NA
NA
NA
NA
+
NA
NA
NA
+
23
36
No
Left
13.5
Yes
No
No
+
+
NA
NA
NA
8
42
No
Right
12
No
No
Yes
+
+
+
−
+
0.5
44
Yes
Left
NA
Yes
NA
NA
+
NA
NA
NA
NA
1
49
No
Right
18
No
Yes
Yes
+
+
+
+
NA
2
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Kempers, 1970 [3] Lefort, 1981 [16] Lazarus, 1987 [15] Kung, 1989 [14] Bayot, 1995 [9] a Grandet, 2000 [11] Kano, 2000 [13] Mimura, 2001 [2] Sussman, 2002 [17] Guida, 2005 [12] Bartel, 2005 [8] Teale, 2006 [4] Chiofalo, 2007 [10] Wong, 2009 [18] our case, 2013
Age Ovarian malignancy
TSHR-Ab, thyrotropin receptors autoantibodies; TPO-Ab, thyroid-peroxidase autoantibodies; TG-Ab, thyroglobulin autoantibodies; CA-125, cancer antigen 125; NA, not available a It is not clear whether the cause of hyperthyroidism was Graves’ disease.
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(“graves disease”[MeSH Terms] OR (“graves”[All Fields] AND “disease”[All Fields]) OR “graves disease”[All Fields]) AND (“hyperthyroidism”[MeSH Terms] OR “hyperthyroidism”[All Fields]). Afterwards, the bibliographic search was extended to the “Related Articles” link next to each selected article in PubMed and its references. Finally, automatic alerts were activated in PubMed (“My NCBI”) to add relevant articles published after the initial search (last update 15 February 2013). The cases of coexistent struma ovarii and Graves’ disease retrieved from this systematic search are summarized in Table 1 [2–4,8–18].
4.
Discussion
Struma ovarii is usually non-functional while only 8% of the patients present with symptoms and signs of hyperthyroidism [1,18]. Struma ovarii has been associated with PseudoMeigs syndrome in 5% of the cases [19]. In case of coexistent Graves’ disease and struma ovarii, the diagnosis of the latter almost always follows the diagnosis of the former, up to more than twenty years (range 0–26 years; Table 1). Presumably, the circulating TSHR-Ab in Graves’ disease exert a long-lasting stimulatory effect on the thyroid tissue in the ovary, resulting in gradual growth and increasing thyroid hormone production. Thus, in patients with relapse of hyperthyroidism years after the initial management, the possibility of functioning struma ovarii should be considered. At diagnosis of hyperthyroidism, our patient had increased thyroid uptake of Tc99m, thus an additional source of ectopic hormone production was not suspected. Because initial Tc99m thyroid scan was positive and she remained hyperthyroid after ovarian mass removal, we speculated that the main source of excess thyroid hormones was the thyroid gland. The diagnosis of functioning struma ovarii in the presence of Graves’ disease may be a challenge. Increased uptake of Tc99m or I123 by the ovarian tumor in whole-body scan is indicative of a functioning struma ovarii [2], but false negative [12] and false positive [20] results have been reported. It has also been proposed that, in case of coexistent Graves’ disease and struma ovarii, ovarian expression of TSHR in the presence of circulating TSHR-Ab indicates direct stimulation of thyroid hormone production from struma ovarii [4]. However, this approach has also a risk of false negative results, because TSHR-Ab are high in 95%, but not all patients with Graves' disease [9]. In our patient, a whole-body scan was not performed for the reasons mentioned above. On the other hand, we identified immunohistochemically the presence of TSHR in the struma ovarii tissue, implying that struma ovarii was functional in our patient. Struma ovarii is a teratoma, usually containing other tissues besides thyroid, such as skin, teeth, nails. However, our patient had a monophasic teratoma, consisting exclusively of thyroid tissue. Other cases of coexistent Graves’ disease and struma ovarii have also reported the same histological features [2,14], implying that a high content of
thyroid tissue in the teratoma may be required for a hyperfunctioning struma ovarii to ensue. As far as we know, our case is the first with coincident Graves’ disease, thyroid malignancy and struma ovarii. It is surprising that a 0.9 cm nodule was misdiagnosed in the US, although the disorganized, micronodular, highly-vasculated appearance of the thyroid gland in Graves’ disease may render the localization of such lesions difficult. Thyroid microcarcinomas, incidentally discovered during histological examination of an excised thyroid gland, represent the most common presentation of thyroid tumors in patients with Graves’ disease [6]. There is growing evidence that TSH promotes tissue growth in normal and malignant thyroid tissue [21]. However, TSH levels are low in Graves’ disease; thus, another factor, presumably TSHR-Ab may be responsible for the tumor growth. This hypothesis, if applied to the struma ovarii could result in increased risk of malignant transformation in the presence of TSHR-Ab. In our patient, the thyroid tumor tissue showed a strong immunoreaction for TSHR, which was mainly located in the cytoplasm (perinuclear). In line with our finding, immunohistochemical expression of TSHR has been reported to be higher in thyroid cancer than in normal tissue, but mainly located in the cytoplasm [22]. These finding may be related to the inability of the TSHR protein to correctly migrate to the cellular membrane and the reported lower TSHR mRNA levels compared to normal tissue [22,23]. Therefore, we cannot imply that the increased cytoplasmic expression of TSHR that we found in our case is translated in increased responding to TSH control and thus related to Graves' disease. In our patient, hyperthyroidism persisted despite treatment with antithyroid drugs. High TSHR-Ab levels that remain during time, as in our case, are associated with low remission rates of hyperthyroidism. TSHR-Ab cut off levels at 6, 12 and 18 months after antithyroid treatment initiation, which could predict the likelihood of remission, have been reported [24]. Furthermore, it has been proposed that definitive treatment of the hyperthyroidism could be decided on this basis [24]. An interesting feature of our case was that a benign condition was presented with ascites and pleural effusion. This possibility should be kept in mind in order to avoid major surgical procedures that could be traumatic for the patient. Meigs syndrome is defined as the triad of ovarian fibroma with ascites and pleural effusion that resolves after resection of the tumor [25]. In case of pleural effusion and ascites in benign tumors of the ovary other than fibromas, including mature teratomas and struma ovarii, the term Pseudo-Meigs syndrome is used [26]. The pathophysiology of ascites is unknown. Ascitic and pleural fluid is typically transudative and tumor size, rather than the specific histologic type, is thought to be important for their formation. Our patient had modest quantity of ascitic, but large quantity of pleural fluid. To our knowledge, there is no other reported case of coexistence of Graves’ disease and struma ovarii causing pleural effusion. In the same setting, ascites has been previously described [10-12,15]. As in our patient, the pleural effusion in Meigs syndrome is most commonly right-sided [27]. As expected, both pleural effusion and ascites resolved rapidly after tumor resection. There are case reports of pseudo-Meigs syndrome associated with both benign [1,28,29] and malignant [19,30] struma
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ovarii and elevated CA-125 levels. The neoplasm could be non functional [1] or cause hyperthyroidism [19]. CA-125 may be elevated in Meigs and pseudo-Meigs syndrome, but the degree of elevation does not correlate with the risk for malignancy [31]. CA-125 was strikingly high in our patient, despite the benign nature of the ovarian tumor. There is a similar case in the literature [12]. On the contrary, normal CA-125 levels have been reported in patients with malignant struma ovarii and Graves’ disease [13,17]. Although the combination of ovarian tumor, ascites, pleural effusion, and elevated CA-125 is highly predictive of epithelial ovarian cancer, the possibility of Meigs syndrome must always be considered [32].
In conclusion, a patient with functioning struma ovarii masked by coexisting Graves’ disease is reported. The diagnosis of struma ovarii was set postoperatively after removal of an ovarian tumor causing large pleural effusion and accompanied by increased CA-125. In the subsequent thyroidectomy, incidental papillary thyroid cancer was identified. Expression of TSHR in the struma ovarii tissue in the presence of circulating TSHR-Ab could stimulate growth and thyroid hormone production. In patients with Graves’ disease and persistent or recurrent hyperthyroidism, the possibility of functioning struma ovarii should be considered. Ascites, pleural effusion and increased CA-125 may ensue in benign struma ovarii.
Contribution Codes
Authors Athanasios D. Anastasilakis Rosaria-Maddalena Ruggeri Stergios A. Polyzos Polyzois Makras
Conception and design
Analysis and interpretation of the data
Drafting of the article
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Critical revision of the article
Final approval of the article
Provision of study materials or patients
Statistical expertise
Obtaining of funding
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Dimitra Molyva Alfredo Campennì Athina Gkiomisi Christos Balaris Panagiotis P. Fotiadis Giovanni Tuccari Stergios Papachatzopoulos
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Collection and assembly of data
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Administrative, technical, or logistic support
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Conflict of interest None.
REFERENCES
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[16] Lefort G, Commenges-Ducos M, Denechaud M, et al. Ovarian goiter in basedow's disease. Role of thyroid-stimulating immunoglobulins? Nouv Presse Med 1981;10(26):2209–10. [17] Sussman SK, Kho SA, Cersosimo E, et al. Coexistence of malignant struma ovarii and Graves' disease. Endocr Pract 2002;8(5):378–80. [18] Wong LY, Diamond TH. Severe ophthalmopathy developing after treatment of coexisting malignant struma ovarii and Graves' disease. Thyroid 2009;19(10):1125–7. [19] Loizzi V, Cormio G, Resta L, et al. Pseudo-Meigs syndrome and elevated CA125 associated with struma ovarii. Gynecol Oncol 2005;97(1):282–4. [20] Joja I, Asakawa T, Mitsumori A, et al. I-123 uptake in nonfunctional struma ovarii. Clin Nucl Med 1998;23(1):10–2. [21] Boelaert K, Horacek J, Holder RL, et al. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab 2006;91(11):4295–301. [22] Wang ZF, Liu QJ, Liao SQ, et al. Expression and correlation of sodium/iodide symporter and thyroid stimulating hormone receptor in human thyroid carcinoma. Tumori 2011;97(4): 540–6. [23] Brabant G, Maenhaut C, Köhrle J, et al. Human thyrotropin receptor gene: expression in thyroid tumors and correlation to markers of thyroid differentiation and dedifferentiation. Mol Cell Endocrinol 1991;82(1):R7-12. [24] Eckstein A, Esser J, Mann K, et al. Clinical value of TSH receptor antibodies measurement in patients with Graves' orbitopathy. Pediatr Endocrinol Rev 2010(Suppl 2):198–203. [25] Meigs JV, Cass JW. Fibroma of the ovary with ascites and hydrothorax: with a report of seven cases. Am J Obstet Gynecol 1937;33:249–67. [26] Dunn Jr JS, Anderson CD, Method MW. Hydropic degenerating leiomyoma presenting as pseudo-Meigs syndrome with elevated CA 125. Obstet Gynecol 1998;92(4 Pt 2):648–9. [27] Nemeth AJ, Patel SK. Meigs syndrome revisited. J Thorac Imaging 2003;18(2):100–3. [28] Mitrou S, Manek S, Kehoe S. Cystic struma ovarii presenting as pseudo-Meigs' syndrome with elevated CA125 levels. A case report and review of the literature. Int J Gynecol Cancer 2008;18(2):372–5. [29] Mui MP, Tam KF, Tam FK, et al. Coexistence of struma ovarii with marked ascites and elevated CA-125 levels: case report and literature review. Arch Gynecol Obstet 2009;279(5):753–7. [30] Zannoni GF, Gallotta V, Legge F, et al. Pseudo-Meigs' syndrome associated with malignant struma ovarii: a case report. Gynecol Oncol 2004;94(1):226–8. [31] Jones OW, Surwit EA. Meigs syndrome and elevated CA 125. Obstet Gynecol 1989;73(3 Pt 2):520–1. [32] Morán-Mendoza A, Alvarado-Luna G, Calderillo-Ruiz G, et al. Elevated CA125 level associated with Meigs' syndrome: case report and review of the literature. Int J Gynecol Cancer 2006;16(Suppl 1):315–8.
Available online at www.sciencedirect.com
Metabolism www.metabolismjournal.com
Brief Report
Coexistence of Graves’ disease, papillary thyroid carcinoma and unilateral benign struma ovarii: Case report and review of the literature Athanasios D. Anastasilakis a,⁎, Rosaria-Maddalena Ruggeri b , Stergios A. Polyzos c , Polyzois Makras d , Dimitra Molyva e , Alfredo Campennì f , Athina Gkiomisi g , Christos Balaris a , Panagiotis P. Fotiadis h , Giovanni Tuccari i , Stergios Papachatzopoulos g a
Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece Department of Clinical and Experimental Medicine and Pharmacology, Section of Endocrinology, University of Messina, Messina, Italy c Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration General Hospital, Thessaloniki, Greece d Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece e Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece f Department of Radiological Sciences, Nuclear Medicine Unit, University of Messina, Messina, Italy g Department of Obstetrics and Gynaecology, 424 General Military Hospital, Thessaloniki, Greece h 1st Department of General Surgery, 424 General Military Hospital, Thessaloniki, Greece i Department of Human Pathology, University of Messina, Messina, Italy b
A R T I C LE I N FO Article history: Received 27 March 2013 Accepted 20 May 2013
AB S T R A C T Background. Struma ovarii is a rare cause of hyperthyroidism, while coexistence with Graves’ disease has been scarcely reported. Patient Findings. We report a patient with Graves’ disease and unilateral benign functioning struma ovarii, accompanied by ascites, pleural effusion and elevated cancer antigen-125 (CA-125)
Keywords:
levels. In subsequent thyroidectomy, incidental papillary thyroid carcinoma was also identified.
Hyperthyroidism
The functionality of struma ovarii tissue in our patient was supported by the immuno-
Meigs syndrome
histochemical identification of TSH receptors (TSHR), which may stimulate growth and thyroid
Pleural effusion
hormone production in the presence of circulating TSHR stimulating antibodies (TSHR-Ab).
Thyroid cancer TSH receptor
Review of the literature. A systematic review of reported cases of coexistent Graves’ disease and struma ovarii was performed. Conclusions. The diagnosis of struma ovarii may be masked by Graves’ disease and, therefore, be delayed for several years. Furthermore, ascites, pleural effusion and increased CA-125 may result from a benign struma ovarii. The presence of TSHR in the struma ovarii tissue along with their absence in the surrounding ovarian tissue indirectly suggests that struma ovarii is functional. It is unclear whether TSHR-Ab play a role in the development of thyroid carcinomas in such patients. © 2013 Elsevier Inc. All rights reserved.
Abbreviations: CA-125, cancer antigen-125; CT, computed tomography; TFTs, thyroid function tests; TG-Ab, thyroglobulin autoantibodies; TPO-Ab, thyroid peroxidase autoantibodies; TSH, thyrotropin; TSHR, thyrotropin receptors; TSHR-Ab, thyrotropin receptors autoantibodies; US, ultrasound. ⁎ Corresponding author. Tel.: +30 2310 381 697; fax: + 30 2310 381 010. E-mail address: [email protected] (A.D. Anastasilakis). 0026-0495/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2013.05.013
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1.
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Introduction
Struma ovarii is a rare ovarian teratoma consisting predominantly (more than 50%) of mature thyroid tissue. It usually presents as a pelvic mass, whereas only rarely does it present as hyperthyroidism or pseudo-Meigs syndrome (pleural effusion and ascites in benign ovarian tumors other than fibromas). Malignant transformation is rare (5%–10%) and may be papillary, follicular or mixed type [1]. Graves’ disease represents the most common cause of hyperthyroidism, and may rarely coexist with struma ovarii [2]. In patients with coexistent struma ovarii and hyperthyroidism, the increased thyroid hormone production could result from: 1) hyperfunctioning struma ovarii alone, 2) both hyperfunctioning thyroid gland and struma ovarii or 3) a hyperfunctioning thyroid gland with incidental presence of non-functioning struma ovarii [3]. Thus, it may be difficult to determine the precise cause of hyperthyroidism in such patients. Increased radioiodine uptake by the ovary in whole-body scan [2] and expression of TSHR in the ovarian tissue in presence of TSHR-Ab are indicative of a functioning struma ovarii [4]. Thyroid cancer may occur in patients with Graves’ disease and recent studies confirm higher than expected incidental thyroid cancer rates in patients subjected to thyroidecromy for Graves’ disease [5]. On the other hand, patients with microcarcinomas and Graves' disease were found to have longer survival and excellent prognosis when compared to euthyroid patients with cancer of the same size [6]. Serum CA-125 is a tumor marker derived from tissues originated from the fetal coelomic epithelium (müllerian epithelium, pleura, pericardium, peritoneum). Besides ovarian malignancy, elevated CA-125 levels may also indicate endometriosis, pelvic inflammatory disease or peritoneal damage [7]. Herein, we report a unique case of coexistent Graves’ disease, papillary thyroid carcinoma and unilateral benign functioning struma ovarii, accompanied by ascites, pleural effusion and elevated CA-125 levels.
2.
Case description
A 49-year-old woman, admitted to the Gynaecology Department of 424 General Military Hospital, Thessaloniki, Greece, for a large right pelvic mass, possibly originating from the ovary, was referred to Endocrinology Clinics for preoperative evaluation due to coexistent hyperthyroidism. The mass had been diagnosed two weeks earlier, when the patient presented with a large right pleural effusion (Fig. 1A); thoracentesis showed transudative fluid with no neoplastic cells, while subsequent pelvic US examination revealed a large, right-sided, lobulated mass, a normal uterus, and moderate ascites. CT examination of the abdomen and pelvis showed a 15-cm solid mass with cystic components and microcalcifications, possibly arising from the right ovary (Fig. 1B). CA-125 levels were clearly high (404.7 IU/mL; normal values < 35). Given the combination of large abdominal tumor, ascites, pleural effusion, and elevated CA-125, ovarian malignancy was suspected. Graves’ disease was diagnosed in 2010 and, since then, the patient had been insufficiently treated with propylthiouracil
Fig. 1 – Computed tomography findings in our patient: (A) large right pleural effusion, (B) abdominal mass and moderate ascites, (C) Substernal goiter.
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50 mg three times a day. At clinical examination, the patient was clinically hyperthyroid, with a diffusely enlarged thyroid gland, but without orbital disease. The TFTs were consistent with thyrotoxicosis, while TSHR-Ab, TPO-Ab and TG-Ab were clearly above the upper limit of reference range (TSHR-Ab 3.16 IU/L, normal values < 1.75; antiTPO 854.9 IU/mL, normal values < 5.6; antiTG 157.4 IU/mL, normal values < 4.1). Thyroid US showed a large, substernal goiter with diffusely increased blood flow, which was also evident in the thoracic CT performed during the pleural effusion evaluation (Fig. 1C). Thyroid scan showed diffuse enlargement of the gland with increased technetium-99 m (Tc 99m) uptake (6.4%, normal values 0.3%–3%), despite propylthiouracil treatment. Since the patient was hyperthyroid, we changed her medication to methimazole 20 mg twice a day until surgery. The patient subsequently underwent total abdominal hysterectomy and bilateral oophorectomy. Histology revealed an 18 × 12 × 10-cm monophasic teratoma, consisting exclusively of thyroid tissue with no features of malignancy. Both pleural effusion and ascites resolved rapidly after tumor resection. In postoperative evaluation, CA-125 was within normal range (27.0 IU/mL), while TFTs were still abnormal. Subsequently, methimazole was continued along with oral Lugol’s iodine preparation, until the performance of total thyroidectomy two weeks later. Histology of the thyroid gland confirmed Graves’ disease and revealed a 0.9-cm papillary thyroid carcinoma of the follicular variant in the right lobe, without blood or lymphatic vessel invasion or extrathyroidal extension. Postoperatively, the patient was started on suppression therapy with 150 μg L-thyroxine once daily. We retrospectively performed immunohistochemical analysis to detect the presence of TSHR in tissue samples from the struma ovarii and thyroid tissue (Fig. 2). Normal human thyroid tissue (archival specimen) was used as a positive control (Fig. 2B) with ovarian tissue surrounding struma ovarii as negative control (Fig. 2C). A semiquantitative evaluation was performed, based on the intensity of immunostaining and the percentage of cells positively stained. Most thyroid follicular cells in our samples (the control normal thyroid tissue, the Graves’ disease the papillary carcinoma and the struma ovarii tissue) expressed the TSHR with various degrees of staining intensity in the same tissue sample, but without difference in the intensity of the staining between different tissues. The intensity of the staining was even higher in the papillary carcinoma tissue than in benign (Graves’ disease) or normal thyroid tissue, but it was only cytoplasmic (Fig. 2D). The surrounding ovarian tissue was not stained, indicating absence of TSHR (Fig. 2C).
3.
Literature search
Computerized advanced search for primary evidence was performed in PubMed (Public/Publisher MEDLINE) electronic database in 15 January 2013 by the combination of terminological (MeSH terms) and methodological search filters. Search was not limited by publication time and not restricted to English literature. The original detailed query was: (“struma ovarii”[MeSH Terms] OR (“struma”[All Fields] AND “ovarii”[All Fields]) OR “struma ovarii”[All Fields]) AND
Fig. 2 – The TSH-receptor immunostaining was diffusely appreciable in the cytoplasm of follicular cells revealed in the struma ovarii (A), in a pattern similar to the control normal thyroid epithelium (B), while the adjacent follicular cysts were unstained (C). The follicular variant of papillary carcinoma exhibited a strong para-nuclear immunoreactivity (D).
Table 1 – Cases of coexistent struma ovarii and Graves’ disease. Author, year
Side
Maximum Exophthalmos Pleural Ascites TSHR-Ab TPO-Ab TG-Ab CA-125 Ovarii scan Years after Graves’ diameter (cm) effusion diagnosis
64
No
NA
NA
Yes
NA
NA
NA
NA
NA
NA
NA
18
38
No
Right
7
Yes
No
No
+
NA
NA
NA
+
12
48
No
Left
9
Yes
No
Yes
+
−
−
NA
+
26
40
No
Right
5
No
No
No
+
NA
NA
NA
NA
4
30
NA
Right
7
No
No
No
−
+
NA
NA
+
0
78
No
Bilateral
10
NA
No
Yes
NA
NA
NA
NA
+
4
50
Yes
Left
7
NA
NA
NA
+
NA
NA
−
NA
NA
26
No
Left
16
No
No
No
+
+
−
NA
+
4
53
Yes
Right
1
No
No
No
NA
NA
NA
−
NA
5
42
No
Right
12
Yes
No
Yes
NA
NA
+
+
−
1
54
No
Left
NA
NA
NA
NA
+
NA
NA
NA
+
23
36
No
Left
13.5
Yes
No
No
+
+
NA
NA
NA
8
42
No
Right
12
No
No
Yes
+
+
+
−
+
0.5
44
Yes
Left
NA
Yes
NA
NA
+
NA
NA
NA
NA
1
49
No
Right
18
No
Yes
Yes
+
+
+
+
NA
2
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Kempers, 1970 [3] Lefort, 1981 [16] Lazarus, 1987 [15] Kung, 1989 [14] Bayot, 1995 [9] a Grandet, 2000 [11] Kano, 2000 [13] Mimura, 2001 [2] Sussman, 2002 [17] Guida, 2005 [12] Bartel, 2005 [8] Teale, 2006 [4] Chiofalo, 2007 [10] Wong, 2009 [18] our case, 2013
Age Ovarian malignancy
TSHR-Ab, thyrotropin receptors autoantibodies; TPO-Ab, thyroid-peroxidase autoantibodies; TG-Ab, thyroglobulin autoantibodies; CA-125, cancer antigen 125; NA, not available a It is not clear whether the cause of hyperthyroidism was Graves’ disease.
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(“graves disease”[MeSH Terms] OR (“graves”[All Fields] AND “disease”[All Fields]) OR “graves disease”[All Fields]) AND (“hyperthyroidism”[MeSH Terms] OR “hyperthyroidism”[All Fields]). Afterwards, the bibliographic search was extended to the “Related Articles” link next to each selected article in PubMed and its references. Finally, automatic alerts were activated in PubMed (“My NCBI”) to add relevant articles published after the initial search (last update 15 February 2013). The cases of coexistent struma ovarii and Graves’ disease retrieved from this systematic search are summarized in Table 1 [2–4,8–18].
4.
Discussion
Struma ovarii is usually non-functional while only 8% of the patients present with symptoms and signs of hyperthyroidism [1,18]. Struma ovarii has been associated with PseudoMeigs syndrome in 5% of the cases [19]. In case of coexistent Graves’ disease and struma ovarii, the diagnosis of the latter almost always follows the diagnosis of the former, up to more than twenty years (range 0–26 years; Table 1). Presumably, the circulating TSHR-Ab in Graves’ disease exert a long-lasting stimulatory effect on the thyroid tissue in the ovary, resulting in gradual growth and increasing thyroid hormone production. Thus, in patients with relapse of hyperthyroidism years after the initial management, the possibility of functioning struma ovarii should be considered. At diagnosis of hyperthyroidism, our patient had increased thyroid uptake of Tc99m, thus an additional source of ectopic hormone production was not suspected. Because initial Tc99m thyroid scan was positive and she remained hyperthyroid after ovarian mass removal, we speculated that the main source of excess thyroid hormones was the thyroid gland. The diagnosis of functioning struma ovarii in the presence of Graves’ disease may be a challenge. Increased uptake of Tc99m or I123 by the ovarian tumor in whole-body scan is indicative of a functioning struma ovarii [2], but false negative [12] and false positive [20] results have been reported. It has also been proposed that, in case of coexistent Graves’ disease and struma ovarii, ovarian expression of TSHR in the presence of circulating TSHR-Ab indicates direct stimulation of thyroid hormone production from struma ovarii [4]. However, this approach has also a risk of false negative results, because TSHR-Ab are high in 95%, but not all patients with Graves' disease [9]. In our patient, a whole-body scan was not performed for the reasons mentioned above. On the other hand, we identified immunohistochemically the presence of TSHR in the struma ovarii tissue, implying that struma ovarii was functional in our patient. Struma ovarii is a teratoma, usually containing other tissues besides thyroid, such as skin, teeth, nails. However, our patient had a monophasic teratoma, consisting exclusively of thyroid tissue. Other cases of coexistent Graves’ disease and struma ovarii have also reported the same histological features [2,14], implying that a high content of
thyroid tissue in the teratoma may be required for a hyperfunctioning struma ovarii to ensue. As far as we know, our case is the first with coincident Graves’ disease, thyroid malignancy and struma ovarii. It is surprising that a 0.9 cm nodule was misdiagnosed in the US, although the disorganized, micronodular, highly-vasculated appearance of the thyroid gland in Graves’ disease may render the localization of such lesions difficult. Thyroid microcarcinomas, incidentally discovered during histological examination of an excised thyroid gland, represent the most common presentation of thyroid tumors in patients with Graves’ disease [6]. There is growing evidence that TSH promotes tissue growth in normal and malignant thyroid tissue [21]. However, TSH levels are low in Graves’ disease; thus, another factor, presumably TSHR-Ab may be responsible for the tumor growth. This hypothesis, if applied to the struma ovarii could result in increased risk of malignant transformation in the presence of TSHR-Ab. In our patient, the thyroid tumor tissue showed a strong immunoreaction for TSHR, which was mainly located in the cytoplasm (perinuclear). In line with our finding, immunohistochemical expression of TSHR has been reported to be higher in thyroid cancer than in normal tissue, but mainly located in the cytoplasm [22]. These finding may be related to the inability of the TSHR protein to correctly migrate to the cellular membrane and the reported lower TSHR mRNA levels compared to normal tissue [22,23]. Therefore, we cannot imply that the increased cytoplasmic expression of TSHR that we found in our case is translated in increased responding to TSH control and thus related to Graves' disease. In our patient, hyperthyroidism persisted despite treatment with antithyroid drugs. High TSHR-Ab levels that remain during time, as in our case, are associated with low remission rates of hyperthyroidism. TSHR-Ab cut off levels at 6, 12 and 18 months after antithyroid treatment initiation, which could predict the likelihood of remission, have been reported [24]. Furthermore, it has been proposed that definitive treatment of the hyperthyroidism could be decided on this basis [24]. An interesting feature of our case was that a benign condition was presented with ascites and pleural effusion. This possibility should be kept in mind in order to avoid major surgical procedures that could be traumatic for the patient. Meigs syndrome is defined as the triad of ovarian fibroma with ascites and pleural effusion that resolves after resection of the tumor [25]. In case of pleural effusion and ascites in benign tumors of the ovary other than fibromas, including mature teratomas and struma ovarii, the term Pseudo-Meigs syndrome is used [26]. The pathophysiology of ascites is unknown. Ascitic and pleural fluid is typically transudative and tumor size, rather than the specific histologic type, is thought to be important for their formation. Our patient had modest quantity of ascitic, but large quantity of pleural fluid. To our knowledge, there is no other reported case of coexistence of Graves’ disease and struma ovarii causing pleural effusion. In the same setting, ascites has been previously described [10-12,15]. As in our patient, the pleural effusion in Meigs syndrome is most commonly right-sided [27]. As expected, both pleural effusion and ascites resolved rapidly after tumor resection. There are case reports of pseudo-Meigs syndrome associated with both benign [1,28,29] and malignant [19,30] struma
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ovarii and elevated CA-125 levels. The neoplasm could be non functional [1] or cause hyperthyroidism [19]. CA-125 may be elevated in Meigs and pseudo-Meigs syndrome, but the degree of elevation does not correlate with the risk for malignancy [31]. CA-125 was strikingly high in our patient, despite the benign nature of the ovarian tumor. There is a similar case in the literature [12]. On the contrary, normal CA-125 levels have been reported in patients with malignant struma ovarii and Graves’ disease [13,17]. Although the combination of ovarian tumor, ascites, pleural effusion, and elevated CA-125 is highly predictive of epithelial ovarian cancer, the possibility of Meigs syndrome must always be considered [32].
In conclusion, a patient with functioning struma ovarii masked by coexisting Graves’ disease is reported. The diagnosis of struma ovarii was set postoperatively after removal of an ovarian tumor causing large pleural effusion and accompanied by increased CA-125. In the subsequent thyroidectomy, incidental papillary thyroid cancer was identified. Expression of TSHR in the struma ovarii tissue in the presence of circulating TSHR-Ab could stimulate growth and thyroid hormone production. In patients with Graves’ disease and persistent or recurrent hyperthyroidism, the possibility of functioning struma ovarii should be considered. Ascites, pleural effusion and increased CA-125 may ensue in benign struma ovarii.
Contribution Codes
Authors Athanasios D. Anastasilakis Rosaria-Maddalena Ruggeri Stergios A. Polyzos Polyzois Makras
Conception and design
Analysis and interpretation of the data
Drafting of the article
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Critical revision of the article
Final approval of the article
Provision of study materials or patients
Statistical expertise
Obtaining of funding
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Dimitra Molyva Alfredo Campennì Athina Gkiomisi Christos Balaris Panagiotis P. Fotiadis Giovanni Tuccari Stergios Papachatzopoulos
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Collection and assembly of data
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Administrative, technical, or logistic support
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Conflict of interest None.
REFERENCES
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