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Malignant struma ovarii Leila Yassa, Peter Sadow and Ellen Marqusee*
S U M M A RY
THE CASE
Background A 25-year-old woman presented to her gynecologist with
pelvic pain. Pelvic ultrasonography showed a 9 cm left ovarian mass. The patient underwent left oophorectomy, omental biopsy, and lymph node sampling. The ovarian mass proved to be a struma ovarii with numerous microscopic foci of papillary thyroid carcinoma. The patient had no symptoms of hyperthyroidism, and her thyroid function and serum thyroglobulin levels were normal. Investigations Investigations included a pelvic ultrasound scan, histological examination of the ovarian mass and omental nodules, and lymph node sampling. Diagnosis Malignant struma ovarii. Management The patient was referred to an endocrinology clinic for further investigations. Serum levels of TSH, thyroglobulin and thyroglobulin antibodies were measured. In addition, the patient underwent thyroid ultrasonography, which showed a 1 cm nodule that proved benign on biopsy. She was treated with thyroxine to reduce TSH secretion. Follow-up pelvic ultrasonography 1 year later showed no evidence of recurrent disease, and her serum thyroglobulin levels remained normal. Keywords malignant struma ovarii, ovarian teratoma, radioactive iodine, struma ovarii, thyroid carcinoma
L Yassa is an Assistant in Medicine at Newton Wellesley Hospital, Wellesley and at Massachusetts General Hospital, Boston, MA, P Sadow is an Assistant Pathologist at Massachusetts General Hospital and E Marqusee is an Associate Physician at Brigham and Women’s Hospital, Boston, MA, USA. Correspondence *Thyroid Division, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
[email protected] Received 15 February 2008 Accepted 12 May 2008 Published online 17 June 2008 www.nature.com/clinicalpractice doi:10.1038/ncpendmet0887
august 2008 vol 4 no 8
A 25-year-old woman presented to her gynecologist with pelvic pain. Physical examination revealed a left-sided pelvic mass. Transvaginal ultrasonography showed a 9 cm diameter, thickwalled, septated cystic left ovarian mass with solid components that did not have the typical appearance of a dermoid cyst. The patient had no history of thyroid dysfunction. Her past medical history included gastroesophageal reflux disease, asthma and polycystic ovarian syndrome. She did not smoke cigarettes, but used marijuana approximately three times per week. She had been taking albuterol, as needed, for asthma. She had no family history of ovarian or endocrine tumors. The patient underwent a laparotomy, which revealed a large, left ovarian mass, adherent to the sigmoid colon and uterus, and a nodular omentum. The ovarian mass was separated from the colon and uterus and then resected. The omentum was biopsied and multiple lymph nodes were excised. On pathological examination, the ovarian mass proved to be a 10 cm struma ovarii consisting predominantly of normal thyroid tissue with multiple foci of papillary thyroid micro carcinoma (Figure 1); the largest focus of carcinoma was 9 mm in the largest dimension. The omental nodules (the largest nodule measured 2.5 cm) had the histologic characteristics of benign strumosis (Figure 2; indicating the diagnosis of a mature teratoma), consisting entirely of benign thyroid tissue with no evidence of carcinoma. No neoplastic cells were found on examination of the excised lymph nodes and the peritoneal washings. The patient was referred to an endocrinology clinic for further management. Physical examination of the patient revealed no abnormalities. Her serum TSH concentration was 2.1 mIU/l (reference range: 0.5–5.0 mIU/l) and her serum thyroglobulin concentration was 28.5 µg/l (reference range: 2.0–35.0 µg/l); serum thyroglobulin antibodies were not detected. Ultrasonography of the thyroid revealed a 1 cm nodule in the left lobe; fine-needle aspiration revealed a benign thyroid nodule.
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The patient was treated with thyroxine to reduce TSH secretion, but did not take this treatment regularly. After 1 year her TSH and thyroglobulin concentrations were normal (1.4 mIU/l and 43 µg/l, respectively). At that time, repeat thyroid ultrasonography showed no change in the thyroid nodule, pelvic ultrasonography showed a normal remaining right ovary with no masses, and CT of her abdomen and pelvis showed no masses. DISCUSSION OF DIAGNOSIS
Figure 1 Microscopic focus of papillary thyroid carcinoma, follicular variant, within benign, unremarkable spindled ovarian stroma (hematoxylin and eosin [H & E] staining; magnification ×400). Of note, lesional cells show extensive grooving and occasional intracytoplasmic pseudoinclusions.
Figure 2 Benign thyroid tissue (strumosis) present as nodular, circumscribed foci within the omentum (hematoxylin and eosin [H & E] staining; magnification ×100). Follicular cells show rounded, dark nuclei without grooves, membrane irregularities, clearing or pseudoinclusions, with a lack of invasive borders.
CT of the abdomen and pelvis and transvaginal ultrasonography, performed 6 months after surgery, showed no recurrence in the surgical bed, no evidence of metastatic disease, and a normal-appearing right ovary. 470 nature clinical practice ENDOCRINOLOGY & METABOLISM
Twenty percent of ovarian tumors are teratomas, and up to 20% of teratomas contain thyroid tissue. Struma ovarii, defined as containing 50% or more thyroid tissue, is less common, accounting for approximately 5% of all ovarian teratomas. Most patients with struma ovarii present with a pelvic mass, and pelvic ultra sonography characteristically shows a hetero geneous, solid mass, occasionally with ascites. The patient commonly undergoes surgery, because an ovarian malignancy is suspected. Intraoperative frozen section often only reveals a teratoma, and the diagnosis of struma ovarii is usually made postoperatively. Benign thyroid tissue can also be found in small foci on the peritoneal surface, and this finding is termed strumosis. Clinical and biochemical hyperthyroidism is unusual, occurring in less than 5% of cases. Histologic features of thyroid carcinoma are found in 5–37% of struma ovarii (referred to as malignant struma ovarii). The nuclear features of papillary carcinoma are usually used as the criteria for diagnosis of malignant struma ovarii, and most cases reported are papillary carcinoma.1–3 Some cases initially reported as follicular carcinoma might in fact represent a follicular variant of papillary carcinoma.4 Immunohistochemical staining with HBME-1 (Hector Battifora mesothelial [cell] 1) and galectin-3, often positive in papillary thyroid carcinoma, can also help confirm the diagnosis.5,6 BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations, common in papillary thyroid carcinoma, were present in twothirds of malignant struma ovarii with papillary features.7 RET proto-oncogene rearrangements (RET/PTC) were seen in 7 of 10 malignant struma ovarii with histologic features of follicular variant papillary thyroid carcinoma.8 One case of benign struma ovarii was, however, also found to have a RET proto-oncogene rearrangement.9 Although rare, thyroid carcinoma, metastatic to YASSA ET AL. august 2008 vol 4 no 8
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the ovary, has been reported and should not be confused with malignant struma ovarii. In the case of thyroid metastasis, the ovarian mass has no teratomatous features.10 The behavior of malignant struma ovarii is based on summaries of single case reports and small case series.11–13 The mean age at diagnosis of malignant struma ovarii in one series of 24 patients was 43 years.11 In a summary of 39 patients with malignant struma ovarii, 9 (23%) had metastases.12 The predominant sites of metastasis were adjacent pelvic structures, including the contralateral ovary, but some patients had distant metastases, including metastases to the lungs, bone, liver, and brain; however, in other small series the rates of meta stasis were lower.2 Because systematic reviews of thyroidectomy specimens in patients with malignant struma ovarii have not been performed, the percentage of patients with coexisting primary thyroid carcinoma is unknown. Recurrence rates after initial surgical treatment vary, but were as high as 35% in one summary of 24 case reports, with a median time to recurrence of 4 years.11 Of note, all recurrences in this series occurred in patients who had no additional surgical or radioiodine treatment after their initial pelvic surgery. In our own review of 56 cases reported in the literature since 1966, sites of recurrence included adjacent pelvic structures, lung, liver, bone, lymph nodes, skin and brain2,4,11–16 (Table 1). Treatment with thyroxine was not documented consistently enough to determine its impact on recurrence rates. TREATMENT AND MANAGEMENT
Currently, no consensus exists on the surgical and postoperative treatment of patients with malignant struma ovarii. Because ovarian malignancy is often suspected preoperatively, initial pelvic surgery may include a total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy, peritoneal washings and lymph node sampling. To preserve fertility, however, a unilateral oophorectomy or strumectomy is often performed.11 After the initial surgery, once the malignant struma ovarii is discovered, treatment options include further pelvic surgery, with total abdominal hysterectomy and oophorectomy (Box 1). Some authors advocate near-total thyroidectomy followed by radioactive iodine ablation.11 In a manner analogous to treatment of patients with thyroid carcinoma, monitoring of serum thyroglobulin can then be performed august 2008 vol 4 no 8 YASSA ET AL.
Table 1 Frequency, sites and detection of disease recurrence in patients with malignant struma ovarii. Disease recurrence
Number of casesa
No recurrence reported
42
Recurrence reported
14
Site of
recurrenceb
Adjacent pelvic structuresc
9
Lung
4
Bone
2
Contralateral ovary
1
Liver
1
Brain
1
Lymph nodes
2
Skin
1
Method of detection of recurrence Patient presenting with symptoms
10
Iodine scanning
1
Incidental finding on pathological examination after unrelated surgery
2
Not reported
1
aTotal number of cases reported = 56. bSome patients had recurrence at multiple sites. cPeritoneum, omentum, fallopian tubes and mesenteric surfaces of the spleen and diaphragm.
with greater sensitivity. In addition, after neartotal thyroidectomy, radioactive iodine can then be used for the treatment of recurrent disease.14 A few patients with metastatic malignant struma ovarii have been treated with external beam radia tion and chemotherapy; however, on the basis of the similarities between malignant struma ovarii and thyroid carcinoma, we think radioactive iodine should be first-line therapy for treatment of recurrent disease. A risk stratification of malignant struma ovarii similar to that used in thyroid carcinoma can help determine the most appropriate post operative treatment. Patients with thyroid carcinoma confined to the struma ovarii, measuring less than 2 cm, with no worrisome histologic features, can be considered low risk. Conversely, patients with larger thyroid carcinomas, disease outside the struma ovarii, or more aggressive histologic features should be considered high risk. The case patient was young and wished to preserve fertility. Her malignant struma consisted of multiple microscopic foci of classic papillary carcinoma. Pelvic imaging studies showed no evidence of additional tumor and there was no evidence of carcinoma in her thyroid gland. nature clinical practice ENDOCRINOLOGY & METABOLISM 471
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Competing interests The authors declared no competing interests.
Box 1 Treatment options for malignant struma ovarii. Pelvic surgery ■ Cystectomy ■
Unilateral oophorectomy
■
Total hysterectomy and bilateral salpingooophorectomy
■
Total hysterectomy, bilateral salpingooophorectomy with omentectomy and lymph node sampling
Adjuvant treatment ■ None ■
Thyroxine, to reduce TSH secretion
■
Near-total thyroidectomy with radioactive iodine ablation
In addition, the presence of teratomatous features in her ovarian mass argued against a diagnosis of metastases from a papillary thyroid carcinoma. Given these findings, we recommended only thyroxine therapy, to reduce TSH secretion, periodic measurements of serum thyroglobulin and periodic pelvic imaging. In view of her low-risk disease, we recommended a target serum TSH between 0.1 and 0.5 mIU/l. It is our opinion that the goal for serum TSH suppression in patients with malignant struma ovarii should be similar to that for patients with thyroid carcinoma. Although serum thyroglobulin is unlikely to become undetectable in patients without thyroidectomy on thyroxine therapy, any rise in thyroglobulin above baseline should prompt further evaluation for recurrent disease. Near-total thyroidectomy followed by radio iodine to detect and potentially treat recurrent disease should be considered at that time. CONCLUSIONS
In summary, for younger patients with malignant struma ovarii who wish to preserve fertility, oophorectomy may be the most appropriate surgery if pelvic imaging and surgical exploration do not reveal extra-ovarian disease. For those patients with low risk of persistent or
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recurrent thyroid carcinoma, we recommend thyroxine therapy, pelvic imaging and periodic measurements of serum thyroglobulin. For those patients with a higher risk of recurrence based on the pathology of the carcinoma, near-total thyroidectomy with radioactive iodine ablation is indicated. References 1 Medeiros F et al. (2006) Germ cell tumors of the ovary. In: Diagnostic Gynecologic and Obstetric Pathology, 920–921 (eds Crum CP and Lee KR) Philadelphia: Elsevier Saunders 2 Devaney K et al. (1993) Proliferative and histologically malignant struma ovarii: a clinicopathologic study of 54 cases. Int J Gynecol Pathol 12: 333–343 3 Robboy SJ et al. (1995) Prognostic indices in malignant struma ovarii: a clinicopathologic analysis of 36 patients with 20-year follow up. Mod Pathol 8: 95A 4 Dardik RB et al. (1999) Malignant struma ovarii: two case reports and a review of the literature. Gynecol Oncol 73: 447–451 5 Nakamura N et al. (2006) Immunohistochemical separation of follicular variant of papillary thyroid carcinoma from follicular adenoma. Endocr Pathol 17: 213–223 6 Casey MB et al. (2003) Distinction between papillary thyroid hyperplasia and papillary thyroid carcinoma by immunohistochemical staining for cytokeratin 19, galectin-3, and HBME-1. Endocr Pathol 14: 55–60 7 Schmidt J et al. (2007) BRAF in papillary thyroid carcinoma of ovary (struma ovarii). Am J Surg Pathol 31: 1337–1343 8 Boutross-Tadross O et al. (2007) Follicular variant papillary thyroid carcinoma arising in struma ovarii. Endocr Pathol 18:182–186 9 Elisei R et al. (2005) RET/PTC3 rearrangement and thyroid differentiation gene analysis in a struma ovarii fortuitously revealed by elevated serum thyroglobulin concentration. Thyroid 15: 1355–1361 10 Brogioni S et al. (2007) A special case of bilateral ovarian metastases in a woman with papillary carcinoma of the thyroid. Exp Clin Endocrinol Diabetes 115: 397–400 11 DeSimone CP et al. (2003) Malignant struma ovarii: a case report and analysis of case reported in the literature with focus on survival and I131 therapy. Gynecol Oncol 89: 543–548 12 Makani S et al. (2004) Struma ovarii with a focus of papillary thyroid cancer: a case report and review of the literature. Gynecol Oncol 94: 835–839 13 Navarro MD et al. (2004) Malignant struma ovarii. Ann Clin Lab Sci 34: 107–112 14 Rose PG et al. (1998) Malignant struma ovarii: recurrence and response to treatment monitored by thyroglobulin levels. Gynecol Oncol 70: 425–427 15 Rotman-Pikielny P et al. (2000) Recombinant human thyrotropin for the diagnosis and treatment of a highly functional metastatic struma ovarii. J Clin Endocrinol Metab 85: 237–244 16 Ryder M et al. (2007) Follicular variant papillary thyroid carcinoma arising with an ovarian teratoma. Thyroid 17: 179–180
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