Struma ovarii

INTRODUCTION — Struma ovarii is a specialized or monodermal teratoma predominantly composed of mature thyroid tissue [1]. Thyroid tissue must comprise more than 50 percent of the overall tissue to be classified as a struma ovarii. Struma ovarii accounts for approximately 5 percent of all ovarian teratomas [2-4]. Depending on the histologic features, struma ovarii can be classified as benign or malignant [5]. The clinical presentation, diagnosis, and management of struma ovarii will be reviewed here. Ovarian teratomas are reviewed in detail elsewhere. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis", section on 'Teratomas'.)

CLINICAL MANIFESTATIONS — Women with struma ovarii usually present with pain and/or a pelvic mass and less frequently with ascites. Clinical and biochemical features of hyperthyroidism are uncommon in women with struma ovarii, occurring in less than 5 to 8 percent of cases [3,5-8]. The clinical manifestations of struma ovarii are based upon single case reports and small case series [2-5,9,10].

General findings — Struma ovarii is most common between the ages of 40 and 60 years, but has been reported in patients as young as 10 years old [11]. In case series of 20 to 30 patients with histologically confirmed struma ovarii, abdominal or pelvic pain was present in 17 patients and a palpable lower abdominal mass in 22 [4,8]. In one series, no definite symptoms were present in 14 of 34 patients, in whom the presence of an ovarian tumor was incidentally noted on ultrasonography performed for other reasons [4]. Ascites was present in 4 patients. CA-125 was elevated in 4 of 13 women in whom it was measured (one of three who were found to have malignant struma ovarii).

Hyperthyroidism — Clinical and biochemical features of hyperthyroidism are uncommon in women with struma ovarii. In hyperthyroid patients, the serum thyroid-stimulating hormone (TSH) is low and free thyroxine (T4) and/or triiodothyronine (T3) are elevated. The thyroid gland typically is not enlarged, but serum thyroglobulin is elevated. Radioiodine uptake is low or absent in the thyroid gland but present in the pelvis. Rarely, women with struma ovarii and hyperthyroidism also have a goiter [7]. There are at least two possible explanations for this association:

●The coexistence of Graves' disease and struma ovarii, which has been reported rarely in the literature [12,13]. Serum thyroid-stimulating immunoglobulins (thyrotropin-receptor antibodies [TRAb]) would be expected to stimulate function of thyroid tissue in the ovary as well as in the neck.

●A toxic nodular goiter with parallel formation of thyroid autonomy in an ovarian teratoma.

These women would have radioiodine accumulation in both locations.

Imaging — On ultrasound, struma ovarii appears as a heterogeneous solid mass [14,15]. There are no distinguishing ultrasound features unique to struma ovarii. Ascites is occasionally present.

Histology — Most women undergo surgical resection for diagnostic purposes. The histologic pattern may show microfollicular, macrofollicular, or oxyphil adenoma, with or without papillary hyperplasia [2,16]. As in follicular tumors of the thyroid gland, the thyroid epithelium in the teratoma may be organized in a solid, embryonal, or pseudotubular pattern, rather than thyroid follicles [7] (see "Atlas of thyroid cytopathology"). Immunohistochemical staining for thyroglobulin may be required to identify the cells as being of thyroid origin [17].

Histologic features of thyroid cancer are found in 5 to 37 percent of struma ovarii [3,4,9]. One study evaluated 96 patients with struma ovarii [18]. Sixteen patients had malignant struma; 10 had cytologic features of papillary cancers, one follicular cancer, and five well-differentiated neuroendocrine stromal tumors. Features indicative of malignancy include nuclear grooves, ground-glass appearance of the nuclei, and vascular invasion [19]. Cancer is more likely in larger tumors (75 percent of tumors greater than 16 cm) and rare in tumors under 5 cm [7]. The tumor can spread to the contralateral ovary and adjacent pelvic structures [20]. In one review, distant metastases were reportedly uncommon, occurring in 5 percent [8]. When present, the predominant sites of metastases are the lung, bone, liver, and brain [14].

Rarely, seeding of the peritoneum by a benign tumor, a condition called strumosis, occurs [6].

DIAGNOSIS

Struma ovarii — In women presenting with a pelvic mass, struma ovarii is typically diagnosed postoperatively based upon histologic findings of thyroid follicles in the resected ovary.

In women presenting with hyperthyroidism (elevated free T4 and/or T3, low TSH), the diagnosis of struma ovarii should be considered in a woman with persistent hyperthyroidism (>3 to 6 months), no goiter, absent radioiodine uptake in the neck, and a detectable serum thyroglobulin level. However, even among women with hyperthyroidism, without goiter, and with minimal or absent thyroid uptake of radioiodine, struma ovarii is rare. If struma ovarii is suspected, pelvic ultrasound should be obtained, and if pelvic ultrasound reveals an ovarian mass, pelvic radioimaging (using iodine-123 [123-I] or iodine-131 [131-I]) is performed to confirm the presence of functional thyroid tissue within the mass [21,22]. Because the bladder concentrates radioiodine, single-photon emission computed tomography (SPECT) images using any of the iodine radioisotopes may provide better clarity than planar imaging [23].

Malignant struma ovarii — The diagnostic criteria for malignant struma ovarii are similar to those for differentiated thyroid cancer. A definite diagnosis of carcinoma requires tumor invasion, metastases, or recurrence (for follicular cancer) or the typical cytopathologic features of papillary thyroid cancer. (See "Atlas of thyroid cytopathology", section on 'Papillary cancer'.)

The diagnosis of follicular thyroid cancer in an ovarian teratoma (malignant struma ovarii) may be difficult and parallels the difficulty in distinguishing benign thyroid microfollicular adenomas from differentiated follicular thyroid cancer [7]. (See "Atlas of thyroid cytopathology", section on 'Follicular neoplasm'.)

DIFFERENTIAL DIAGNOSIS

Pelvic mass — The differential diagnosis of a pelvic mass is extensive and is reviewed elsewhere (see "Adnexal mass: Differential diagnosis"). Thyroid cancer metastatic to the ovary can be confused with true struma ovarii [24], but primary thyroid cancer rarely metastasizes to the ovary [25]. In such cases, the ovarian tissue does not have teratomatous features. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis", section on 'Teratomas'.)

Hyperthyroidism — Among women with hyperthyroidism, without goiter, and with minimal or absent thyroid uptake of radioiodine, likely causes include exogenous thyroid hormone administration and lymphocytic (painless) thyroiditis. (See "Disorders that cause hyperthyroidism", section on 'Hyperthyroidism with a near absent radioiodine uptake'.)

In most patients with thyroiditis, thyroid function normalizes within several weeks. Patients with persistent hyperthyroidism (>3 to 6 months) are unlikely to have thyroiditis. (See "Painless thyroiditis" and "Subacute thyroiditis" and "Postpartum thyroiditis".)

Serum thyroglobulin concentrations are low in patients with exogenous hyperthyroidism in the absence of goiter or thyroid cancer. Thyroglobulin should be measured to exclude factitious use of thyroid hormone in patients with persistent hyperthyroidism, without goiter, and with minimal or absent thyroid uptake of radioiodine. In contrast, thyroglobulin is high in hyperthyroid patients with endogenous hyperthyroidism, including functional metastatic thyroid cancer, struma ovarii, and thyroiditis. Whenever serum thyroglobulin is measured, a test for antithyroglobulin antibodies should be performed at the same time (many laboratories do the latter first) because serum thyroglobulin measurements are unreliable if antithyroglobulin antibodies are present. (See "Exogenous hyperthyroidism" and "Overview of thyroiditis".)

Patients with Graves' disease typically have a goiter and elevated radioiodine uptake in the neck. The uptake may be lower than expected if iodine-rich drugs (amiodarone) or contrast agents used for angiography or computed tomography (CT) were recently administered. An exogenous iodine load will dilute the administered radioiodine tracer, and the uptake will be lowered depending upon the amount of the exogenous iodine load, whether the exposure is continuous (eg, amiodarone), and the interval since the iodine exposure. However, a single iodine load (eg, radiocontrast for a CT scan) may transiently reduce the radioiodine uptake in patients with Graves' disease to less than 10 percent for up to two to four weeks but rarely reduces the uptake to less than 1 percent as occurs in patients with painless thyroiditis or struma ovarii. (See "Diagnosis of hyperthyroidism", section on 'Radioiodine uptake' and "Iodine-induced thyroid dysfunction".)

TREATMENT — The initial treatment of struma ovarii is oophorectomy. Patients with malignant struma ovarii may need additional therapy, particularly in the presence of metastatic disease. (See 'Malignant struma ovarii' below.)

For patients with struma ovarii and newly discovered overt hyperthyroidism, surgery should be postponed until the patient has achieved adequate control of their thyroid condition (usually three to eight weeks). (See 'Control of hyperthyroidism before nonthyroid surgery' below.)

Benign struma ovarii — The treatment of benign struma ovarii is surgical resection of the ovarian tumor, typically unilateral oophorectomy. However, some patients undergo total hysterectomy with unilateral or bilateral salpingo-oophorectomy (BSO) because of the preoperative concern for ovarian cancer.

Peritoneal strumosis — Seeding of the peritoneum by a benign struma ovarii tumor is called peritoneal strumosis. Surgical excision of the tumor is the main treatment. In a series of 19 cases of peritoneal strumosis (estimated incidence 1.3 percent of struma ovarii cases), 18 had pelvic surgery, 6 had thyroidectomy and radioiodine [26]. After a mean follow-up of 53 months, 12 had no evidence of disease and 5 were alive with disease.

Malignant struma ovarii

Oophorectomy — The initial treatment of malignant struma ovarii is surgical resection of the primary tumor. The optimal ovarian surgical procedure (eg, unilateral or BSO, with or without hysterectomy) is reviewed separately. (See "Treatment of malignant germ cell tumors of the ovary", section on 'Surgical staging and primary cytoreduction'.)

Risk stratification — Patients with malignant struma ovarii may need additional therapy, such as thyroidectomy and radioiodine, particularly in the presence of metastatic disease. Radioiodine has been used to treat women with functional metastatic struma ovarii [3,8,27], analogous to its use in the treatment of metastatic differentiated thyroid cancer. After ovariectomy but before radioiodine scanning is performed, the woman must have a near-total thyroidectomy so that radioiodine uptake by the cancer can be detected and high-dose radioiodine therapy can be given.

The decision to perform a thyroidectomy and administer radioiodine after oophorectomy should be based upon the presence of metastatic disease and the risk of recurrence. An extremely high thyroglobulin suggests metastatic disease. The risk of recurrence is higher in patients with:

●Gross extraovarian extension of the tumor

●Large lesions (>4 cm, corresponding to thyroid T3 lesions)

●Presence of a BRAF mutation

●Histology other than classic papillary cancer

BRAF and RAS mutations have been reported in tumors of patients with malignant struma ovarii and may prove useful in the diagnosis and management of difficult cases [28-30]. BRAF-positive papillary cancer is more aggressive, and presumably, this mutation in a malignant struma ovarii also indicates the potential for more aggressive disease. However, in a review of 178 cases from the literature between 1983 and 2020, histology other than classic papillary cancer was the only independent adverse prognostic factor in multivariate analysis (hazard ratio [HR] 3.30, 95% CI 1.12-9.75) [31]. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer", section on 'BRAF mutations'.)

Subsequent treatment based on risk of recurrence — There is no consensus on the optimal treatment after oophorectomy. Our approach is as follows:

●Low risk of recurrence and no metastatic disease – Women with malignant struma ovarii confined to the ovary typically do not require radioiodine therapy after oophorectomy. We suggest T4 (levothyroxine) to suppress TSH to the lower limit or just below normal. We measure serum thyroglobulin annually.

In one case series, four patients with malignant struma ovarii confined to the ovary (ie, no extraovarian extension or distant metastases) were reviewed [19]. Surgical procedures included unilateral and BSO (one patient each) and total abdominal hysterectomy (TAH)-BSO (two patients). Only one patient had a thyroidectomy and treatment with radioiodine. This patient was found to have a synchronous papillary thyroid cancer. After a median follow-up of nine years, all patients remained without evidence of disease. In a review of a total of 57 cases of malignant struma ovarii confined to the ovary, 50 of whom did not undergo thyroidectomy-radioiodine therapy, the pooled recurrence rate was 7.5 percent at 25 years [19].

●High risk of recurrence or metastatic disease – For patients with known distant metastases, gross extraovarian extension of the tumor, large lesions (>4 cm, corresponding to thyroid T3 lesions), the presence of a BRAF mutation, or synchronous primary thyroid cancer, we suggest thyroidectomy followed by radioiodine treatment. These patients also require T4 therapy. The goal of T4 therapy is to maintain the TSH at levels corresponding to those for conventional thyroid cancer, with TSH values maintained in the 0.1 to 0.5 mU/L range for the first five years and then in the normal range thereafter in patients with no evidence of disease. Patients with persistent disease following initial therapy require maintenance of a serum TSH <0.1 mU/L.

●Equivocal risk – In patients with a malignant struma ovarii and equivocal indications for radioiodine therapy based upon the ovarian findings, we obtain a thyroid ultrasound to evaluate for synchronous primary thyroid gland abnormalities. Fine-needle aspiration (FNA) of detected thyroid nodules is warranted. Assessment of the ovarian tumor for the presence of a BRAF mutation may also be helpful.

Treatment suggestions are based upon reports of single cases or case series [5,19,32-36]. In a review of 24 cases of malignant struma ovarii, 4 of 24 patients with initial complete response were treated with adjuvant thyroidectomy and radioiodine after ovarian surgery; none of these patients had a recurrence [8]. There were eight recurrences (after an initial complete response to surgery), all of which occurred in the 16 patients treated conservatively after initial surgery (ie, followed clinically with or without serum thyroglobulin levels). The median time to recurrence among those patients was 48 months. Seven of eight women with recurrences were treated with radioiodine at the time of recurrence (along with thyroidectomy). Four patients had no evidence of disease at 3, 5, 6, and 324 months following radioiodine. Three patients recurred after radioiodine (at one, three, and six months). One patient did not receive further therapy and died of disease six months after recurrence.

A risk stratification system modeled after the American Thyroid Association (ATA) 2015 risk stratification system for thyroid cancer has been proposed to identify patients with increased risk of mortality who might benefit from radioiodine therapy [37]:

●Low risk – Tumors <4 cm, no metastases, no extraovarian extension, well-differentiated histology, and negative margins.

●Intermediate risk – Tumors >4 cm, lymphovascular invasion, local capsular rupture during surgery, and moderately differentiated.

●High risk – Positive pelvic washings or pelvic invasion, positive nodes or margins, metastases, and poorly differentiated.

The risk stratification system was evaluated in two cancer databases. The majority of high-risk patients did not receive radioiodine. As an example, the National Cancer Database had 158 patients between 2004 and 2016; Of the 21 patients deemed to be at high risk, only 30 percent received radioiodine. The Surveillance, Epidemiology and End Results (SEER) database had 95 patients between 2000 and 2018, and 41 percent of high-risk patients received radioiodine. High-risk patients had reduced overall survival (HR 4.0, 95% CI 1.11-14.26). Patient numbers were too small for further analysis based on radioiodine treatment. Additional studies are warranted.

Control of hyperthyroidism before nonthyroid surgery — There are no published studies evaluating the risks of nonthyroid surgery in hyperthyroid patients. In patients with untreated or poorly controlled overt hyperthyroidism (low TSH, high free T4 and/or T3), an acute event such as surgery can precipitate thyroid storm, a potentially life-threatening condition (see "Thyroid storm"). Thus, surgery should be postponed in patients with newly discovered overt hyperthyroidism until the patient has achieved adequate control of their thyroid condition (usually three to eight weeks). Treatment of hyperthyroidism in preparation for nonthyroid surgery is reviewed in detail elsewhere and briefly below. (See "Nonthyroid surgery in the patient with thyroid disease", section on 'Hyperthyroidism'.)

In women with struma ovarii and symptomatic or substantial biochemical hyperthyroidism, we administer a beta blocker (typically atenolol 25 to 50 mg daily, with the dose increased as needed to maintain the pulse rate below 80) and a thionamide (typically methimazole, 10 mg two to three times daily or 20 to 30 mg once daily) for four to six weeks before surgery. Beta blockers should be continued until the patient's thyroid disease is under control, and then tapered. Thionamides can be discontinued immediately after surgery. If hyperthyroidism is severe and the need for surgery is urgent, potassium iodide solution (SSKI, one to five drops three times daily) can be added one hour after thionamide administration. Iodine blocks release of T4 and T3 from the gland (and presumably the ovarian tumor) and thereby shortens the time to achieving a euthyroid state. (See "Thionamides in the treatment of Graves' disease" and "Thionamides: Side effects and toxicities" and "Beta blockers in the treatment of hyperthyroidism".)

Patients with subclinical hyperthyroidism (low TSH, normal free T4 and T3) can typically proceed with elective surgeries. Unless contraindicated, we administer a beta blocker preoperatively to older patients (>50 years) or younger patients with cardiovascular disease and taper after recovery. (See "Nonthyroid surgery in the patient with thyroid disease", section on 'Hyperthyroidism'.)

MONITORING — Patients with malignant struma ovarii require long-term (at least 10 years) follow-up [5,14]. Annual monitoring of stimulated serum thyroglobulin is reasonable for the first two years postoperatively and, if negative, unstimulated levels annually thereafter. Patients with biochemical evidence of persistent disease should have pelvic imaging with computed tomography (CT), with single-photon emission CT (SPECT) imaging using radioiodine when appropriate, or ultrasound. (See "Differentiated thyroid cancer: Overview of management", section on 'Monitoring response to therapy'.)

For women with low risk of recurrence (no extraovarian extension or distant metastases), we suggest T4 (levothyroxine) to suppress TSH to the lower limit or just below normal and monitoring with yearly serum thyroglobulin.

PROGNOSIS — Survival outcomes are generally good [38]. In a review of 194 cases with a mean age of 46, 27 percent had extraovarian extension, of whom 75 percent had no evidence of disease on follow-up (mean follow-up 5.2 years, longest follow-up 42 years) [36]. Disease-specific survival was 94, 90, and 86 percent after 5, 10, and 15 years, respectively. Risk factors for poor survival were stage 4 disease, age >45, and poorly differentiated histology.

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Struma ovarii is a specialized or monodermal teratoma predominantly composed of mature thyroid tissue. Thyroid tissue must comprise more than 50 percent of the overall tissue to be classified as a struma ovarii.

Women with struma ovarii usually present with pain and/or a pelvic mass and less frequently with ascites. Clinical and biochemical features of hyperthyroidism are uncommon in women with struma ovarii, occurring in less than 5 to 8 percent of cases. On ultrasound, struma ovarii appears as a heterogeneous solid mass. The histologic pattern may show microfollicular, macrofollicular, or oxyphil adenoma, with or without papillary hyperplasia. Histologic features of thyroid cancer are found in 5 to 37 percent of women with struma ovarii. (See 'Clinical manifestations' above.)

●Diagnosis

•Pelvic mass on presentation – In women presenting with a pelvic mass, struma ovarii is typically diagnosed postoperatively based upon histologic findings of thyroid follicles in the resected ovary. The diagnostic criteria for malignant struma ovarii are similar to those for differentiated thyroid cancer. A definite diagnosis of carcinoma requires tumor invasion, metastases, or recurrence (for follicular cancer) or the typical cytopathologic features of papillary thyroid cancer. (See 'Diagnosis' above.)

•Hyperthyroidism on presentation – In women presenting with hyperthyroidism (elevated free thyroxine [T4] and/or triiodothyronine [T3], low thyroid-stimulating hormone [TSH]), the diagnosis of struma ovarii should be considered in a woman with persistent hyperthyroidism (>3 to 6 months), no goiter, absent radioiodine uptake in the neck, and a detectable serum thyroglobulin level. In such women, pelvic ultrasound should be obtained, and if pelvic ultrasound reveals an ovarian mass, pelvic radioimaging (using iodine-123 [123-I] or iodine-131 [131-I] with single-photon emission computed tomography [SPECT]) is performed to confirm the presence of functional thyroid tissue within the mass. (See 'Diagnosis' above.)

●Differential diagnosis – Among women with hyperthyroidism, without goiter, and with minimal or absent thyroid uptake of radioiodine, likely causes include exogenous thyroid hormone administration and lymphocytic (painless) thyroiditis. Thyroid cancer metastatic to the ovary can be confused with true struma ovarii. Primary thyroid cancer rarely metastasizes to the ovary. In such cases, the ovarian tissue does not have teratomatous features. (See 'Differential diagnosis' above and "Adnexal mass: Differential diagnosis".)

●Treatment

•Benign struma ovarii – The treatment of benign struma ovarii is surgical resection of the ovarian tumor. (See 'Benign struma ovarii' above.)

•Malignant struma ovarii – The initial treatment of malignant struma ovarii is surgical resection of the primary tumor. The optimal ovarian surgical procedure (eg, unilateral or bilateral salpingo-oophorectomy [BSO], with or without hysterectomy) is reviewed separately. (See "Treatment of malignant germ cell tumors of the ovary", section on 'Surgical staging and primary cytoreduction'.)

Patients with malignant struma ovarii may need additional therapy, such as thyroidectomy and radioiodine. The decision is based on the presence of metastatic disease and the risk of recurrence. (See 'Risk stratification' above.)

-Low risk of recurrence, no metastases – For women with low risk of recurrence (no extraovarian extension) or distant metastases, we suggest T4 (levothyroxine) to suppress TSH to the lower limit or just below normal (Grade 2C). Such women typically do not require radioiodine therapy after oophorectomy. We measure serum thyroglobulin annually. (See 'Subsequent treatment based on risk of recurrence' above.)

-High risk of recurrence or metastatic disease – For patients with known distant metastases, gross extraovarian extension of the tumor, large lesions (>4 cm, corresponding to thyroid T3 lesions), the presence of a BRAF mutation, or a synchronous primary thyroid cancer, we suggest thyroidectomy followed by radioiodine treatment (Grade 2C).

These patients also require T4 therapy. The goal of T4 therapy is to maintain the TSH at levels corresponding to those for conventional thyroid cancer, with TSH values maintained in the 0.1 to 0.5 mU/L range for the first five years and then in the normal range thereafter in patients with no evidence of disease. (See 'Subsequent treatment based on risk of recurrence' above.)

●Presurgical treatment of hyperthyroidism – For patients with untreated or poorly controlled overt hyperthyroidism, we suggest postponing surgery until the patient has achieved adequate control of their hyperthyroidism (usually three to eight weeks) (Grade 2C). In such patients, an acute event such as surgery can precipitate thyroid storm, a potentially life-threatening condition. (See 'Control of hyperthyroidism before nonthyroid surgery' above and "Nonthyroid surgery in the patient with thyroid disease", section on 'Hyperthyroidism'.)

In our experience, patients with subclinical hyperthyroidism (low TSH, normal free T4 and T3) can typically proceed with elective surgeries. Unless contraindicated, we administer a beta blocker preoperatively to older patients (>50 years) or younger patients with cardiovascular disease and taper after recovery. (See 'Control of hyperthyroidism before nonthyroid surgery' above and "Nonthyroid surgery in the patient with thyroid disease", section on 'Hyperthyroidism'.)

●Monitoring – Patients with malignant struma ovarii require long-term (at least 10 years) monitoring of serum thyroglobulin and, if there is biochemical evidence of persistent or recurrent disease, appropriate imaging, which should also include the pelvis. (See 'Monitoring' above and "Differentiated thyroid cancer: Overview of management", section on 'Monitoring response to therapy'.)