Struma ovarii is a rare monodermal tumor of the ovaries, comprised mainly of thyroid tissue ^[1]. In order to qualify as a struma ovarii, an ovarian teratoma must be composed of at least 50% mature thyroid tissue ^[2]. Struma ovarii represents 1% of all ovarian tumors and 2.7% of dermoid tumors ^[3]. Although the majority of struma ovarii are benign, as many as 5–10% of them are proven histologically malignant, with papillary thyroid carcinoma being the most commonly identified histological subtype [4,5,6]^[4][5][6].

Nomenclature regarding struma ovarii subtypes was recently updated by the WHO, in light of concerns about the possible malignant potential of tumors comprised of thyroid tissue without histologic neoplastic features identified in extra-ovarian sites ^[7]. Until recently, all these cases were collectively referred to as “peritoneal strumosis” or “struma peritonei” in the literature, due to the absence of histological features of malignancy and despite their biologic behavior with a tendency to spread and recur ^[8]. In the 2020 WHO Classification of Female Genital Tumors, an extremely rare histological subtype called highly differentiated follicular carcinoma arising from struma ovarii (HDFCO) was introduced, representing the entity formerly described as peritoneal strumosis, in order to highlight its low-grade malignant potential ^[7]. The term was initially introduced by Roth et al. in 2008, in an attempt to reexamine the cases collectively referred to as “peritoneal strumosis”. Due to its mature histological appearance, HDFCO is only diagnosed when signs of spread beyond the ovary are exhibited, proving its malignant behaviour ^[7].

This emerging clinical entity is extremely rare, with only few cases published in the literature. The treatment most commonly involves local excision of the tumor and thyroidectomy followed by high-dose radio iodine therapy, in a similar fashion as for metastatic thyroid carcinoma and malignant struma ovarii [2,9,10,11,12,13,14]^{[2][9][10][11][12][13][14]}. However, the safety, efficacy, and oncologic outcome of these interventions have not been validated [2,4,7,8,9,10,11,12,13,14,15]^{[2][4][7][8][9][10][11][12][13][14][15]}.

2. Case Report

A 25-year-old, otherwise healthy, nulliparous woman presented to gynecologic department due to recurrence of an ovarian mass. She had initially been subjected to excision of a mature cystic teratoma of the right ovary six years ago, which contained thyroid tissue, although lacked sufficient diagnostic criteria to qualify as a struma ovarii at the time. Four years later, a right adnexal mass with ascites and elevated CA-125 levels (1778 U/mL) was discovered. The mass was excised along with multiple peritoneal inclusion cysts and the pathology report was consistent with struma ovarii, without signs of malignant nature. During the follow-up period, MRI imaging of the abdomen revealed a mass measured at 6 × 5.7 × 4.2 cm in the remaining left ovary. In addition to that, the presence of multiple nodules was noted in the peritoneal cavity, suggestive of peritoneal infiltrations. Thyroglobulin (Tg) levels were 2047.55 ng/mL, although thyroid function tests were within normal range (TSH 1.27 μIU/mL, anti-Tg 17.23 IU/mL, anti-TPO < 28.0 U/mL). The patient was referred to gynecologic oncology department for further management. After appropriate counselling with the patient, there was a strong wish to preserve fertility. The case was discussed at an MDT, including gynecologic oncologists, pathologists, surgical oncologists, endocrinologist, and a nuclear medicine specialist. Unfortunately, the patient was referred to gynecologic oncology department only after the recurrence. At this point, no oocytes had been cryopreserved. Before surgery, the patient received extensive counselling and all options for fertility preservation were discussed. This patient had only one ovary left, which was completely occupied by the lesions. According to the MDT’s suggestions and the patients’ wish, an attempt at cytoreduction with uterine preservation, if deemed oncologically safe, was undertaken. A laparotomy was performed with a midline incision. At initial inspection, the mass was located at the left ovary and seemed to extend to the ovarian capsule. The evaluation of the abdominal cavity revealed multiple, nodule-like lesions on the parietal and visceral peritoneum, on the mesentery, on the serosa of the bowel, and the sub-diaphragmatic peritoneum. Surgical staging was consistent with FIGO stage III B, as macroscopic lesions did not exceed 2 cm of maximal diameter. Extensive cytoreductive surgery was performed and optimal debulking was achieved with no macroscopic residual tumor. Based on intraoperative findings, the uterus was preserved to allow for a potential pregnancy with donor oocytes in the future. The final histopathologic diagnosis was consistent with a highly differentiated follicular carcinoma arising in struma ovarii. The patient underwent total thyroidectomy and radioiodine treatment (145 mCi). Tg levels decreased to 18 ng/mL one month after the abdominal operation. Follow-up was undertaken by a multi-disciplinary team including a gynecological oncologist, pathological oncologists, endocrinologists, and a nuclear medicine specialist. During follow-up, an abdominal MRI is obtained every 4–6 months and thyroid function tests (TSH, Tg) are checked every 3 months. Patient’s latest Tg and TSH levels are within normal range, and MRI scans suggest no signs of recurrence.

3. Characteristics of the Included Patients

 The mean age of the patients at diagnosis was 47.15 years (range 24–74). Mean follow-up period was 42.9 (range 4–204) months. In 92.9% of the reported cases, there was a previous gynecologic surgery ranging from cystectomy to total abdominal hysterectomy with bilateral oophorectomy. From those cases, a previous histologic diagnosis of struma ovarii was present in 62.5%, and a mature teratoma in 12.5%. In the remaining patients, the report was consistent with benign pathology other than struma ovarii, or not available. A history of HDFCO or struma peritonei was present in two patients, in both cases associated with a previous diagnosis of struma ovarii [25,30]^[16][17]. Interestingly, the only case reported to have parenchymal metastasis to the spleen, liver, and lung was associated with a previous diagnosis of “struma peritonei” that was surgically treated 12 years ago. This case highlights the insidious biologic behaviour of this clinical entity, which, despite its low malignant potential, has the tendency to recur and metastasize even years after initial surgery. In a percentage as high as 57.1%, the patients were asymptomatic and the finding was incidental. Symptoms, if present, mainly included abdominal and pelvic pain and bloating. In one case, the lesions involved facial bony structures and the symptoms included temporomandibular joint pain and facial swelling. In another case with vertebral involvement, the presenting symptom was lower back pain. Ascites were present in only three cases, accounting for 42.9% among the studies that provided relevant data.

4. Characteristics of the Lesions (Location, Size)

The mean size of ovarian lesions was estimated at 8.3 cm (range 2–15). The predominant location of the lesion was the ovary in 60% of the cases. In the remaining cases, the lesions were localized in the peritoneum, the omentum, the uterus/uterine serosa, the para-aortic lymph nodes, the bowel serosa, and the epicardial lymph nodes. Extraperitoneal spread was encountered in 15% in the lungs, multiple facial bony structures, the heart, and the lumbar vertebrae.

5. Surgical Technique and Outcomes

Data concerning the surgical approach and the type of surgery are available for 17 patients. Surgery greatly varied from resection of the ovarian lesion to hysterectomy and bilateral salpingo-oophorectomy. Type of surgery included conservative management (fertility/uterine-sparing) in 35.3% (six patients), radical surgery (non-fertility/uterine-sparing) in 41.2% (seven patients), biopsies in 11.8% (two patients), and local excision after a previous history of total hysterectomy and bilateral salpingo-oophorectomy in 11.8% (two patients). Complete excision was reported in 88.3% of the cases. Mean age in the conservative surgical treatment group was 37.2 years (range 25–50), while in the radical treatment group it was 49.1 years (range 32–74). Omentectomy was performed for staging purposes in six (35.3%) and pelvic lymphadenectomy in four (23.5%) patients. In one case, lymphadenectomy was extended to the para-aortic lymph nodes. A minimally invasive approach (laparoscopy) was applied in 17.6% (3/17 patients) of the cases, and in one of them the approach was robotic-assisted. Dobi et al. described the involvement of the sigmoid colon by the disease, which was managed by rectosigmoid resection and anastomosis. In thiscase, optimal debulking included left salpingo-oophorectomy; peritoneal resection of the pelvic, paracolic, bladder, and subdiaphragmatic peritoneum; omentectomy; and appendectomy. Macroscopically enlarged peritoneal lymph nodes were also removed. The final pathologic report confirmed the presence of neoplastic tissue with focal stromal invasion in all specimens, apart from the lymph nodes and the appendix. Where relevant data were available, adjuvant therapy included thyroidectomy combined with radioactive iodine therapy in 62.5%% (10/16 cases), no additional therapy in 31.3% (5/16), and chemotherapy only in 6.25% (1 case treated with combination adriamycin 60 mg and farmorubicin 80 mg). The was one reported case with a previous history of thyroidectomy several years before the diagnosis of HDFCO. Another case described by Carey et al. had a diagnosis of concurrent thyroid carcinoma (well-differentiated papillary carcinoma), with maximal diameter of 0.5 cm, which was classified as stage PT1. The peritoneal lesions, however, were classified as HDFCO due to the distinctive histologic features and the unlikely possibility of metastasis from the thyroid carcinoma. Concerning the prognosis, in the total of 16 patients with reported relevant outcomes, 81.25% (13/16) of the patients did not present any signs of disease during the follow-up period, 12.5% (2/16) were alive with disease, and 6.25% (1/16) had a recurrence. The recurrence pertains to a patient incidentally diagnosed with the disease during laparotomy for cholecystectomy. The treatment included excision of peritoneal disease, paraortic lymphadenectomy followed by thyroidectomy and radioiodine therapy. Τhe patient had a previous history of surgically excised struma ovarii. The disease recurred 2.5 years after the surgical treatment and was managed with repeat radioiodine therapy. The patient was living with the disease when the study was published. In the subgroup of patients that did not receive any adjuvant therapy and were treated by surgery alone (four patients), no recurrences were reported. One patient received postoperative chemotherapy and had no evidence of disease during a follow-up period of 3 years. All cases but one were managed by radical surgical treatment.