Ovarian SCT-NOS have not been studied across a large number of cases, except for Hayes and Scully’s investigation of 63 cases [1]. We searched PubMed, EBSCO, OVID, and Web of Science for cases of SCT-NOS in English with the search string ((“steroid cell tumor” OR “steroid cell neoplasm”) AND (ovary OR ovaries OR ovarian)) AND (“not otherwise specified” OR “nos”). A total of 329 articles were found, of which 129 were duplicates, 117 were irrelevant, 10 were non-English, and five contained incomplete information. These unmatched articles were excluded and 12 other case reports were added through references. Ultimately, we found 80 articles describing 95 cases of SCT-NOS. We excluded 39 of these cases due to lack of follow-up information or follow-up periods that were too short (less than 3 months), which left 56 cases (Table 3). We did not include the information from the 63 cases in Hayes and Scully’s article because details were lacking in each of these cases.
Table 3
Clinical features of 65 cases reported (This table can be insert between page 6 and page 7.)
Case | First author | Age (years) | Surgical procedure | Tumor diameter (cm) | Pathological features | Adjuvant therapy | Follow-up (months) |
Necrosis | Hemorrhage | Mitosis (≥ 2 per 10 HPF) | Nuclear atypia (grade Ⅱ/Ⅲ) |
1 | Haroon [9] | 3 | LSO | 7 | - | - | - | - | - | No recurrence (25) |
2 | Yoshimatsu [10] | 4 | RSO | 8 | + | + | + (3) | - | BEP×3 | No recurrence (7) |
3 | Qian [11] | 5 | RSO | 8 | - | - | - | - | - | No recurrence (60) |
4 | Gupta [12] | 5 | Tumor resection | NA | NA | NA | NA | NA | - | No recurrence (4) |
5 | Sawathiparnich [13] | 6 | LSO | 7 | + | - | + (2–5) | - | - | No recurrence (6) |
6 | Lee [14] | 8 | RO | 5 | - | - | - | - | - | No recurrence (16) |
7 | Bas [6] | 9 | HE, BSO | 2.5 | - | - | - | - | Glucocorticoid | No recurrence (52) |
8 | Yilmaz [4] | 13 | Tumor resection | 2.5 | - | - | - | - | - | No recurrence (6) |
9 | Schnuckle [15] | 14 | LSO | 3.2 | - | + | - | - | - | No recurrence (24) |
10 | Yokozawa [5] | 16 | Tumor resection | 4 | - | - | - | - | - | No recurrence (15) |
11 | Yuan [16] | 17 | Tumor resection | 8 | - | - | - | - | - | No recurrence (6) |
12 | Sielert [17] | 20 | RO | 5.5 | - | - | - | - | - | No recurrence (18) |
13 | Jiang [18] | 21 | HE, BSO, OE | L 20, R 15 | + | + | + (༞10) | + | PVB×4 | Continued and died (10) |
14 | Santo [19] | 21 | RSO | 11.5 | - | + | + (4) | - | - | No recurrence (43) |
15 | Zhang [20] | 21 | LSO, OE | 5.8 | - | - | - | - | - | No recurrence (3) |
16 | Matsukawa [21] | 22 | Tumor resection | 3 | - | - | - | - | - | No recurrence (60) |
17 | Arora [22] | 22 | HE, LSO | 2 | NA | NA | NA | NA | - | Recurred (108) |
18 | Jiang [18] | 23 | Tumor resection | 6 | No | - | - | - | - | No recurrence (36) |
19 | Wong [23] | 24 | RSO | 4.5 | - | - | - | - | - | No recurrence (9) |
20 | Haroon [9] | 26 | RSO | 4.5 | - | - | - | - | - | No recurrence (15) |
21 | Menghua [24] | 28 | LO | 2.5 | + | NA | Active cell growth | NA | - | Recurred (42), died (58) |
22 | Swain [25] | 28 | LSO | 5.9 | NA | NA | NA | NA | - | No recurrence (12) |
23 | Haroon [9] | 28 | HE, BSO | 3 & 2.5 | - | No | + (2) | - | - | No recurrence (49) |
24 | Li [26] | 29 | RSO | 6 | + | + | + | + | Docetaxel + Ne-daplatin ×8 | Recurred (18), died (24) |
25 | Tai [7] | 29 | RSO | 10 | - | + | - | - | - | No recurrence (24) |
26 | Alves [3] | 30 | Tumor resection | 2 | - | - | - | - | - | No recurrence (36) |
27 | Liu [27] | 30 | Tumor resection | 3 | - | - | - | - | - | No recurrence (12) |
28 | Haroon [9] | 32 | HE, BSO | 4 | - | - | - | - | - | No recurrence (71) |
29 | Chung [28] | 35 | HE, BSO, PLND, OE, AE | 4.9 | - | - | - | - | GnRHa ×6 | No recurrence (43) |
30 | Stephens [29] | 35 | RSO | 5 | NA | NA | - | NA | - | No recurrence (6) |
31 | Faten [8] | 36 | RO | 4.5 | - | - | - | - | - | No recurrence (12) |
32 | Haroon [9] | 37 | LSO | 7 | - | - | - | - | - | No recurrence (23) |
33 | Ben [30] | 39 | LSO | 3.4 | NA | NA | NA | NA | - | No recurrence (8) |
34 | Chen [31] | 40 | RSO | 6 | NA | NA | NA | NA | - | No recurrence (36) |
35 | Varras [32] | 40 | HE, BSO | 6.8 | - | - | - | - | - | No recurrence (18) |
36 | Haroon [9] | 43 | RSO | 10 | - | - | + (5) | + | - | Recurred (34) |
37 | Zang [33] | 46 | LSO | 12 | NA | NA | NA | - | - | No recurrence (12) |
38 | Kim [34] | 46 | HE, BSO, PLND, OE | 7.7 | NA | NA | NA | NA | - | Recurred (60) |
39 | Reedy [35] | 46 | HE, LSO, PLNS, OE | 3.6 | - | - | - | - | - | No recurrence (12) |
40 | Lee [36] | 47 | HE, BSO, OE | 11 | - | + | + (5) | + | BEP ×3 | No recurrence (24) |
41 | Wang [37] | 48 | HE, RSO, PLND, OE | 4 | - | - | - | + | - | No recurrence (6) |
42 | Nakasone [38] | 50 | HE, BSO, PLNS | 9 | - | - | NA | - | - | Recurred (70) |
43 | Haroon [9] | 50 | RSO | 7 | - | - | - | - | - | No recurrence (11) |
44 | Haroon [9] | 51 | HE, BSO, PLND, OE | 13 | + | + | + (8) | + | - | Recurred and died (8) |
45 | Chun [39] | 52 | LSO | 6 | - | - | + (5) | - | - | No recurrence (21) |
46 | Kim [40] | 52 | BSO, PLNS, OE | 7.5 | - | - | - | - | - | No recurrence (24) |
47 | Haroon [9] | 52 | LSO | 9 | - | - | + (4) | + | PVB ×4 & radioth-erapy | No recurrence (43) |
48 | Cooray [41] | 54 | HE, BSO | L 3, R 4 | - | - | - | - | - | No recurrence (12) |
49 | Faraj [42] | 55 | BO | 4.5 | NA | NA | NA | NA | - | No recurrence (12) |
50 | Layla [43] | 65 | BSO, TD | 7 | - | NA | + (2) | - | BEP ×6 | Continued (18) |
51 | Brewer [44] | 58 | HE, BSO, TD | 10 | NA | NA | + (9) | + | BEP ×2, GnRHa | Recurred (28) |
52 | Sedhom [45] | 67 | HE, BSO, TD | 9.8 | NA | + | + (22) | NA | - | Died after operati-on |
53 | Stephens [46] | 67 | HE, BSO | 1.2 | - | - | - | - | - | No recurrence (3) |
54 | Haroon [9] | 67 | BSO | 3.4 | - | - | - | - | - | No recurrence (27) |
55 | Singh [47] | 70 | RO | 5 | NA | NA | NA | NA | - | No recurrence (5) |
56 | Powell [48] | 93 | HE, BSO, sigmoid-ectomy, colostomy | 21 | + | NA | + | + | - | Recurred and multi metastasis (10) |
LSO: left salpingo-oophorectomy; RSO: right salpingo-oophorectomy; BSO: bilateral salpingo-oophorectomy; LO: left oophorectomy; RO: right oophorectomy; BO: bilateral oophorectomy; HE: hysterectomy; OE: omentectomy; PLND: pelvic lymph node dissection; PLNS: pelvic lymph node sampling; AE: appendectomy; TD: tumor debulking; NA: not available; BEP: bleomycin + etoposide + cisplatin; PVB: cisplatin + vincristine + bleomycin |
Of the 56 cases, the age span of SCT-NOS patients was 3–93 years (median, 33.5 years). Excessive weight gain and virilization features such as hirsutism, acne, baldness, hoarseness, clitoromegaly, along with elevated testosterone were common at any age. For patients of reproductive age, amenorrhea was persistent because of hormonal parasecretion. For premenarchal girls, isosexual precocious puberty and advanced growth affected most. In our cases, virilization manifestations such as hirsutism, acne, and amenorrhea, as well as excessive weight gain were also quite common due to testosterone elevation. Isosexual precocious puberty occurred in one nine-year-old patient from our set of cases, and presented as premature mammary development. Other less common manifestations such as hypertension, abdominal pain, vaginal bleeding, Cushing’s syndrome, and acanthosis nigricans were also reported in the cases analyzed in this study. The symptoms caused by SCT-NOS vanished within 1–16 months post-operation, among the cases with no recurrence. However, Yilmaz and Yokozawa discovered that some changes, including hoarseness, were irreversible even after hormone secretion abnormalities were corrected by tumor elimination [4, 5]. Whether grown adolescent height and weight were normalized could not be determined due to lack of follow-up data. A previous study by Bas reported that a 9-year-old SCT-NOS patient had coexistent congenital adrenal hyperplasia due to classic 11 beta-hydroxylase deficiency, and the patient had initial hypertension that progressed and showed hypertensive retinopathy 2 years post-operation [6]. Alves, Faten, and Tai each published cases involving infertility with follow-up periods of 36 months, 12 months, and 24 months, respectively; none of the cases reported successful pregnancy [3, 7, 8]. Data related to infertility were limited due to lack of long-term follow-up. Some menopausal cases exhibited elevated estradiol as well as low LH and FSH levels, which may have induced endometrial disease from persistent estradiol influence. In our cases, two postmenopausal patients also presented with endometrial adenocarcinoma. Although reproductive hormone levels corresponded with postmenopausal levels in both patients, one also experienced vaginal bleeding until age 65 year. It is suspicious that long-term, persistent estradiol stimulation resulted in vaginal bleeding symptoms, and this suggests the potential presence of STC-NOS along with induced endometrial adenocarcinoma.
Approximately 25–43% SCTs-NOS have malignant potential [1]. The previous study by Hayes and Scully pointed out five pathological features that were correlated with malignancy potential: 1) two or more mitotic fields per 10 high power fields (92% malignant); 2) necrosis (86% malignant); 3) tumor diameter ≥ 7 cm (78% malignant); 4) hemorrhage (77% malignant); and 5) grade II–III nuclear atypia (64% malignant) [1]. Among the 65 cases searched, with the exception of eight cases with missing pathological details, approximately half (28/57) presented with at least one malignant feature. Metastasis was observed in seven cases with primary operation, and at least two malignant pathological features were reported in six cases. Another case was reported according to only one feature. Two other cases showed capsule and vascular infiltration or vascular growth, respectively, and both presented with at least two features. In patients 40 years or younger, the rate of malignant pathological features was 44.83% (13/29), and the rate for patients over 40 years of age was 78.95% (15/19) (P˂0.05, χ2 test). Metastasis, infiltration, and vascular growth occurred in 10.34% (3/29) of the patients 40 years or younger and in 31.58% (6/19) of the patients over 40 (P˃0.05, χ2 test). It seems that SCTs-NOS in patients over the age of 40 are more likely to have malignant behavior. In our cases, a 68-year-old patient experienced hemorrhage and nuclear atypia grade Ⅱ–Ⅲ, and a 9-year-old patient presented with nuclear atypia grade Ⅱ–Ⅲ. The sample size was limited in this study, and larger scale clinical studies comparing different ages are still needed to provide more conclusive evidence.
Table 4
Clinical features, treatments, and outcomes of recurred or progressed cases
Case | Age (years) | Clinical features | Second therapy | Outcome (months)* |
13 | 21 | Virilization, amenorrhea, ascites, acanthosis nigricans, initial surgery delayed 4 years | PVB×4 | Continued and died (10) |
17 | 22 | Virilization, amenorrhea, with hereditary leiomyomatosis and renal cell carcinoma syndrome | RSO, RPLND | Not mentioned |
21 | 28 | Virilization, Cushing’s syndrome, hypertension, irregular menstruation | Metastatic lesions resection | Recurred (12), died (16) |
24 | 29 | Lower back and leg pain, normal reproductive hormone | Not mentioned | Died (6) |
38 | 46 | Ascites | Metastatic lesions resection, BEP | Tumor free (9) |
42 | 50 | Virilization | BEP×3, TP×8, chemotherapy invalid, GnRHa | No symptom (22 after first GnRHa) |
44 | 51 | Lower abdominal pain, vaginal spotting, anorexia | Not mentioned | Died |
51 | 58 | Virilization, pelvic discomfort | Increased dose of GnRHa | Not mentioned |
50 | 65 | Virilization, abdominal pain, ascites, bilateral lower limb edema | BEP×3 | Continued (18), lost to follow up |
56 | 93 | Virilization, abdominal pain, bilateral lower limb edema, aggressive and violent behavior | GnRHa & weekly paclitaxel for 1 month | Refused therapies and progressed |
*The interval time after recurrence or progress; PVB: cisplatin + vincristine + bleomycin; BEP: bleomycin + etoposide + cisplatin; TP: paclitaxel + carboplatin; RSO: right salpingo-oophorectomy; RPLND: right pelvic lymph node dissection. |
Disease recurrence or progression occurred in 10 cases (17.86%) (Table 4). The tumor-free interval ranged from 0–108 months, with a median time of 23 months. The age of recurrence ranged from 21–93 years, and none of patients younger than 20 years of age reported disease recurrence or progression. The recurrence rate was 11.43% (4/35) for patients aged 40 years or younger, 28.57% (6/21) for those older than 40 years. In the group above 40 years of age, malignant behavior and disease recurrence were more likely to happen. Ascites was a unique manifestation for this group and may serve as an indicator of recurrence following initial therapy. One case that recurred did not report any malignant pathological features, with the longest tumor-free interval of 9 years. Six cases displayed at least two malignant pathological features, whereas three cases displayed only one. The tumor-free interval increased considerably as the feature numbers decreased (Fig. 2).
The reported treatments for disease recurrence or progression in SCT-NOS were tumor excision operations, chemotherapy, and GnRHa therapy. Two recurrent cases received surgery alone, with one reporting 12 months tumor free and a survival time of 16 months. In two reported cases, tumor progression showed no response to chemotherapy alone. Another relapsed case did not respond to chemotherapy but recovered after shifting to GnRHa therapy, and remained tumor free for 22 months. This suggested that for relapsed SCT-NOS patients, GnRHa therapy may be an appropriate choice for adjuvant treatment. Brewer reported a case with aggravated symptoms as well as computed tomography (CT) showing enlarged lymph nodes and uronephrosis during chemotherapy alone after the primary operation; however, the symptoms faded, lymph nodes were diminished, and uronephrosis was improved after switching from chemotherapy to GnRHa. This again indicated an important role for GnRHa as an SCT-NOS adjuvant treatment.
Tumor resections alone were performed in eight patients over 40-years-old with no reported disease recurrence. Unilateral salpingo-oophorectomies or oophorectomies were performed in 20 patients over 40, and there were two reports of disease recurrence. These surgeries helped to preserve ovarian function and fertility for young patients with an occurrence rate of 7.14%, which was lower than the overall rate. As discussed above, the malignancy potential and occurrence appeared to be lower in people younger than 40 years and, therefore, surgeries that preserve fertility and ovarian function can be considered when obvious malignant features are absent.