RARE MALIGNANT FEMALE ADNEXAL TUMOR OF WOLFFIAN ORIGIN (FATWO) WITH MULTIPLE RELAPSES AND CHEMOTHERAPY REGIMENS

Abstract

Context

Female adnexal tumors of probable Wolffian origin (FATWO) represent very rare borderline ovarian tumors with low malignant potential. Only 15 cases of malignant FATWO are described in the current literature, among which, only 5 are reported as being recurrent.

Objective

Due to the rare presentation of the recurrence of the malignant FATWO and the few cases reported in the scientific database, there are no clear therapy recommendations. This paper should help practitioners to choose the best therapy approach.

Design

This paper presents the 6^th case of malignant recurrent FATWO and will compare all the cases available in the literature.

Subjects and Methods

We present a review of the literature comparing the therapeutic approaches and outcomes of all the five cases of recurrent malignant FATWOs. Also, we introduce the case of a stage III Wolffian origin adnexal tumor with multiple recurrences appeared after 6 years of disease free interval.

Results

Our case presents the longest survival reported in the literature and underwent most surgical procedures of the recurrences and more than 4 lines of chemotherapy regimens.

Conclusions

This paper shows possible therapeutic approaches to be used as example by the practitioners according to the drug availability in their centers.

INTRODUCTION

Female adnexal tumors of probable Wolffian origin (FATWO) represent genital tumors developing from the remnants of the mesonephric duct (1). These rare tumors generally appear as benign ovarian masses and less than 90 cases have been reported in the literature (1–3). According to the World Health Organization (WHO) Classification of Tumors they are considered as borderline tumors with low malignant potential (4–6). However, since 1973 when Kariminejad and Scully described the first case in the literature (7), few recurrent cases have been reported (6), mostly by metastasis to the liver and lungs (8) and there are only 15 cases of malignant FATWOs described (9).

General symptoms for an ovarian cancer have been described, therefore patients generally present with abdominal mass and pain, postmenopausal vaginal bleeding and urinary frequency (4,10). FATWOs present as unilateral tumors of solid or solid and cystic consistency, of a grey-white, tan or yellow color and their size ranges between 2–20 cm (4).

The histopathological pattern is represented by flattened cysts of variable size closely packed and solid spindled cells foci in a prominent and distinctive ‘sieve-like’ pattern, cuboidal, columnar or trabecular patterns comprised of well-formed hollow to solid tubules, diffuse solid patterns or variable combinations. Wolffian tumors may resemble to sexcord stromal tumors including Sertoli and Sertoli-Leydig cell tumors, but lacking the interglandular Leydig cells, to granulosa cell tumors and surface epithelial ovarian cancers, both serous and endometrioid carcinomas. Usually, the cells are bland and the mitotic rate is low (4). Adverse prognostic factors include large size, capsular invasion with rupture and tumor implants. Pathology features associated with malignant behavior include hypercellularity, cytological atypia, nuclear pleomorphism and increased mitotic activity (3,11,12). However, few tumors with minimal nuclear atypia and a very low mitotic rate have recurred (3,6,10,12).

Immunohistochemistry is important in defining the diagnosis of borderline tumor or poorly differentiated tumor. Most Wolffian tumors present a specific immunohistochemical pattern, positive for inhibin, calretinin, vimentin, CD10, cytokeratin, such as CK 7 and CK19, and the melanoma marker A103 (13). The presence of the hormonal receptors is variable, estrogen and progesterone receptors might be strongly expressed or absent (11). These tumors are exclusively negative for the EMA immunomarker (6) and mostly negative for the monoclonal ACE (10,14).

Although some Wolffian tumors are reported to be strongly immunopositive for c-Kit, the polymerase chain reaction amplification of c-Kit genes on exons 9, 11, 13 and 17 and of the PDGFR gene on exons 12 and 18 proved no mutations (15).

The aim of the current research is to expose the clinical and pathological presentation of a malignant recurrent FATWO tumor, to present a therapeutic approach of such a case in a tertiary oncology center in Romania, in order to expand the existing database and help practitioners implement as treatment protocol according to the drug availability in their countries. Finally, this paper intends to bring together the existing literature referring to a treated malignant recurrent FATWO and compare the treatment outcomes in terms of response of the disease.

MATERIALS AND METHODS

To exemplify an approach of a FATWO malignancy, we present the case of a 43 years old female diagnosed with a stage III Wolffian origin adnexal tumor with multiple recurrences. The institutional review board approved the use of anonymized patient data in support of this study and waived the need for additional ethical approval; we obtained the general institutional informed consent, both for therapies and diagnostic procedures and for the possible use of anonymized data in scientific reports.

Initially, in November 2010, the patient underwent total hysterectomy with unilateral resection of the right ovarian cyst. The pathology report describes a 7/4.5/2.5 nodular tumor with soft consistency and white-grey color situated in the left broad ligament. Spindled or epithelioid tumor cells and monomorphic nuclei were described. The mitotic rate was at 8 mitosis/10HPH. There was no capsular rupture and no necrosis (Fig. 1). This microscopic aspect corresponded to a Wolffian origin adnexal tumor with an uncertain malignant potential, considered a borderline ovarian tumor (4). Due to the uncertain malignant potential, it was considered that no further adjuvant therapy is needed and follow-up of the patient was proposed.

Figure 1.

Microscopic aspect of the Wolffian origin adnexal tumor with an uncertain malignant potential. A - Spindle cell tumor with solid distribution and highly cellular, 40x HE. B - Trabecular insular pattern with central spaces,100x HE.

Six years later, in April 2016 the positron emission tomography/computed tomography (PET/CT) with F18-fluorodeoxyglucose (F18-FDG) scan describes multiple oval lesions up to 50mm in dimension, with high F18-FDG uptake in the liver, highly suggestive for malignancy. In the retroperitoneal and pelvic regions, multiple nodes of 99/57/57mm with high metabolic activity were described. A high amount of ascites and peritoneal lesions were also described (Fig. 2). The PET/CT lesions described, along with the high values of the CA125 tumor marker of 420.5 U/mL, were highly suggestive for recurrence of the ovarian disease. During the same month, the patient undergoes surgery and both of the annexes were resected along with the omentum and the lymph nodes in the Douglas and subhepatic region. A residual mass still remained in the peritoneum as carcinomatosis nodes smaller than 1cm. The pathology report showed the recurrence of the previously described ovarian tumor. On the immunohistochemistry report, the tumor cells were positive for ER, CK19, CK7, calretinin, inhibin and negative for EMA (Fig. 3). In the adjuvant setting, six cycles of Carboplatin (AUC 5) of a total dose of 420mg every three weeks for 4 months were administered.

Figure 2.

F18-FDG PET/CT showing in axial view at pelvic region large ascites (A); axial view revealing high F18-FDG uptake in metastatic lymph nodes in retroperitoneal area (B); large multiple hepatic lesions with high uptake and left peritoneal lesion of carcinomatosis (C).

Figure 3.

Immunohistochemistry examination of the recurrent ovarian tumor, 400x: A - Ck19 positive, B - Ck7 positive, C - estrogen receptors strongly positive, D - EMA negative, E – calretinin positive, F- inhibin positive.

In September 2016 a magnetic resonance imaging (MRI) of the abdomen described right parauterine space replacement lesion of mixt structure, cystic and solid with maximum diameter of 86/25mm and left internal iliac lymph node of 5mm, but the CA125 tumor marker was within the normal range. Due to uncertain correlation of the biologic and imagistic investigations, in November 2016 a PET-scan was performed showing two retrovesical lesions with very different metabolic behavior, one of 46/30mm right from the rectum with cystic aspect without 18-fluorodeoxyglucose (18-FDG) caption and another lesion of 39/49/42mm with pathologic SUV lbm of 5.18.

In December 2016 the surgical excision of the lymph nodes was performed followed by the peritoneal diathermy. The pathology report of the surgical procedure shows rypT3cN1bLxV0 recurrence of the same primary adnexal tumor of Wolffian origin with a slightly different immunohistochemistry panel, PanCk AE1/AE3, EMA, Calretinin, Inhibin, WT1 positive and negative alpha-fetoprotein and vimentin. Considering the second recurrence setting, after the surgery, 6 cycles of adjuvant chemotherapy were given using the Paclitaxel and Carboplatin 5 area under the curve (AUC5) protocol between January and May 2017. In June 2017 the MRI of the abdomen showed another recurrence of the peritoneal masses and in September 2017 the optimal cytoreduction was performed with a pathology report that confirmed the relapse. Following the surgery 3 cycles of the Carboplatin (AUC5) and Etoposide 100mg regimen were administered from November 2017 to January 2018. In January 2018 the MRI of the abdomen showed again a relapse in the subcapsular hepatic region and in the peritoneal fat. In June 2018, the surgical excision of the masses described on the MRI was performed and chemotherapy in the Topotecan 1.2mg/m² total dose of 185mg regimen was given up to 4 cycles to the moment of loss of evidence of the patient.

RESULTS

Due to the very rare presentation of the recurrence of the malignant FATWO, only few cases have been reported in the literature (6,16,17) and no clear recommendations can be made regarding the therapeutic approach of the tumor. In order to obtain a clear diagnosis of the tumor, a specific immunostaining should be performed according to the WHO Classification of the Tumors (4).

Until this moment a clear recommendation for the primary treatment does not exist, still a complete abdominal resection of an ovarian malignant tumor should be made. However, because of the progress made in the field of gynecologic oncology, a primary objective in these cases is to improve the quality of life of patients. Therefore, the techniques for fertility preservation can be very important in the multidisciplinary decision, but it is required to be applied only in cases with good prognosis and a close follow-up protocol (18–20). This surgical therapy option should be discussed mostly when facing a borderline ovarian histology.

The need of adjuvant therapy following the complete resection of the tumor is not proved yet and neither is the efficacy of the palliative chemotherapy. In general, transformed ovarian cells may undergo an immunoediting process, become drug-resistant and escape first-line chemotherapy. The therapeutic efficacy of chemotherapy goes against differentiated cancer cells, whereas the high rate of recurrence is based on the remaining drug-resistant cells (21–23).

In case of recurrence of the disease, the polymerase chain reaction of the c-kit should be performed (2,9,15). Tumors that present the amplification of c-kit genes on exons 9, 11, 13 and 17 may benefit of Imatinib (17).

The PubMed database was screened for malignant FATWO cases and only 15 cases have been found. We have manually selected among the 14 malignant cases the ones that have presented recurrence and only five cases have been found (6,16,17,24). In Table 1, the five cases of recurrent malignant FATWO have been described, they all underwent complete tumor excision and total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by a disease free-survival interval during which follow-up was made. After the recurrence, surgical debulking of the tumor was made, if possible, followed by platinum based adjuvant chemotherapy, with very poor response. Among the studies included in the review, the best therapeutic response was obtained after the treatment with Imatinib for the c-kit positive tumors (Table 1).

Table 1.

Summary of five cases of recurrent malignant FATWO, describing the primary treatment, the site and time to recurrence, the second line of treatment and its final outcome

Study	Age	Primary treatment	Time to recurrence	Site of recurrence	Palliative treatment	Response to treatment
Ramirez, 2002 Case 1 (6)	38	Pelvic washings, lysis of adhesions, excision of pelvic mass, bilateral salpingo-oophorectomy, omentectomy, excision of perihepatic masses, and appendectomy	4 months	Liver, left upper quadrant, spleen, pelvis, subcutaneous on the right anterior abdominal wall	3 courses of carboplatinum (AUC 5) and paclitaxel (175 mg/m ) +1 dose of intra-muscular leuprolide (22.5 mg)	Progressive disease
Ramirez, 2002 Case 2 (6)	71	Exploratory laparotomy, omentectomy, and tumor reductive surgery	8 months	Left upper pelvis and the liver	No treatment	Stable disease
Qiu, 2017 (16)	53	Hysterectomy, bilateral oophorectomy, and resection of the left mesosalpinx tumor and omentum	2 years	Lower abdomen and pelvic cavity, left adrenal nodules, spleen, and bilateral pleural effusions	Resection of the pelvic masses and partial resection of the omentum. Cisplatin intraperitoneally 70 mg and 120 mg of docetaxel intravenously (10 days after surgery). Oxaliplatin intraperitoneally 150mg and 120 mg docetaxel intravenously (33 days after surgery)	Death due to post-surgical complications
Syriac, 2011 (17)	38	Resection of the mass on the broad ligament hysterectomy and bilateral salpingo-oophorectomy with lymphadenectomy and omentectomy	3 years	Left ovary	Hysterectomy and bilateral salpingo-oophorectomy with lymphadenectomy and omentectomy + 400 mg imatinib mesylate for 6 months	Complete response
Wakayama, 2017 (18)	37	Left salpingo-oophorectomy	15 months	Local and peritoneal recurrence	Total abdominal hysterectomy, right SO and extirpation of the disseminated tumors followed by Imatinib mesylate for 6 months   Paclitaxel and carboplatin for 10 cycles.	Complete response

The recurrent malignant presented case, reported the longest disease-free survival of 6 years and has reached the most lines of chemotherapy regimens among all the recurrent cases reported. Considering the poor response to the systemic therapy the primary treatment should be reconsidered to a more extensive approach and genetic markers and prognostic factors should be established as burdens for the adjuvant therapy indications.

Because of the small number of cases of recurrent metastatic FATWO tumors, there are no clear recommendations regarding the treatment options. Although, a recommendation of total abdominal hysterectomy with bilateral salpingo-oophorectomy for a primary FATWO could be made. Considering the heterogeneous aspect of the tumor and the variable manifestations of the disease a close monitoring of the patients is indicated. Due to the poor response to chemotherapy and radiotherapy of these tumors, a possible option of treatment for the recurrent disease could be the c-kit inhibitor for the c-kit positive lesions.

In conclusion, according to the aim of our paper, for a better therapeutic approach of the malignant recurrent FATWOs, their recurrence prevention and for a longer disease free survival or overall survival, all cases should be reported and published. Mutational observations should be made in order to determine any possible negative prognostic factors by which the need of adjuvant therapy to be established. Also, using the mutational and genetic profile of the tumors, new molecules could be developed and further studies should be performed in order to determine optimal therapeutic approaches. To our knowledge, the presented case reports the longest disease-free survival of 6 years and has reached the most lines of chemotherapy regimens among all the recurrent cases.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This research was supported by the grant “Knowledge transfer of biogenomics in oncology and related domains in clinical applications – BIOGENONCO” (MySMIS Code: 105774, contract no. 10/01.09.2016).