The incidence rate of triple or more synchronous primary neoplasms of the female genital system is exceedingly uncommon. To the best of our knowledge, only 13 such cases have been reported in the PubMed-indexed English literature. Herein, we report a single case of triple synchronous primary neoplasms of the cervix, endometrium, and left ovary with three distinct histological patterns that were not reported previously. Moreover, we briefly present a summary table of all the English PubMed-indexed cases of triple or more synchronous primary neoplasms of the female genital system (
Synchronous primary neoplasms are defined when two or more neoplasms take place concurrently in the same patient. These neoplasms should be histologically discrete and separated from each other by means of healthy tissues, such as basal lamina or stroma [
A 55-year-old multiparous woman was referred to our hospital as a case of pelvic/abdominal mass for 2 months. The mass was associated with progressive abdominal distention, left lower abdominal pain, and occasional vaginal bleeding. Her past medical and surgical histories were unremarkable. Upon pelvic examination, a cystic, mobile, nontender pelvic mass was palpated up to the umbilicus. There were no abnormal cervical growths. Laboratory findings showed a slightly elevated CA-125 level of 36.6 U/mL (normal range: 0–35 U/mL).
Two imaging studies were conducted: ultrasound (US) and computed tomography (CT) scan. US showed a 15 cm pelvic mass at the left adnexal site. The mass was cystic and contained solid areas. CT scan showed a heterogeneous 14 × 12 cm pelvic/abdominal mass with solid components, along with multiple prominent left pelvic and para-aortic lymph nodes that were highly suspicious for metastasis. The mass was seen between uterus and rectum. The mass was most likely originating from the left ovary and inseparable from the posterior uterus (Figure
Axial CT scan showing heterogeneous 14 × 12 cm pelvic-abdominal mass between uterus and rectum, most likely originating from the left ovary and inseparable from the posterior uterus.
The surgical staging operation consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, sampling from the pelvic lymph nodes and para-aortic lymph nodes, and multiple biopsy specimens from various peritoneal sites. During the laparotomy, the pelvic mass was found to be most likely originating from the left ovary. The uterus was bulky and the right ovary was grossly normal. There were no ascites or other gross intra-abdominal lesions. All resected specimens were examined for histopathological analysis.
Histopathological examination showed grade-I endometrioid adenocarcinoma of the uterus with no lymphovascular invasion and less than 50% invasion into the myometrium (Figure
Histopathological examination showing grade-I endometrioid adenocarcinoma of the uterus (H&E stain).
Histopathological examination showing clear-cell carcinoma of left ovary (H&E stain).
Histopathological examination showing poorly differentiated squamous cell carcinoma of the cervix (H&E stain).
Therefore, the final histopathological diagnosis was triple synchronous primary stage 1B1 poorly differentiated squamous cell carcinoma of the cervix (pTNM: T1B1 Nx M0), stage 1A grade-I endometrioid adenocarcinoma of the uterus (pTNM: T1A Nx M0), and stage 1A clear-cell carcinoma of the left ovary (pTNM: T1A Nx M0).
The case was discussed in the multidisciplinary tumor board meeting and the recommendation was to start adjuvant therapy. The adjuvant therapy consisted of chemotherapy and radiation therapy. The adjuvant chemotherapy was primarily intended for the high-risk ovarian cancer (clear-cell carcinoma) and included six cycles of paclitaxel 175 mg/m2 plus carboplatin (area under the curve [AUC] 6). The adjuvant radiation therapy was primarily intended for the high-risk cervical cancer (poorly differentiated squamous cell carcinoma) and consisted of external beam radiation therapy (EBRT) of 51 Gy delivered in 26 fractions.
The management plan was discussed with the patient; however, she refused the adjuvant treatment. Three months later, she presented to clinic with radiological evidence of recurrence, as follows: large local recurrence in the left iliac fossa, multiple metastatic masses in the abdominal and pelvic cavities, and multiple metastatic retroperitoneal and pelvic lymph nodes.
The incidence rate of double synchronous primary gynecological neoplasms is relatively uncommon and ranges from 0.6% to 5.4% [
A summary table of all existing cases of triple or more synchronous primary neoplasms of the female genital system (
Ref | Author | Year | Age (yr) | Presentation | Site | Tumor histology | Tx | FU (mon) | Outcome |
---|---|---|---|---|---|---|---|---|---|
Anorexia | Ovary | Papillary serous cystadenocarcinoma | |||||||
[ |
Matlock et al. | 1982 | 77 | Abdominal pain | Ovary | Mucinous cystadenocarcinoma | CT | 4 | DOD |
Weight loss | Uterus | papillary adenocarcinoma with psammoma bodies | |||||||
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NM | Ovary | Mucinous adenocarcinoma | |||||||
[ |
Ayhan et al. | 1992 | NM | Uterus | Endometrioid adenocarcinoma | NM | 28 | DOD | |
Cervix | Carcinoma in situ | ||||||||
|
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Vaginal bleeding | Ovary | Endometrioid adenocarcinoma | |||||||
[ |
Jobo et al. | 1997 | 35 | Uterus | Endometrioid adenocarcinoma | CT | 25 | NED | |
Cervix | Carcinoma in situ | ||||||||
|
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Vaginal bleeding | Ovary | Clear-cell carcinoma | |||||||
[ |
Ree et al. | 2003 | 46 | Ovary | Borderline mucinous cystadenoma | CT | 17 | NED | |
Uterus | Endometrioid adenocarcinoma | ||||||||
|
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Pelvic pain | Ovary | Mucinous adenocarcinoma | |||||||
[ |
Isin Dogan Ekici et al. | 2006 | 56 | Vaginal bleeding | Uterus | Endometrioid adenocarcinoma | CT | 24 | NED |
Uterus | Leiomyosarcoma | ||||||||
|
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Menorrhagia | Ovary | Mucinous adenocarcinoma | |||||||
[ |
Phupong et al. | 2007 | 50 | Ovary | Low malignant potential | RT | 3 | DOD | |
Uterus | Endometrioid adenocarcinoma | ||||||||
Cervix | Endocervical adenosquamous carcinoma | ||||||||
|
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Spotting | Ovary | Brenner tumor | |||||||
[ |
Pekin et al. | 2007 | 62 | Vaginal bleeding | Ovary | Granulosa tumor | NM | NM | NM |
Cervix | Squamous cell carcinoma | ||||||||
|
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Postmenopausal bleeding | Ovary | Mucinous adenocarcinoma | |||||||
[ |
Saglam et al. | 2008 | 63 | FT | Early papillary adenocarcinoma | CT | 12 | NED | |
Abdominal distention | Uterus | Endometrioid adenocarcinoma | |||||||
Cervix | Endocervical adenocarcinoma | ||||||||
|
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Pelvic pain | Ovary | Papillary serous adenocarcinoma | |||||||
Lower abdominal distention | FT | Microinvasive carcinoma in situ | |||||||
[ |
Atasever et al. | 2009 | 50 | FT | Microinvasive carcinoma in situ | CT | 29 | DOD | |
Uterus | Intraepithelial adenocarcinoma | ||||||||
Cervix | Endocervical in situ carcinoma | ||||||||
|
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Fatigue | Ovary | Mucinous, clear cell, and endometrioid carcinoma | |||||||
[ |
Hale et al. | 2011 | 49 | Ankle edema | Uterus | Endometrioid adenocarcinoma | NM | NM | NM |
Abdominal distention | Cervix | Endometrioid adenocarcinoma | |||||||
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Abdominal distention | Ovary | Leydig cell | |||||||
[ |
Zhang and Lerwill | 2011 | 79 | Abdominal pain | Uterus | Myxoid leiomyosarcoma | None | 10 | NED |
Dyspnea | Uterus | Mucinous adenocarcinoma | |||||||
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Metrorrhagia | Ovary | Serous adenocarcinoma | |||||||
[ |
Takatori et al. | 2014 | 50 | Uterus | Endometrioid adenocarcinoma | CT | 18 | NED | |
Cervix | Endometrioid adenocarcinoma | ||||||||
|
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Pelvic pain | Ovary | Mucinous adenocarcinoma | |||||||
[ |
Chiofalo et al. | 2016 | 38 | Vaginal bleeding | Uterus | Endometrioid adenocarcinoma | CT | 18 | NED |
Cervix | Mucinous adenocarcinoma | ||||||||
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Abdominal distention | Ovary | Clear-cell carcinoma | |||||||
Our case | 2017 | 55 | Abdominal pain | Uterus | Endometrioid adenocarcinoma | None | 3 | DP | |
Vaginal bleeding | Cervix | Poorly differentiated squamous cell carcinoma |
Ref: reference; yr: years; Tx: therapy; mon: months; CT: chemotherapy; RT: radiotherapy; NM: not mentioned; DOD: died of disease; NED: no evidence of disease; DP: disease progression.
The etiology of synchronous primary neoplasms of the female genital system remains poorly defined. It has been assumed that in genetically predisposed individuals, the Mullerian tissues with similar embryological origin may respond as a single structural entity when simultaneously exposed to carcinogenic, hormonal, therapeutic, or other triggering factors [
Several clinicopathological criteria have been suggested to assist clinicians and pathologists in distinguishing synchronous primary gynecological neoplasms from related metastatic foci. These criteria include either one major criterion or all the four minor criteria. The one major criterion is the existence of distinct histological types of the neoplasms. The four minor criteria include (a) neoplasms which are limited to primary locations, (b) absence of direct extension between neoplasms, (c) absence of lymphovascular neoplastic invasion, and (d) absence of distant metastasis [
It is critically crucial to differentiate between synchronous primary gynecological neoplasms and related metastatic diseases. This is because both management and prognosis vary substantially. Regarding prognosis, synchronous primary gynecological neoplasms are associated with better survival rates than metastatic or advanced primary ones [
There are no specific guidelines regarding the management of synchronous primary gynecological neoplasms. Proper management should be largely individualized taking into consideration several parameters, such as age of patient, disease type, disease stage, disease grade, and extent of the neoplastic invasion [
Clear-cell carcinoma (CCC) of the ovary is regarded as a grade III and high-risk neoplasm, irrespective of the disease stage. Also, CCC of the ovary is recognized to be less sensitive to first-line platinum-based chemotherapy [
Poorly differentiated squamous cell carcinoma of the cervix is regarded as a high-risk factor influencing the likelihood of recurrence. Hence, an adjuvant therapy may be recommended. The administration of concurrent cisplatin-based chemotherapy and radiation therapy (in the form of EBRT or brachytherapy) has been shown to substantially improve progression-free and overall survival for high-risk, early-stage patients with cervical cancer [
Although exceedingly uncommon, the likelihood of triple synchronous primary neoplasms should be considered when evaluating neoplasms of the female genital system. Careful pathological examination of the surgical specimens can substantially aid in recognizing such synchronous neoplasms.
The authors declare that they have no conflicts of interest.