|Ahead of print
Successful treatment of a patient with recurrent metastatic clear cell carcinoma of the uterine cervix
Su Jung Shim1, Nae Yoo Kim2, Ho Jung Lee3, Soo Jung Gong2
1 Department of Radiation Oncology, Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
2 Department of Internal Medicine, Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
3 Department of Pathology, Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
|Date of Submission||23-Jul-2020|
|Date of Decision||24-Jul-2020|
|Date of Acceptance||09-May-2021|
|Date of Web Publication||29-Jun-2022|
Soo Jung Gong,
Department of Internal Medicine, Eulji Medical Center, Eulji University School of Medicine, Seoul
Source of Support: None, Conflict of Interest: None
Clear cell carcinoma (CCC) of the uterine cervix is a rare gynecologic cancer that accounts for 4–9% of adenocarcinoma of the uterine cervix. Two types of uterine cervical CCCs are known: A type that is associated with in utero exposure to diethylstilbestrol (DES) and idiopathic type that is unrelated to DES exposure. Due to its rare incidence, the clinical behavior and pathological characteristics of CCCs are not fully described and treatment recommendations are not standardized. Moreover, only a few cases are reported on the recurrent metastatic CCCs and the results of various treatment trials are inconsistent. We present a case of successfully treated idiopathic metastatic CCC of the uterine cervix that recurred after concurrent chemoradiotherapy.
Keywords: Chemoradiotherapy, clear cell carcinoma, idiopathic, metastatic, recurrent
| » Introduction|| |
Clear cell carcinoma (CCC) of the uterine cervix is a rare gynecologic cancer and is generally associated with in utero exposure to diethylstilbestrol (DES), which had been commonly prescribed to prevent abortion in pregnancy. Since the ban on prescribing DES in the 1970s, the cases of CCC of the uterine cervix reported in the literature are mostly unrelated to DES exposure (idiopathic CCC)., Due to its rarity, the clinical behavior and pathological characteristics of CCCs are not fully described and treatment recommendations are not standardized. Moreover, only a few cases are reported on the recurrent metastatic CCCs and the results of various treatment trials are inconsistent. The treatment of these rare cancers is challenging.
We described a case of successfully treated idiopathic metastatic CCC of the uterine cervix that recurred after concurrent chemoradiotherapy.
| » Case Report|| |
A 58-year-old (gravida 4, para 3) postmenopausal woman was referred to our hospital for the evaluation of uterine cervical mass, which was detected on routine check-up. She had vaginal bleeding after papanicolaou smear and no underlying systemic disorders, such as hypertension, diabetes, or cardiac disease.
CCC was confirmed by histopathologic examination of cervical tissue obtained from uterine cervical punch biopsy [Figure 1]a. The patient denied any in utero exposure to DES. Abdominal magnetic resonance imaging (MRI) showed a 6-cm-sized exophytic mass in the uterine cervix, which extended to the upper third of the vagina. Parametrial invasion and multiple lymphadenopathy in paraaortic, aortocaval, retrocaval, presacral, and perirectal space were also revealed. Positron emission tomography–computed tomography (PET-CT) confirmed the MRI findings with no evidence of distant metastasis [Figure 2]a. International federation of gynecology and obstetrics stage IIB cervical cancer was diagnosed. The patient underwent concurrent chemoradiotherapy. External beam radiation was delivered to the whole pelvis and paraaortic region as an extended target field with a dose of 4,140 cGy/23 fraction using a four-field box technique. An external beam boost of 1,400 cGy/7 fractions to the enlarged lymph node and 2,400 cGy/12 fraction to the cervical mass were delivered using intensity modulated radiation therapy (IMRT). Weekly cisplatin (40 mg/m2) was administered concurrently with external radiation therapy for 7 weeks. Three months after treatment completion, MRI showed complete remission of the culprit lesions.
|Figure 1: Pathologic features of clear cell carcinoma of uterine cervix (a) and neck lymph node (b) showing tubulocystic and the focally solid growth pattern. The tubules are lined by large tumor cells with hyperchromatic nuclei project into the lumen forming hobnail appearance (H and E, 200×). In IHC stains, the tumor cells show only strong positivity in CK7 expression (c). Estrogen receptor (d), CD10 (e), and p63 expression (f) are negative (200×)|
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|Figure 2: PET-CT showed hypermetabolic uterine cervical mass and intraabdominal lymph nodes (a) and newly appeared metastatic lymph nodes in left cervical levels IV and VI, left supraclavicular, and left axillary areas (b) and disappeared metastatic lymph nodes (c)|
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One year after treatment, she had a palpable mass in left supraclavicular area. PET-CT showed hypermetabolic enlarged lymph nodes in left cervical levels IV and VI (maxSUV=6.3), left supraclavicular (maxSUV=20.2), and left axillar levels I and I/II (maxSUV=7.1) areas [Figure 2]b. Excisional biopsy was taken from the neck node and the histopathology revealed tubulocystic and focally solid growth pattern, and tubules are lined by large tumor cells with hyperchromatic nuclei projecting into the lumen forming a hobnail appearance [Figure 1]b. Also, in immunohistochemical stains, the tumor cells showed strong cytokeratin 7 (CK7) expression and negative estrogen receptor (ER), CD10, and p63 expression, suggestive of CCC [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f. She received systemic chemotherapy with paclitaxel (175 mg/m2) plus carboplatin (AUC 6) every 3-week schedule, but computed tomography (CT) scan showed increased lymph nodes in supraclavicular and axillary area. External beam radiation was delivered to the supraclavicular and axillary area to a dose of 6,000 cGy/20 fractions using IMRT. After treatment completion, there were still residual lesions on the neck and axillary area. She was treated with second line chemotherapy with VIP, etoposide (100 mg/m2, day 1–3), ifosfamide (1500 mg/m2, day 1–3), and cisplatin (75 mg/m2, day 2). After six cycles of VIP therapy, PET-CT showed no hypermetabolic lesions. Additional two cycles of VIP therapy were administered, and she has no evidence of disease after 2 years of follow-up [Figure 2]c.
| » Discussion|| |
Primary CCC of the uterine cervix is a very rare cancer and accounts for 4–9% of adenocarcinoma of the uterine cervix. An association between prenatal DES exposure and increased risk for vaginal and cervical CCC has been proposed in middle 1960s. DES was used during pregnancy since the 1950s in an attempt to prevent adverse pregnancy outcomes. In 1971, the significant association between in utero exposure to DES and development of vaginal and cervical CCC in adolescents and young women were revealed and DES was abandoned.
Over the 30 years after the discard of DES, DES-associated CCC of cervix is observed much less frequently than non-DES-associated CCC (idiopathic CCC). There are different biologic features between two types of tumor. Idiopathic CCC progresses more quickly and recurs earlier than DES-associated CCC.
Compared to the clearly two separated age peaks in the incidence in DES-exposed women, non-DES-exposed women have a single median peak incidence of 53 years. Our patient was 58 years old without history of in utero exposure to DES, which is compatible with idiopathic CCC.
Recently, International Endocervical Adenocarcinoma Criteria and Classification (IECC) was proposed due to a caveat of management of cervical adenocarcinoma with cell type-based histomorphological classification. IECC differentiated cervical adenocarcinoma into two groups, human papillomavirus-associated adenocarcinomas and non-HPV-associated (NHPVA) adenocarcinomas based on morphology such as luminal or floating mitoses and/or apoptotic bodies. Also, then NHPVA subtypes were subdivided based on existing morphological (cytoplasmic and architectural) criteria. Because of lower human papillomavirus (HPV) prevalence in CCC of the uterine cervix, we did not perform the test for HPV in this patient. Immunohistochemical stains for hepatocyte nuclear factor 1β and napsin A were not carried out due to several limitations. However, luminal or floating mitoses and/or apoptotic bodies were not found and based on microscopic findings and immunohistochemical study, we could diagnose CCC.
The early-stage CCC of the uterine cervix is known as a controllable disease. The overall 5-year survival rates were 86.1% in DES-associated type and 81.2% in idiopathic type. However, the clinical courses of advanced-stage CCC of the uterine cervix were still obscure. Only very limited data regarding the response to either chemotherapy or radiotherapy were reported from a few patients with stage IV CCC of the uterine cervix.
Meanwhile, for locally advanced uterine cervical cancer including CCC, concurrent chemoradiotherapy with platinum significantly improves survival rate compared to radiotherapy alone and is considered to be a standard therapy. Various chemotherapeutic drugs such as cisplatin, carboplatin, docetaxel, paclitaxel, topotecan, ifosfamide, gemcitabine, and bevacizumab are often used in recurrent or metastatic cervical cancer. We depicted various combination chemotherapies in cervical cancer [Table 1]. Lachiewicz et al. reported a successful treated case with long-term remission from radiotherapy followed by 109 courses of paclitaxel in locally advanced CCC.
|Table 1: Combination chemotherapy in recurrent or metastatic cervical cancera|
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In this case, she experienced recurrence with distant metastasis after 1-year complete remission and her lesions did not respond to concurrent chemoradiotherapy with paclitaxel and platinum chemotherapy. Although there are limited data in recurrent metastatic CCC, we applied second line chemotherapy with etoposide (V), ifosfamide (I), and cisplatin (P) (VIP). VIP protocol is a relatively intensive regimen and has been used in various cancers including testicular cancer, germ cell tumor, soft tissue sarcoma, and so on. Fortunately, in this patient, VIP protocol was tolerable and the result has been so far successful, and she was 2-year long-term complete remission.
In this rare case report, we described a successful management of recurrent metastatic CCC of the uterine cervix, so we suggested the VIP protocol for nonresponder to paclitaxel with cisplatin chemotherapy.
Declaration of patient consent
We obtained appropriate patient consent form. In the form the patient gave her consent for her images and other clinical information to be reported in the journal. The patient understood that her name and initial will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]