Molecular pathology and
clinical treatment of primaryserous
carcinoma of the uterine cervix: A case report Lina Niu1, Fangying Ruan2, Qisheng Yang2, Chaoran Xia2, Bifeng Zhang2,
Tao Xu3, Fei Dong4, Lizhen Zhang1, Sheng Guo1, Weiqin Lv1, Junxia
Wang1, Yun Shang1
1 Department of
Gynecology, Yuncheng Central
Hospital, Shanxi
Province, Yuncheng 044000,
China;
2
Zhejiang
Shaoxing Topgen Biomedical Technology CO.,LTD., Shanghai 201321,
China;
3 Department of Pathology,
Yuncheng Central Hospital, Shanxi
Province, Yuncheng 044000, China;
4 Department of medical imaging, Yuncheng Central Hospital, Shanxi
Province, Yuncheng 044000, China.
*Corresponding author
Name: Yun Shang
Postal address: Department of Gynecology, Yuncheng Central Hospital,
Shanxi Province, No. 3690 Hedong East Street, Salt Lake District ,
Yuncheng 044000, China
Tel: 13513599158 Fax: 0359-6396222 Email Address:
8634050@qq.comAbstract A
69 years old Chinese female patient presented with independent HPV
serous carcinoma uterine cervix. The genetic testing identified gene
variants of PAX8 and TP53, microsatellite instability stable, TMB
7.33Muts/Mb. The patient had a good response to Docetaxel, carboplatin,
and radiation with 18 months of free disease survival.Keywords: cancer of cervix, neoadjuvant chemotherapy, molecular
diagnostics.Running head: A case report of rare cervical carcinomaIntroductionSerous carcinoma of the uterine cervix (USCC) is classified as a rare
subtype of cervical adenocarcinoma, which has the same morphological
features as serous carcinoma of the ovary, the fallopian tubes, the
endometrium, and the
peritoneum1. It is a
challenge to diagnose primary USCC due to the limited number of
published reports. USCC was classified by World Health Organization
(WHO) Classification of Tumors-Female Genital Tumors in 2014 and
morphologically featured as complex papillary and/or micropapillary
structures2, whereas the
2020 WHO classification regrouped this
category3. The most
recent WHO classification (2020) focused on the association between HPV
infection and cervical
carcinoma4. Accordingly,
USCC was subdivided into HPV-associated and HPV-independent tumors. The
treatment guidelines of HPV-independent cervical adenocarcinoma have yet
to be established, possible due to lack of knowledge of its
pathology5.
In this report, we provided the
pathological diagnosis and detailed treatment of USCC (or
HPV-independent invasive adenocarcinomas uterine cervix) of a Chinese
female with 20 months free of disease
progression.Case statementA 69 years old Chinese female patient was admitted to Yuncheng Hospital
on October 23,2020 with five months of history of postmenopausal
bleeding and lower abdominal pain. In May 2020, she complained of
occasional vaginal bleeding which ceased spontaneously 4 to 5 days
later. Blood was occasionally spotted in stool, but not in urine. Her
last menstrual period occurred more than 14 years before.
The gynecological examination showed vulvar hypopigmentation, atrophy,
and smooth vagina. A small amount of dark red blood, and
cauliflower-like mass about 5 cm in diameter were observed in the front
lip of the uterine cervix. The uterine cervix is mobile with crispy
texture, atrophy shallow vaginal fornix. There was not palpable
abnormality in bilateral adnexal areas.
The color Doppler ultrasound of the pelvis showed that the cervix was
enlarged, the echo was unevenly reduced, and the size of tumor measured
as 5.7*4.0 cm. The first differential was cervical cancer. On October
19th, 2020, cervical cone biopsy was performed and pathology showed high
grade endometrioid glands lined by columnar cells with eosinophilic
cytoplasm and pseudostratified nuclei. Typical papillary and
micropapillary architectures and highly atypical nuclei were found
(Figure 1A,B). The immunohistochemistry results focally positive for PR
and ER, and positive for p16, p53, EMA and WT-1, withKi67 index of 70%
in the tumor tissue (Figure 2). However, the immunohistochemistry result
was negative for Vimentin, Napsin A, HNF1β and CEA. The HPV test was
also negative.
On October,2020, pelvic MRI showed an anteverted uterus, left deviation,
abnormalities of anterior and posterior lips, and an irregular mass with
a size of 3.0 × 5.0 × 4.1 cm (Figure 3A). The diffusion-weighted MRI was
mildly heterogenous increased. The fundus of the uterus was unevenly
thickened and the internal signal was heterogenous. The shape and signal
of bilateral appendages showed no obvious abnormality, and scattered
small lymph nodes were seen adjacent to the right iliac vessels. There
were scattered small lymph nodes adjacent to the right iliac vessels and
glandular glands at the bottom of the uterus (Figure 3A). Pathology
suggested the cervical tumor with FigoII A stage. Thus, our diagnosis
favored USCC (according to the 2014 WHO-the Female Genital Tumors
classification) or other adenocaricinoma of the uterine cervix, which is
HPV-independent and the diagnosis is made after exclusion of other
differentials (according to 2020 WHO-the Female Genital Tumors
classification).
In order to further study the molecular pathology and effective
treatment strategy, the patient was tested with NGS-based 603 panel gene
detection, and two variant PAX8 c.1230C>G (p.Tyr 410 Ter)
and TP53 c.740A>T (p.Asn247Ile) were discovered. The
microsatellite status of tumor was stable, the Tumor Mutation Burden
score was 7.33Muts/Mb, and the tumor neoantigen load was high.TreatmentThe patient was treated with 3 cycles of neoadjuvant chemotherapy with
docetaxel (100mg/3h/intravenous),
carboplatin(450mg/1h/intravenous) and thiopefilgrastim (6 mg
/injection). On December 25, 2020, pelvic MRI scan showed that the tumor
size was significantly reduced to about 2.5 × 1.9 × 3.0 cm (Figure 3B).
On January 20, 2021, radical hysterectomy was performed including
bilateral adenoxetomy, pelvic paraaortic lymph node dissection and
omentectomy. The pathological examination showed serous carcinoma of the
uterine cervix (Supplementary Figure 1D), the tumor has invaded into the
muscle layer of the vaginal fornix and the lower uterine segment.
Moreover, the H&E staining showed that the histology of bilateral
parametrium, endometrium, bilateral fallopian tubes and ovaries were
normal (Supplementary Figure 1 A,B,C). Adenomyosis or endometriosis was
not found, and lymph nodes were negative for malignancy. Postoperative
immunohistochemical results showed CDX-2(-), p53 (mutant), PAX-8(+),
SATB-2(-). After the operation, patient remained on chemoradiation
therapy for another3 cycles (docetaxel (100mg/3h, intravenous),
carboplatin (500mg/1h, intravenous), and25 cycles of intensity modulated
radiotherapy DT46Gy/2Gy/23f with concurrent cisplatin (450mg/1h). The
patient developed Grade IV myelosuppression (Supplementary Table 1).
After the treatment, the patient was followed up every three months. The
CT on August 3, 2022did not show evidence of recurrence (Supplementary
Figure 2).Discussion Primary cervical HPV-independent
invasive adenocarcinomas with serous-like is characterized by the
morphological features of complex papillary and/or micropapillary
structures with high-grade nuclear
atypia6. This report
provides a case of primary HPV-independent invasive adenocarcinoma of
the uterine cervix in a patient with the molecular analysis and the
patient was effectively treated and free of disease recurrence for 18
months as of now.
Immunohistochemistry (IHC) is very helpful in diagnosis and
classification of uterine cervical carcinomas7. IHC of p53 and p16
were positive in serous
carcinoma1,
8. WT-1 and estrogen receptor (ER) were
positive in serous carcinoma of the
ovary9, whereas USCC
showed weak or negative
expression10. In fact,
our case was positive for p16, p53, WT-1 (weakly) and ER (weakly). CEA
and Vimentin were sometimes positive in USCC. Napsin A and HNF-1β
arefrequently positive for clear carcinoma of the uterine cervix, ovary
and endometrium11. The
IHC were negative for Vimentin, Napsin A, HNF1 and
CEA biomarkers. In previous
reports, micro-satellite status and TMB status are rarely adopted in
uterine
serous carcinoma12. In
fact, the patient in this report had MSS and TMB of 7.33Muts/Mb, and
high tumor neoantigen load. Furthermore, two variant PAX8
c.1230C>G (p.Tyr 410 Ter) and TP53 c.740A>T
(p.Asn247Ile) were detected. To date, few studies have reported the
genetic features of HPV-negative serous carcinoma of the cervix. Jenkins
et al. recently reported that cervical serous carcinoma (n = 6,
HPV-negative) harbors mutations in TP53 (50%), KRAS (33%), PIK3CA
(17%), and PTEN (17%)13. Our case enriched the
molecular features of cervical serous carcinoma and helped to understand
the underlying molecular mechanisms.
Neoadjuvant chemotherapy was first used to treat cervical cancer in 1988
with a response rate 75.7% and since then it has gradually become a
treatment of this cancer in clinic14. In our study,
the patient showed good response to neoadjuvant chemotherapy free of
disease for 18 months as of now 2-3 cycles of neoadjuvant chemotherapy
were recommended for patients with stage IB3 or IIA2 uterine cervical
cancer, while in this study the clinician used 3 cycles of neoadjuvant
chemotherapy and 3 cycles of adjuvant chemoradiation therapy to treat
this rare type of carcinoma. Our treatment has showed longer
disease-free time. As of now, the patient does not have recurrence.
Cervical serous carcinoma is a very rare tumor with no reported
pathological and molecular profile. In this report, we elaborated
molecular features of a typical serous carcinoma and treatment strategy
maybe help form the best management and diagnosis methods in the near
future.Conflict of interest We declare that we do not have any commercial or associative interest
that represents a conflict of interest in connection with the work
submitted.Acknowledgements Not applicable.Funding No funding was received.Authors’ contributions Fangying Ruan and Qisheng Yang was responsible for the
conceptualization of the present study and writing the manuscript. Lina
Niu, Sheng Guo, Junxia Wang, Tao Xu, Fei Dong and Weiqin Lv acquired the
majority of the data, analyzed the data, performed literature research
and prepared the original draft. Lina Niu and Lizhen Zhang guided the
diagnosis and treatment of patients.Yun Shang, Chaoran Xia and Bifeng
Zhang were responsible for editing and performing critical review of the
manuscript. All authors read and approved the final manuscript for
publication.Ethics approval and consent to participate The study involving a human participant was reviewed and approved by
The Yuncheng Central Hospital, Shanxi, China. Written informed consent
was obtained from the patient and all procedures were conducted in
accordance with the Declaration of Helsinki.Patient consent for publication The patient provided consent for publication.Competing interests The authors declare that they have no competing interests.References 1. Kitade S, Ariyoshi K, Taguchi K,
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Figure 1. Histology of serous carcinoma of the uterine cervix shows
endometrioid gland lined by columnar cells with eosinophilic cytoplasm
and pseudostratified nuclei, H&E staining, ×100(A), X400(B).Figure 2. Immunohistochemistry was focally positive for PR, and
ER and positive for p16, WT-1, p53, and EMA with a Ki67 index of 70% in
the cervix carcinoma, (magnification: 100X).Figure 3. Responses to neoadjuvant chemotherapy treatment
assessed by MRI before (A) and after (B) 3 cycles of chemotherapy show
regression of the paracervical mass.Supplementary Figure 1. H&E stainingshows histology of
endometrium (A), ovary (B), fallopian tube(C)(40X), uterine cervix (D)
was abnormal tissue with serous carcinoma, (100x).Supplementary Figure 2. Computed tomography scan.
CT
scan,(A) lung window, demonstration, (B) mediastinal window, (C)
abdomen, (D) abdomen, (E) pelvic cavity, (F) pelvic bone window, (G)
chest lung window.Table Supplementary
Table 1. The blood parameter of patient during treatment