Keywords
uterine cervical neoplasms - neoplasm metastasis - immunotherapy - neoplasm staging
- metastasectomy
Introduction
Cancer of the uterine cervix is the third most common gynecologic cancer diagnosis
and cause of death among them. Human papillomavirus (HPV) is pivotal in the development
of cervical neoplasm and is found in 99.7% of cervical cancers. The most prevalent
types are squamous cell carcinoma (70%) and adenocarcinoma (25%).[1] A number of serum markers have been investigated for their utility in assessing
prognosis, monitoring response to therapy, and detecting recurrence. The most common
are squamous cell carcinoma (SCC) antigen, tissue polypeptide antigen, carcinoembryonic
antigen (CEA), cancer antigen 125 (CA 125), and CYFRA 21-1.[2]
Cervical cancer spreads by direct, hematogenous, or lymphatic dissemination. The locations
most affected by direct metastasis are the uterine body, parametrium, vagina, peritoneal
cavity, or rectum. Rarely, there will be metastasis to the ovaries. Hematogenous dissemination
mainly affects the lungs and, secondarily, the liver and bones.[3]
The presentation of hematogenous metastatic disease is a poorer prognostic indicator
and is associated with higher mortality rates compared to lymphatic dissemination.[4] The management of cervical malignancy is directly related to the stage of the disease,
the patient's clinical condition and factors associated to the tumor.[5]
Still, the tumor mutational burden (TBM) studies have found that it is a potential
prognostic factor for worse survival in patients with cervical cancer treated with
definitive radiotherapy, thereby providing a rationale for treatment of TBM-high cervical
cancers with a combination of immune checkpoint inhibitors (ICIs) plus radiotherapy.[6]
Curative options for advanced stage disease are limited. Systemic therapy is the first
line of treatment for cervical cancer with the indication of platinum-based chemotherapy
associated with paclitaxel and bevacizumab. For patients with a positive PD-L1 biomarker,
there is also the option of platinum-based chemotherapy combined with oncology immunotherapy
with pembrolizumab, with or without bevacizumab, as it has a longer progression-free
survival and overall survival.[7]
This paper aims to report a case of liver metastasis due to cervical cancer and clarify
therapeutic updates regarding the combination of chemotherapy, immunotherapy, and
associated surgery. Based on the KEYNOTE-826 trial, the use of pembrolizumab combined
with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent,
or metastatic PD-L1 cervical cancer, was approved by the food and drug administration
(FDA) and the Brazilian health regulatory agency (ANVISA).[8] This case report was submitted to and approved by the Ethics Committee of the Universidade
de Passo Fundo under submission number 6.911.615.
Case Report
A female patient, 52-years-old, with a history of radical hysterectomy for a high-grade
squamous intraepithelial lesion in the cervix 10 years ago due to local recurrence
of previous conizations. After 3-years of the procedure, the patient developed dyspareunia,
with vaginal bleeding and lesion located in the vagina wall. A biopsy was performed,
which revealed squamous cell carcinoma in situ, which was followed by brachytherapy.
After 5 years, the patient evolved with edema in the lower limbs and signs of unilateral
ureteral obstruction, identifying retroperitoneal lymph node enlargement over the
iliac vessels and ureter. The patient underwent double J-stent placement and chemotherapy
(CT) with paclitaxel, carboplatin, and associated immunotherapy with pembrolizumab
for PD-L1 positive cervical neoplasm. At 1-year after the emergence of the symptoms
described, during oncological follow-up, despite being asymptomatic, the patient developed
changes in tomography ([Fig. 1]) and positron emission tomography computed tomography (PET-CT) ([Fig. 2]), which evidenced the presence of liver lesions and increased uptake of liver lesions
and also in portocaval lymph nodes, compatible with metastasis.
Fig. 1 The computed tomography scan with the presence of liver lesions in segments VI and
VII.
Fig. 2 The positron emission tomography-computed tomography scan with the presence of hyperuptake
of liver lesions in segments VI and VII.
The largest lesion was located between segments VI and VII, measuring 7.8 cm, and
another lesion was also identified in segment VII, measuring 4.7 cm. Right hepatectomy
([Fig. 3]) was performed followed by retroperitoneal lymphadenectomy. In pathology, the presence
of metastasis from squamous cell carcinoma, due to cervical cancer, was identified
in the liver, paracaval, and common bile duct lymph node samples. The patient remains
in outpatient care with no signs of active disease.
Fig. 3 Metastatic hepatic lesions due to malignant neoplasm of the uterine cervix. Liver
sample resulting from right hepatectomy for metastatic lesions originating from malignant
neoplasm of the uterine cervix.
Discussion
Although rare at initial diagnosis, metastatic disease will develop in 15 to 61% of
women with cervical cancer. In most cases, metastatic cervical cancer is not curable.
However, for some patients who present with recurrent disease in the pelvis or with
limited distant metastatic disease, surgical treatment is curative. Considering the
probability of developing metastasis, it is shown that liver metastasis is one of
the most common types of cervical cancer, occurring in around 33% of cases.[9]
Patients with metastatic cervical cancer usually have no symptoms or nonspecific complaints,
such as fatigue, nausea, or weight loss. However, they may present symptoms related
to the site of metastasis. For diagnosis, the PET scan is suggested to evaluate local
and distant disease. Those who present with isolated metastatic findings on imaging
studies should undergo a biopsy to prove metastatic disease.[10]
[11]
For women with recurrent, metastatic, or advanced cervical cancer, treatment consisting
of a combination of cisplatin, an angiogenesis inhibitor bevacizumab and an immune
checkpoint inhibitor is recommended. In the first-line setting, a combination of cisplatin
and paclitaxel is suggested. Due to the toxicity seen with combination chemotherapy,
carboplatin is a reasonable alternative to cisplatin. Chemotherapy combined with bevacizumab
has been shown to provide a significant improvement in overall survival compared to
chemotherapy alone.[12]
For patients with metastatic or recurrent cervical cancer who are not amenable to
localized curative therapies, the addition of atezolizumab or pembrolizumab is recommended.
For women who have progressed after first-line treatment and for patients who are
not candidates for combination chemotherapy, single-agent therapy is indicated. The
single most active agents are carboplatin, paclitaxel, topotecan, and tisotumab.[13]
In spite of atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent,
or recurrent cervical cancer resulting in an increase in progression-free survival
and overall survival, according to the BEATcc trial, it has not yet been approved
by regulatory agencies.[14]
Patients in FIGO 2014 stage III-IVA of cervical cancer, who have not undergone curative
surgery, radiation, or chemotherapy, were evaluated in the KEYNOTE-A18 study regarding
the combination of therapies containing cisplatin with pembrolizumab. The multicenter,
randomized, double-blind, placebo-controlled trial with 596 patients showed improved
outcomes when radiochemotherapy was combined with immunotherapy. For patients with
PD-L1 positive status, pembrolizumab is the biological agent of choice, whereas atezolizumab,
bevacizumab and chemotherapy with cisplatin can be used regardless of PD-L1 status.[15]
[16] And more recently, tisotumab was incorporated, which is a tissue factor-directed
antibody and microtubule inhibitor drug conjugate, an option for second- or third-line
therapy.[17]
It is important to highlight that the liver is one of the most affected organs by
metastasis, and the efficacy of resecting hepatic metastasis from colorectal origin
has been established. However, there is limited data on the treatment of noncolorectal
metastasis, such as the case described with a primary lesion originating in the cervix.
In the past, the presence of hepatic metastasis was considered a criterion of incurability
for gynecological neoplasms. Nevertheless, recent studies suggest that hepatectomy
combined with lymphadenectomy for metastasis from noncolorectal primary tumors improves
prognosis, especially in cases of primary tumors from the urogenital tract and gynecological
origins. Therefore, surgical treatment has been implemented for hepatic metastasis
from noncolorectal tumors, provided there is control of the primary lesion, as described
in this case. Finally, metastasectomy, when applied to selected cases, along with
treatment of the primary tumor, prolongs disease-free survival, as observed in the
described case.[18]
[19]
Regarding surgical approaches for treating hepatic metastasis, some studies provide
relevant data. In a comparative study between hepatectomies performed for metastasis
of colorectal and non-colorectal non-neuroendocrine origin, the authors found similarities
in surgical specifics such as type of hepatectomy and surgical duration, as well as
in survival rates, with a 50% survival rate at 3 years and 20% at 5 years.[20]
Additionally, Costa et al.[20] demonstrated that patients with colorectal origin metastasis had more hepatic recurrences,
whereas those without colorectal or neuroendocrine origins had higher rates of multiple
and systemic recurrences in comparison. The authors also emphasize the relevance of
hepatectomies as surgical treatment for metastatic cases, representing a technique
that ensures a good degree of success and significant survival when compared to chemotherapy
alone. Multivariate analysis by the authors also identified two important prognostic
factors for patients with hepatic metastasis: lymph node involvement and number of
lesions.
In another case report, Pais-Costa and Lupinacci[18] demonstrated hepatectomy performed on a 45-year-old patient with metastatic cervical
carcinoma, previously treated for the primary cancer with extended radical hysterectomy
with lymphadenectomy. Similar to the present report, the patient presented with hepatic
metastasis in segments VI and VII, undergoing right hepatectomy, with histopathological
analysis confirming squamous cell carcinoma. The authors highlight the potential for
improved prognosis with hepatectomies performed in cases of hepatic metastasis with
gynecological origin in patients without other comorbidities. The authors also note
the rarity of hepatic metastasis from cervical carcinoma, citing a study from 1998
which reported this condition in only 1.2% of cervical cancer patients over a 6-year
period.[18]
Furthermore, a retrospective analysis by Bacalbasa et al.[21] followed 15 patients who underwent hepatectomy due to hepatic metastasis from cervical
carcinoma, with the majority diagnosed with metachronous liver lesions. After their
analysis, the authors considered factors associated with better prognosis for those
with metachronous lesions: lower tumor differentiation grade, overall health status,
and absence of extrahepatic lesions. They also demonstrated that both major and minor
hepatectomies did not differ significantly in terms of outcomes, concluding that surgical
resection of hepatic metastasis can be highly beneficial, safe, and potentially providing
a better prognosis, especially in cases without extrahepatic involvement.[21]
Conclusion
In this case, we described a patient who underwent hepatic resection for disseminated
cervical cancer treated almost a decade ago. Staging this case as T2aN2pM1 according
to the 2018 FIGO classification categorizes it as stage IVB metastatic cervical cancer,
and the expected prognosis is a 0 to 15% survival rate at 5 years.[22] The indicated treatment was surgical resection and continuation of chemotherapy
combined with biological therapy using pembrolizumab, a drug recommended for PD-L1
positive cases. Recent trials also showed improved prognosis in patients with disseminated
cervical cancer, regardless of PD-L1 status, when Atezolizumab was combined with chemotherapy
with Cisplatin plus bevacizumab, or tisotumab, which was recently incorporated into
the treatment team for cervical cancer, increasing options and consequently survival.[14]
[17]
Bibliographical Record
Luís Gustavo Ramos Raupp Pereira, Luísa Motter Comarú, Micael Guzzon, Eduarda Alberti
Lopes Silva, Júlhia Spuldaro Rabuske, Larissa Roberta Negrão, Raíssa dos Santos Copatti,
Paulo Roberto Reichert. Metastatic Cervix Uterine Cancer and Therapeutics Updates:
A Case Report and Literature Review. Brazilian Journal of Oncology 2025; 21: s00441800925.
DOI: 10.1055/s-0044-1800925
