Misdiagnosis and fatal outcome of advanced cervical adenosquamous carcinoma in pregnancy: A case report

Abstract

BACKGROUND

The special physiological changes during pregnancy pose a huge challenge to the diagnosis of cervical cancer in pregnancy (CCIP). However, due to the poor prognosis of advanced-stage CCIP, there is currently no consensus or guideline for diagnosis and treatment.

CASE SUMMARY

In this case report, we presented the case of a 30-year-old woman at 30 weeks of gestation who presented with irregular vaginal bleeding and was admitted to a local hospital at 35 weeks of gestation with a sudden gush of fluid and underwent a C-section. During the surgery, a rotten fish-like solid mass in the lower segment of the posterior wall of the uterus was excised for biopsy. The patient was referred to our hospital because she experienced heavy vaginal bleeding 13 days after one chemotherapy session. The solid mass was initially misdiagnosed as uterine clear-cell carcinoma at local hospital but later confirmed as cervical adenosquamous carcinoma by a multidisciplinary team. Three months posttreatment, she succumbed to multiple tumor metastases. The infant was healthy at the latest 2-year follow-up.

CONCLUSION

Obstetricians should expand differential diagnoses when obstetric factors cannot explain symptoms of persistent vaginal bleeding during pregnancy. Atypical and insidious clinical presentations are often concealed by physiological changes during pregnancy, which may increase the difficulty of diagnosis and result in misdiagnosis.

Key Words: Cervical cancer; Pregnancy; Misdiagnosis; Adenosquamous carcinoma; Chemotherapy; Case report

Core Tip: Timely and precise diagnosis and management of advanced cervical cancer in pregnancy remain challenging, with limited reports available. We describe a case of advanced-stage cervical cancer initially misdiagnosed after cesarean section, leading to an adverse maternal outcome. Accurate pathological assessment and multidisciplinary collaboration are crucial for timely diagnosis and optimal management. This case highlights the importance of vigilance in diagnosis to improve maternal outcomes and prevent treatment delays.

INTRODUCTION

Cervical cancer in pregnancy (CCIP), also termed cervical cancer associated with pregnancy, is defined as a tumor present during pregnancy, puerperium, and 6 months postpartum[1]. CCIP is rare, with an incidence of 1.4-4.6 per 100000 pregnancies[2]. The clinical manifestations are atypical, easily confused with pregnancy-associated diseases, often concealed by physiological pregnancy changes, and easily misdiagnosed. Consensus and guidelines on the optional treatment of CCIP were established recently and are mainly based on limited data from a few cases and expert opinions[2]. Advanced-stage CCIP is an extremely rare but serious complication of pregnancy that is associated with adverse pregnancy outcomes such as maternal death.

The diagnosis and management of CCIP presented unique and multifactorial challenges compared with non-pregnant patients[3-5]. The reason lies in non-specific symptoms masked by pregnancy[3,4], hormone-induced cytologic and histologic alterations[2,3], and restricted use of diagnostic modalities[3]. Managing CCIP is exceptionally complex because clinicians must simultaneously consider maternal prognosis, fetal well-being, and ethical constraints[2]. Herein, we present a case of specific diagnostic pitfall, which was misdiagnosis and fatal outcome of advanced cervical adenosquamous carcinoma in pregnancy. By reporting this case, we aim to provide information for future clinicians to pursue the best oncological and obstetric outcomes and prevent treatment delays.

CASE PRESENTATION

Chief complaints

A 30-year-old female patient (gravida 1, para 1) was diagnosed with intrauterine pregnancy by ultrasonography at 7 gestational weeks. Intermittent spotting and pale pink excreta starting at 30 weeks of gestation.

History of present illness

The color Doppler ultrasonography examination during the first trimester, at 12 weeks of gestation, showed a myoma in the posterior wall of the uterus, measuring 3.7 cm × 3.1 cm × 3.1 cm. She received regular antenatal care and showed normal nuchal translucency, low risk on Down’s screening, and a normal oral glucose tolerance test result at a local hospital. At 23 weeks, color Doppler ultrasonography indicated a single viable fetus with no structural anomalies and normal amniotic fluid volume. The placenta was attached to the bottom of the uterus, and there was no abnormality in its appearance or location. At approximately 30 weeks, she experienced minor intermittent, irregular vaginal bleeding, accompanied by irregular abdominal tightness and firmness at night. During a routine prenatal visit at 32 weeks of gestation, a gynecologic pelvic examination revealed cervical hypertrophy, cervical ectropion, and cervical contact bleeding. Routine laboratory examinations showed no major abnormalities. Routine color Doppler ultrasonography examination showed that the fetus was well developed, but the myoma at the uterine posterior wall near the cervix had grown to approximately 6.1 cm × 5.0 cm, for which a local doctor recommended observation and rest. The patient presented at 35 weeks of gestation with a sudden gush of fluid, redness, and no uterine contractions and was hospitalized with a diagnosis of preterm premature rupture of membranes (PPROM) with a Bishop score of 3 points. The patient did not experience onset of labor after PPROM; oxytocin was administered for labor induction, and cefoxitin was administered to prevent maternal and neonatal infections. A cesarean section was performed 72 hours later because the patient’s cervix did not show effacement or dilation. A healthy infant, weighing 2050 g, was born with 1-minute, 5-minute, and 10-minute Apgar scores of 10, 10, and 10, respectively, and an umbilical arterial pH of 7.201. During the caesarean surgery, a rotten fish-like solid mass with a diameter of approximately 6 cm was observed in the lower segment of the posterior wall of the uterus that had reached the internal cervical orifice, with unclear boundaries and irregular morphology. After obtaining informed consent from the patient and her family, the solid mass tissue was collected for biopsy.

History of past illness

The patient had a pre-pregnancy examination 11 months prior to this pregnancy. ThinPrep cytologic test (TCT) and human papillomavirus (HPV) test results were negative. Transvaginal Ultrasonography revealed that the intramural uterine myoma was approximately 1.5 cm in diameter and located in the inferior-posterior wall of the uterus (Figure 1A).

Figure 1 Transvaginal ultrasound images and enhanced computed tomography of the tumor and metastases. A and B: The intramural uterine myoma located in the inferior-posterior wall of the uterus (A) 11 months before this pregnancy and (B) 13 days after chemotherapy (black arrow: The intramural uterine myoma); C: An uneven and weak-echo mass in the inferior uterine segment and cervical canal that invaded the entire layer of the muscle wall (black arrow: Tumor infiltration in the cervix ); D-F: Enhanced computed tomography of the tumor and metastases; yellow arrow: Tumor infiltration in the cervix and uterine cavity; black arrow: Tumor infiltration in the bilateral obturator lymph nodes; blue arrow: Tumor metastasis to subcutaneous tissue of the scar area of the abdominal wall; white arrow: Tumor metastasis to para-aortic lymph nodes; orange arrow: Tumor metastasis to spleen.

Personal and family history

Her menstrual, surgical, and family history was unremarkable.

Physical examination

One month after a cesarean section, when the patient developed a large amount of vaginal discharge after receiving chemotherapy at a local hospital, a gynecological oncologist from our hospital performed a thorough physical examination. Visual inspection revealed a barrel-shaped cervix. A gynecological pelvic examination revealed that the uterus was significantly enlarged, tumors invaded the fornix, and the parametrial tissue was thickened and hardened.

Laboratory examinations

After delivery, serum tumor marker tests were performed, and the results revealed that the level of cancer antigen (CA) 125 was 244.5 U/mL and that of CA199 was 444.1 U/mL, while squamous cell carcinoma antigen, human chorionic gonadotropin (hCG), carcinoembryonic antigen, alfa fetoprotein (AFP), and CA15-3 were negative.

Imaging examinations

Transvaginal ultrasonography revealed the intramural uterine myoma have not changed (Figure 1B), and an uneven, weak-echo mass of approximately 5 cm in diameter in the inferior uterine segment and cervical canal that invaded the entire layer of the muscle wall (Figure 1C). An enhanced computed tomography (CT) scan revealed the presence of a large mass, measuring 5.2 cm × 5.6 cm × 2.6 cm, located in the cervix and middle and lower uterine cavity (Figure 1D). The tumor involved the upper one-third of the vagina and the entire myometrium and broke through the uterine serous layer. Both the pelvic and para-aortic lymph nodes showed metastases. Meanwhile, the tumor metastasized to paracolic sulci, subcutaneous tissue of the scar area of the abdominal wall, spleen, and left subclavian lymph nodes (Figure 1E and F).

MULTIDISCIPLINARY EXPERT CONSULTATION

A multidisciplinary team (MDT) consisting of specialists in gynecology, pathology, oncology, maternal-fetal medicine, radiology, ultrasonography, and palliative care convened to discuss this case. The patient was diagnosed with stage IIIC cancer, according to the International Federation of Gynecology and Obstetrics (FIGO) (2018) classification system. Concurrent chemoradiotherapy was recommended, and surgery was ruled out.

FINAL DIAGNOSIS

Histological examination revealed that the tumor was an adenosquamous carcinoma of cervix rather than uterine clear-cell carcinoma (CCC) that had invaded the uterine wall, and the carcinoma thrombus had permeated the muscular wall vessel by expert pathologists at our hospital. Glycogen-rich adenosquamous carcinoma can exhibit clear or vacuolated cytoplasm on hematoxylin–eosin staining due to glycogen depletion, closely resembling the “clear-cell” morphology of CCC (Figure 2A-C). Extensive pathological examination of the placenta and umbilical cord revealed no metastasis of maternal malignancy. Immunohistochemical (IHC) staining demonstrated that the tumor cells were positive for hepatocyte nuclear factor (HNF)-1β, epithelial membrane antigen, p16, cytokeratin (CK) 7, vimentin, CK18, β-catenin, CK5/6, insulin-like growth factor-II mRNA-binding protein 3, CA125, and a mutant-type P53 immunostaining pattern, and all tumor cells were negative for estrogen receptor, progesterone receptor, GATA binding protein 3, AFP, α-inhibin, P63, sall-like protein 4, placental alkaline phosphatase, Lin-28 homologue A, human placental lactogen, hCG, CD146, CK20, Wilms tumor protein-1, and NapsinA (Figure 2D-I); the Ki67 proliferative index was approximately 90%. The tumor had a positive DNA result for HPV16.

Figure 2 Histopathological and immunohistochemical results of the rotten fish-like solid mass. A: The typical “carcinomatous nest” structure of adenosquamous cell carcinoma of the cervix was not observed [hematoxylin-eosin (HE), × 200]; B: Glycogen-rich tumor cells are dehydrated to form similar clear cells (HE, × 100); C: The carcinoma thrombus infiltrated the uterine wall vessel (HE, × 200); D-I: The representative immunohistochemical of tumor cells was positive for (D) HNF-1β, (E) P16, (F) cytokeratin (CK) 7, and (G) CK5/6 and negative for (H) estrogen receptor and (I) progesterone receptor (immunohistochemical, × 100 magnification).

TREATMENT

Postoperative pathologic examination revealed CCC of the solid mass in the uterine intramural cavity, and the patient was readmitted to the local hospital 1 month after the cesarean section for chemotherapy with intravenous paclitaxel and carboplatin. The patient was admitted to our hospital with massive and consistent active vaginal bleeding 13 days after chemotherapy. She received multiple blood transfusions for severe anemia. Bilateral uterine artery embolization was performed immediately, which eventually stopped the profuse vaginal bleeding.

OUTCOME AND FOLLOW-UP

The patient exhibited symptoms such as persistent high fever and general pain. Her general condition rapidly deteriorated, and she was unable to withstand subsequent treatments. The tumor marker levels were progressively elevated, and abnormal signals on enhanced CT examination was detected in multiple locations, including the intrapelvic and bilateral paracolic vessels, paracolic sulci, subcutaneous tissue of the scar area of the abdominal wall, spleen, and left subclavian lymph nodes, suggesting metastasis. Unfortunately, 3 months after treatment, the patient succumbed to multiple distant tumor metastases, leading to severe infection and systemic multiple organ failure. Despite this tragic outcome, the infant was discharged in a healthy condition. The infant underwent a 2-year follow-up and is currently in good health without any complications or tumor metastasis.

DISCUSSION

The clinical manifestations of CCIP are atypical, easily confused with pregnancy-related diseases, easily concealed by pregnancy status, and difficult to diagnose. Pregnant women often neglect prenatal examinations, which makes tumor detection difficult[3]. The early stages of cervical cancer are asymptomatic. Vaginal bleeding is the main complaint, which might often be mistaken for potential miscarriage or misdiagnosed as premature labor or placenta previa when the patient visits the clinic in mid or late pregnancy[4]. Physiological changes during pregnancy can delay the proper investigation of an underlying neoplasm[6]. In the present case, the patient experienced minor irregular vaginal bleeding at 30 weeks of gestation. The local obstetrician thought that this was a normal physiologic change during pregnancy and did not perform further examinations, such as magnetic resonance imaging, TCT and HPV test, colposcopy, or biopsy.

An accurate pelvic examination, including speculum and bimanual examination, is necessary, regardless of the gestational age. The cervical size, shape, and consistency were assessed during the bimanual examination. In the presence of pregnancy symptoms that cannot be explained by obstetric causes (e.g., irregular vaginal bleeding), the differential diagnosis should be expanded to consider the possibility of a cervical neoplasm. Biopsies performed during colposcopic examinations are considered safe for the fetus in all trimesters and reliable for diagnosis[7]. Therefore, obstetricians should pay close attention to vaginal bleeding and discharge during pregnancy and perform vaginal examinations promptly to avoid delays in diagnosis and treatment. When indicated, liquid-based cytology examination and colposcopy are performed as routine examinations for diagnosing pre-invasive lesions during pregnancy. If early cytology or colposcopy results are unsatisfactory, these can be repeated during the third trimester of pregnancy.

However, the diagnosis of gynecologic malignancies during pregnancy is very difficult and depends mainly on pathologic examinations. The misdiagnosis in this case resulted primarily from overlapping histomorphologic and immunophenotypic features between glycogen-rich SCC and CCC, compounded by pregnancy-related cellular alterations. Glycogen-rich SCC can exhibit clear or vacuolated cytoplasm on hematoxylin–eosin staining due to glycogen depletion, closely resembling the “clear-cell” typical morphology of CCC. However, true CCC usually shows hobnail cells, tubulocystic and papillary architecture, and frequent hyalinized stromal cores, whereas glycogen-rich SCC lacks these structural hallmarks and shows intercellular bridges and focal keratinization. In our case, limited sampling and tumor heterogeneity led to the absence of these hallmark features. CCC typically shows HNF-1β (+), Napsin A (+), p16(–), and diffuse p53 aberration; in contrast, adenosquamous carcinoma demonstrates strong p16(+), p53 wild-type pattern, and high Ki-67 (> 80%), consistent with HPV-driven cervical carcinoma. Our specimen exhibited p16 positivity, p53 wild-type staining, high Ki-67, and HPV16 DNA positivity, supporting a diagnosis of cervical rather than endometrial origin. The focal HNF-1β positivity likely reflected nonspecific expression in adenosquamous differentiation rather than a true Müllerian-type CCC phenotype[8].

Under the influence of high estrogen and progesterone levels during pregnancy, morphologic changes in tumor cells are often atypical. Pregnancy has various effects on benign conditions that may mimic malignancies, presenting challenges in the diagnosis of the pathologic types of malignant tumors[9]. During pregnancy, the increase of estrogen and progesterone leads to the displacement of the squamous column junction, glandular hyperplasia, basal-cell proliferation, and the enlargement and irregularity of the cell nucleus, making it easy for cytological examination to misdiagnose it as high-grade squamous intraepithelial lesion or invasive carcinoma. The Arias-Stella reaction of the endocervical glands may present as enlarged irregular cells with hyperchromatic nuclei, mimicking cervical adenocarcinoma in situ or CCC[10]. Meanwhile, Arias-Stella reaction, decidual-like changes and trophoblastic reaction can produce "malignant" morphologies, increasing the difficulty of pathological diagnosis[10].

For pregnant women with advanced cervical cancer, as in this case, a unified treatment plan is currently lacking, and the principle of individualized treatment by a MDT should be followed[11]. When a large cervical mass is accidentally discovered during cesarean section, immediate frozen-section consultation and intraoperative communication among obstetrics, pathology, and gynecologic oncology are essential. If the initial pathology report appears clinically inconsistent, an automatic MDT review should be convened. Moreover, the members of the MDT must be senior experts with rich clinical experience. The process should involve re-evaluation of clinic presentation, slides, imaging, and tumor markers before initiating treatment.

Further treatment strategies are required according to the gestational stage at the time of diagnosis, tumor stage, histopathological type, fetal viability and growth, and the patient’s wishes concerning continuation vs termination of pregnancy, which need to consider both maternal and fetal conditions. Previous studies have reported that neoadjuvant chemotherapy (NACT) is the only strategy to preserve pregnancy and achieve fetal maturity in advanced stages of cervical cancer[4,12]. Radiation therapy is not routinely recommended during pregnancy because of potential risks, including spontaneous abortion, congenital malformations, and pediatric malignancies[13]. Satisfactory tumor responses in pregnant women with locally advanced cancer have been reported, with complete or partial response after NACT[14]. Chemotherapy during the second and third trimesters is considered relatively safe but recommended to be discontinued 3 weeks before the expected delivery date or after ≥ 35 weeks of gestation to reduce hematologic risk to the fetus[6,15]. If the pregnancy is ≥ 34 weeks and fetal lung maturity is expected: A cesarean section is planned as soon as possible, and a standard concurrent radiochemotherapy is initiated within 2 weeks to 4 weeks[2]. National Comprehensive Cancer Network guideline insighted that in non-pregnant patients, stage II–III–IVA cervical cancer is treated with definitive concurrent chemoradiation as the treatment of choice[16]. For a FIGO IIIC cervical cancer diagnosed at 35 weeks’ gestation with a near-term fetus, the preferred strategy is immediate delivery (usually cesarean section) followed by standard definitive chemoradiation, rather than NACT[17].

Patients with poor prognosis were reported to be more likely to have an advanced-stage disease at the time of diagnosis[18], possibly due to the increased metabolism in pregnancy, hyperdynamic circulation, rich uterine blood supply, increased estrogen-progesterone levels, and altered immunologic function[19]. To our knowledge, surgical extrusion may lead to tumor spread, which is closely related to the timing and surgical incision selection. These factors can accelerate the proliferation of tumor cells, which may metastasize through the pelvic lymph and blood circulation, as in this case. Therefore, more active management is needed for patients with CCIP to improve their prognosis.

Based on this case, we propose several recommendations. First, although cervical cancer was detected after cesarean section, it was present during pregnancy; therefore, more attention needs to be paid to the impact of physiological changes during pregnancy. Endometrial carcinoma is rarely associated with pregnancy because it is a state of naturally increased progesterone levels, which act protectively on the endometrium. Second, pathologists should focus on cell morphology and IHC marker results and carefully consider the medical history, clinical presentation, imaging, and serum tumor marker results, which are crucial for making an accurate pathologic diagnosis. Finally, highly experienced pathologists must decide who can examine and draw a conclusion from the film to reduce misdiagnoses.

CONCLUSION

The identification and management of CCIP remain challenging. This case serves to remind obstetricians of the necessity for a broad differential diagnosis when symptoms of abnormal vaginal bleeding are encountered that cannot be explained by obstetric factors. Owing to physiologic changes in pregnancy, the lack of typicality from laboratory testing to microscopic cytologic morphology greatly increases the difficulty of diagnosis. This case serves to remind pathologist that pathological diagnosis of pelvic masses in pregnancy must integrate clinical presentation, hormonal status, imaging findings, and IHC results. Glycogen-rich squamous carcinomas are prone to misclassification as CCC, and HPV status with p16 expression are critical discriminators. Management requires “a delicate balance between maternal benefit and fetal risk”, achieved through individualized, multidisciplinary decision-making. Implementing a mandatory, efficient MDT consultation mechanism is fundamental to preventing such tragic outcomes.

ACKNOWLEDGEMENTS

We thank the patient for participation and her family for facilitating the clinical reports preparation.