Multimodal management of primary intestinal type endocervical adenocarcinoma of cervix: a rare case report

Introduction

According to Global Cancer Statistics 2022, cervical cancer is the eighth most common cancer worldwide with an incidence of 661,021 cases (1). Globally, squamous cell carcinoma (SCC) is the most common histologic subtype of cervical cancer followed by endocervical adenocarcinoma (EAC), the later accounting for 10–25% of all histologic subtypes (2,3). The EAC is broadly divided into human papilloma virus (HPV) associated and HPV independent types. Intestinal type is a very rare variant of EAC that is associated with HPV.

Although SCC and EAC of cervix are different histologic variants, the first line of treatment is basically the same, i.e., concomittant radiochemotherapy followed by image-based intra-cavitary brachytherapy (ICBT). Gallardo-Alvarado et al. conducted a retrospective analysis on 1,291 patients with locally advanced cervical cancer of SCC (89.4%) and EAC (10.6%) histologic subtypes. They found that the 5-year disease-free survival (DFS) was better in SCC (70%) than EAC (62.2%) and the 5-year overall survival (OS) was also higher in SCC (74.3%) compared to EAC (60%). Thus, they opined that adenocarcinoma is a different clinical entity than SCC (4). However, EAC is a heterogeneous group of cervical cancer wherein more than 90% of cases are due to persistent HPV infections (5).

In this case report, we present the case details of localized invasive intestinal type EAC of cervix. Here, the patient was diagnosed as intestinal variant of EAC and was managed with concurrent chemoradiation followed by ICBT and complementary surgery for the residual disease. To the best of our knowledge, this is the third reported case of management of intestinal type EAC of cervix in the English literature and the first from India. We present this article in accordance with the CARE reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-24-28/rc).

Case presentation

A 34-year-old female with a history of 3 pregnancies and 3 living children presented with a history of bleeding per vaginum for 5 months. She had no history of fever, non-smoker with body mass index of 26.66 kg/m², fatigue or any other symptoms. She had no history of diabetes mellitus, hypertension, tuberculosis or episodes of similar history in the past. She had neither been screened for cervical cancer nor received any vaccination for it. There is no history of cancer in her family. On per speculum examination, there was a 5 cm × 5 cm proliferative growth seen replacing entire cervix that involved upper 2/3^rd of the vagina. On bimanual rectovaginal evaluation, both the lateral fornices were obliterated and bilateral parametria were felt indurated however, the rectal mucosa was free. There was no palpable cervical or inguinal lymphadenopathy. Biopsy was taken from the cervical lesion. The histopathology examination revealed pleomorphic tumor cells arranged in acinar and papillary configuration with moderate nuclear atypia, hyperchromatic irregular nucleus and prominent nucleoli with intestinal differentiation and thus was reported as adenocarcinoma (Figure 1A,1B). On Immuno-histochemistry evaluation, the malignant cells were positive for p16, carcino embryonic antigen (CEA), cytokeratin 7 (CK7) and casual-type homeobox 2 (CDX2) and negative for estrogen receptor (ER), CK20 and progesterone receptor (PR) and Ki-67 was 50–60% suggestive of intestinal type EAC (Figure 2A-2E). The intestinal type of EAC is different from the gastric type owing to p16 positivity. Whole body ¹⁸F-fluoro-deoxy glucose (FDG) positron emission tomography-computed tomography (PET-CT) scan showed focal increased FDG uptake in heterogeneously enhancing irregular necrotic soft tissue mass lesion of size 3.8 cm × 4.8 cm × 4.1 cm [standardized uptake value maximum (SUVmax) =9.2] involving cervix, proximal vagina and lower aspect of uterus suggestive of primary cervical malignancy (Figure 3A,3B). There was no pelvic wall involvement. No abnormal hypermetabolic abdominal or pelvic lymph nodes were noted. There was no evidence of abnormal metabolic activity in rest of the body. Thus, the diagnosis was confirmed to be localized EAC of cervix with intestinal differentiation. Finally, the patient was staged as International Federation of Obstetrics and Gynaecology (FIGO) stage IIB according to the recent staging by FIGO 2021 update (6).

Figure 1 Photomicrographs of hematoxylin and eosin stained sections showing (A) an infiltrating neoplasm composed of pleomorphic tumor cells arranged in acinar and papillary configuration with moderate nuclear atypia, hyperchromatic nucleus and prominent nucleoli (×400) and (B) intestinal metaplasia (×400).

Figure 2 Immunohistochemical staining of tumor cells showing (A) diffuse cytoplasmic positivity for CK7 (×200); (B) diffuse cytoplasmic or membrane positivity for CEA; (C) diffuse, strong nuclear and cytoplasmic block positivity for p16 (×200); (D) nuclear positivity in nearly all intestinal metaplastic cells for CDX2 (×200); (E) Ki-67 proliferative index 50–60% (×200). CDX2, casual-type homeobox 2; CEA, carcino embryonic antigen; CK7, cytokeratin 7.

Figure 3 ¹⁸F-FDG PET-CT scan showing in (A) sagittal view and (B) axial view—focal increased FDG uptake in heterogenously enhancing irregular necrotic lesion (white arrows) involving cervix, proximal vagina and lower aspect of uterus (yellow arrow). FDG, fluoro-deoxy glucose; PET-CT, positron emission tomography-computed tomography.

Radiotherapy

According to the multidisciplinary tumour board, the patient was planned for concomittant radiochemotherapy to a dose of 50.4 Gy in 28 fractions at 1.8 Gy per fraction in 5.3 weeks along with weekly Cisplatin at 40 mg/m² for 5 weeks. The patient was immobilised in a pelvic thermoplastic mask with knee rest. The CT simulation was done with CT slice thickness of 3 mm from xiphisternum to mid-thigh along with intravenous contrast. The target volumes were contoured as per PGI guidelines for delineation of clinical target volume for intact carcinoma cervix while various organs at risk (OARs) such as bladder, bowel bag, rectum and femoral heads were contoured as per pelvic normal tissue normal contouring guidelines (7,8). The external beam radiotherapy (EBRT) planning was done using Volumetric Modulated Arc Radiotherapy (VMAT) technique that covered 95% isodose to 100% of target volume, respecting the dose constraints to all the OARs (Figure 4A,4B). The treatment was delivered using 2 ARCs with 6 MV photon linear accelerator after daily cone beam CT for alignment of patient for radiotherapy. One week after completion of EBRT, she received ICBT to a dose of 28 Gy in 4 fractions weekly respecting the OARs dose constraints (Figure 4C). Three months’ post-completion of radiotherapy (including both EBRT + ICBT), a whole body ¹⁸F-FDG PET-CT scan was done for response assessment. It showed focal increased FDG uptake in irregular necrotic soft tissue lesion of size 2.2 cm × 2.8 cm × 2.1 cm (SUVmax =10.4) involving cervix and proximal vagina indicative of residual disease (Figure 5A,5B). This was confirmed as residual tumour cells on cervical biopsy.

Figure 4 Depicting the radiotherapy treatment plan of the patient. The 2 arcs of VMAT are shown in (A); dose volume histogram of the target and organs at risk in the VMAT plan in (B) and (A) based intra-cavitary brachytherapy plan in (C). VMAT, volumetric modulated arc therapy.

Figure 5 ¹⁸F-FDG PET-CT scan 3 months post-radiotherapy completion showing in (A) sagittal view and (B) axial view—focal increased FDG uptake in irregular necrotic lesion (white arrows) involving cervix, proximal vagina indicative of residual disease. FDG, fluoro-deoxy glucose; PET-CT, positron emission tomography-computed tomography.

Surgery

The case was again put in multi-disciplinary tumour board for discussion regarding further management. As there was residual disease post-radiochemotherapy, it was decided to treat the patient with complimentary surgery. The patient underwent radical hysterectomy after 12 weeks post-completion of concomittant radiochemotherapy. The per operative findings showed growth involving anterior lip of the cervix with induration extending upto upper 2/3^rd of vagina. There were no ascites and no deposits on liver surface or peritoneum. Uterus, ovaries and fallopian tubes appeared grossly normal with post-radiotherapy changes. Post-op histopathology report confirmed residual viable adenocarcinoma. The Timeline of treatment received by the patient in this case is depicted in Figure 6.

Figure 6 Depicting the time-line of treatment received by the patient. CCRT, concurrent chemoradiotherapy; ICBT, intra-cavitary brachytherapy; PET-CT, positron emission tomography-computed tomography.

Follow-up

The patient tolerated well the whole course of treatment with only grade 2 gastro-intestinal toxicity and grade 1 genito-urinary toxicity during the course of radiochemotherapy and she is now doing well 12 months’ post-treatment completion. During this period the patient has been followed up 3 monthly post-completion of all treatment for past 12 months with clinical examination which included per speculum, per-vaginal and per-rectal examinations without any significant complaints.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. There is no identifiable personal information of the patient in this article. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

EAC is a diverse group of cervical cancer wherein majority of cases are associated with high-risk HPV 16, 18, 45 infections while about 15% of cases are not (i.e., HPV independent). The 2004 World Health Organization (WHO) Classification system of cervical cancer was based on morphology of EAC, i.e., tumour architecture and intracytoplasmic mucin (9). Due to its various shortcomings such as poor reproducibility and lack of any clinical significance, 2014 WHO classification was replaced by the new International Endocervical Adenocarcinoma Criteria and Classification (IECC) System 2018 (10). The new IECC system has incorporated various parameters such as clinical information, HPV status, p16 expression and response to treatment that are of immense significance in the treatment decision making. Thus, the new IECC system for EAC formed the basis for the WHO 2020 Classification.

Broadly, IECC 2018/WHO 2020 classification has categorised EAC into HPV-associated and HPV-independent type. The histological features of intestinal variant of EAC are characterised by presence of goblet cells in >50% of cells in mucinous or usual background also seen in this case (9,11). It is HPV associated and on immunohistochemistry (IHC) it is positive for p16 and is negative for ER and PR as is seen in the current case (10). Majority (>80%) of cases are positive for CDX2 and CK20 positivity in >20% cases while in the present case, CDX2 was positive while CK20 was negative (12,13). Thus, taking into both histological and IHC status, this case is in accordance with all these features describing it as EAC intestinal type. This intestinal type is different from the gastric type. Based on immuno-histochemistry study, the gastric type is p16 negative, while the intestinal type is p16 positive as is seen in our case.

As intestinal type EAC is a very rare clinical entity and only few case reports are published worldwide in English literature as is depicted in (Table 1), there is no consensus guidelines in its management. Thus, treatment of such cases can be done by extrapolating the results of treated cases of EAC. When treated with EBRT alone, the OS was worse in locally advanced EAC as compared to SCC, while DFS and OS were better when treated with cisplatin based concurrent radiochemotherapy (15,16). Thus, the current case, being stage IIB, was treated with radical EBRT with concurrent weekly cisplatin-based chemotherapy that was followed by ICBT which is in accordance with treatment of EAC of cervix.

In a retrospective study by Nijhuis et al., 169 patients of cervical cancers were evaluated by gynaecological examination under anaesthesia 8 to 10 weeks after completion of treatment and cervical biopsy was taken from 111 patients, in which residual tumour cells were found in 21 (19%) of patients. The loco-regional control in above study was better in patients receiving complementary surgery as compared not receiving complementary surgery (17). Further, a meta-analysis by van Kol et al. highlights that in locally advanced cervical cancer post-radiochemotherapy, residual disease should be confirmed by biopsy and managed by complementary surgery in order to prevent unnecessary surgery and complications (18). Three months post-radiotherapy completion, as the current case was confirmed to have residual disease both radiologically by PET CT and histologically by biopsy, she underwent complementary surgery and is disease free for 12 months.

Conclusions

Intestinal type EAC of cervix with differentiation is a very rare entity of EAC that requires IHC testing for establishment of its diagnosis. There is no consensus guideline on its management owing to its rare nature. Thus, such cases are to be treated with radical EBRT with concurrent cisplatin-based chemotherapy followed by ICBT as is done in other cases of EAC. The follow up evaluation should be done under anesthesia and any suspicious residual disease should be confirmed on biopsy. In case of positive residual disease, such patients can undergo complementary surgery with the aim of achieving cure and improving survival.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-24-28/rc

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-24-28/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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