Peculiarities of the rare histopathological types of invasive cervical cancer – A three-year experience at a regional cancer institute

INTRODUCTION

According to Globocan 2020, over 6.5% of women all around the globe, with over 7,28,034 new cases each year in India alone, are affected by cervical carcinoma.^[1] Human Papillomavirus is an essential factor for the development of the majority of these cancers. The most common histological type is the squamous cell carcinomas (SCC) (70-80%), followed by adenocarcinoma (15-20%), which can be human papillomavirus (HPV)-associated or HPV-independent.^[2]

Approximately 5.5–11% of all cervical cancers are reported to be HPV-negative. Cervical SCCs are rarely HPV-negative and are mentioned only in case reports. For adenocarcinoma, the HPV negativity rate is approximately 15–38%.^[3]

Various screening tests and vaccines play a role as preventive measures against cervical cancer. Most of the preventive measures are aimed at the detection of HPV and the associated changes. Evidence pertaining to the rare types of invasive cervical cancers, their HPV association, and their management options are limited.

The rare types (5%) include the adenosquamous carcinoma, neuroendocrine carcinoma, glassy cell carcinoma, clear cell carcinoma, sarcoma, lymphoma, and melanoma of the cervix. They are a heterogeneous group, with morphologic and immunohistochemical overlap, and most of them have a glandular origin. They are aggressive tumors with a poor prognosis. In this descriptive study, we have listed the rare histotypes of invasive cervical cancer and their peculiarities, the knowledge of which might help in early detection and treatment.

MATERIAL AND METHODS

Rare histotypes of cervical invasive cancer, including neuroendocrine carcinoma, glassy cell carcinoma, clear cell carcinoma, sarcoma, lymphoma, and melanoma of the cervix that were encountered from Sept 2019 to Sept 2022 at our institute were retrospectively analyzed. The patient’s data files were reviewed from the Medical Records Department. Cases of squamous cell carcinomas, adenocarcinoma, usual type, and adenosquamous type were excluded.

RESULTS

Major pre- and peri - operative findings with management peculiarities are summarized in Tables 1 and 2.

A total of 12 patients were analyzed. The age group in our study ranged from 21 to 72 with a median age of 40 years. Seven rare histotypes that were encountered were adenosarcoma, basaloid cell carcinoma, clear cell carcinoma, leiomyosarcoma, lymphoma, malignant melanoma, and neuroendocrine carcinoma (NEC) of the cervix. Among these, the most common histologies were neuroendocrine tumors and malignant melanoma of the cervix at our center. Varied presentations ranged from amenorrhea to abnormal uterine bleeding and white discharge to per -rectal bleeding, but the most common complaint was post-menopausal bleeding. A characteristic examination finding of hyperpigmentation of the cervix was classically seen in all melanoma cases.

We did a computed tomography (CT) scan of the thorax, abdomen, and pelvis in all cases. Magnetic resonance imaging (MRI) Brain was done in cases of neuroendocrine tumors, as a positron emission tomography (PET) scan was unavailable at our center. A pre-operative accurate diagnosis was made in 83.33% cases (10 out of 12), except in Basaloid cell carcinoma, where the cervix was grossly normal, and High grade B cell lymphoma, where outside biopsy review showed a mesenchymal tumor. 2 cases of neuroendocrine histology received neoadjuvant chemotherapy (NACT) with three cycles of etoposide and cisplatin. Re-assessment CT scan showed complete resolution of the tumor. There were three patients in stage I, 3 in Stage II, 2 in stage III, and 4 in Stage IV tumors.

In 4 cases, type 3 radical hysterectomy with bilateral oophorectomy with pelvic lymph node dissection was done. In 5 of the cases, a Type 1 radical hysterectomy was done. 1 amongst them, the case of adenosarcoma of the cervix, done through a laparoscopic approach. Overall, the IHC of most of the histologies was overlapping. However, they were ancillary to the primary histological diagnosis. Only clear cell adenocarcinoma was distinctly HPV independent.B-cell lymphoma and basaloid cell type had high-risk factors positive on the final specimen.

Ten cases received adjuvant chemotherapy, except one case of clear cell (IB2 stage), and one case of NEC was lost to follow-up. 2 cases, one of Basaloid carcinoma and one of Neuroendocrine tumor, received multimodality treatment with post-operative chemotherapy and radiotherapy. All the cases have been followed up with a complete physical examination and pelvic ultrasound 3 months later. 6 of 12 mentioned cases are asymptomatic in follow-up.

DISCUSSION

Rare types of cervical histology constitute around 5%. They can be HPV or non-HPV-associated types. Overall, around 5-11% of cervical cancer cases are deemed to be HPV non-associated. Non-HPV-associated cervical cancer includes mainly adenocarcinoma subtypes such as clear cell, gastric, mesonephric, endometrioid, and serous types. This article is not an exhaustive list of the spectrum of rare cervical cancer histologies, but a descriptive analysis of the uncommon histologies encountered in our clinics and their management options.

Adenosarcomas comprise tumors with benign epithelial components and malignant stromal elements. The malignant stromal elements can either be homologous, such as fibroblasts or smooth muscle, or heterologous, like cartilage, striated muscle, or bone.^[4] Adenosarcomas of the cervix are very rare (<1%) compared to the incidence in other sites of the female reproductive tract and pelvis. Symptoms include abnormal vaginal bleeding, pelvic pain, or a mass. No standardized treatment protocols are available; considering its rarity, a combination of surgery and chemotherapy is advised. Local recurrences are not uncommon. The prognosis is worse if > 25% of the primary tumor has sarcomatous growth and the presence of heterologous elements.^[5]

Primary cervical lymphomas are rare extranodal tumors that account for 0.5-1% of cervical malignancies. They can be high grade or low grade. They resemble other cervical lesions in their presentation. Considering lymphoma as a differential diagnosis may be crucial while investigating, as prognosis and treatment differ entirely from other forms of cervical malignancies. A multimodal approach, including surgery, chemotherapy, and/or radiotherapy, is used for management, as standard therapeutic protocols are not available.^[6]

Neuroendocrine carcinomas of the cervix make up less than 3 % of all cervical cancers. Small cell carcinomas are a subtype of NEC. These tumors are highly aggressive and often diagnosed in advanced stages, and hence have a poor prognosis. A complete metastatic workup is needed. Treatment options often mimic those of small-cell lung cancer and include a combination of surgery, chemotherapy, and radiotherapy.^[7]

Malignant melanoma arising from the melanocytes of the cervix is extremely rare. It is the second most common type of female melanoma in women aged between 15 and 44 years worldwide. Symptoms like abnormal vaginal bleeding can occur. Hyperpigmented lesions are classic, whereas amelanotic melanoma is also a possibility. It has a poor prognosis, and recurrence rates are very high. Often diagnosed in a metastasized state, a thorough workup is mandatory prior to planning therapy. No standard consensus exists regarding the best treatment therapy. Nevertheless, surgery - radical hysterectomy and pelvic lymphadenectomy-remains the preferred treatment option. Lymph node metastasis is a poor prognostic indicator. Those who have undergone a non-radical hysterectomy should consider adjuvant therapy.^[8]

Clear cell type is a rare variant of adenocarcinoma, accounting for only 4% of all cervical carcinomas. The etiology and pathogenesis of clear cell carcinoma of the cervix are unclear. HPV likely does not play an etiologic role in clear cell carcinoma of the cervix. Cervical endometriosis, the use of the oral contraceptive pill, and HIV infection are the suspected etiological factors. Radical hysterectomy and pelvic lymphadenectomy constitute standard surgical treatment for patients with early-stage cervical carcinoma, international federation of gynecology and obstetrics (FIGO) stage IB or IIA. External beam radiotherapy is the standard of care for locally advanced cases. Some report equivalent outcomes with conventional cervical adenocarcinoma, whereas others report it as more aggressive. High-risk factors for recurrence include positive parametrial extension, positive pelvic lymph nodes, and positive vaginal margins. In patients with these high-risk factors, chemoradiation is the postoperative adjuvant treatment of choice.^[9]

Basaloid squamous cell carcinoma is an uncommon tumor, and there are only a few cases in the medical literature. It is characterized by an ulcerated, infiltrating growth pattern and poor clinical outcome. Only six cases of squamous basaloid cervical cancer have been described yet. Due to the rare occurrence and lack of good knowledge of its biology, it is difficult to define the prognosis and optimal treatment.^[10]

Leiomyosarcoma of the cervix is extremely rare; management of cervical leiomyosarcoma (LMS) is extrapolated from management for uterine LMS. It accounts for 1% of overall tumors of the cervix. Diagnosis is made on the basis of histopathological findings and immunohistochemical analysis. The treatment of choice is a triple therapy comprising surgery, chemotherapy, and radiation therapy.^[11]

CONCLUSION

Rare histopathological variants of cervical cancer are heterogeneous tumors with overlapping morphology, frequent diagnostic uncertainty, and limited evidence-based treatment options. Immunohistochemistry aids in refining diagnosis, but clinical suspicion remains vital in atypical presentations.HPV independent cervical cancers seem to have a poorer prognosis.

These histologies have variable prognostic and therapeutic considerations; hence, high suspicion in case of atypical presentation is required. Overtreating these tumors seems a sensible approach. Collaborative multicenter studies and registries are essential to generate standardized management guidelines and improve outcomes.