Orbital metastasis of squamous cell cervical cancer: A case report and review of literature

Highlights • Even though very rare, cervical cancer can present as isolated metastasis to orbit.• Should get imaging and biopsy for confirmation when suspected.• Treatment consists of radiation therapy, steroids, chemotherapy, and/or surgery.• Prompt intervention may salvage vision and improve quality of life.


Background
Worldwide, cervical cancer is the fourth most common malignancy diagnosed in women with approximately 500,000 new cases diagnosed annually and remains the most common gynecologic malignancy (Ferlay et al., 2018). The principal subtype of cervical cancer is squamous cell carcinoma, accounting for approximately 70% of cases (Ries et al., 2007). Cervical cancer is known to be locally invasive with the most common spread via direct extension in the pelvis. As the tumor grows, lymphatic spread to the pelvic and retroperitoneal lymph nodes is commonly observed (Bhandari et al., 2016). While rare, distant metastases resulting from hematogenous dissemination can occur, with the lungs, liver, and bone most frequently affected (Bhandari et al., 2016). Here, we present a rare case of a woman with squamous cell carcinoma of the cervix with metastasis to the orbit.

Case
A 72-year-old Caucasian female with past medical history significant for remote history of supracervical hysterectomy for uterine fibroids presented to the emergency room with complaints of diplopia, left eye pain, and gradually worsening left-sided headache of one week duration. She had also been experiencing mild intermittent vaginal bleeding for several months. Ophthalmologic exam revealed left lateral rectus muscle restriction and was otherwise unremarkable. She didn't have history of abnormal pap smear; however, her last pap smear had been over thirty years ago. Pelvic examination revealed a large necrotic mass occupying the vaginal vault approximately 7 cm in size with parametrial involvement appreciated on bimanual exam. Remainder of physical examination was unremarkable. Past medical history was only significant for a 45-pack year history of smoking and history of iron deficiency anemia related to GI arteriovenous malformation.
Biopsy of the cervical mass revealed an infiltrating poorly differentiated squamous cell carcinoma. MRI of the pelvis revealed a large mass in the expected area of the cervix measuring 6.7 × 3.6 × 7.3 cm in size with extension through the left lateral parametrium into the mesorectal fat, as well as a 2 cm long segment of abutment to the posterior bladder wall, partial encasement of the urethra, and invasion into the anterior rectal wall (Fig. 1A-C). MRI of the orbit was performed, which revealed an enhancing mass measuring 1.2 × 1.1 × 1.4 cm in the lateral aspect of the left orbit displacing the left lateral rectus muscle superiorly and medially resulting in lateral rectus palsy ( Fig. 1D and E). A transvaginal ultrasound revealed a 6.9 cm solid mass replacing the expected location of the cervix and/or vaginal cuff. A contrast enhanced computerized tomography (CT) scan revealed a 5.2 × 8.1 cm mass in the region of the cervix extending into the vagina. Laboratory work-up was significant for anemia, with hemoglobin of 10.1 and hematocrit of 30.6. A basic metabolic panel was unremarkable with a normal creatinine of 0.67.
To further evaluate for metastasis, a whole-body positron emission tomography (PET) scan revealed intense uptake in the cervix with a maximum standard uptake value (SUV) of 20.3 as well as uptake of two adjacent pelvic lymph nodes in the left pelvis lateral to the cervix with SUV of 5.0. There was also asymmetrical FDG uptake in the left posterior orbit and no evidence of uptake in other distant organs such as liver, lung, or distant lymph nodes.
Orbital biopsy was performed and revealed poorly differentiated carcinoma, consistent with nonkeratinizing squamous cell carcinoma. Immunohistochemical stains performed were positive for CK5/6 and P16 ( Fig. 2A and B) and negative for P40 supporting HPV associated malignancy in this patient with a cervical primary neoplasm. Given that the biopsy confirmed metastasis to the left orbit, she was ultimately diagnosed with Stage IVB squamous cell carcinoma of the cervix.
She completed palliative 3D conformal radiation to the left retroorbital mass and pelvis with 30 Gy over 10 fractions for both locations. Concurrent radiosensitizer chemotherapy wasn't administered. She tolerated radiation well with mild vulvar and perineal skin toxicity, which subsequently healed without complications. Following completion of radiation, chemotherapy was initiated with carboplatin AUC 6, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg every 3 weeks. Carboplatin was selected opposed to cisplatin (unlike GOG 240) due to favorable toxicity profile.
She completed a total of six planned cycles of chemotherapy. Subsequently surveillance was planned and repeat imaging with contrast enhanced CT scan after completing six cycles of chemotherapy showed a positive response ( Fig. 3A and B). She tolerated chemotherapy without significant side effects, and her double vision had resolved since radiation treatment to the left orbit. About 4 months after completing chemotherapy, she was found to have diffuse brain metastases detected on MRI. She received whole brain radiation therapy with 30 Gy over 10 fractions. Shortly after that she developed right cerebellar intracranial hemorrhage from hemorrhagic metastasis, obstructive hydrocephalus and bilateral cerebellar tonsillar herniation leading to brain stem compression and death.

Discussion
Orbital metastases account for only 3-5% of all orbital tumors (Amemiya et al., 2002). Malignancies most commonly associated with orbital metastases include lung, breast, and prostate cancers (Amemiya et al., 2002;Shields et al., 2004). Cervical cancer is an extremely rare cause of orbital metastasis (Amemiya et al., 2002). Here, we report an unusual case of newly diagnosis primary cervical cancer with the orbit as the only site of distant metastasis.  In the United States, cervical cancer is the third most common cancer diagnosis and cause of death among gynecologic cancers, and approximately 14,000 new cases of invasive cervical cancer occur each year (Siegel et al., 2020). The incidence is expected to decrease in upcoming years with the use of HPV vaccination. In the US, approximately 44% of patients present at an early stage due to the widespread utilization of cervical cancer screening (https://www.cancer.org/content/dam/canc er-org/research/cancer-facts-and-statistics/annual-cancer-facts -and-figures/2020/cancer-facts-and-figures-2020.pdf). Current guidelines recommend routine screening for cervical cancer with pap smear and high risk HPV testing until the age of 65 (Solomon et al., 2007). In this case, our patient had a supracervical hysterectomy thirty years prior to presentation. Following surgery, the patient was lost to gynecological follow-up and never completed routine cervical cancer screening. Cervical cancer usually spreads by local extension to contiguous areas and by the lymphatic drainage to the lymph nodes (Bhandari et al., 2016). Early stage cervical cancer is frequently asymptomatic and may remain undiagnosed until it spreads locally or leads to distant metastasis. Approximately 15 percent of patients have distant metastases at the time of diagnosis. Common sites for distant metastasis via hematogenous spread include lung and liver. Orbital metastasis is rarely seen in cervical malignancies (Ferlay et al., 2018). Spread to the orbit appears to occur via the venous plexus of Batson and the inner vertebral plexus (Tangjitgamol et al., 2004).
We performed a detailed PUBMED search for cases involving cervical cancer with orbital metastasis. We identified 5 cases similar to our case in which orbital metastasis was simultaneously diagnosed at the time of cervical cancer diagnosis (Table 1) (Nash et al., 2017;Nair et al., 2015;Shibeeb et al., 2014;Singh et al., 2011;Hertzanu et al., 1987). In these five cases, the most common site of metastasis within the orbit was the choroid (Nair et al., 2015;Shibeeb et al., 2014). This is likely because the choroid is a highly vascular structure. Pathology from these similar cases included two cases with adenocarcinoma of the cervix (Nash et al., 2017;Nair et al., 2015) and three cases with squamous cell carcinoma of the cervix (Shibeeb et al., 2014;Hertzanu et al., 1987). In three of the five similar cases, there was no evidence of other distant metastasis present (Nash et al., 2017;Singh et al., 2011;Hertzanu et al., 1987). Furthermore, among these 5 cases, the disease followed a progressive  course with three patients reportedly dead of disease within 1-3 months following diagnosis (Nash et al., 2017;Nair et al., 2015;Shibeeb et al., 2014) and the remaining two patients with unknown outcomes (Singh et al., 2011;Hertzanu et al., 1987). The treatment of metastatic cervical cancer includes palliative chemotherapy and radiation. Given the rarity of orbital metastatic disease from cervical cancer, biopsy confirmation is important. Our patient had no evidence of distant disease in any other sites besides the orbit and thus biopsy confirmation was obtained to confirm metastatic cervical cancer. The approach to orbital metastasis from cervical cancer is not standardized given its rare nature. Treatment is palliative for symptom control and may consist of radiation therapy, steroids, chemotherapy, and/or surgery. Surgical excision may increase morbidity and lead to poor quality of life but can be considered if radiation therapy fails to control symptoms. Management of the five cases similar to our own varied significantly. Two patients declined further treatment and died of their disease within one and two months of diagnosis (Nash et al., 2017;Nair et al., 2015). A third patient received palliative external beam radiotherapy to the orbits bilaterally and subsequently died three months following initial presentation (Shibeeb et al., 2014). The final two patients did not have disease outcomes reported in the literature. Of these, one patient was started on palliative chemotherapy with carboplatin and paclitaxel with plans for palliative radiation therapy (Singh et al., 2011) and the second patient received palliative chemotherapy only (Hertzanu et al., 1987). Our patient was treated with palliative radiation to her ocular metastatic disease resulting in marked improvement in her ocular symptoms. Her treatment course also included radiation to the pelvis followed by chemotherapy. At the time of publication of this manuscript, our patient has survived 10 months since initial diagnosis.
In summary, our case demonstrates an unusual case of an elderly patient presenting with sudden visual changes and found to have orbital metastasis from cervical cancer. Physicians should be aware that cervical cancer may metastasize to the eye and can lead to significant morbidity and substantial effects on quality of life. When ocular symptoms such as eye protrusion, eye pain, and visual changes appear suddenly, malignancy should be suspected. When metastasis from cervical cancer is suspected in a patient with an isolated orbital mass without any evidence of other distant metastasis, biopsy should be performed for confirmation. The presence of orbital metastasis may suggest a poor prognosis as the majority of patients reported in the literature died within a year of diagnosis, however prompt intervention may be able to salvage one's vision and improve quality of life. A reasonable approach for localized metastasis is targeted radiation followed by systemic chemotherapy or clinical trial.