Leptomeningeal Metastasis from Cervix Squamous-Cell Carcinoma: A Case Report and Review of Literature

Metastatic spread of uterine cancer is generally infrequent and late, mainly involving lymph nodes, lung, bone and liver. We report the case of a 55-year-old woman who underwent conization for microinvasive cervical cancer in 2005. In 2014, a confirmed local and oligo-metastatic bone relapse of invasive squamous cell carcinoma, treated with radio-chemotherapy and orthopaedic surgery to stabilize the bone lesion, and the patient was placed under surveillance. Two years later, lymph node progression was confirmed, and the patient was put on chemotherapy with targeted therapy. Further progression led to several lines of treatment. In 10/2023, she presented to the emergency room with deteriorating general condition and a clinical syndrome of intracranial hypertension. A brain MRI revealed two cerebral metastatic lesions with signs of leptomeningeal carcinomatosis, which was confirmed by cerebrospinal fluid cytology. The patient was admitted to the intensive care unit, but died five days later after the start of her encephalic radiotherapy. In this article, we present the clinical, histological and therapeutic aspects of this localization, together with a review of the literature.

Background

Leptomeningeal carcinomatosis (LC) is defined by the spread of cancer cells to the central nervous system (CNS) and the creation of secondary lesions inside the thin membranes defending the brain [1].

LC is an uncommon but lethal cancer complication; without adequate therapy, the median survival time is only 6–8 weeks [2].

Leptomeningeal disease can result from original central nervous system malignancies or secondary metastatic disease from primary tumor locations outside the central nervous system [3].

Breast cancer, as well as lung cancer and melanoma, are the most common causes of leptomeningeal metastases [4], [5].

Meningeal carcinomatosis caused by malignant uterine cervix tumors is exceedingly rare, with only a few cases reported in the literature [2].

We present a clinical case of advanced squamous cell carcinoma of the cervix with leptomeningeal carcinomatosis to show the diagnosis and clinical presentation of it, and to emphasize the importance of population-based cervical cancer screening programs.

Clinical Case

We report the case of a 55-year-old woman, treated in 2015 for hormone receptor-positive breast cancer in remission, who underwent conization of microinvasive cervical cancer in 2005.

In 2015, following pain in the left lower limb and weight loss of 10 kg in 6 months, an X-ray of the pelvis showed a vast area of bone lysis on the lateral side of the left iliac bone. A surgical bone biopsy in August 2015 revealed an HPV-positive squamous cell carcinoma. A PET-scanner extension workup showed an intensely hypermetabolic pelvic mass developed in the soft tissues of the medial aspect of the left iliac crest, causing bone lysis, with no other bone lesions. On pelvic MRI, a left iliac bone mass with cortical effraction, with infiltration of the left iliac muscle and muscle.

She underwent cisplatin-based pelvic radio-chemotherapy and orthopedic surgery for acetabulum stabilization and subsequent monitoring. Two years later, after confirmation of axillary and supra-clavicular lymph node progression, she received paclitaxel-cisplatin-bevacizumab-based treatment, followed by bevacizumab maintenance until the end of 2017.

At progression in 2020, the same immuno-chemotherapy was resumed until March 2022, with further lymph node progression. The patient was included in the Tisotumab Vedotin arm of the ENGOT cx12 trial, which was stopped due to disease progression in bone and lymph nodes. She then received a new line of chemotherapy based on paclitaxel and cisplatin, followed, in the event of progression in August 2023, by cemiplimab-based immunotherapy.

In October 2023, the patient was taken to the emergency room because of deteriorating general state, headache, and vomiting indicative of intracranial hypertension. A brain MRI revealed two cerebral metastatic lesions with signs of leptomeningeal carcinomatosis (Fig. 1), which was confirmed by cerebrospinal fluid cytology (Fig. 2).

Fig. 1. Right occipital lesion measuring 1.5 × 1 cm with ring enhancement, no significant mass effect or vasogenic oedema. Leptomeningeal carcinomatosis.

Fig. 2. Immunohistochemical staining of a cerebrospinal fluid cytology specimen showing p16-positive atypical cells, fairly conclusive for metastatic cancer from the uterine cervix.

The patient was admitted to the intensive care unit but died five days later after the initiation of whole brain irradiation.

Discussion

Cervical cancer is one of the most frequent malignancies in women, ranking fourth after breast, colorectal, and lung cancer [6]. It is now recognized as a rare, long-term result of chronic infection of the lower genital tract with one of the 15 high-risk HPV varieties, which is considered to be the primary cause of cervical cancer [7].

These discoveries have led to the development of new proactive and early detection efforts with two approaches: preventing invasive cancer by HPV vaccination and screening for precancerous lesions [8].

The 5-year survival rate for metastatic cervical cancer is 16.5%, compared to 91.5% for localized disease [9].

Cervical leptomeningeal meningeal diseases (LMD) are extremely infrequent 0.4%–2.3% and are typically considered incurable [10]. Patients with cervical cancer-related LMD have a dismal prognosis, particularly if they are diagnosed late in the disease’s progression.

As of this writing, the literature records 27 cases; in this case study, we report the 28^th patient (Table I).

Table I. Cervical Cancer Patients with Leptomeningeal Metastasis (LM) [11], [12]

Case N	Histology	Initial stage	Primary TRT	Other metastasis	Time to LM diagnosis	Treatment for LM	Survival after LM
#1	SCC	Localized	N/A	LNs (cervical, pelvic)	25 weeks	N/A	17 weeks
#2	SCC	Localized	N/A	Brain, buttock	190 weeks	N/A	9 weeks
#3	ASC	Localized	N/A	Lung, brain	228 weeks	N/A	46 weeks
#4	AC	Localized	N/A	Cervix, endometrium	9 weeks	N/A	14 weeks
#5	NEC	Localized	Surgery SC	Breast, lung, LNs (mediastinum, abdominal)	19 months	RT	2 weeks
#6	SCC	Localized	Surgery RT	LNs (pelvic), Bone	836 weeks	RT	12 weeks
#7	SCC	Localized	RT	LNs (pelvic, PA)	39 months	SC	2 weeks
						ITC
#8	SCC	Metastatic	SC	Lung	6 weeks	Supportive care (analgesics)	2 weeks
			RT
#9	SCC	Localized	Surgery SC	N/A	56 weeks	RT	4 weeks
#10	AC	Localized	RT	LNs (PA, SCF)	2 years	ITC	1 week
						RT
#11	ASC	Localized	RT	Bone	52 weeks	RT	8 weeks
						SC
#12	SCC	Localized	CRT	LNs (SCF)	2 years	ITC	13 weeks
#13	ASC	Metastatic	SC	None	At diagnosis	ITC	35 weeks
						RT
						SC
#14	SCC	Localized	CRT + Surgery	Brain, lung, LNs, vagina	58weeks	RT	3 weeks
#15	ASC	Localized	CRT	Liver	31 months	RT	8 weeks
#16	NEC	Localized	CRT	Brain, bone, liver, mediastinum	19 months	RT	28 weeks
						SC
#17	SCC	Metastatic	N/A	None	At diagnosis	N/A	N/A
#18	SCC	Localized	CRT	Bone, sciatic nerve	10 months	N/A	N/A
#19	SCC	Localized	CRT	LNs (PA, SCF)	34 months	ITC	26 weeks
						RT
#20	SCC	Localized	CRT	Lung, liver, peritoneum, skin	35 weeks	RT	N/A
#21	NEC	Metastatic	N/A	None	At diagnosis	N/A	N/A
#22	SCC	Localized	Surgery	LNs (PA, pelvic)	13 years	RT	9 weeks
						ITC
#23	NEC	Metastatic	SC	Bone, LNs (pelvic, PA)	2 weeks	None	2 weeks
#24	AC	Localized	SC + CRT	LNs (PA, pelvic)	10 months	Palliative therapy	7 weeks
#25	SCC	Metastatic	SC	LNs (pelvic, PA)	At diagnosis	RT	20 weeks
						SC
#26	SCC	Localized	Surgery RT	Lung, LNs (neck, mediastinum, axilla)	240 weeks	RT	3 weeks
#27	SCC	Metastatic	SC + CRT	Bone, liver, LNs (pelvic, PA)	68 weeks	ITC	12 weeks
						RT
#28Our case	SCC	Localized	CRT	Bone, nodes, brain	18 years	RT immunotherapy	3 weeks

Headaches, altered mental state, back pain or radiculalgia, nausea, vomiting, limb weakness, sensory abnormalities, diplopia, dysphagia, dysarthria, and incoordination are the most common clinical presentations. The most prevalent symptoms are spinal (>60%), followed by cerebral (50%) and cranial nerve symptoms (40%) [4].

Despite the strong clinical suspicion of leptomeningeal metastases, diagnosis remains difficult.

MRI with contrast is the standard assessment for the diagnosis of LMC. Given the prevalence of multifocal involvement, imaging of the whole neuraxis is required. Most patients exhibit leptomeningeal enhancement, which is regularly paired with nerve enhancement. MRI may thus have diagnostic significance, especially if CSF cytology is negative. Despite this, a negative MRI following a negative CSF doesn’t rule out LMC [13], [14].

Confirmation requires the discovery of malignant cells in the CSF during cytological examination, but at least 3 lumbar punctures may be necessary to establish the diagnosis [15]. Cytological results may be falsely negative, which may be due to the strong adhesion of malignant cells to the leptomeninges or to the presence of a focal rather than generalized leptomeningeal tumor [16].

There is currently no viable or successful standardized therapy for LMD patients [17], carcinomatous meningitis is difficult to treat, however detecting it early can increase patient survival [18].

For all the cases recorded until now, multimodal treatment combinations including systemic and intrathecal chemotherapy, as well as radiation (RT), were employed [11]. Topotecan, etoposide, docetaxel, cisplatin, and cisplatin with ifosfamide were among the chemotherapy protocols used [9]. Whole brain radiotherapy is used to treat leptomeningeal disease by relieving symptoms and improving neurological functioning caused by cranial involvement.

The concomitant intrathecal chemotherapy with radiotherapy for LM raises greater concerns because of the likelihood of harm [19], [20], consequently, it should be avoided. Despite these intensive treatment combinations, the literature reports a median survival time of 4–8 weeks following the discovery of leptomeningeal metastases (LM). Given that LM patients have a short life expectancy, every effort must be taken to prevent reducing their quality of life and causing further, potentially fatal, toxicity.

Conclusion

In summary, our case report brings to light an extremely uncommon clinical situation involving an invasive cervical squamous cell carcinoma with a poor prognosis that could have been prevented or detected earlier.

This emphasizes two key points: first, the significance of structured cervical cancer screening, conducted in an environment that provides high-quality follow-up, for successful disease prevention; and second, the importance of paying close attention to neurological symptoms and meningeal irritation indicators.