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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 154-156 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.3180
Leptomeningeal Carcinomatosis Due to Squamous Cell Carcinoma of the Uterine Cervix Associated With HPV-45Department of Internal Medicine, Division of Hematology/Oncology, William Beaumont Hospital, Royal Oak, MI
Department of Pathology, William Beaumont Hospital, Royal Oak, MI
Department of Gynecologic Oncology, William Beaumont Hospital, Royal Oak, MI A 58-year-old African American woman with a history of Ménière's disease and gastric bypass was diagnosed with squamous cell carcinoma of the uterine cervix, confirmed by a positive endocervical curettage, in December 2003. She received concurrent chemoradiotherapy with cisplatin and radiation therapy (45 Gy, fractions of 1.8 Gy). She remained disease free until April 2006, when she presented with a palpable left supraclavicular lymph node. Fine-needle aspiration biopsy of the node showed malignant cells morphologically and immunohistochemically (CK 5/6 and p63 positive) compatible with metastatic nonkeratinizing squamous cell carcinoma. Computed tomography (CT) scan imaging of the chest, abdomen, and pelvis also showed retroperitoneal lymphadenopathy. She then received chemotherapy with cisplatin and vonorelbine beginning in April 2006. Six months after diagnosis of recurrence, the patient presented to the emergency department with intermittent headaches, dizziness, and photophobia. Physical examination revealed an obese African American woman in no apparent distress. She had no significant lymphadenopathy of the supraclavicular, axillary, or inguinal areas. Neurologic examinations, including cranial nerve function, and motor and sensory systems were normal, with the exception of slight memory loss. Computed tomography scan of the brain was unremarkable for any acute process. CSF cytology revealed numerous discohesive neoplastic cells with similar cytomorphology and immunohistochemical staining characteristics as the prior fine-needle aspiration of the supraclavicular lymph node (Figs 1A, lower power; and Figs 1B, higher power; Papanicolaou stain). There was no evidence of systemic disease recurrence.
Given her excellent performance status, an Omaya reservoir was placed and she received intrathecal chemotherapy with methotrexate (6 mg two times per week for 10 doses). This was followed by 12 mg alternating with thiotepa (10 mg for three doses). She responded to the intrathecal chemotherapy with reduction in headaches, but the CSF remained positive on cytology. After only 2.5 months, she clinically deteriorated with decreasing cognitive function and awareness, so intrathecal therapy was discontinued. The patient was readmitted to the hospital with seizures and headache in February 2007. At that time, magnetic resonance imaging of the brain revealed intense enhancement of the meninges over the bilateral occipital lobes and cerebellum (Figs 2A and 2B). She was then given whole-brain radiation. Despite the radiation, the patient had progressive cognitive and neurologic decline and ultimately died as a result of leptomeningeal disease within 26 weeks of diagnosis. No postmortem examination was performed; however, human papilloma virus (HPV) subtyping by nested polymerase chain reaction was performed on the paraffin block of the original endocervical biopsy and confirmed HPV subtype 45.
There are believed to be four mechanisms by which leptomeningeal spread occurs: meningeal seeding from a previous metastasis, direct extension from subdural or extradural tumors, direct extension from sites outside but adjacent to the CNS, or hematogenous spread.1,2 Prior reviews and case reports have supported the concept that leptomeningeal metastases from cervical cancer occur via hematogenous spread,3 whereas those secondary to oropharyngeal cancer occur via direct extension or perineural spread.4-7 It has been found that the risk of hematogenous dissemination increases in more advanced stages of cervical cancer.2 Cervical cancer is the second most common cancer in women worldwide, with nearly 500,000 new cases diagnosed and nearly 275,000 deaths reported in 2002.8 The mortality rate for cervical cancer in African American women is more than twice that in white women.9 This is in part due to regular screening in the white population, leading to earlier diagnosis and earlier time to treatment.9 Given that the clinical symptoms of leptomeningeal carcinomatosis are so limited and the radiologic findings are often normal, this rare manifestation of cervical cancer is difficult to diagnose.10 Despite treatment with radiation and chemotherapy, these patients have a poor prognosis, with rapid decline, resulting in death within 6 months of diagnosis.2 In nearly 100% (99.7%) of cervical cancer patients, some variant of HPV has been detected.11 There are several reported types of HPV associated with cervical cancer and recent reports have linked oropharyngeal cancer to HPV subtype 16.12,13 The two most common subtypes, which have been found in 71% of cervical cancers, are HPV-16 and HPV-18.14 An additional 10% of cervical cancers are attributed to HPV-31 and HPV-45 worldwide.14 In this case, the HPV subtype was 45, which is far less common than HPV-16 and HPV-18. One vaccine for HPV is commercially available for HPV-6, HPV-11, HPV-16, and HPV-18; others are in development.14 Given the rarity of leptomeningeal involvement from cervical cancer, and the rarity of HPV-45, it is possible that HPV-45–associated squamous cell carcinoma of the cervix has a higher predilection for leptomeningeal disease.1-3,15-17 This also could potentially explain the rarity of this manifestation in patients with squamous cell carcinomas of oropharynx, which have recently been shown to be associated with HPV subtype 16.13 To our knowledge, this is the first reported case of leptomeningeal carcinomatosis due to squamous cell carcinoma of the cervix associated with an HPV subtype. In our institution, this was the only case of documented positive CSF cytology due to metastatic cervical squamous cell carcinoma, of 97 positive CSF specimens, from 44 patients examined from 2000 to 2007. Given the poor prognosis of leptomeningeal disease and the limited options of therapy, whether a subtype association exists in leptomeningeal presentations could have treatment implications. Specifically, exploring postdiagnosis vaccination or intrathecal vaccination may be beneficial. It also may be important to type all squamous cell cervical cancers as well as head and neck cancers to elucidate further the clinical behavior of squamous carcinoma caused by different HPV subtypes. In the future, patients with squamous cell carcinoma with leptomeningeal spread should be evaluated for HPV subtype. The goal is to gain a better understanding of the pathophysiology of squamous cell carcinoma and the different HPV subtypes to improve the management of squamous cell carcinoma of the cervix and its subsequent complications. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Weithman AM, Morrison G, Ingram EA: Meningeal metastasis of squamous-cell carcinoma of the uterine cervix: Case report and review of the literature. Diagn Cytopathol 3:170-172, 1987[CrossRef][Medline] 2. Aboulafia DM, Taylor LP, Crane RD, et al: Carcinomatous meningitis complicating cervical cancer: A clinicopathologic study and literature review. Gynecol Oncol 60:313-318, 1996[CrossRef][Medline] 3. Wuntkal R, Maheshwari A, Kerkar RA, et al: Carcinoma of uterine cervix primarily presenting as carcinomatous meningitis: A case report. Aust N Z J Obstet Gynaecol 44:268-269, 2004[CrossRef][Medline] 4. Grossman SA, Krabak MJ: Leptomeningeal carcinomatosis. Cancer Treat Rev 25:103-119, 1999[CrossRef][Medline] 5. Wang CJ, Wang CY: Nasopharyngeal carcinoma with leptomeningeal dissemination: Case report. Chang Gung Med J 23:118-122, 2000[Medline] 6. Sullivan LM, Smee R: Leptomeningeal carcinomatosis from perineural invasion of a lip squamous cell carcinoma. Australas Radiol 50:262-266, 2006[CrossRef][Medline] 7. Zhu JJ, Padillo O, Duff J, et al: Cavernous sinus and leptomeningeal metastases arising from a squamous cell carcinoma of the face: Case report. Neurosurgery 54:492-498, 2004[Medline] 8. Parkin DM, Bray F, Ferlay J, et al: Global cancer statistics, 2002. CA Cancer J Clin 55:74-108, 2005 9. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43-66, 2007 10. Posner JB, Chernik NL: Intracranial metastases from systemic cancer. Adv Neurol 19:579-592, 1978[Medline] 11. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12-19, 1999[CrossRef][Medline] 12. Mork J, Lie AK, Glattre E, et al: Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344:1125-1131, 2001 13. D'souza G, Kreimer AR, Viscidi R, et al: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356:1944-1956, 2007 14. Muñoz N, Bosch FX, Castellsague X, et al: Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 111:278-285, 2004[CrossRef][Medline] 15. Weed JC Jr, Creasman WT: Meningeal carcinomatosis secondary to advanced squamous cell carcinoma of the cervix: A case report—Meningeal metastasis of advanced cervical cancer. Gynecol Oncol 3:201-204, 1975[CrossRef][Medline] 16. Rentinck ME, Schrijver HM, Kneppers E, et al: Carcinomatous meningitis in cancer of the uterine cervix. J Neurooncol 70:87-90, 2004[CrossRef][Medline] 17. Portera CC, Gottesman RF, Srodon M, et al: Optic neuropathy from metastatic squamous cell carcinoma of the cervix: An unusual CNS presentation. Gynecol Oncol 102:121-123, 2006[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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