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Journal of Clinical Oncology, Vol 25, No 35 (December 10), 2007: pp. 5658-5661 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.3800
Mycosis Fungoides With Leptomeningeal InvolvementCURE Children's Hospital of Uganda, Mbale, Uganda
Center for Neurologic Diseases, Brigham and Women's Hospital; Harvard Medical School, Boston, MA
Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital; Harvard Medical School, Boston, MA
Dana-Farber/Brigham and Women's Cancer Center, Center for Neuro-Oncology; Department of Neurology, Division of Cancer Neurology, Brigham and Women's Hospital; Harvard Medical School, Boston, MA
The patient is a 68-year-old man with a 20-year history of psoriasis who presented with progressive pain and weakness in his lower extremities. He was previously treated with local steroids and phototherapy and in the past 10 years with methotrexate. Throughout the last 1.5 years he was on etanercept, resulting in significant improvement of both the psoriasis and arthritis. Four months before admission, he developed an acute onset of a generalized erythrodermic flare. Biopsy of skin lesions showed a dense, band-like, superficial, perivascular and perifollicular atypical lymphoid infiltrate with significant epidermotropism (Figs. 1A and 1B). This infiltrate was composed of small- to predominantly intermediate-sized lymphoid cells with irregular, convoluted, cerebriform nuclear contours and scant to moderate cytoplasm. Many cells had indistinct nucleoli with occasional larger nucleolated forms present as well (Fig 1C). Immunohistochemistry revealed the majority of neoplastic cells to be positive for CD3 (Fig 1D) and for CD4 (Fig 1E). These findings were consistent with involvement by a cutaneous T-cell lymphoma. CD30 (Fig 1F) was reactive in approximately 10% to 20% of the cells and, along with the presence of the larger cells, raises the possibility of concurrent transformation into a large T-cell lymphoma. A computed tomography scan of the torso revealed diffuse lymphadenopathy, and a biopsy of a lymph node in the neck revealed an atypical lymphoid infiltrate, which showed follicular hyperplasia and an interfollicular expansion with small lymphocytes, eosinophils and scattered large atypical forms. These large cells formed small clusters in several areas and are suggestive of partial involvement of a lymphoproliferative disorder. Flow cytometry analysis of blood showed increase in large, atypical CD4+, CD7– T cells consistent with Sézary cells. Polymerase chain reaction for T-cell receptor
CNS involvement by cutaneous T-cell lymphoma is rare.1,2 Cutaneous T-cell lymphoma (mycosis fungoides [MF]) has an insidious onset that is usually preceded by psoriasis and characterized by erythematous rashes, plaques, or patches. CNS involvement is usually a late presentation and predominantly involves the parenchyma.1 Leptomeningeal involvement is usually demonstrated by finding atypical cells in the CSF. A high degree of suspicion is needed, as early diagnosis is associated with better prognosis. We report a case of fulminant leptomeningeal T-cell lymphoma with rapid progression to CNS involvement within several weeks after diagnosis. MF is a rare disease with an incidence of 0.36 per 100,000 person-years.3,4 Although the etiology is not yet established, the majority of patients are seropositive for cytomegalovirus, suggesting a potential viral etiology that have previously found in other cutaneous T-cell lymphomas.5,6 Sézary syndrome is an aggressive form of cutaneous T-cell lymphoma in which the skin and the blood are affected. Prognosis also depends on the presence of large cell transformation, especially if it happens in the first 2 years after diagnosis7; in this case, it happened a few weeks after diagnosis, indicating an unusual and highly aggressive course. Cutaneous T-cell lymphoma may remain confined to the skin for many years, but the abnormal cells may eventually infiltrate other tissues including lymph nodes, liver and spleen, and rarely the CNS. Unlike some other lymphomas, it has been suggested that at presentation, the disease is usually limited to the skin, with lesions that resemble eczema or psoriasis. Our patient presented with an acute eczematous rash, an erythrodermic flare preceded by a 20-year history of psoriatic rash. The relationship between psoriasis and MF is still obscure, and MF can be mistaken for psoriasis. For instance, a case report of a patient with a history of atopic dermatitis followed by psoriasis that rapidly developed exfoliative erythroderma and axillary lymphadenopathy, following treatment with cyclosporine,8 was eventually diagnosed as a case of MF, and the erythrodermic flare is part of the progression to more aggressive phenotype in the tumor. Neurological and neuropsychiatric9 involvement in MF like our case is rare, and such temporal and fulminant progression is even rarer. Epidemiology registry data10 suggest that CNS involvement is observed in 1.6% of the 187 patients with T-cell lymphoma. There have been cases of parenchymal and meningeal involvement.11,12 Most cases of CNS involvement with MF occur in advanced disease. In patients with newly diagnosed MF, the greatest risk of CNS involvement has been reported to be within the first several years after diagnosis and may involve advanced stages with lymph node or visceral involvement.13 According to a retrospective series the clinical presentation of MF in the CNS resemble lymphomatous meningitis, and include altered mental status in all cases that may progress to coma as in our patient,14 and other neurologic symptoms may include cranial nerve involvement. Neuroimaging with magnetic resonance imaging can show involvement in the corpus callosum,15 brainstem,16-18 cranial nerves,19 and other parenchymal locations.20 Meningeal involvement21 is rare, and other possibilities such as inflammation and infection should be ruled out. Treatment of leptomeningeal MF may include systemic (eg, steroids) and intrathecal treatments (eg, methotrexate), and radiotherapy. The cutaneous component may be managed with topical steroids, UVB phototherapy or psoralen and UVA photochemotherapy. Our patient received photopheresis and predinisone, and unfortunately, the patient's condition deteriorated rapidly and died shortly after. Such fatal rapid deterioration has been reported previously.22,23 This case emphasizes the need for a high degree of suspicion and thorough investigation for CNS involvement by MF in a patient who develops neurologic symptoms. In contrast to the previously reported cases, this case demonstrates that early and fulminant CNS involvement can occur within 2 months after the initial diagnosis is made, suggesting that a complete neurologic evaluation that includes CSF studies and imaging may be warranted if any neurological symptoms arise. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Zackheim HS, Lebo CF, Wasserstein P, et al: Mycosis fungoides of the mastoid, middle ear, and CNS: Literature review of mycosis fungoides of the CNS. Arch Dermatol 119:311-318, 1983 2. Lundberg WB, Cadman EC, Skeel RT: Leptomeningeal mycosis fungoides. Cancer 38:2149-2153, 1976[CrossRef][Medline] 3. Weinstock MA, Horm JW: Mycosis fungoides in the United States: Increasing incidence and descriptive epidemiology. JAMA 260:42-46, 1988 4. Weinstock MA, Horm JW: Population-based estimate of survival and determinants of prognosis in patients with mycosis fungoides. Cancer 62:1658-1661, 1988[CrossRef][Medline] 5. Herne KL, Talpur R, Breuer-McHam J, et al: Cytomegalovirus seropositivity is significantly associated with mycosis fungoides and Sezary syndrome. Blood 101:2132-2136, 2003 6. Poiesz B, Dube D, Dube S, et al: HTLV-II-associated cutaneous T-cell lymphoma in a patient with HIV-1 infection. N Engl J Med 342:930-936, 2000 7. Diamandidou E, Colome-Grimmer M, Fayad L, et al: Transformation of mycosis fungoides/Sezary syndrome: Clinical characteristics and prognosis. Blood 92:1150-1159, 1998 8. Pielop JA, Jones D, Duvic M: Transient CD30+ nodal transformation of cutaneous T-cell lymphoma associated with cyclosporine treatment. Int J Dermatol 40:505-511, 2001[CrossRef][Medline] 9. Lindae ML, Luy J, Abel EA, et al: Mycosis fungoides with CNS involvement: Neuropsychiatric manifestations and complications of treatment with intrathecal methotrexate and whole-brain irradiation. J Dermatol Surg Oncol 16:550-553, 1990[Medline] 10. Weinstock MA: A registry-based case-control study of mycosis fungoides. Ann Epidemiol 1:533-539, 1991[Medline] 11. Hengstman GJ, van Rossum MM, van der Kerkhof PC, et al: Chorea due to mycosis fungoides metastasis. J Neurooncol 73:87-88, 2005[CrossRef][Medline] 12. Li N, Kim JH, Glusac EJ: Brainstem involvement by mycosis fungoides in a patient with large-cell transformation: A case report and review of literature. J Cutan Pathol 30:326-331, 2003[CrossRef][Medline] 13. Chua MS, Veness MJ: Mycosis fungoides involving the oral cavity. Australas Radiol 46:336-339, 2002[CrossRef][Medline] 14. Hallahan D, Griem M, Griem S, et al: Mycosis fungoides involving the central nervous system. J Clin Oncol 4:1638-1644, 1986 15. Law M, Teicher N, Zagzag D, et al: Dynamic contrast enhanced perfusion MRI in mycosis fungoides. J Magn Reson Imaging 18:364-367, 2003[CrossRef][Medline] 16. del Carpio-O'Donovan R, Freeman C: Brainstem involvement with mycosis fungoides: An unusual central nervous system complication. AJNR Am J Neuroradiol 23:533-534, 2002 17. Downs AM, Love S, Kennedy CC: Sudden death secondary to mycosis fungoides of the midbrain. Acta Derm Venereol 79:475, 1999[CrossRef][Medline] 18. Tien RD, Brown M, Massey EW: CNS mycosis fungoides: CT and MR findings. J Comput Assist Tomogr 16:529-533, 1992[Medline] 19. Chua SL, Seymour JF, Prince HM: Deafness from eighth cranial nerve involvement in a patient with large-cell transformation of mycosis fungoides. Eur J Haematol 64:340-343, 2000[CrossRef][Medline] 20. Guilloton L, Drouet A, Estival JL, et al: [Transformation of mycosis fungoides to pleomorphic T-cell lymphoma and central nervous system involvement]. Rev Med Interne 22:1244-1247, 2001[Medline] 21. Ward JH, Kjeldsberg CR: Spinal cord compression in mycosis fungoides. Cancer 50:2510-2512, 1982[CrossRef][Medline] 22. Makepeace AR, Sebag-Montefiore D, Spittle MF, et al: Mycosis fungoides of the central nervous system. J R Soc Med 82:116-117, 1989[Medline] 23. Ramesh V, Saxena U, Misra RS, et al: Mycosis fungoides with fatal brain involvement. Australas J Dermatol 30:73-75, 1989[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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chain gene rearrangement showed a pair of rearranged bands with the Vgamma 9 primer set, but analysis was limited due to poor amplification from paraffin embedded sections. A presumptive diagnosis of stage II T-cell lymphoma was made, and the patient was initially treated with prednisone and bethamethasone. Two weeks later, blood evaluation revealed an increased number of CD30+ cells with likely large T-cell transformation. A few weeks after the initiation of photopheresis with narrow band UVB, the patient developed progressive lower extremity weakness with intermittent pain initially located over the thighs and subsequently becoming constant and involving the lower extremities. Narcotics did not help with pain; however, gabapentin offered some improvement. The patient then developed progressive weakness in his lower extremities with bilateral limb weakness that rapidly worsened over a few weeks despite an increase in prednisone dose. He was admitted to the hospital and examination was notable for a generalized, scaly erythematous rash and lymphadenopathy. Neurologically, he had mild inattention, decreased short-term memory, proximal lower leg weakness, decreased temperature sensation below the midcalves and midforearms, decreased vibration and joint position sense below the knees, absent reflexes, and the inability to stand or walk. The initial neurological impression was a mixed myopathy and polyneuropathy since the patient has had two recent courses of high-dose steroids and underlying cancer. Electromyography and nerve conduction studies showed a mixed axonal-demyelinating polyradiculopathy predominantly involving the lower extremities consistent with chronic demyelinating polyradiculoneuropathy. Magnetic resonance imaging of the brain and spine initially was read as unrevealing but closer inspection of lumbar spine revealed subtle leptomeningeal enhancement (
