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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4684-4686 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.8397
Perineural CNS Invasion in Primary Cutaneous Follicular Center LymphomaDepartment of Medicine, Hematology-Oncology Service, Walter Reed Army Medical Center, Washington, DC
Department of Radiology, Hematology-Oncology Service, Walter Reed Army Medical Center, Washington, DC
Department of Pathology, Hematology-Oncology Service, Walter Reed Army Medical Center, Washington, DC A 25-year-old white man presented with a slowly growing left cheek mass without local or systemic symptoms. The patient first noticed a recurring, small, blood-filled blister on his left upper cheek while shaving approximately 2.5 years before presentation. Results from an initial cutaneous punch biopsy, and repeat punch biopsies from the center and the periphery of the lesion 1 year later, were interpreted as atypical follicular lymphoid hyperplasia, negative for BCL-2 and negative for both t(14;18) and immunoglobulin (Ig) heavy chain rearrangement. The patient was treated with intralesional steroid injection with no response. By report, a facial magnetic resonance imaging (MRI) approximately 6 months later showed nonspecific infiltrative process of soft tissue and no intraorbital extension, but the patient was lost to follow-up for 1 year, over which time, the facial lesion continued to grow slowly, prompting a return to clinic for re-evaluation. Physical examination on return revealed a 4 x 4.5 cm nodular cystic mass, with erythema and telangiectasis, surrounded by mildly indurated nonscaly plaques, involving more than 50% of the left face, extending from the lower eyelid superiorly, to the nasal fold in midline and the mandibular ridge inferiorly (Fig 1A). The rest of the physical examination was negative. Histopathology of an incisional skin biopsy revealed a dense diffuse dermal infiltrate with vaguely nodular architecture (Fig 2B). The most superficial dermis and epidermis were not involved. There was a mixture of centroblasts and small and large centrocytes (Fig 2A). Immunohistochemical stains showed the large transformed lymphoid cells and small lymphocytes were positive for CD20 and bcl-6, and negative for CD10 and bcl-2; MIB-1 was increased within the nodular areas. There were admixed CD3 and CD5 positive T cells. CD30 was positive focally in large atypical cells, consistent with immunoblasts. The pathologic diagnosis was B-cell non-Hodgkin's lymphoma consistent with cutaneous follicle-center lymphoma. MRI of the brain and face showed an enhancing large soft tissue mass overlying the left maxilla with perineural spread of tumor along an enlarged V2 branch of the left trigeminal nerve to its origin in the brainstem, with involvement of the proximal portion of V3 and extension along the dura into the VII and VIII cranial nerves. There was also expansion of the pterygopalatine fossa, the foramen rotundum, and the cavernous sinus on the left (Fig 3A); lymph nodes in the digastric region of the posterior triangle were not pathologic by size criteria, none exceeding 1 cm. Further staging work-up including computed tomography (CT) of the chest, abdomen, and pelvis and whole-body positron emission tomography/CT were negative for distant disease. HIV-1 antibody was negative, serum lactate dehydrogenase and bone marrow aspirate and biopsy were normal and CSF cytology was negative for malignant cells. The patient was treated with combination of rituximab and systemic chemotherapy (intravenous cyclophosphamide, doxorubicin, vincristine, and dexamethasone), and intrathecal chemotherapy (methotrexate and cytarabine).1 MRI of the brain after two cycles of treatment showed near complete resolution of disease with mild residual enlargement and enhancement of V2 and proximal V3 (Fig 3B). The facial lesion showed a dramatic response with only mild residual erythema (Fig 1B). After six cycles of treatment, the positron emission tomography/CT showed no evidence of active recurrent or residual disease. Subsequent MRI of the brain continued to show stable appearance of minimal residual enhancement along the course of V2 and V3.
Skin involvement with lymphoma can occur more commonly as an extranodal manifestation of a systemic lymphoma, or more rarely as a primary cutaneous lymphoma (PCL).2 PCLs are recently recognized distinct clinical entities defined as those that present in the skin with no evidence of extracutaneous disease at the time of diagnosis, despite careful staging, and may be either of T-cell or B-cell origin.2 More than 65% of PCLs are T-cell disorders and approximately 25% are of B-cell origin, and up to 10% are unspecified. The WHO-European Organisation for Research and Treatment of Cancer classification recognizes four main sub-types of primary cutaneous B-cell lymphomas (PCBCL): primary cutaneous marginal-zone B-cell lymphoma, primary cutaneous follicle-center lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphomas (leg type and other).2 Of the PCBCLs, the PCFCL is the most common and accounts for approximately 57% of occurrences.3 Although the PCFCL is morphologically identical to the systemic nodal follicular lymphoma (FL), its behavior is clinically different and requires different management. The bcl-2 protein is frequently negative in PCFCL, whereas the bcl-2 protein expression is seen in the majority of cases of primary systemic nodal FL, ranging from 75% to 100%.4 CD10 is usually expressed in primary systemic nodal FL and PCFCL with a nodular pattern, whereas CD10 expression is uncommon in PCFCL with a diffuse pattern. The PCFCL characteristically presents with solitary or grouped plaques and tumors, usually on the scalp, forehead or trunk and rarely on the extremities.2,3 Erythematous papules and slightly indurated plaques can precede the development of tumorous lesions for up to several years and gradually increase in size if left untreated. However, dissemination to extracutaneous sites is uncommon. Diagnosis may be delayed with inadequate tissue sampling and a large incisional (elliptical) biopsy is preferred over a small punch biopsy for histologic confirmation and to facilitate optimal evaluation. Local therapy, with irradiation or surgery, is the preferred mode of treatment in patients with localized or multifocal PCFCL, although recurrences are common. The optimal treatment of PCFCL in the presence of very extensive cutaneous disease is less well defined. Multiagent chemotherapy has been used in the absence of prospective trials demonstrating efficacy. When extracutaneous involvement is present, treatment as for systemic nodal lymphoma has been used in reported patients.2,7,8 Multiple studies have shown that PCBCL subclassification and the extent of cutaneous involvement are the two most relevant prognostic factors.2,3,5 One retrospective analysis showed a 10-year overall survival rate of 85%, a 92% CR rate after the first treatment, and a low tendency to extracutaneous spread (9.8%) for the PCBCLs.3 The PCFCL subtype has an excellent prognosis with a 5-year survival of more than 95%, except in those with bcl-2 positivity.6 Perineural spread may occur in a variety of systemic and cutaneous malignancies and is associated with increased aggressiveness, and may contribute to increased morbidity and mortality.9,10 Head and neck carcinomas and sarcomas are well known for insidious perineural spread of disease,9,11 but perineural spread is exceedingly rare in low-grade B-cell lymphomas. Only two cases have been reported in association with extranodal primary cutaneous marginal-zone B-cell lymphoma involving the head and neck region. Both cases had an indolent course and were successfully treated with radiotherapy.12 Perineural involvement is most often asymptomatic (in 60% to 70%), despite histologic confirmation, and most commonly involves the facial and trigeminal nerves because of their extensive subcutaneous distribution.9,10 CNS involvement in PCBCL is exceedingly rare. A retrospective review found a 2% prevalence in 168 patients with PCBCLs.13 The majority of these (three of four) were of the PCFCL subtype. The prognosis of patients with secondary CNS involvement was poor even with intensive treatment. The median life expectancy was 7 months after CNS involvement was confirmed. The molecular mechanism underlying this peculiar dissemination pattern in PCFCL is unknown at present. Inactivation of p15 and p16 tumor suppressor genes by promoter hypermethylation has been reported in approximately 10% and 30% of PCFCLs, respectively.14 Gene expression profiling has shown that PCFCLs and germinal center-like large B-cell lymphomas have similar profiles.15 Further understanding of the molecular pathways involved in the development and progression of these lymphomas is likely to result in new molecular targets for diagnosis and therapeutic intervention. Our case represents an unusual manifestation of a rare PCFCL with perineural spread and CNS involvement, shedding further light into the natural history of this otherwise indolent B-cell lymphoma. This report further illustrates that initial diagnosis of cutaneous lymphoma can be difficult, requiring a high index of suspicion and adequate tissue sampling. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or US Government. REFERENCES 1. Lacasce A, Howard O, Li S, et al: Modified Magrath regimens for adults with Burkitt and Burkitt-like lymphomas: Preserved efficacy with decreased toxicity. Leuk Lymphoma 45:761-767, 2004[CrossRef][Medline] 2. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005 3. Zinzani PL, Quaglino P, Pimpinelli N, et al: Prognostic factors in primary cutaneous B-cell lymphoma: The Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 24:1376-1382, 2006 4. Lai R, Arber DA, Chang KL, et al: Frequency of bcl-2 expression in non-Hodgkin's lymphoma: A study of 778 cases with comparison of marginal zone lymphoma and monocytoid B-cell hyperplasia. Mod Pathol 11:864-869, 1998[Medline] 5. Smith BD, Smith GL, Cooper DL, et al: The cutaneous B-cell lymphoma prognostic index: A novel prognostic index derived from a population-based registry. J Clin Oncol 23:3390-3395, 2005 6. Slater DN: The New World Health Organization-European Organisation for Research and Treatment of Cancer Classification for cutaneous lymphomas: A practical marriage of two giants. Br J Dermatol 153:874-880, 2005[CrossRef][Medline] 7. Grange F, Bekkenk MW, Wechsler J, et al: Prognostic factors in primary cutaneous large B-cell lymphomas: A European multicenter study. J Clin Oncol 19:3602-3610, 2001 8. Cerroni L, Arzberger E, Putz B, et al: Primary cutaneous follicle center cell lymphoma with follicular growth pattern. Blood 95:3922-3928, 2000 9. Parker GD, Harnsberger HR: Clinical-radiologic issues in perineural tumor spread of malignant diseases of the extracranial head and neck. Radiographics 11:383-399, 1991[Abstract] 10. Feasel AM, Brown TJ, Bogle MA, et al: Perineural invasion of cutaneous malignancies. Dermatol Surg 27:531-542, 2001[CrossRef][Medline] 11. Ojiri H: Perineural spread in head and neck malignancies. Radiat Med 24:1-8, 2006[CrossRef][Medline] 12. Garcia-Serra A, Mendenhall NP, Hinerman RW, et al: Management of neurotropic low-grade B-cell lymphoma: report of two cases. Head Neck 25:972-976, 2003[CrossRef][Medline] 13. Bekkenk MW, Postma TJ, Meijer CJ, et al: Frequency of central nervous system involvement in primary cutaneous b-cell lymphoma. Cancer 89:913-919, 2000[CrossRef][Medline] 14. Child FJ, Scarisbrick JJ, Calonje E, et al: Inactivation of tumor suppressor genes p15INK4b and p16INK4a in primary cutaneous B cell lymphoma. J Invest Dermatol 118:941-948, 2002[CrossRef][Medline] 15. Hoefnagel JJ, Dijkman R, Basso K, et al: Distinct types of primary cutaneous large b-cell lymphoma identified by gene expression profiling. Blood 105:3671-3678, 2005
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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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