HOLLYWOOD, FLA. The differential diagnosis and management of primary cutaneous lymphoma rely to a great extent on whether lesions appear on the leg or elsewhere, according to the first guidelines released by the National Comprehensive Cancer Network.
"Diffuse B-cell lymphoma on the leg often leads to death," Dr. Steven M. Horwitz said. In contrast, other forms of primary cutaneous lymphoma, including follicle center and marginal zone disease, generally are indolent, and a majority of patients survive a decade or more after diagnosis.
"One of the questions is: Why have a guideline? Why not just treat this like other lymphomas?" Dr. Horwitz said at the annual conference of the National Comprehensive Cancer Network (NCCN). "A take-home point is there are notable differences between cutaneous B-cell lymphomas that affect treatment."
The genesis of the first guidelines was an observational study that found 5-year survival was 94% for non-leg-type cutaneous lymphoma patients versus 52% for leg-type disease (J. Clin. Oncol. 2001;19:360210). "Keep in mind the leg patients tend to be older," Dr. Horwitz said. Another study by the European Organization for Research and Treatment of Cancer (EORTC) confirmed this overall survival disparity out to 11 years (Curr. Opin. Oncol. 2006;18:42531).
Clinical presentation, pathology, imaging, and "more and more" immunophenotyping can aid diagnosis, he said. For example, primary cutaneous follicle center lymphoma (FCL) is more common than the deadlier primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type. "In lymphoma we are not shy about giving things really long names," said Dr. Horwitz of Memorial Sloan-Kettering Cancer Center, New York.
FCL is typically an erythematous nodule with smooth skin on top. "And it doesn't have to be a small lesion, even though it's indolent," Dr. Horwitz said. In addition, FCL has a predilection for the scalp and forehead and tends to grow slowly and spontaneously regress.
In contrast, DLBCL leg-type is associated with rapid growth and features frequent mitosis. "But be a little careful. It could be a pseudolymphoma. Just a high proliferation rate only does not automatically mean leg disease," said Dr. Horwitz.
Histopathology differences are outlined in the guidelines. It is essential that a pathologist with expertise in diagnosis of primary cutaneous B-cell lymphoma review all tumor slides. A punch, incisional, or excisional biopsy is recommended. "Shave biopsies we don't like because the infiltrate is dermal," said Dr. Horwitz, a member of the NCCN panel that developed the guidelines.
Also essential to differential diagnosis is an immunophenotyping panel. For example, "A CD5 positive result means it is probably a skin manifestation of a systemic lymphoma," Dr. Horwitz said. Primary cutaneous lymphoma is a definition of exclusion, diagnosed when there is no evidence of extracutaneous disease on complete staging with physical examination, CT, bone marrow biopsy, and/or PET scan.
Diagnostic methods "useful in certain circumstances" include peripheral blood flow cytometry, molecular genetic testing for antigen receptor gene rearrangements, and cytogenetics or fluorescent in situ hybridization assays.
Work-up is also divided into essential and sometimes useful strategies. Complete history and physical examination, including a complete skin exam, are essential, for example. "I know it slows you down, but you really want to get patients to take all their clothes off and look at all of their skin. Even ask them to take their socks off and examine their feet," Dr. Horwitz said.
Order a complete blood count with differential, comprehensive metabolic panel, lactase dehydrogenase assay, and test for hepatitis B, if treatment includes rituximab (Rituxan, Genenetch).
Essential imaging includes a chest/abdominal/pelvic CT scan. A PET-CT scan is useful in certain circumstances. Dr. Horwitz said, "If you really think the person has local disease, PET is probably better for finding evidence of extracutaneous disease."
A bone marrow biopsy is considered essential with DLBCL, leg type. It also is useful for patients with FCL but is optional if the patient has marginal zone lymphoma (MZL), the other major form of indolent primary cutaneous disease.
The NCCN guidelines include a section to identify appropriate candidates for localized radiation therapy. Solitary skin involvement, regional disease, and systemic disease are differentiated according to clinical judgment. For solitary or regional T1-T2 FCL and MZL disease, for example, "almost all patients will respond" to locoregional radiation therapy or excision, he said.
Dr. Horwitz is a consultant for Eisai, Genenetch Inc., Merck & Co., and Therakos. He also is on the speakers bureau for Merck and receives grant and research support from Allos Therapeutics, Genzyme Corp., and Gloucester Pharmaceuticals.
'I know it slows you down, but you really want to get patients to take all their clothes off and look at all of their skin.' DR. HORWITZ