Mar 20, 2016 - The relationship between lymphomatoid papulosis, anaplastic large cell lymphoma, and Hodgkin's disease is fraught with sig- nificance and ...
AMERICAN JOURNAL OF CLINICAL PATHOLOGY Editorial
Hodgkin's Disease, Anaplastic Large Cell Lymphoma, and Lymphomatoid Papulosis Another Scalpel Blunted
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are considered separately from T-cell or null cell ALCLs in the recent READ classification of lymphoma.6 Some cases of ALCL behave similarly to LYP with spontaneous regression of lesions, but the prognosis is not favorable. Indeed, two patients with what would now be termed ALCL but reported as "regressing atypical histiocytosis" later died with disseminated lymphoma.7,8 Primary cutaneous CD30+ ALCL has a favorable prognosis, but cases with secondary spread to the skin behave aggressively. An interesting observation is the presence of Epstein-Barr virus genome in ALCL, especially in immunocompromised patients.9 As implied above, the threads of LYP and ALCL lead to Hodgkin's disease.10 The links between LYP and Hodgkin's disease are that both conditions are associated with mycosis fungoides, and occasionally with each other. Both have large atypical cells that are CD30+, and they may have a common activated helper T-cell associated antigens if immunophenotypic studies are performed with optimal antigen localization. There are some subtle immunophenotypic differences—the large atypical cells of LYP are usually CD 15— and EMA—, unlike those of Hodgkin's disease1' and although Epstein-Barr viral latent membrane protein-1 is found on the cells of many patients with Hodgkin's disease, it is absent from those of LYP.12 The two conditions respond differently to therapy even when they coexist in the same patient, so that if they have a common clonal origin, it can sometimes be well described.13 Anaplastic large cell lymphoma is also linked to Hodgkin's disease. The morphologic resemblance to lymphocyte-depleted Hodgkin's disease is striking and indeed the border separating the two conditions is sometimes indistinct.6 Their immunophenotypes can be identical, although more cases of ALCL are CD 15 negative than positive, whereas the reverse is true for Hodgkin's disease. Epstein-Barr virus is more commonly found in Hodgkin's disease, especially in the nodular sclerosis and mixed cellularity types than in ALCL, but cases of ALCL from Asia and in immunosuppressed Western patients often harbor the virus. Given the array of morphologic and immunophenotypic similarities between the atypical cells of these three conditions, any tool that could be used to discriminate between them would be a valuable one indeed. The claim that the monoclonal antibody designated BLA.36, which can be used to probe routinely processed tissues, stained the cells of Hodgkin's disease but not those of LCL, promised to be one such device. In two early studies of the reactivity of this antibody, BLA.36 also marked B-cell lymphomas, but not T-cell neoplasms.14'5 The paper by Cohen, Butmarc, and Kadin in this issue of the Journal appears to render such an approach to the differential diagnosis of ALCL and Hodgkin's disease invalid. It is not clear why their results differ from those of previous workers. The dis-
The relationship between lymphomatoid papulosis, anaplastic large cell lymphoma, and Hodgkin's disease is fraught with significance and mystery. There are tantalizing similarities between the neoplastic cells of these three conditions, all of which behave differently. Perhaps if we understood why the ReedSternberg-like cells of lymphomatoid papulosis (LYP) disappear after a few weeks, whereas their authentic counterparts in Hodgkin's disease do not, we would gain important insights into the nature of cancer. There are only a few ways in which the cells of these conditions can be told apart, and these have not shed great light on the essential differences between these three processes. Lymphomatoid papulosis is a peculiar condition in which cutaneous papules appear and regress spontaneously after a period of a few weeks to a few months.1,2 Although innocuous in its clinical appearance, LYP is typified histologically by the presence of strikingly atypical lymphocytes resembling the Reed-Sternberg cells of Hodgkin's disease in some cases and the cerebriform cells of mycosis fungoides. Cases with Hodgkin's-like atypical cells have been designated type A, and those with mycosis fungoides-like cells have been designated type B.3 The histologic findings in type A cases include: wedge-shaped infiltrates, an admixture of eosinophils and neutrophils, and sometimes vasculitis (evidenced byfibrinin the walls of venules surrounded and permeated by atypical lymphocytes), whereas in type B lesions, the configuration can be bandlike. Coupled with psoriasiform epidermal hyperplasia and infiltration of the lower half of the epidermis by lymphocytes, the overall configuration can resemble mycosis fungoides. Most cases of LYP express T-cell associated antigens as well as CD30, an antigen first identified on the cells of Hodgkin's disease. Lymphomatoid papulosis is associated with mycosis fungoides, Hodgkin's disease, anaplastic large cell lymphoma (ALCL) or other lymphomas in roughly 10% to 20% of cases in university-based series. In many cases, LYP either presents with a lymphoma or follows one. Additionally, series compiled in academic centers tend to overreport "interesting" cases (ie, those in which terrible things happen to patients), so that the prognosis for patients presenting with LYP alone may be far more favorable than the literature suggests.4 I have not personally diagnosed a case in which a lymphoma followed LYP. Anaplastic large cell lymphoma (ALCL) is a more recently described condition in which the neoplastic infiltrates consist of sheets of cells with abundant cytoplasm and large, irregularly shaped nuclei, many with multiple and sometimes peripherally situated nucleoli. The condition can be primary in the skin, or spread to it from nodal or other extranonal sites.5 The cells of this neoplasm usually express CD30, as do those of LYP and Hodgkin's disease. Most cases have a T-cell or null cell phenotype. Rare CD30+ ALCLs have a B-cell antigenic pattern and
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AMERICAN JOURNAL OF CLINICAL PATHOLOGY Editorial
PHILIP E. LEBOIT, MD
Department ofPathology University of California, San Francisco San Francisco. California
REFERENCES 1. el-Azhary RA, Gibson LE, Kurtin PJ, et al. Lymphomatoid papulosis: A clinical and histopathologic review of 53 cases with leukocyte immunophenotyping, DNA flow cytometry, and Tcell receptor gene rearrangement studies. J Am Acad Dermatol 1994;30:210-218. 2. Karp DL, Horn TD. Lymphomatoid papulosis. J Am Acad Dermalol 1994;30:379-398.
3. Willemze R. Lymphomatoid papulosis. Dermatol Clin 1985;3: 735-747. 4. Ralfkiaer E, Stein H, Wantzin GL, et al. Lymphomatoid papulosis: Characterization of skin infiltrates by monoclonal antibodies. Am J Clin Pathol 1985;84:587-593. 5. Beljaards RC, Kaudewitz P, Berti E, et al. Primary cutaneous CD30-positive large cell lymphoma. Definition of a new type of cutaneous lymphoma with a favorable prognosis: A European multicenter study of 47 patients. Cancer 1993;71:2097-2104. 6. Harris NL, Jaffa ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 1994; 84:13611392. 7. Flynn KJ, Dehner LP, Gajl-Peczalska KJ, et al. Regressing atypical histiocytosis: A cutaneous proliferation of atypical neoplastic cells with unexpectedly indolent biologic behavior. Cancer 1982;49:959-970. 8. Headington JT, Roth MS, Schnitzler B. Regressing atypical histiocytosis: A review and critical reappraisal. Semin Diagn Pathol 1987;4:28-37. 9. Kerschman RL, Berger TG, Weiss LM, et al. Cutaneous lymphoma in human immunodeficiency viral disease: Predominance of T-cell lineage with two clinicopathological presentations. Arch Dermatol\\n press). 10. Kadin ME. Common activated helper T-cell origin for lymphomatoid papulosis, mycosis fungoides, and some types of Hodgkin's disease. Lancet 1985;2:864-865. 11. Sioutos N, Kerl H, Murphy SB, Kadin ME. Primary cutaneous Hodgkin's disease: Unique clinical, morphologic, and immunophenotypicfindings.Am J Dermatopathol 1994; 16:2-8. 12. Kadin ME, Vonderheld EC, Weiss LM. Absence of Epstein-Barr viral RNA in lymphomatoid papulosis. J Pathol 1993; 170:145148. 13. Zackheim HS, LeBoit PE, Gordon BI, Glassberg AB. Lymphomatoid papulosis followed by Hodgkin's lymphoma: Differential response to therapy (see comments). Arch Dermatol 1993; 129: 86-91. 14. Delia Croce DR, Imam A, Brynes RK, et al. Anti-BLA.36 monoclonal antibody shows reactivity with Hodgkin's cells and B lymphocytes in frozen and paraffin-embedded tissues. Hematol Oncol 1991;9:103-114. 15. Imam A, Stathopoulos S, Holland SL, Taylor CR. Characterization of a developmentally associated molecule expressed on B and Hodgkin's cells. Cancer Res 1990;50:1650-1658. 16. Kadin ME, Cavaille CM, Gertz R, et al. Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci USA 1994;91:6002-6006.
AJ.C.P.'July 1995
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crepancy in results should caution pathologists against the uncritical use of new antibodies—ideally, a panel of cases whose nature has been verified by established methods should be used to confirm the reactivity of a new reagent. Immunophenotyping may not prove to be a useful approach to separating the triad of LYP, ALCL, and Hodgkin's disease, should it be that the cells in question are identical, or even nearly so. The use of antibodies that react with activated lymphocytes and are not lineage specific may be an unrewarded detour. More fundamental studies are needed. Recent work points to a major role for B-transforming growth factor (BTGF) in these conditions.16 Other substances related to nerve factors are ligands for CD30, an antigen common to the three conditions under discussion. Binding of B-TGF appears to downregulate cell proliferation, and escape from this regulatory mechanism may account for progression from LYP to Hodgkin's disease. Studies on the control of mitotic activity and cell death in these three conditions, and on other cytokines that could control these attributes, may be more profitable than searching for an immunohistochemical scalpel with which to separate them. The odd fact remains that in 1995, if one could line up 100 patients with LYP, primary cutaneous ALCL, and cutaneous dissemination of Hodgkin's disease, a skilled clinician could more accurately sort the patients into diagnostic groups than a pathologist could by looking only at the immunophenotype of the large atypical cells.
