Case 1 -

Primary Cutaneous Anaplastic Large Cell Lymphoma Marsha C. Kinney University of Texas San Antonio, TX

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Clinical History This 57 year-old female presented in March 2004 with a several week history of a 1.5 x 1.0 cm focally ulcerated, nodular lesion on the right elbow. There was no past history of similar lesions or any other pertinent disease process. The clinical impression was a pyogenic granuloma. A pathologic diagnosis was rendered, and the lesion was totally excised and treated with local irradiation to the area. Within a few weeks, new lesions developed on the left elbow and the left upper arm. The skin of the right elbow was free of disease. The patient was referred to a university hospital in July of 2004 where she was noted to have a > 1 cm lesion on the left upper arm and several plaques with satellite nodules on the left elbow. The largest lesion measured 2 x 1.3 cm and the satellite nodules measured from 0.6-1.0 x 0.5-0.7 cm. There was no lymphadenopathy or hepatosplenomegaly. The skin lesions were totally excised. The specimen for review is from one of the satellite lesions on the left elbow. CT scans were negative. Bone marrow examination was not performed. Case 1 - Figure 1 - Skin biopsy shows a dense lymphoid infiltrate extending from the superficial through the deep dermis to the subcutaneous tissue (H&E, original magnification X20). Case 1 - Figure 2 - The epidermis has pseudoepitheliomatous hyperplasia (H&E, original magnification X40). Case 1 - Figure 3 - The epidermis is focally ulcerated (H&E, original magnification X100). Case 1 - Figure 4 - The lymphocytes are predominantly large. Small lymphocytes surround the tumor mass and focally infiltrate the epidermis (H&E, original magnification, X400). Case 1 - Figure 5 - The large lymphocytes have dysplastic, large, folded, indented or U-shaped nuclei with dispersed chromatin, prominent nucleoli, and abundant eosinophilic cytoplasm. Small lymphocytes with somewhat irregular, hyperchromatic nuclei focally infiltrate the epidermis (H&E, original magnification X600). Case 1 - Figure 6 - The tumor cells have a sheet-like growth pattern and numerous mitotic figures are present (H&E, original magnification X600). Case 1 - Figure 7 - The large dysplastic lymphocytes and the small lymphocytes are CD3+ T-cells (Clone PSI, Novocastra, paraffin immunoperoxidase, original magnification X60). Case 1 - Figure 8 - The large dysplastic lymphocytes are CD4+ T-cells (Clone 1F6, Novocastra, paraffin immunoperoxidase, original magnification X600). Case 1 - Figure 9 - Scattered small lymphocytes are CD8+, and the large dysplastic lymphocytes are CD8 negative. Most of the small lymphocytes at the edges of the tumor mass and infiltrating the epidermis (as shown in Figure 4) are CD8+, reactive lymphocytes (not illustrated in this image) (Clone C8/144B, Dako Cytomation, paraffin immunoperoxidase, original magnification X600). Case 1 - Figure 10 - The lymphocytes are strongly CD30+ in a sheet-like distribution. (Clone BerH2, Neomarker, paraffin immunoperoxidase, original magnification X100). Case 1 - Figure 11 - Virtually all of the large lymphocytes are strongly CD30+ with a membrane and Golgi pattern of staining (Clone BerH2, Neomarker, paraffin immunoperoxidase, original magnification X600). Case 1 - Figure 12 - The epidermis strongly expresses epithelial membrane antigen (EMA) and the large lymphocytes are EMA- (Clone E29, Dako Cytomation, paraffin immunoperoxidase, original magnification X600). Case 1 - Figure 13 - Some of the large lymphocytes and scattered small lymphocytes have cytoplasmic expression of the cytolytic granule protein TIA-1. (Clone 2G9, Immunotech, paraffin immunoperoxidase, original magnification X600). Case 1 - Figure 14 - The large lymphocytes lack expression of anaplastic lymphoma kinase (ALK) protein. (Clone ALK01, Ventana, paraffin immunoperoxidase, original magnification X600). Histology A large tumor mass extends from the papillary dermis into the subcutaneous tissue. The neoplastic cells are pleomorphic, cohesive appearing, large lymphocytes with abundant pale to eosinophilic cytoplasm. The nuclei are large with dispersed chromatin and one or more prominent nucleoli. The nuclei vary from round to oval and many are folded, indented and have an "embryoid" appearance. There is a high mitotic rate. Admixed small lymphocytes are present, particularly at the edges of the infiltrate. The epidermis overlying the tumor mass is ulcerated and shows pseudoepitheliomatous hyperplasia. There is focal epidermotropism by small lymphocytes. Immunophenotypic Studies Paraffin immunoperoxidase studies reveal the tumor cells are CD3+, CD4+ T-cells with strong expression of CD30 in a membrane and Golgi pattern. The tumor cells lack EMA, ALK-1, and BCL-2; TIA-1 expression is focally present in rare large cells and some small lymphocytes. The small lymphocytes surrounding the tumor and infiltrating the epidermis are predominantly CD8+. Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma (ALCL) Follow-up The patient declined CHOP chemotherapy. One month later there was no evidence of disease, however, by the end of September of 2004 the patient had developed a small lesion on the buttock but declined biopsy at that time. In November of 2004, the buttock lesion had grown to a 3 X 1.5 cm erythematous raised lesion, compatible with recurrent disease. Discussion Primary cutaneous ALCL is an indolent CD30+ lymphoma usually treated with local therapy. [1, 2] It must be distinguished from systemic ALCL, an aggressive disease that requires multiagent, systemic chemotherapy and from lymphomatoid papulosis (LyP) which spontaneously regresses. Topics for Discussion: Clinical and pathologic features of primary cutaneous ALCL Treatment of primary cutaneous ALCL Distinguishing primary cutaneous ALCL from systemic ALCL Relationship of primary cutaneous ALCL to LyP Other lymphomas and reactive processes in the differential diagnosis Definition of primary cutaneous ALCL: [3] Skin involvement without evidence of systemic disease for 6 months after diagnosis† No antecedent history of LyP, mycosis fungoides or Hodgkin lymphoma †Cases with regional (draining) node involvement are problematic; it is uncertain if they have a different prognosis or if they should be included as primary cutaneous ALCL. [3] One recent study has shown only a slightly decreased overall 5 year survival for primary cutaneous ALCL versus ALCL with regional node involvement (83% vs. 76%, respectively); however, it should be noted that 82% of the patients in this study received multiagent chemotherapy. [4] Clinical features of primary cutaneous ALCL: [5, 6, 7, 8, 9, 10, 11] Older age, median 40-67 yrs (range 2-95 yrs; most over 50 yrs) Male to female ratio of 2-3:1 Nodule (>2 cm)>tumor (>2 cm rapidly growing)>papule (< 1 cm) or plaque (3-5 cm) Solitary>multiple; regional>generalized Larger lesions often ulcerated Extremities>head and neck>trunk>genitalia Rarely described in the post transplant setting [12, 13, 14] Note: Localized disease refers to a few clustered lesions restricted to one anatomic area, and generally not exceeding 15 x 15 cm. Multifocal disease has skin involvement of two or more anatomic sites. [4] Histologic features of primary cutaneous ALCL: [6, 7, 9] Dense and diffuse dermal infiltrate often extending into subcutaneous tissue Epidermal ulceration in 30%-50%; no significant epidermotropism Pseudoepitheliomatous epidermal hyperplasia may mimic carcinoma [15] Tumor cells are present in sheets or large clusters Most cases are anaplastic with large cells having folded or indented nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm 10% -25% have non-anaplastic morphology (pleomorphic folded nuclei with denser chromatin or an immunoblastic appearance) Vascular invasion or perivascular cuffing, but not destruction, by tumor cells often present [9, 16, 17] Variable numbers of multinucleated, Reed-Sternberg-like giant cells Neutrophils and/or eosinophils may be prominent [3, 18] Reactive lymphocytes are often present at the periphery of the lesion Large numbers of eosinophils may be predictive of subsequent lymph node disease [6] Note: Regressing atypical histiocytosis is now considered as ALCL [6, 19, 20, 21] Immunophenotype of primary cutaneous ALCL Strong CD30 expression in virtually all (>75%) tumor cells CD4+>> CD8+; variable loss of pan T-cell antigens CD2, CD3, CD5 EMA+ in ≤ 32% of cases; CD15+ in <10% [7, 22] † CD56+ in 12% - 75%; does not appear associated with a worse prognosis [23, 24, 25, 26] Roughly 75% express at least one cytotoxic protein (TIA-1, granzyme B, perforin) [27] ALK protein expression is uncommon, but is seen in rare cases of primary cutaneous ALCL [28, 29, 30] . In most cases ALK positivity suggests systemic disease [31] EBV- in > 90% [32, 33, 34] Clusterin + (41% - 100%) [35, 36, 37] † Cytoplasmic (not membrane) CD15 expression has been reported in up to 40% of cases Note: Two molecules have been identified as important in predicting whether cutaneous lesions may or may not regress. BCL-2 expression correlates with non-regression [38] CD30L (ligand) correlates with regression. [39] Pathogenesis of primary cutaneous ALCL As primary cutaneous ALCL is ALK negative, the pathogenesis is different from the usual systemic ALCL. HOX homeobox gene HOXC5 is preferentially expressed in primary cutaneous ALCL and MALT lymphoma. HOX genes are important in regulating trafficking, as their target is genes encoding adhesion molecules. [40] Amplification of JUNB has been reported in 70% of primary cutaneous ALCL and JUNB protein expression has been detected in 100% in the small number of cases tested. [41, 42] Diagnosing Primary Cutaneous ALCL Two common difficulties face pathologists in making a diagnosis of primary cutaneous ALCL: Determining if the disease is indeed primary and limited to the skin Distinguishing ALCL from lymphomatoid papulosis Importance of distinguishing primary versus secondary ALCL Primary cutaneous ALCL has an excellent prognosis (83% - 100% overall 5 year survival; disease related survival is > 90%), whereas the prognosis of systemic ALCL with associated skin involvement is less favorable [6, 8] (see Table 1) Table 1. Five-Year Cumulative Survival in Various Cutaneous Forms of ALCL [6, 8] Clinical type of ALCL 5-year cumulative survival (%) Primary cutaneous 83% - 100% Skin involvement in systemic disease 29% - 44% Simultaneous presentation of skin and extracutaneous lesions 15% Cutaneous ALCL following LyP/MF/Hodgkin lymphoma 65% - 85%* * ALCL developing in LyP appears to have a good prognosis [4] Note: Most series report overall 5-year survival for ALCL (includes adults and children, all clinical types) as 65% - 85%. Distinguishing primary cutaneous ALCL from systemic disease Careful staging is imperative; there are no foolproof markers to distinguish Close follow-up is indicated as 10% - 25% develop extracutaneous disease [4, 6] ALK expression correlates with systemic disease (but is rarely seen in primary cutaneous ALCL) [29, 30, 31] Monomorphic histology is more often seen in systemic disease Clusterin was initially reported as being exclusively expressed in systemic ALCL; Wellman et al., 2000 [43] reported 100% of systemic ALCL and no primary cutaneous ALCL were positive, however a small number of cases were tested. Recent larger studies have shown clusterin expression in approximately 41% - 100% of cases of primary cutaneous ALCL. [35, 36, 37] Rashes are rare in ALCL overall and are more often seen in reactive CD30+ infiltrates (see below); but, if present in lymphoma suggest systemic disease Note: EMA expression is not useful in distinguishing primary cutaneous disease versus systemic ALCL as it has been reported in 54% of simultaneous cutaneous and systemic ALCL, 100% of secondary skin involvement, and up to one third of primary cutaneous ALCL [22] Note: Remember primary cutaneous ALCL is uncommon in children; careful staging and follow-up to rule out systemic disease is important. Disease course, prognosis, and treatment: Spontaneous regression (partial or complete) in up to 23% - 44% [6, 22] Indolent course [5, 6, 11, 22, 44]   Overall 5 year survival (83% - 100%) with a disease related survival > 90% versus ~ 65% - 85% in nodal (systemic) ALCL [4, 45]   Cutaneous relapse common (32% - 44%) [4, 6, 46] , particularly with multifocal disease [47] Overall, 10% - 25% (17% - > 40% in patients with multifocal disease) develop nodal (or other extracutaneous) disease [4, 7, 47]   Median of 24 months (range 2-117 mos.) after initial diagnosis   Aggressive disease appears associated with early spread to nodes other than regional nodes; approximately 50% with disseminated disease die Treatment varies with extent of disease:   excision, with or without radiation in localized lesions is usual   imiquimod (Aldara) an immune reponse modifier may be helpful [48]   generalized cutaneous disease appears to be more aggressive and at greater risk to develop extracutaneous disease; methotrexate, systemic retinoids w/ or w/o interferon alpha; monoclonal anti-CD30 therapy may be used with muticentric disease; combination chemotherapy and transplant have not been shown to prevent relapse [4, 45, 47, 49] Remember: Patients with systemic ALCL and secondary skin lesions require aggressive multi-agent chemotherapy. Note:Primary cutaneous ALCL is rare in children and has a high relapse rate despite systemic chemotherapy; however there is no systemic spread and the course is still favorable. Optimal therapy is not known. [10] Differential Diagnosis of Primary Cutaneous ALCL: ALCL versus Lymphomatoid Papulosis (LyP) Overlapping clinical and pathologic features indicate LyP and some cutaneous ALCL represent a continuous spectrum [50, 51] Clinical and pathologic features of LyP: Multiple papular lesions, usually <1 cm Extremities and trunk>>face, genitalia Lesions usually ulcerate and heal with a scar in 4-6 weeks Large atypical cells mixed with small lymphocytes, acute inflammatory cells Three histologic types [52, 53]   Type A   • Wedge shaped infiltrate, perivascular   • Scattered CD30+ large atypical cells   • Dense background of inflammatory cells, neutrophils, and/oreosinophils may be particularly prominent   Type B (less common)   • Band-like dermal distribution   • Lymphocytes with convoluted "cerebriform" nuclei   • Some epidermotropism may be present   • Large CD30+ cells are rare or absent   • Distinguished from mycosis fungoides on clinical parameters; (LyP) remits spontaneously and does not have extensive patches and plaques   Type C (diffuse large cell type)   • Indistinguishable from ALCL except invasion of the subcutis is minimal or absent   • History of regression is the most important distinguishing feature   • May have extracutaneous spread, so true "borderline" lesion EMA present in up to 31% of LyP [22] CD15+ in up to 33% in frozen tissue [54] Clinical (Table 2) and pathologic (Table 3) features are used to distinguish ALCL and LyP: Table 2. Clinical Features Useful in Distinguishing ALCL and LyP Clinical Features LyP ALCL Type of lesion Papules, nodules Nodules, tumors, rarely rash Number Multiple Single or grouped Size Usually < 1 cm* > 2 cm* Sites Extremities, trunk Extremities, head and neck Regression Yes, usually with scar colspan=2 25% of cases * > 3 cm more predictive of lymphoma; borderline lesions are usually intermediate in size, 1-2 cm. Table 3. Pathologic Features Useful in Distinguishing ALCL and LyP Histology/Immunophenotype LyP ALCL Pattern of infiltration Wedge-shaped perivascular/periadnexal More diffuse Subcutaneous involvement Absent (or minimal) Present Mixed inflammatory cells Many Few to many CD30+Cells Scattered single or small clusters Large groups or sheets EMA Present in 10% to 30% of cases Present in 10% to 30% of cases ALK Usually negative Usually negative EMA = epithelial membrane antigen Primary Cutaneous ALCL versus Transformed Mycosis Fungoides (MF): Transformation of mycosis fungoides to large cell lymphoma: [55, 56, 57] Occurs in ~20-25% of cases of MF at a median of 12 months (range 0-128 months) Large cells form microscopic nodules or represent >25% of total cells Epidermotropism may be absent CD30+ in 25%-50% of cases Aggressive disease   Median survival 29-37 months from diagnosis compared to 163 months for MF without transformation   Median survival after transformation 12-19 months Features useful in distinguishing transformed mycosis fungoides (MF) and primary cutaneous ALCL: Antecedent or coexistent patch or plaque stage lesions Small residual cerebriform lymphocytes usually present Remember: Do immunohistochemistry for CD4 and CD8; Small, reactive CD8+ lymphocytes with irregular nuclei may surround and infiltrate primary cutaneous ALCL. Primary Cutaneous ALCL versus Primary Cutaneous Hodgkin Lymphoma Hodgkin lymphoma (0.5%-3.4%) may secondarily involve the skin as secondary retrograde lymphatic spread from involved lymph nodes or infiltration of soft tissue in advanced (terminal) disease; primary cutaneous Hodgkin lymphoma is very rare. Primary cutaneous Hodgkin lymphoma: [58, 59, 60] Very rare Clinical course is variable; usually indolent; can develop nodal involvement 2 mos-46 years; rare cases with aggressive course Extremities >>trunk Tumor cells are scattered, not sheet-like Diagnostic, multinucleate RS cells present CD45-, CD30+, CD15+, EBV+/- Table 4. Pathologic Features Useful in the Differential Diagnosis of CD30+ Cutaneous lymphomas/LyP Type of lesion No. of Tumor Cells RS- cells CD15 CD30 EMA CD45 EBV T cell Antigens Other ALCL Many +/- -/+ + -/+ +/- - +   LyP Few Rare +/- + -/+ + -/+ + Multiple papules with regression Transformed Mycosis Fungoides Many Rare -/+ +/- NT + NT + Admixed cerebriform lymphocytes; patches and plaques Hodgkin Lymphoma Few + + + - - +/- - Very rare + = > 50% of cases +/- = 25% - 49% of cases -/+ = 5% - 24% of cases - = < 5% of cases Beware: CD30 expression has been reported in granulocytic sarcoma, which can occur in the skin [61] ; CD30 can beweakly expressed in malignant melanoma. [62] CD30 expression in these other tumors is usually weak and more diffuse. Primary Cutaneous ALCL versus Cutaneous Nasal Type NK/T Cell Lymphoma ALCL may show vascular invasion (angiocentricity) but lacks angiodestruction Zonal necrosis is rare or absent EBV expression is uncommon in ALCL The immunophenotype is not definitive; CD56 is present in some cases of ALCL and CD30 expression is seen in ~20% of nasal type NK/T cell lymphoma Note: ALCL often involves the subcutaneous tissue, but the sheetlike growth of large tumor cells and strong CD30 expression distinguishes it from subcutaneous panniculitis-like T-cell lymphoma. Primary Cutaneous ALCL versus Reactive Infiltrates: Reactive cutaneous T-cell infiltrates often have CD30+ large cells and may mimic ALCL or LyP in the following circumstances: After multiagent chemotherapy for large cell lymphoma or leukemia [63] Following marrow ablative therapy and growth factor administration at the time of lymphocyte recovery (eruption of lymphocyte recovery) [64] Hypersensitivity reaction to carbamazepine [65] Herpesvirus infection [66] Note: These reactions generally have the gross appearance of a rash and CD30+ cells are often scattered rather than sheet-like; however, some may have a perivascular distribution with clustering of CD30+ cells [64] Note: Scattered CD30+ large lymphocytes can be seen in reactive cutaneous infiltrates that contain a prominent neutrophilic or eosinophilic component including insect and spider bites, hidradenitis suppurativa, Sweet syndrome. [67] Summary A diagnosis of primary cutaneous ALCL can only be made after careful staging and lack of systemic disease for 6 months. Regional node involvement is controversial and currently most cases are treated with systemic chemotherapy. ALK expression is rarely present in primary cutaneous ALCL and usually indicates systemic disease. Borderline lesions between ALCL and LyP should be diagnosed as LyP type C if there is lack of involvement of the subcutaneous tissue and a clinical history of regression. If CD4+ cerebriform small lymphocytes are present, or if there is an antecedent history of patch or plaque lesions, transformation of mycosis fungoides to "secondary" ALCL should be considered. The treatment of primary cutaneous ALCL is conservative and usually local (complete excision with or without local irradiation); systemic treatment may be indicated in multicentric disease. CD30+ large cells may be present in reactive conditions; the CD30+ cells are usually scattered and do not form large clusters. References Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol 111: S56-67, 1999. Kadin ME, Carpenter C. Systemic and primary cutaneous anaplastic large cell lymphomas. Semin Hematol 40: 244-56, 2003. Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90: 354-71, 1997. Bekkenk MW, Geelen FA, van Voorst Vader PC, et al. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 95: 3653-61, 2000. de Bruin PC, Beljaards RC, van Heerde P, et al. Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology 23: 127-35, 1993. 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 71: 2097-104, 1993. Krishnan J, Tomaszewski MM, Kao GF. Primary cutaneous CD30-positive anaplastic large cell lymphoma. Report of 27 cases. J Cutan Pathol 20: 193-202, 1993. Paulli M, Berti E, Rosso R, et al. CD30/Ki-1-positive lymphoproliferative disorders of the skin--clinicopathologic correlation and statistical analysis of 86 cases: a multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J Clin Oncol 13: 1343-54, 1995. Macgrogan G, Vergier B, Dubus P, et al. CD30-positive cutaneous large cell lymphomas. A comparative study of clinicopathologic and molecular features of 16 cases. Am J Clin Pathol 105: 440-50, 1996. Tomaszewski MM, Moad JC, Lupton GP. Primary cutaneous Ki-1(CD30) positive anaplastic large cell lymphoma in childhood. J Am Acad Dermatol 40: 857-61, 1999. Brice P, Cazals D, Mounier N, et al. Primary cutaneous large-cell lymphoma: analysis of 49 patients included in the LNH87 prospective trial of polychemotherapy for high-grade lymphomas. Groupe d'Etude des Lymphomes de l'Adulte. Leukemia 12: 213-9, 1998. Coyne JD, Banerjee SS, Bromley M, et al. Post-transplant T-cell lymphoproliferative disorder/T-cell lymphoma: a report of three cases of T-anaplastic large-cell lymphoma with cutaneous presentation and a review of the literature. Histopathology 44: 387-93, 2004. Lucioni M, Ippoliti G, Campana C, et al. EBV positive primary cutaneous CD30+ large T-cell lymphoma in a heart transplanted patient: case report. Am J Transplant 4: 1915-20, 2004. Kim HK, Jin SY, Lee NS, et al. Posttransplant primary cutaneous Ki-1 (CD30)+/CD56+ anaplastic large cell lymphoma. Arch Pathol Lab Med 128: e96-9, 2004. Krasne DL, Warnke RA, Weiss LM. Malignant lymphoma presenting as pseudoepitheliomatous hyperplasia. A report of two cases. Am J Surg Pathol 12: 835-42, 1988. Sioutos N, Kadin ME. Perivascular Ki-1 + lesions. Int J Hematol 55: 275-9, 1992. Derringer GA, Cotton JP, Melemed AS, et al. Extranodal spread of anaplastic large cell (CD30+) lymphoma presenting as a cutaneous perivascular infiltrate. J Cutan Pathol 23: 323-7, 1996. Mann KP, Hall B, Kamino H, et al. Neutrophil-rich, Ki-1-positive anaplastic large-cell malignant lymphoma. Am J Surg Pathol 19: 407-16, 1995. Flynn KJ, Dehner LP, Gajl-Peczalska KJ, et al. Regressing atypical histiocytosis: a cutaneous proliferation of atypical neoplastic histiocytes with unexpectedly indolent biologic behavior. Cancer 49: 959-70, 1982. Headington JT, Roth MS, Schnitzer B. Regressing atypical histiocytosis: a review and critical appraisal. Semin Diagn Pathol 4: 28-37, 1987. Motley RJ, Jasani B, Ford AM, et al. Regressing atypical histiocytosis, a regressing cutaneous phase of Ki-1-positive anaplastic large cell lymphoma. Immunocytochemical, nucleic acid, and cytogenetic studies of a new case in view of current opinion. Cancer 70: 476-83, 1992. Vergier B, Beylot-Barry M, Pulford K, et al. Statistical evaluation of diagnostic and prognostic features of CD30+ cutaneous lymphoproliferative disorders: a clinicopathologic study of 65 cases. Am J Surg Pathol 22: 1192-202, 1998. Felgar RE, Salhany KE, Macon WR, et al. The expression of TIA-1+ cytolytic-type granules and other cytolytic lymphocyte-associated markers in CD30+ anaplastic large cell lymphomas (ALCL): correlation with morphology, immunophenotype, ultrastructure, and clinical features. Hum Pathol 30: 228-36, 1999. Chang SE, Park IJ, Huh J, et al. CD56 expression in a case of primary cutaneous CD30+ anaplastic large cell lymphoma. Br J Dermatol 142: 766-70, 2000. Natkunam Y, Warnke RA, Haghighi B, et al. Co-expression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemical and molecular analyses of seven cases. J Cutan Pathol 27: 392-9, 2000. Suzuki R, Kagami Y, Takeuchi K, et al. Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype. Blood 96: 2993-3000, 2000. Boulland ML, Wechsler J, Bagot M, et al. Primary CD30-positive cutaneous T-cell lymphomas and lymphomatoid papulosis frequently express cytotoxic proteins. Histopathology 36: 136-44, 2000. Morris SW, Xue L, Ma Z, et al. Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. Br J Haematol 113: 275-95, 2001. DeCoteau JF, Butmarc JR, Kinney MC, et al. The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large-cell lymphoma of nodal origin. Blood 87: 3437-41, 1996. Sasaki K, Sugaya M, Fujita H, et al. A case of primary cutaneous anaplastic large cell lymphoma with variant anaplastic lymphoma kinase translocation. Br J Dermatol 150: 1202-7, 2004. ten Berge RL, Oudejans JJ, Ossenkoppele GJ, et al. ALK expression in extranodal anaplastic large cell lymphoma favours systemic disease with (primary) nodal involvement and a good prognosis and occurs before dissemination. J Clin Pathol 53: 445-50, 2000. Meijer CJ, Presence of Epstein-Barr viral DNA and EBV latent gene products in Hodgkin and non-Hodgkin lymphoma with variable numbers of CD-30 positive cells, in Basic mechanisms of physiologic and aberrant lymphoproliferation in the skin, W.C. Lambert, et al., Editors. 1994, Plenum Press: New York. p. 205-16. Lopategui JR, Gaffey MJ, Chan JK, et al. Infrequent association of Epstein-Barr virus with CD30-positive anaplastic large cell lymphomas from American and Asian patients. Am J Surg Pathol 19: 42-9, 1995. Borisch B, Boni J, Burki K, et al. Recurrent cutaneous anaplastic large cell (CD30+) lymphoma associated with Epstein-Barr virus. A case report with 9-year follow-up. Am J Surg Pathol 16: 796-801, 1992. Saffer H, Wahed A, Rassidakis GZ, et al. Clusterin expression in malignant lymphomas: a survey of 266 cases. Mod Pathol 15: 1221-6, 2002. Lae ME, Ahmed I, Macon WR. Clusterin is widely expressed in systemic anaplastic large cell lymphoma but fails to differentiate primary from secondary cutaneous anaplastic large cell lymphoma. Am J Clin Pathol 118: 773-9, 2002. Nascimento AF, Pinkus JL, Pinkus GS. Clusterin, a marker for anaplastic large cell lymphoma immunohistochemical profile in hematopoietic and nonhematopoietic malignant neoplasms. Am J Clin Pathol 121: 709-17, 2004. Paulli M, Berti E, Boveri E, et al. Cutaneous CD30+ lymphoproliferative disorders: expression of bcl-2 and proteins of the tumor necrosis factor receptor superfamily. Hum Pathol 29: 1223-30, 1998. Mori M, Manuelli C, Pimpinelli N, et al. CD30-CD30 ligand interaction in primary cutaneous CD30(+) T-cell lymphomas: A clue to the pathophysiology of clinical regression. Blood 94: 3077-83, 1999. Bijl JJ, van Oostveen JW, Walboomers JM, et al. HOXC4, HOXC5, and HOXC6 expression in non-Hodgkin's lymphoma: preferential expression of the HOXC5 gene in primary cutaneous anaplastic T-cell and oro-gastrointestinal tract mucosa-associated B-cell lymphomas. Blood 90: 4116-25, 1997. Mao X, Orchard G, Lillington DM, et al. Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas. Blood 101: 1513-9, 2003. Mao X, Orchard G, Lillington DM, et al. BCL2 and JUNB abnormalities in primary cutaneous lymphomas. Br J Dermatol 151: 546-56, 2004. Wellmann A, Thieblemont C, Pittaluga S, et al. Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas. Blood 96: 398-404, 2000. Lindholm JS, Barron DR, Williams ME, et al. Ki-1-positive cutaneous large cell lymphoma of T cell type: report of an indolent subtype. J Am Acad Dermatol 20: 342-8, 1989. Liu HL, Hoppe RT, Kohler S, et al. CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 49: 1049-58, 2003. Trumper L, Pfreundschuh M, Bonin FV, et al. Detection of the t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals. Br J Haematol 103: 1138-44, 1998. Shehan JM, Kalaaji AN, Markovic SN, et al. Management of multifocal primary cutaneous CD30 anaplastic large cell lymphoma. J Am Acad Dermatol 51: 103-10, 2004. Didona B, Benucci R, Amerio P, et al. Primary cutaneous CD30+ T-cell lymphoma responsive to topical imiquimod (Aldara). Br J Dermatol 150: 1198-201, 2004. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol 34: 470-81, 1996. Demierre MF, Goldberg LJ, Kadin ME, et al. Is it lymphoma or lymphomatoid papulosis? J Am Acad Dermatol 36: 765-72, 1997. Tomaszewski MM, Lupton GP, Krishnan J, et al. A comparison of clinical, morphological and immunohistochemical features of lymphomatoid papulosis and primary cutaneous CD30(Ki-1)-positive anaplastic large cell lymphoma. J Cutan Pathol 22: 310-8, 1995. Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 28: 973-80, 1993. El Shabrawi-Caelen L, Kerl H, Cerroni L. Lymphomatoid papulosis: reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C. Arch Dermatol 140: 441-7, 2004. Kadin M, Nasu K, Sako D, et al. Lymphomatoid papulosis. A cutaneous proliferation of activated helper T cells expressing Hodgkin's disease-associated antigens. Am J Pathol 119: 315-25, 1985. Salhany KE, Cousar JB, Greer JP, et al. Transformation of cutaneous T cell lymphoma to large cell lymphoma. A clinicopathologic and immunologic study. Am J Pathol 132: 265-77, 1988. Diamandidou E, Colome-Grimmer M, Fayad L, et al. Transformation of mycosis fungoides/Sezary syndrome: clinical characteristics and prognosis. Blood 92: 1150-9, 1998. Cerroni L, Rieger E, Hodl S, et al. Clinicopathologic and immunologic features associated with transformation of mycosis fungoides to large-cell lymphoma. Am J Surg Pathol 16: 543-52, 1992. Kumar S, Kingma DW, Weiss WB, et al. Primary cutaneous Hodgkin's disease with evolution to systemic disease. Association with the Epstein-Barr virus. Am J Surg Pathol 20: 754-9, 1996. Sioutos N, Kerl H, Murphy SB, et al. Primary cutaneous Hodgkin's disease. Unique clinical, morphologic, and immunophenotypic findings. Am J Dermatopathol 16: 2-8, 1994. Guitart J, Fretzin D. Skin as the primary site of Hodgkin's disease: a case report of primary cutaneous Hodgkin's disease and review of its relationship with non-Hodgkin's lymphoma. Am J Dermatopathol 20: 218-22, 1998. Fickers M, Theunissen P. Granulocytic sarcoma with expression of CD30. J Clin Pathol 49: 762-3, 1996. Polski JM, Janney CG. Ber-H2 (CD30) immunohistochemical staining in malignant melanoma. Mod Pathol 12: 903-6, 1999. Su LD, Duncan LM. Lymphoma- and leukemia-associated cutaneous atypical CD30+ T-cell reactions. J Cutan Pathol 27: 249-54, 2000. Horn T, Lehmkuhle MA, Gore S, et al. Systemic cytokine administration alters the histology of the eruption of lymphocyte recovery. J Cutan Pathol 23: 242-6, 1996. Nathan DL, Belsito DV. Carbamazepine-induced pseudolymphoma with CD-30 positive cells. J Am Acad Dermatol 38: 806-9, 1998. Crawford RI, McCalmont TH. The specificity of CD30 immunohistochemical staining in the diagnosis of cutaneous CD30-positive lymphoproliferative disease. J Cutan Pathol 24: 92, 1997. Cepeda LT, Pieretti M, Chapman SF, et al. CD30-positive atypical lymphoid cells in common non-neoplastic cutaneous infiltrates rich in neutrophils and eosinophils. Am J Surg Pathol 27: 912-8, 2003.