Primary cutaneous Ki-1(CD30) positive anaplastic large cell lymphoma in childhood Maria-Magdalena Tomaszewski, MD, John C. Moad, MD, and George P. Lupton, MD Washington, District of Columbia Primary cutaneous Ki-1(CD30) positive anaplastic large cell lymphoma (ALCL) is an unusual tumor in the pediatric population. However, the nodal-based form of the disease compared with other histologic subsets of childhood non-Hodgkin’s lymphomas (NHL) more frequently involves skin, soft tissue, and bone. The objective of this article is to determine the histologic and immunologic characteristics of childhood primary cutaneous Ki1(CD30) positive ALCL and its prognosis. The clinical data, histologic features and immunohistochemical profiles of skin biopsy specimens from 3 children with cutaneous Ki-1(CD30) positive lymphoma were reviewed. A literature search was performed and disclosed information on 5 childhood cases. The 3 patients with primary cutaneous Ki1(CD30) positive ALCL all presented similarly as rapidly growing masses initially and clinically believed to be infectious/reactive processes. The diagnosis was established on the basis of histopathologic examination and immunohistochemical studies. Histologic sections revealed an extensive infiltrate of tumor cells extending throughout the entire dermis into the subcutaneous fat with frank ulceration in 1 patient. No significant epidermotropism was noted. Tumor cells exhibited striking cellular pleomorphism and a high mitotic rate with numerous atypical mitoses. Inflammatory cells were present in all patients. The tumor cells stained positively for Ki-1 antigen (CD30), epithelial membrane antigen, and for T-cell markers (UCHL-1, CD3). One of 3 cases, however, failed to stain for leukocyte common antigen (LCA). No clinically apparent adenopathy was observed in any of the patients. In all instances the patients developed recurrent disease in the skin at sites separate from the primary location. None of the patients demonstrated any involvement of lymph nodes, bone marrow, or other organ systems. All patients were treated with chemotherapy with good response. Primary cutaneous Ki-1(CD30) positive lymphoma is rare in children and is characterized by recurrences. The prognosis seems to be favorable. (J Am Acad Dermatol 1999;40:857-61.)
Ki-1(CD30) positive anaplastic large cell lymphoma (ALCL) was originally described by Stein et al1 as a primary nodal disease with frequent cutaneous and extra-cutaneous involvement. Subsequently, a primary cutaneous form of Ki1(CD30) positive lymphoma was described that was characterized by the absence of nodal or visceral involvement at presentation, an indolent course, spontaneous remissions, a low recurrence This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. The opinions expressed in this article are the personal views of the authors and are not to be construed as representing the views of the Department of the Army or the Department of Defense. From the Department of Dermatopathology, Armed Forced Institute of Pathology. Reprint requests to: M-M. Tomaszewski, COL, MC, USA, Department of Dermatopathology, AFIP, Washington, DC 20306-6000. E-mail: [email protected]
rate after therapy, and infrequent dissemination.2-9 Both primary nodal and primary cutaneous Ki1(CD30) positive lymphomas have identical morphologic features but differ in age of onset, immunophenotype, and prognosis. Primary cutaneous Ki-1(CD30) positive ALCL is uncommon before age 20, consists of tumor cells that rarely express epithelial membrane antigen (EMA), and has a favorable prognosis. In contrast, primary nodal Ki-1(CD30) positive ALCL is common in childhood and adolescence, has a bimodal age distribution, frequently shows expression of EMA by the tumor cells, exhibits a unique chromosomal abnormality t(2;5)(p23:q35), and has a less favorable prognosis.10-14 Although nodal-based and systemic Ki-1(CD30) positive ALCL is a well-recognized entity in the pediatric age group, very few cases of primary cutaneous Ki-1(CD30) positive ALCL are reported in childhood.6,15-18 We are presenting an additional 3 pediatric patients with pri857
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858 Tomaszewski, Moad, and Lupton
Table I. Histopathologic findings in 3 children with primary cutaneous Ki-1(CD30) positive lymphoma Histology
Ulceration Dense, diffuse cellular infiltrate in dermis/subcutis Marked atypia/pleomorphism Mitoses Immunohistochemical stains Antibody(CD)/Specificity LCA/panleukocyte L-26(CD20/B lymphocytes UCHL-1(CD45RO)/T lymphocytes CD3/T lymphocytes Ber-H2(CD30)/activated lymphocytes EMA/epithelia
mary cutaneous Ki-1(CD30) positive ALCL and compare them with previously reported cases. MATERIAL AND METHODS
Three children were diagnosed in our institution as having primary cutaneous Ki-1(CD30) positive lymphoma. All specimens were embedded in paraffin and stained with hematoxylin and eosin. On additional sections, immunohistochemistry was performed by the avidin-biotin-peroxidase complex technique (Vector Laboratories, Burlingham, Calif). The antisera used were obtained from Dakopatts (Carpinteria, Calif) and are listed in Table I. Clinical information and follow-up data were obtained by reviewing the medical records and by contacting the primary physician or contributing pathologist. The collected clinical and histologic data were compared with cases already reported in the literature.
Focal erosion yes yes yes
yes yes yes yes
no yes yes yes
+ – + + + +
+ – + + + +
– – + + + +
A diagnosis of cutaneous Ki-1(CD30)-positive ALCL was rendered. The patient’s physical examination and work up, including bone marrow, cerebrospinal fluid examination, and bone scan evaluation, showed no evidence of tumor dissemination. The patient was treated with Pediatric Oncology Group (POG) protocol 9219 for low stage non-Hodgkin’s lymphoma (NHL) consisting of 7 weeks chemotherapy of vincristine, adriamycin, cytoxan, and prednisone. Complete remission was achieved; however, 6 months later she developed a small 1 to 2 cm nodule, just lateral to the left breast. The lesion was surgically removed and, on histopathologic examination, showed similar, diffuse dermal infiltration by the atypical T lymphocytes, which expressed Ki-1(CD30) and EMA. This recurrent lesion, distant from the original tumor, prompted reinduction of intensive chemotherapy for 4 weeks, including vincristine, adriamycin, cytoxan, methotrexate, arabinoside-C, and intrathecal methotrexate. Again, complete remission was achieved.
A 14-year-old boy carried a clinical diagnosis of “pityriasis lichenoides” for several years. These lesions were never biopsied for histologic confirmation. Subsequently, the patient was diagnosed with lymphomatoid papulosis. The lesions have progressively increased over the last few years. Recently, 1 of the lesions on the left lower quadrant of the abdomen enlarged, ulcerated, and began to drain. The patient had no lymphadenopathy, except for some shotty lymph nodes in the left inguinal area. He did not complain of fever, weight loss, or night sweats. His peripheral blood count was normal. His only medications over the last several years had been erythromycin and recently rocephilin (cefriaxone sodium). The lesion was excised. The clinical differential diagnosis was between reac-
An 8 year-old girl originally presented with an asymptomatic mass in the left inguinal area that did not respond to antibiotic treatment. The overlying skin changes were of impending ulceration. No adenopathy was noted. The mass was excised. Histopathologic evaluation of the excised mass revealed an extensive and diffuse infiltration of the entire dermis with extension into the subcutaneous fat by markedly pleomorphic and atypical lymphocytes with increased mitotic activity and extensive necrosis. Many atypical mitoses were noted, as was infiltration of vascular walls by atypical lymphocytes. There was no evidence of origin from a lymph node. Immunoperoxidase staining of the tumor cells is summarized in Table I.
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Fig 1. Neoplastic, pleomorphic cells with prominent nucleoli, ample cytoplasm and mitoses. (Hematoxylineosin stain; original magnification, ×750.)
Fig 2. Immunoreactivity for CD30(Ki-1) along cell membrane. (Original magnification, ×400.)
tive/inflammatory and neoplastic lymphoid processes. Histopathologic examination revealed an ulcerated skin lesion with a nodular proliferation of large atypical and pleomorphic lymphocytes that involved the entire dermis and extended into the subcutaneous fat with abundant mitoses. Immunoperoxidase staining of the tumor cells is summarized in Table I. Five months later the patient developed a new lesion in his chest wall that was excised. Histopathologic examination and immunohistochemical stains revealed the same tumor structure and staining pattern (T cells) and showed reactivity for Ki-1(CD30). The patient was treated with chemotherapy through POG protocol 8615 consisting of vincristine, doxorubicin, prednisone, methotrexate, 6-mercaptopurine, and intrathecal methotrexate. Follow-up physical examination and a gallium scan performed 2 years later showed no evidence of disease. No lymphadenopathy was observed. However, scattered maculo/papular lesions were observed on the patient’s trunk and upper and lower extremities. These lesions to our knowledge were never biopsied but most likely represented lymphomatoid papulosis. The patient remains in complete remission more than 4 years after the initial chemotherapy.
showed extension into the underlying panniculus. Focal exocytosis of the small lymphocytes into the overlying epidermis was noted. Immunoperoxidase staining of the tumor cells is shown in Table I. A metastatic work-up, including computer tomographic scan of the chest and pelvis, bone marrow, and cerebrospinal fluid examination, showed no evidence of involvement outside the skin. The patient received chemotherapy for POG protocol 9315, including vincristine, adriamycin, prednisone, and methotrexate, 6mercaptopurine, and 5 doses of intrathecal methotrexate. Three months after the initial diagnosis was made, she developed a similar but smaller lesion on the lower left chin that was not biopsied but cleared on completion of the chemotherapy. Clinically, it was considered to be recurrent lymphoma. Follow-up evaluation of the patient, more than 1 year after the diagnosis of Ki1(CD30) lymphoma, showed no evidence of any residual or recurrent disease. The patient remains in complete remission.
Case 3 A 9-year-old girl presented with a lesion on the back of the knee that was thought to be an insect bite. The lesion enlarged over a 2- to 3-month period to approximately 4 cm and was excised. The clinical differential diagnosis was between lymphoma and pseudolymphoma. Histopathologic examination revealed a superficial and deep, dense diffuse infiltrate of large atypical lymphocytes with associated surrounding small reactive lymphocytes, which permeated the entire dermis and
Primary cutaneous Ki-1(CD30) positive ALCL is extremely rare in childhood and adolescence. Review of the literature discloses only 5 such patients. In 1986 Kadin et al15 reported 6 children with Ki-1(CD30) positive lymphoma. Only 1 patient, an 11-year-old boy, presented with lesions limited to the skin on the buttock, thigh, and arm only. He was treated with chemotherapy and 14 months later was in complete remission. In 1988, a series of 19 patients with Ki-1(CD30) positive ALCL was reported by Agnarsson et al,16 14 of
860 Tomaszewski, Moad, and Lupton which were children. Two of them were described with skin lesions only. One of these patients was the previously reported 11-year-old boy. The newly reported case was an 18-year-old girl with a 6-month history of an ulcerated breast lesion. Treatment and follow-up were not discussed. In 1991, Nakamara et al17 studied Ki-1(CD30) positive ALCL among the Japanese. Thirty patients were described and 15 of them were children but only 1 child had the disease restricted to the skin only. The lesion was on the abdomen. Twenty-six months later the patient was alive; however, the modality of treatment was not reported. In 1993, Beljaards6 reported an additional case of primary cutaneous Ki-1(CD30) lymphoma, which presented as a truncal lesion in a 2-year-old patient treated with excision only. The patient was in complete remission 4 years later. Similarly, Kinney et al18 reported a 3-year-old girl with disease restricted to her skin. The treatment consisted of chemotherapy with 1 relapse after 2 months. After subsequent chemotherapy, the patient remained in remission for 4 years. An additional 3 cases of primary cutaneous Ki1(CD30) positive ALCL in children, reported herein, were diagnosed in our institution. These children were 8, 14, and 9 years old. Two of them were female. The lesions were solitary and located in the left groin, left lower quadrant of the abdomen, and behind the left knee, respectively. Clinically, they presented as a rapidly growing mass suspicious for an infectious process. After biopsy/excision and diagnosis, all 3 patients were treated with extensive chemotherapy and they all experienced cutaneous relapses in 8, 5, and 3 months, respectively. The pathologic findings are listed in Table I. The lesions showed extensive involvement of the dermis and subcutaneous fat by a dense proliferation of large tumor cells with abundant cytoplasm, pleomorphic nuclei, and prominent nucleoli (Fig 1). Mitoses were numerous and many atypical forms were noted. The immunohistochemical studies demonstrated tumor cells to be positive for Ki-1(CD30) (Fig 2). The tumor cells marked as T cells and all expressed EMA. Case 3 failed to show reactivity for LCA(CD45). The follow-up period was more than 2 years in case 1, 41⁄2 years in case 2, and a little more than 1 year in case 3. All 3 patients are reported in good health and in complete remission.
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When considering the cases previously reported in the literature and our 3 cases, the age of the patients varied between 2 and 18 years with an average age of 9.5 years and a median age of 11 years. There was a female preponderance and the trunk and lower extremities were most commonly involved. With 1 exception, all the patients were treated with chemotherapy. In 1 instance only, the lesion was excised and no further therapy was instituted. Almost all the children experienced recurrences; however, no death was reported and clinical follow-up for as long as 4 years showed no evidence of disease. Systemic Ki-1(CD30) positive lymphomas are among the moderately aggressive lymphomas in the REAL (Revised European-American Classification of Lymphoid Neoplasms) classification19 and curable with aggressive therapy.20 In adults, when disease is limited to the skin only, the prognosis is generally favorable. Local irradiation or even simple excision is sufficient for localized or solitary lesions in adults.6,20 The treatment strategy for systemic Ki-1(CD30) positive lymphoma in children is directed by stage of disease and incorporates extensive chemotherapy.21 However, there is as yet no consideration for the rare pediatric patients with localized cutaneous disease only. REFERENCES 1. Stein H, Mason DY, Gerdes J, O’Conor N, Wainscoat J, Pallesen G, et al. The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 1985;66:848-58. 2. Beljaards RC, Meijer CJLM, Scheffer E, Toonstra J, van Vloten WA, van der Putte SCJ, et al. Prognostic significance of CD30(Ki-1/Ber-H2) expression in primary cutaneous large cell lymphoma of T-cell origin. Am J Pathol 1989;135:1169-78. 3. Kaudewitz P, Stein H, Dallenbach F, Eckert F, Bieber K, Burg G, et al. Primary and secondary cutaneous Ki1(CD30) positive anaplastic large cell lymphomas. Am J Pathol 1989;135:359-65. 4. Kadin ME. The spectrum of Ki-1+ cutaneous lymphomas. Curr Probl Dermatol 1990;19:132-43. 5. Kaudewitz P, Burg G, Stein H. Ki-1(CD30) positive cutaneous anaplastic large cell lymphomas. Curr Probl Dermatol 1990;19:150-6. 6. Beljaards RC, Kaudewitz P, Berti E, Gianotti R, Neumann C, Rosso R, et al. Primary cutaneous CD30positive large cell lymphoma: definition of a new type of cutaneous lymphoma with favorable prognosis. Cancer 1993;71:2097-104. 7. Krishnan J, Tomaszewski M-M, Kao GF. Primary cutaneous CD30 positive anaplastic large cell lymphoma: report of 27 cases. J Cutan Pathol 1993;20:193-202. 8. Willemze R, Beljaards RC. Spectrum of primary cuta-
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neous CD30(Ki-1)-positive lymphoproliferative disorders. J Am Acad Dermatol 1993;28:973-80. Paulli M, Berti E, Rosso R, Boveri E, Kindl S, Klersy C, 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 1995;13:1343-54. Fujimoto J, Hata J, Ishii E, Kiyokawa N, Tanaka S, Morikawa Y, et al. Ki-1 lymphomas in childhood: immunohistochemical analysis and the significance of epithelial membrane antigen (EMA) as a new marker. Virchows Arch 1988;412:307-14. De Bruin PC, Beljaards RS, van Heerde P, van der Valk P, Noorduyn LA, van Krieken JHJM, et al. Differences in clinical behavior and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null phenotype. Histopathology 1993;23:127-35. Bitter MA, Franklin WA, Larson RA, McKeithan TW, Rubin CM, Le Beau MM, et al. Morphology in Ki1(CD30)-positive non-Hodgkin’s lymphoma is correlated with the clinical features and the presence of a unique chromosomal abnormality, (2;5)(p23;q35). Am J Surg Pathol 1990;14:305-16. Rubie H, Gladieff L, Robert A, Gaubert I, Huguet F, Rochaix P, et al. Childhood anaplastic large cell lymphoma Ki-1/CD30: clinicopathologic features of 19 cases. Med Pediatr Oncol 1994;22:155-61. Sarris AH, Luthra R, Papadimitracipoulou V, Waasdorp M, Dimopoulos MA, McBride JA, et al. Amplification of genomic DNA demonstrates the presence of the
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