Cutaneous Presentation of Follicular Lymphomas Renato Franco, M.D., Amalia Ferna´ndez-Va´zquez, M.D., Manuela Mollejo, M.D., Miguel A. Cruz, M.D., Francisca I. Camacho, M.D., Juan F. García, M.D., Mercedes Navarrete, B.SC., Miguel A. Piris, M.D. Department of Biomorphological and Functional Science, Federico II University of Napoli, Italy (RF); Department of Molecular Pathology, Centro Nacional de Investigaciones Oncologicas Carlos III, Majadahonda-Madrid (AFV, FIC, JFG, MN, MAP), Madrid, Spain; and Departments of Pathology (MM) and Oncology (MAC), Virgen de la Salud Hospital, Toledo, Spain

The morphological features and clinical behavior of The description of primary cutaneous follicular lym- B-cell lymphomas presenting in the skin are phoma has raised interest in the differential diagnosis scarcely recognized in the lymphoma classification of this versus disseminated in- currently in use, the REAL classification (1), which volving the skin. We report here on four cases of Stage has led to the publication of a first proposal of IV follicular lymphoma, diagnosed in skin biopsy, in cutaneous lymphoma by the EORTC group (2). One which cutaneous lesion was the most noticeable fea- of the groups included in this category, so-called ture of clinical presentation. In all cases, the morpho- cutaneous follicular lymphoma (CFL), has fueled a logical features were superimposed over typical nodal debate on the features and differential nature of follicular lymphoma. Apart from classic B-cell mark- this entity. Although the molecular, phenotypical, ers, they were characterized by CD10 and bcl6 posi- tivity, markers of follicle cells; and and morphological traits of these tumors have yet bcl2 expression, with a corresponding t(14;18) trans- to be fully defined, the concept that some bona fide location in three of three cases examined. In all four B-cell lymphomas originating in the lymphoid fol- cases, bone marrow study and clinical staging re- licle may clinically present as cutaneous tumors vealed disease that had disseminated since diagnosis. seems to be clearly established (2–4). Thus the skin Follow-up showed relapsing cutaneous and nodal dis- could be involved by follicular lymphoma (FL), in ease in two cases. The only difference observed with a the form of a secondary lesion (sCFL), the expres- control group of 10 cases of primary cutaneous follic- sion of disseminated disease, or as a primary lesion ular lymphoma was the absence in this group of t(14; (pCFL), localized initially in the skin and usually for 18). Disseminated classical follicular lymphoma has to a long period of time (2–5). be considered in the differential diagnosis of follicular Systemic FL is usually a disseminated neoplasm, lymphoma presenting in the skin. This series of cases with over two thirds of cases being in Stage III or IV suggests that the presence of t(14;18) could imply the at diagnosis (2). It recapitulates both the cytological existence of disease that has disseminated beyond the and immunohistochemical features of secondary skin and that cases harboring this translocation could follicles, and neoplastic cells frequently show a spe- be candidates for systemic polychemotherapy. cific translocation, t(14;18). It may also involve the skin in the form of specific lesions, sCFL, and does KEY WORDS: bcl2, bcl6, CD10, Follicular lym- so in almost 4% of cases (4). phoma, Primary cutaneous follicular lymphoma, The existence of primary cutaneous B-cell lym- Translocation (14;18). phoma, defined as a B-cell non-Hodgkin’s lym- Mod Pathol 2001;14(9):913–919 phoma primarily occurring in and remaining con- fined to the skin for a period of at least 6 months, has now been widely accepted (2, 5, 7–21). Accord- ing to the EORTC, primary cutaneous follicular

Copyright © 2001 by The United States and Canadian Academy of lymphoma (pCFL) shows a relatively good out- Pathology, Inc. come, rarely disseminating to extracutaneous sites. VOL. 14, NO. 9, P. 913, 2001 Printed in the U.S.A. Date of acceptance: March 30, 2001. This could support the selection of local treatment This work was supported by Grant IFD97-0431 from the Ministerio de of the tumor (2, 4, 19, 22, 23). The real frequency of Educacion y Ciencia, Spain. Address reprint requests to: Miguel A. Piris, Centro Nacional de Investi- pCFL and its morphological and molecular charac- gaciones Oncologicas Carlos III, Carretera Majadahonda-Pozuelo, km. 2, teristics are, however, a matter of controversy, as 28220 Majadahonda, Madrid, Spain; e-mail: [email protected]; fax:-34-91-509-70-55. are its differential diagnosis versus marginal zone

913 lymphoma in the skin (7, 24) and disseminated FL TABLE 1. Characteristics of Antibodies involving the skin. Antigen Clone (Manufacturer) Incubation Time Dilution In the course of a review of cases of cutaneous CD20 L26 (DAKO) 40 min 1:50 B-cell lymphoma, we noticed the existence of a CD79a JCB117 (DAKO) 40 min 1:25 CD23 MHM6 (DAKO) 40 min 1:25 group of four cases of FLs that, diagnosed on the CD10 56C6 (Novocastra) Overnight 1:25 basis of skin biopsies, have shown widespread dis- CD3 Polyclonal (DAKO) 40 min 1:50 ease since diagnosis, with clinical signs of progres- CD43 DFT1 (DAKO) 40 min 1:50 CD5 4C7 (Novocastra) 40 min 1:10 sion in at least two cases. Because this suggests that CiclD1 DC56 (DAKO) 40 min 1:100 these tumors must be recognized independently of P53 DO7 (DAKO) 40 min 1:50 pCFL, we reviewed the main features of this group Bcl2 124 (DAKO) 40 min 1:25 Bcl6 PG-B6P (DAKO) 40 min 1:10 of FLs presenting in the skin. MIB1 MIB1 (Immunotech) 40 min 1:50

MATERIALS AND METHODS The presence of positivity was quantified as a Patients and Tissue Samples percentage. In particular, CD20, CD10, bcl6, and Tumor specimens of four cutaneous biopsies bcl2 were scored as positive if the majority of tu- with FL were obtained from routine files of the moral cells showed a distinct reactivity. MIB1 ex- Virgen de la Salud Hospital, Toledo, Spain, corre- pression was scored as low Ki67 when the percent- Ͻ sponding to a period from 1990 to 2000. All patients age of positive tumoral cells was 30%; moderate Ͼ were under study for cutaneous lesions that at bi- when between 30% and 60%; and high when 60% opsy showed FL histology. From the onset of the of tumoral cells were positive. disease, the staging of all the patients included in the series showed widespread involvement, includ- Polymerase Chain Reaction ing bone marrow infiltration. All specimens were DNA isolated by conventional methods from pe- reevaluated, including initial cutaneous lesions, the ripheral (Case 3), bone marrow and periph- staging bone marrow biopsies, secondary cutane- eral blood (Case 2), and cryopreserved (Ϫ80°C) tis- ous lesions, or restaging bone marrow biopsies per- sue of skin biopsies was analyzed for t(14;18) by formed during the follow-up. Cases were classified polymerase chain reaction (PCR). PCR amplifica- into three grades, based on numbers of large cells tion of p53 Exon 8 (249 bp) was used to assess the (centroblasts), according to the criteria of Mann suitability of DNA extracts, using a volume of 100 and Bernard (25) ng. PCR was performed to detect the t(14;18) at the major breakpoint region (MBR). PCR was per- Immunohistochemistry formed with 0.1 ␮g of purified DNA, which was All immunostaining techniques were performed subjected to 35 cycles of PCR amplification using in paraffin-embedded tissue sections, using a pre- MBR and JH consensus primer. The MBR and JH vious step of heat-induced antigen retrieval tech- primers have been described elsewhere (21). Ten nique for all antibodies. Thus, before incubation percent of PCR products was size-fractionated on with the primary antibody, slides were heated in a 1.5% agarose gel. Specimens were observed in ul- pressure cooker for 3 minutes in a solution of 0.01 traviolet B light. The presence of a band between mol/L sodium citrate. 100 and 250 base pairs (bp) was considered positive After incubation with the antibody, immunode- for translocation. tection was performed with biotinylated antimouse immunoglobulins, followed by peroxidase-labeled streptavidin (LSAB-DAKO, Glostrup, Denmark) Controls with diaminobenzidine chromogen as substrate. All A group of 10 cases of pCFL was used as the immunostaining was performed using the Tech- control group for the study of t(14;18). These cases mate 500 (DAKO) automatic immunostaining de- were selected according to clinical findings (com- vice. The antibodies used for immunohistochemi- puted tomography scan, ultrasonography, and cal study were directed against B-cell markers CD20 bone marrow biopsies without signs of lymphoma and CD79a, T-cell marker CD3; specific markers of involvement for at least 6 months after diagnosis), mantle-cell lymphoma CD5, cyclin D1, and IgD; morphological signs (follicular pattern of growth, germinal center markers such as CD10 and bcl6; germinal center cytology), immunophenotypical marker of dendritic cells CD23; oncoproteins p53 criteria (bcl6 and CD10 positivity and the presence and bcl2; and proliferative marker MIB1. The data of follicular dendritic cells), and suitability of the corresponding to the antibodies used are shown in DNA extracted from paraffin-embedded tissue for Table 1. PCR analysis. Samples were from a larger collection

914 Modern Pathology of cutaneous pCBCL obtained from the files of the lateral region of the left leg. Radiotherapy was Spanish hospitals integrated in the Spanish Lym- performed. phoma Club. These cases of pCFL belong to a larger Eight years after diagnosis, the patient is alive, series, whose results concerning the frequency of with disease restricted to the skin. IgH rearrangement and t(14;18) translocation have already been published (26). Case 2 This female 33-year-old presented a solitary pap- RESULTS ule of the scalp, surrounded by an annular ery- thema. No other symptoms were present. One year Clinical features after the initial symptom, a skin biopsy showed The main clinical data are shown in Table 2. lesions diagnosed as FL. Laboratory examination was not significant. Clinical and x-ray examination Case 1 results were negative for other site locations. Bone marrow biopsy showed FL infiltration. A t(14;18) This was a female 61-year-old showing several was then detected in peripheral blood and bone erythematous lesions of Ͼ0.5 cm on the left eye- marrow . The patient had a complete brow (Fig. 1) and in the sternal region, with other clinical remission, with persistence of t(14;18) in smaller ones spread over the trunk. No other symp- peripheral blood. toms were present. Twelve months after the initial Thirty-two months later, she showed weight loss symptoms, a biopsy of the lesions was performed (5 kg) and irregularities of the menstrual cycle. Ret- and showed the features of FL. Laboratory exami- roperitoneal lymphadenopathies and a peritoneal nation did not provide significant results. Clinical mass were found at this time by CT scan. This time, examination revealed significant axillary and ingui- the patient was treated with polychemotherapy, nal adenopathy (node size, Ͼ1.0 cm), and radiolog- and she underwent clinical and molecular remis- ical examination (computed tomography scan and sion. Now, 60 months after the initial diagnosis, she ultrasonography) showed hepatosplenomegaly. is alive and well. Bone marrow biopsy also showed a neoplastic in- filtration. The patient was classified as having Stage IV FL. Case 3 She was treated with polychemotherapy and had This 49-year-old woman presented a cutaneous a complete remission. She was well with the excep- nodule on the right shoulder and a smaller one in tion of nonspecific remittent lymphadenopathy for the sternal region. No symptoms were present. Ten a period of 50 months, when three erythematous months after the initial symptoms, cutaneous bi- infiltrated lesions were observed in the posterolat- opsy showed an FL. Subsequent clinical examina- eral region of the right thigh. Bone marrow biopsy tion showed significant axillary and inguinal was negative. X-ray exams were negative. Biopsy lymphadenopathies. CT scan and ultrasonography showed FL in this case. The patient began to receive did not show any significant alterations. Bone mar- local radiotherapy. row biopsy showed neoplastic infiltration. t(14;18) Fifteen months later, another papule was ob- was detected in bone marrow lymphocytes. The served in the exterior upper left leg, and the biopsy patient was considered to be in Stage IV of the again showed FL. Finally, 14 months later, another disease. After 5 months of polychemotherapy, she lesion positive for FL was observed in the antero- still has persistent disease.

TABLE 2. Main Clinical Data

Site Primitive Lesion Therapy after Follow-Up (Tissues Infiltrated and (Duration in Months of Other Sites of Disease at Status (Months Case Surgical Time from the Diagnosis, in Clinical Symptoms Staging from Diagnosis) Excision Months) before Biopsy) 1 Right eyebrow sternal Liver and ; axillary CT Bone marrow (0, 7); liver, spleen AWD (108) region (10) LNs; bone marrow and axillary LNs (0, 7); skin, right thigh (71); skin, left leg (88); skin, left leg (91) 2 Scalp (12) Bone marrow CT Bone marrow (0, 7); intercavo- CR (60) aortic LNs and peritoneum (48) 3 Right shoulder (10) Neck and axillary LNs; CT Bone marrow (0); neck and AWD (5) bone marrow axillary LNs (0) 4 Frontal region (60) Bone marrow RT Bone marrow (0) CR (36) All cases were Stage IV and female. CT, chemotherapy; RT, radiotherapy; AWD, alive with disease; CR, complete remission; LN, .

Cutaneous Presentation of Follicular Lymphomas (R. Franco et al.) 915 Case 4 of small B cells (Fig. 3). Follow-up bone marrow A female 74-year-old presented a 5-year-old cu- biopsies in Case 1 showed persistent infiltration, taneous nodule with slow growth in the right fron- despite treatment. tal region, associated with smaller peripheral pap- ules. were not present. Skin biopsy Immunohistochemical findings showed FL. Laboratory examinations were not sig- Neoplastic cells showed a B-cell immunopheno- nificant. Clinical and x-ray examinations were neg- type (CD20ϩ, CD79aϩ, CD3Ϫ CD43Ϫ) in skin spec- ative. Bone marrow biopsy showed an infiltration of imens and bone marrow biopsies in all cases. CD10, lymphoma. The patient was considered to be at bcl2, and bcl6 were positive in all cases. Bcl6 ex- Stage IV. pression was observed both in the follicular and In consideration of her age and of the absence of interfollicular compartment. All cases were nega- other lesions, the patient was submitted to local tive for cyclin D1 and CD5. p53 was always nega- radiotherapy. After 7 months, the patient finished tive. MIB1 expression was low to intermediate (Ta- radiotherapy, and cutaneous lesions disappeared. ble 3 and Fig. 4). In all cases, neoplastic follicles The patient is now alive and well 3 years after were outlined by the presence of aggregates of diagnosis. CD23ϩ follicular dendritic cells. Bone marrow biopsy showed CD20 and bcl2- positive paratrabecular nodules (Fig. 3b). Histological Findings Skin samples PCR findings In all cases, we observed a middermal and sub- In the group of disseminated FL presenting in the cutaneous diffuse and/or nodular infiltration by skin, PCR study detected the presence of t(14;18) in germinal center B cells, composed of confluent all three cases in which DNA was available for mo- nodules of variable size. The tumoral cells were lecular study. This study was performed in the cu- represented in variable amounts in each case by taneous samples in two of three cases, whereas in small, cleaved cells and large cells, cleaved or non- the third case, it was done using peripheral blood cleaved, and with a prominent nucleolus. In partic- and bone marrow. The quality of the DNA extracted ular, we observed prevalent centrocytes (Grade I in Case 4 was unsuitable for molecular study (Table FL) in Case 1; a mixture of centrocytes and centro- 3 and Fig. 5). None of the 10 cases of pCFL showed blasts (Grade II FL) in Cases 2 and 3; and a preva- t(14;18). lent population of centroblasts (Grade III FL) in the fourth case. A variable component of reactive DISCUSSION T-cells was also observed in each case. No reactive follicles were observed. The papillary dermis was We described four cases of Stage IV FL presenting spared in all cases in the typical Grenz zone fash- in the skin. All four of these cases showed bone ion, as well as was the epidermis. No epidermotro- marrow infiltration at initial diagnosis, and two of pism was observed (Table 3 and Fig. 2). them displayed lymph node involvement. Despite No appreciable changes were observed in the this, the clinical follow-up revealed a relatively in- consecutive biopsies of these patients, except for a dolent clinical behavior, with relapses in two of four transformation of histological grade in Case 1, in cases. To the best of our knowledge, cases such as which a transition to Grade II was observed during these, disseminated FL in which the first clinical relapses. manifestation was cutaneous infiltration, have not been reported previously, and they may raise diffi- Bone marrow biopsy culties in terms of differential diagnosis between Bone marrow biopsies performed for the staging sCFL and pCFL. Cases so far reported of FL with of disease showed a paratrabecular, nodular infil- cutaneous infiltration antecede the recognition that tration by FL in all cases, whereas in Case 4, the B-cell lymphoma may debut as a purely cutaneous presence of diffuse bone marrow involvement was tumor, differentiating them from rare cases of con- also observed. The cytology was composed mainly current involvement of lymph node and skin at

TABLE 3. Main Morphological and Immunohistochemical Findings in Secondary Cutaneous Follicular Lymphoma

Case Grade CD20 CD10 Bcl2 Bcl6 P53 Ki67 t(14;18) 1I ϩϩϩϩϪLow ϩ 2II ϩϩϩϩϪLow ϩ 3II ϩϩϩϩϪLow ϩ 4 III ϩϩϩϩϪIntermediate ND ND, not determined.

916 Modern Pathology FIGURE 1. Nodular lesion at left eyebrow.

FIGURE 2. Hematoxylin-eosin staining. Nodular pattern of dermal diagnosis (27) or from secondary cutaneous in- infiltration of lymphoma (A, 10.6ϫ; B, 250ϫ) with representation of volvement in the course of the disease (5, 27). centrocytes and centroblasts (C, 630ϫ; D, 1000ϫ). Cutaneous lymphomas represent the second most important group of extranodal lymphomas after gastrointestinal lymphoma (2, 17, 20). Until recent years, no real distinction between pCFL and sCFL was made, and they were all classified, and therefore treated, according to the scheme used for nodal non-Hodgkin’s lymphoma (28, 29). So-called primary cutaneous lymphoma, because of its pecu- liar clinicopathological features, has recently been the subject of specific proposals for classification (2, 7, 20, 23). The aim of recently introduced classifi- cations, such as the Revised European American Lymphoma classification (1) and that by the Euro- pean Organization for Research and Treatment (2), is to differentiate distinct nosological entities with peculiar clinical characteristics. In the staging and treatment of patients with cutaneous lymphoma, the usefulness of distinguishing lymphoma re- stricted to the skin from other generalized lympho- mas involving the skin is of great practical importance. We have shown here that disseminated FL de- buted with only symptomatic and often prolonged FIGURE 3. A, paratrabecular bone marrow infiltration by lymphoma (hematoxylin-eosin staining, 200ϫ). B, bcl2 positivity of bone marrow cutaneous lesions, the initial diagnosis being per- neoplastic cells (200ϫ). formed with a skin biopsy. Only after the initial diagnosis of lymphoma was made did the staging of the patient reveal widespread disease, including between these two different clinical presentations bone marrow infiltration in all cases (2, 6). This of FL. Although pCFLs display the same morphol- emphasizes the usefulness of including a bone mar- ogy and CD10 or bcl6 expression as nodal FL, they row biopsy in the staging of cutaneous lymphoma may differ in the incidence of t(14;18), which has before making a diagnosis of primary cutaneous only rarely been reported in pCFL (4, 12, 24, 31). lymphoma. Thus, in our series, t(14;18) was present in three of Disseminated FL has a 5-year survival probability three cases analyzed, in contrast with its absence in of 30 to 50% and needs to be treated with general 10 of 10 of the cases of pCFL included here for polychemotherapy. This contrasts with data show- comparison. The absence of a t(14;18) in pCFL is ing that in pCFL, the probability of survival is well consistent with the findings by Cerroni et al. (4), above 90% after a 10-year follow-up (2, 4). This who recently described a series of 15 pCFL that difference in survival probability and treatment un- were diagnosed and staged according to classical derscores the importance of finding molecular or criteria. Other authors show the presence of this immunophenotypic markers that can distinguish t(14;18) in a proportion of patients; thus, Volk-

Cutaneous Presentation of Follicular Lymphomas (R. Franco et al.) 917 FIGURE 4. Immunohistochemistry. A, CD20 (200ϫ). B, CD3 (200ϫ). C, CD10 (200ϫ). D, bcl2 (200ϫ). E, bcl6 (200ϫ and detail, 450ϫ). F, CD23 (200ϫ). G, IgD (200ϫ and detail, 450ϫ). H, MIB1 (200ϫ).

these differences could be attributable to variations in the procedure for clinical staging of the patients or the conditions used in molecular study remains to be answered, but in any case, the data here showed are consistent with the findings reported by

FIGURE 5. Polymerase chain reaction results. Cases 1 to 3: secondary Cerroni et al. (4) correlating the presence of t(14;18) cutaneous follicular lymphoma. Cases 4 to 13: primary cutaneous with disseminated extracutaneous disease. follicular lymphoma. The band indicates the presence of t(14;18) in Nevertheless, all of these data suggest that it Cases 1 to 3. Cϩ, positive control. CϪ, negative control. would be advisable to perform additional biological studies on larger groups of patients with different enandt et al. (30) describe this translocation in 1 types of cutaneous lymphoma to better define the case of 10 centroblastic and centrocytic lympho- boundary between primary and secondary cases (2). mas, and Yang et al. (31) describe a very high fre- To conclude, we underline the fact that FL, when quency of t(14;18) in pCFL (6/15 cases). Whether diagnosed in the skin, may correspond to cutane-

918 Modern Pathology ous preferential involvement by disseminated FLs. ments and normal T-cell receptor, bcl2, and c-myc genes in The data collected here seem to support the interest primary cutaneous B-cell lymphomas. Cancer Res 1989;49: of recognizing these tumors, given that they have 4901–5. 14. Faure P, Chittal S, Gorguet B, Caveriviere P, Brousset P, shown a tendency to involve extracutaneous sites Viraben R, et al. Immunohistochemical profile of cutaneous and relapse in nodal and other locations. A partic- B-cell lymphoma on cryostat and paraffin sections. Am J ular contribution to clinical staging was made by Dermatopathol 1990;12:122–33. the performance of bone marrow biopsy. Our find- 15. Garbe C, Stein H, Dienermann D, Orfanos CE. Borrelia Burg- ings also indicate the clinical relevance of the pres- dorferi associated cutaneous lymphoma: clinical and ence of a t(14;18), which was always found to be immunohistologic characterization of four cases. J Am Acad Dermatol 1991;125:373–86. associated with disseminated extracutaneous dis- 16. Giannotti B, Santucci M. Skin-associated lymphoid tissue- ease in this study. related B-cell lymphoma (primary cutaneous B-cell lympho- ma). Arch Dermatol 1993;129:353–5. 17. Isaacson PG, Norton AJ. Cutaneous lymphoma. In: Isaacson REFERENCES PG, Norton AJ, editors. Extranodal lymphoma. London: Churchill Livingstone; 1994. p. 172. 1. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lym- 18. Kempf W, Dummer R, Burg G. Approach to lymphoprolif- phoid neoplasms: a proposal from the International Lym- erative infiltrates of the skin. The difficult lesions. Am J Clin phoma Study Group. Blood 1994;84:1361–92. Pathol 1999;111(1 Suppl 1):S84–93. 2. Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, 19. Sepp N, Weyer K, Haun M, Zelger B, Thaler J, Faber V, et al. et al. EORTC classification for primary cutaneous lympho- Differentiation of primary and secondary cutaneous B-cell mas: a proposal from the Cutaneous Lymphoma Study lymphoma by Southern blot analysis. Am J Clin Pathol 1996; Group of the European Organization for Research and Treat- 106:749–57. ment of Cancer. Blood 1997;90:354–71. 20. Slater DN. MALT and SALT: the clue to cutaneous B-cell 3. Bastion Y, Berger F, Bryon PA, Felman P, Ffrench M, Coiffier lymphoproliferative disease. Br J Dermatol 1994;131:557–61. B. Follicular lymphomas: assessment of prognostic factors in 21. Willemze R, Beljaards RC, Meijer CJ, Rijlaarsdam JR. Classi- 127 patients followed for 10 years. Ann Oncol 1991;2S:123–9. fication of primary cutaneous lymphomas. Historical over- 4. Cerroni L, Arzberger E, Pütz B, Höfler G, Metze D, Sander CA, view and perspectives. Dermatology 1994;189(Suppl 2):8–15. et al. Primary cutaneous follicle center cell lymphoma with 22. Kerl H, Cerroni L. The morphologic spectrum of cutaneous follicular growth pattern. Blood 2000;95:3922–8. B-cell lymphomas. Arch Dermatol 1996;132:1376–7. 5. Dabski K, Banks PM, Winkelmann RK. Clinicopathologic 23. Kurtin PJ, Di Caudo DJ, Habermann TM, Chen MG, Su WP. spectrum of cutaneous manifestations in systemic follicular Primary cutaneous large cell lymphomas. Morphologic, im- lymphoma: a study of 11 patients. Cancer 1989;64:1480–5. munophenotypic, and clinical features of 20 cases. Am J Surg 6. Armitage JO, Weisenburger DD. New approach to classifying Pathol 1994;18:1183–91. non-Hodgkin’s lymphomas: clinical features of the major 24. Willemze R, Rijlaarsdam JU, Meijer CJ. Are most primary histologic subtypes. Non-Hodgkin’s Lymphoma Classifica- cutaneous B-cell lymphomas “marginal cell lymphomas”? tion Project. J Clin Oncol 1998;16:2780–95. Br J Dermatol 1995;133:950–2. 7. Aarts WM, Willemze R, Bende RJ, Meijer CJ, Pals ST, van 25. Mann RB, Bernard CW. Criteria for the cytological subclas- Noesel CJ. VH gene analysis of primary cutaneous B-cell sification of follicular lymphomas: a proposed alternative lymphomas: evidence for ongoing somatic hypermutation method. Hematol Oncol 1983;1:187–92. and isotype switching. Blood 1998;92:3857–3864. 26. Franco R, Fernandez-Vazquez A, Rodriguez-Peralto JL, Bel- 8. Baldassano MF, Bailey EM, Ferry JA, Harris NL, Duncan LM. las C, López-Ríos F, Sáez A, et al. Cutaneous follicular B-cell Cutaneous lymphoid hyperplasia and cutaneous marginal lymphoma. Description of a series of 18 cases. Am J Surg zone lymphoma: comparison of morphologic and immuno- Pathol 2001;25:875–83. phenotypic features. Am J Surg Pathol 1999;23:88–96. 27. Garcia CF, Weiss LM, Warnke RA, Wood GS. Cutaneous 9. Beljaard RC, van Beek P, Willemze R. Relation between ex- follicular lymphoma. Am J Surg Pathol 1986;10:454–63. pression of adhesion molecules and clinical behaviour in 28. The Non-Hodgkin’s Lymphoma Pathologic Classification cutaneous follicle centre cell lymphomas. J Am Acad Der- Project. National Cancer Institute sponsored study of classi- matol 1997;37:34–40. 10. Cerroni L, Kerl H. Diagnostic immunohistology: cutaneous fication of non-Hodgkin’s lymphomas: summary and de- lymphomas and pseudolymphomas. Semin Cutan Med Surg scription of a for clinical usage. Cancer 1999;18:64–70. 1982;49:2112–35. 11. Cerroni L, Signoretti S, Hofler G, Annessi G, Putz B, Lack- 29. Stansfeld AG, Diebold J, Kapanaci Y, Kelenyi G, Lennert K, inger E, et al. Primary cutaneous marginal zone B-cell lym- Mioduszewska O, et al. Updated Kiel classification for lym- phoma: a recently described entity of low-grade malignant phomas. Lancet 1988;1:292–3. cutaneous B-cell lymphoma. Am J Surg Pathol 1997;21:1307– 30. Volkenandt M, Cerroni L, Rieger E, Soyer HP, Koch O, Wie- 15. necke R, et al. Analysis of the 14; 18 translocation in cuta- 12. Cerroni L, Volkenandt M, Rieger E, Soyer HP, Kerl H. bcl-2 neous lymphomas using the polymerase chain reaction. J protein expression and correlation with the interchromo- Cutan Pathol 1992;19:353–6. somal 14; 18 translocation in cutaneous lymphomas and 31. Yang B, Tubbs RR, Finn W, Carlson A, Peatty J, Hsi ED. pseudolymphomas. J Invest Dermatol 1994;102:231–5. Clinicopathologic reassessment of primary cutaneous B-cell 13. Delia D, Borrello MG, Berti E, Pierotti MA, Biassoni D, Gi- lymphomas with immunophenotypic and molecular genetic annotti R, et al. Clonal immunoglobulin gene rearrange- characterization. Am J Surg Pathol 2000;24:694–702.

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