A Multicenter Study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization for Research and Treatment of Cancer (EORTC)

OBSERVATION Granulomatous Mycosis Fungoides and Granulomatous Slack Skin A Multicenter Study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization for Research and Treatment of Cancer (EORTC)

Werner Kempf, MD; Sonja Ostheeren-Michaelis, MD; Marco Paulli, MD; Marco Lucioni, MD; Janine Wechsler, MD; Heike Audring, MD; Chalid Assaf, MD; Thomas Rüdiger, MD; Rein Willemze, MD; Chris J. L. M. Meijer, MD; Emilio Berti, MD; Lorenzo Cerroni, MD; Marco Santucci, MD; Christian Hallermann, MD; Mark Berneburg, MD; Sergio Chimenti, MD; Alistair Robson, MBBS; Martà Marschalko, MD; Dmitry V. Kazakov, MD, PhD; Tony Petrella, MD; Sylvie Fraitag, MD; Agnes Carlotti, MD; Philippe Courville, MD; Hubert Laeng, MD; Robert Knobler, MD; Philippa Golling, MD; Reinhard Dummer, MD; Günter Burg, MD

Background: Granulomatous cutaneous T-cell lympho- Stable or progressive disease was observed in most pa- mas (CTCLs) are rare and represent a diagnostic chal- tients despite various treatment modalities. Extracuta- lenge. Only limited data on the clinicopathological and neous spread occurred in 5 of 19 patients (26%), sec- prognostic features of granulomatous CTCLs are avail- ond lymphoid neoplasms developed in 4 of 19 patients able. We studied 19 patients with granulomatous CTCLs (21%), and 6 of 19 patients (32%) died of their disease. to further characterize the clinicopathological, therapeu- Disease-specific 5-year survival rate in GMF was 66%. tic, and prognostic features. Conclusions: There are clinical differences between GMF Observations: The group included 15 patients with and GSS, but they show overlapping histologic findings granulomatous mycosis fungoides (GMF) and 4 with and therefore cannot be discriminated by histologic ex- granulomatous slack skin (GSS) defined according to the amination alone. Development of hanging skin folds is World Health Organization–European Organization for restricted to the intertriginous body regions. Granulo- Research and Treatment of Cancer classification for cu- matous CTCLs show a therapy-resistant, slowly progres- taneous lymphomas. Patients with GMF and GSS dis- sive course. The prognosis of GMF appears worse than played overlapping histologic features and differed only clinically by the development of bulky skin folds in GSS. that of classic nongranulomatous mycosis fungoides. Histologically, epidermotropism of lymphocytes was not a prominent feature and was absent in 9 of 19 cases (47%). Arch Dermatol. 2008;144(12):1609-1617

HE OCCURRENCE OF SAR- been reported in the literature.9,10 In the coid-like granulomas is a World Health Organization–European Or- well-known phenomenon ganization for Research and Treatment of in malignant lymphoma Cancer (WHO-EORTC) classification for and is most commonly ob- cutaneous lymphomas, GSS is considered served in patients with Hodgkin disease.1,2 a distinct subtype of MF with characteris- T 11,12 In contrast, granulomatous features are tic clinical and histologic features. rarely found in primary cutaneous lympho- There have been only a limited number mas (CLs), with approximately 2% of all CLs of studies on granulomatous CTCLs, par- displaying granulomatous features.3,4 ticularly granulomatous MF (GMF). The Granuloma formation was reported in clinicopathological features and the course a broad variety of primary CLs,5,6 such as of granulomatous CTCLs are still poorly Se´zary syndrome,7 primary cutaneous ana- characterized. The granuloma formation can plastic large T-cell lymphoma,8 subcuta- be very extensive, so that the histologic di- neous panniculitis-like T-cell lymphoma, agnosis of lymphoma may be delayed, and and primary cutaneous B-cell lympho- the findings are often initially misdiag- mas.4 Granulomatous mycosis fungoides nosed as granulomatous dermatitis.4 There (MF) is the most common form of granu- is controversy over whether the presence of lomatous cutaneous T-cell lymphoma granulomas in CLs correlates with a better (CTCL). In contrast, granulomatous slack prognosis.5,13 Thus, a multicenter study was Author Affiliations are listed at skin (GSS) is a very rare form of CTCL, and conducted to analyze the clinical, histo- the end of this article. to date only approximately 50 cases have pathological, immunophenotypic, and ge-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Clinical and Therapeutic Data From a Series of 19 Patients With Granulomatous Cutaneous T-Cell Lymphomas

Patient No./ Treatment Extracutaneous 2nd Outcome/ Sex/Age, y Location Lesion Typea TNM Stage Therapy Response Spread Neoplasia Follow-up, y Granulomatous Mycosis Fungoides 1/F/51 Buttocks, Papules, patches IB, T2N0M0 IFN, PUVA PR None None AWD/8 extremities 2/F/20 Face, arm Patches III, T4N0M0 IFN, chemo SD LN, spleen, ocular None DOD/1 3/M/35 Groin Plaque (unilesional) IA, T1N0M0 CS, MC, RT, IFN CR None None ACR/20 4/F/81 Generalized Plaques (pigm) IB, T2N0M0 CS, MC PR None None AWD/6 5/M/39 Generalized Plaques, nodules IIB, T3N0M0 RT, chemo PR None HL DOD/2 (pigm) 6/M/52 Generalized Patches, plaques, IB, T2N0M0 PUVA, RT PD BM, retroperitoneal None DOD/1 nodules LN, spleen 7/F/64 Trunk Patches IA, T1N0M0 Imiq, IFN, PUVA, RT CR LN None ACR/6 8/F/61 Generalized Patches, plaques IA, T1N0M0 Chemo SD None None AWD/1 (pigm) 9/M/57 Generalized Patches, plaques IVA, T3N2M0 Chemo CR LN None AWD/4 10/M/47 Trunk, legs Plaques IIA, T1N1M0 Pred PD None HL AWD/5 11/M/30 Trunk Plaques IA, T1N0M0 PUVA, IFN PR None None AWD/4 (poikilodermatous) 12/F/28 Trunk Patches, plaques IA, T1N0M0 PUVA, RT, IFN PD LN, BM, liver Myeloid DOD/9 leukemia 13/M/27 Trunk Plaques, nodules IA, T1N0M0 CS, PUVA, IFN, ret SD None None AWD/7 14/M/72 Generalized Plaques, nodules IB, T2N0M0 PUVA, IFN, RT, chemo PD None None DOD/1 15/M/47 Legs Plaques, nodules IA, T1N0M0 CS, IFN, ret, RT PD None Nodal CD30ϩ DOD/5 (pigm) ALCL Granulomatous Slack Skin 16/M/55 Groin Patches, plaques, IA, T1N0M0 PUVA, ret, IFN PR None Cutaneous AWD/10 hanging CD30ϩ LPD 17/M/71 Axilla, groin Plaques, hanging IA, T1N0M0 NA NA None None AWD/16 18/F/35 Trunk, groin, Patches, plaques, IA, T1N0M0 Excision, CS, MC, PUVA, PD None None AWD/15 leg hanging IFN 19/F/22 Trunk including Patches, plaques, IA, T1N0M0 Excision, carmustine PR None None AWD/28 axilla/groin hanging

Abbreviations: ACR, alive with complete remission; ALCL, anaplastic large cell lymphoma; AWD, alive with disease; BM, bone marrow; chemo, chemotherapy; CR, complete tumor regression; CS, topical corticosteroids; DOD, died of disease; hanging, hanging skin folds; HL, Hodgkin lymphoma; IFN, interferon alfa; imiq, imiquimod; LN, lymph nodes; LPD, lymphoproliferative disorder; MC, mechlorethamine hydrochloride; NA, not available; pigm, hyperpigmented; PD, progressive disease; PR, partial tumor regression; pred, oral prednisone; PUVA, psoralen–UV-A light therapy; ret, retinoids; RT, radiotherapy; SD, stable disease. aLesions were multiple in all except patient 3.

notypic features of granulomatous reactions in CTCLs, par- mation on therapeutic interventions, as well as follow-up on ticularly GMF and GSS, as well as the course and prognosis course and outcome. of these granulomatous CTCLs. All biopsy specimens were formalin-fixed and paraffin- embedded. Hematoxylin-eosin staining as well as staining for elastic fibers was performed. Immunohistochemical staining for lym- METHODS phocytic (CD3, CD4, CD8, CD30) and histiocytic (CD68) antigens was visualized by the streptavidin-biotin or alkaline phos- PATIENTS AND BIOPSIES phatase–anti–alkaline phosphatase method according to stan- dard protocols. Rearrangement of T-cell receptor ␥ genes was as- 15,16 Twenty-three skin biopsy specimens from 23 patients with well- sessed by polymerase chain reaction as previously described. documented disease from a total of 18 European centers were sub- Statistical analysis was performed with SPSS version 15.0 mitted as “granulomatous CTCL” by the members of the EORTC software (SPSS Inc, Chicago, Illinois). Cutaneous Lymphoma Histopathology Task Force. Cases to be included and further analyzed had to show prominent granu- RESULTS loma formation or numerous histiocytic giant cells or a histiocyte- rich infiltrate defined by histiocytes accounting for more than 25% of the entire infiltrate. The following clinical data were recorded: According to the WHO-EORTC classification for cutane- sex, age at diagnosis, biopsy site, clinical manifestation includ- ous lymphomas,11,12 19 cases of CTCL could be identified ing location and distribution of skin lesions, TNM stage at diag- 14 and classified as GMF (n=15) or GSS (n=4). Two cases nosis according to TNM classification of malignant tumors, age originally submitted as GSS were reclassified as GMF be- at first symptoms (if available), age at first biopsy specimen displaying granulomatous features, results of staging investiga- cause the skin lesions did not evolve to hanging skin folds tions, treatment, response to treatment, and outcome. during the follow-up period. Four additional cases were Inclusion criteria included hematoxylin-eosin and immu- classified as primary cutaneous peripheral T-cell lym- nohistochemical stainings of diagnostic quality, written de- phoma, unspecified, and were excluded from further analy- tailed data or photographs of clinical presentation, and infor- sis because this study focused on GMF and GSS. In addi-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 2. Histologic, Immunophenotypic, and Genotypic Data From a Series of 19 Patients With Granulomatous Cutaneous T-Cell Lymphomas

Patient Growth Giant El No. Pattern Epidermotropism Cell Size Granuloma Cells Loss Elastophagocytosis Eos Plasm Angio Phenotype Genotype Granulomatous Mycosis Fungoidesa 1 Diffuse ϩ S-M pleo ϩϩϩϩ ϩ− ϩ CD3ϩ,4−,8ϩ, TCRϩ 30−; TIA-1ϩ 2 Diffuse − S-M pleo ϩϩNA NA − − − CD3ϩ,4ϩ NA 3 Perivascular ϩ/− Lining up S ϩϩ(Few) NA NA − − − CD3ϩ,4ϩ TCRϩ 4 Perivascular − S − ϩ (Few) NA NA − − − NA TCRϩ 5 Perivascular/ ϩ S-M pleo ϩ (Few) ϩϩ − ϩ − − CD3ϩ,4ϩ,8−, TCRϩ periadnexal 30−/ϩ; TIA-1ϩ/− 6 Perifollicular/ ϩ S ϩϩϩ − ϩ − − CD3ϩ,4ϩ,8−, TCRϩ periadnexal 30−; TIA-1− 7 Perivascular/ − S-M-L pleo ϩ − ϩ − ϩ (Few) ϩ − CD3ϩ,4−, TCRϩ nodular 8ϩ,30−; TIA-1ϩ/− 8 Nodular − S-M pleo ϩ − ϩ − − − − CD3ϩ,4ϩ,30−; TCRϩ TIA-1ϩ 9 Nodular −/ϩ S ϩ − ϩ − ϩ − − CD3ϩ,4ϩ,8−, TCRϩ 30−; TIA-1− 10 Nodular − S ϩ − ϩ − ϩ − − CD3ϩ,4−,8ϩ TCR− 11 Diffuse − S − ϩϩ −−−ϩ CD3ϩ,4ϩ,8−, TCRϩ 30− ;TIA-1− 12 Diffuse ϩ S-M pleo ϩ − ϩ − ϩ − ϩ CD3ϩ,4ϩ,8−, TCRϩ 30−; TIA-1− 13 Diffuse −/ϩ S ϩ − ϩ − ϩ − ϩ CD3ϩ,4ϩ,8−, TCRϩ 30−; TIA-1− 14 Nodular −/ϩ S ϩ − ϩ − ϩϩ− CD3ϩ,4ϩ,8−, TCRϩ 30−; TIA-1− 15 Diffuse − S ϩϩϩ − − − − CD3ϩ,4ϩ,8−, TCRϩ 30−; TIA-1− Granulomatous Slack Skin 16 Diffuse − S − ϩϩ − ϩ (Few) ϩϩCD3ϩ,4ϩ,8−, TCRϩ 30−; TIA-1− 17 Diffuse − S ϩϩϩϩ ϩ(Few) ϩ − CD3ϩ,4−, TCRϩ 8ϩ,30−; TIA-1−; granzyme B− 18 Diffuse − S-M pleo − ϩϩ ϩ ϩ − − CD3ϩ,4ϩ,8− TCRϩ 19 Diffuse ϩ S-M pleo − ϩϩ − ϩϩϩCD3ϩ,4ϩ,8− TCRϩ

Abbreviations: Angio, angiocentric growth; El Loss, loss of elastic fibers on elastica staining; Eos, eosinophilic granulocytes; L, large; M, medium-sized; NA, not available; Plasm, plasma cells; pleo, pleomorphic; S, small; TIA-1, T-cell intracellular antigen 1; TCR, T-cell receptor rearrangement (ϩ, monoclonal; −, polyclonal); ϩ, present/positive; −, absent/negative; −/ϩ, very few cells positive (Ͻ5%); ϩ/−, few positive cells (10%-20%). aAll except patient 3 had multiple lesions. Patient 6 had folliculotropic disease.

tion to the 23 cases of CTCL, 3 cases of secondary cutaneous diagnosis was 48 years, with a broad range (20-72 years). involvement by systemic T-cell non-Hodgkin lym- In 2 patients, the disease had started in childhood before phoma— including 1 case of nodal Lennert lymphoma (as age 10 years. All patients in this group exhibited patches a variant of nodal peripheral T-cell lymphoma), 1 case of and plaques (Figure 1), some of them with atrophy of angioimmunoblastic T-cell lymphoma, and 1 case of nodal the skin but without cutis laxa–like features. In 1 patient, CD4ϩ T-cell non-Hodgkin lymphoma not otherwise speci- the disease was restricted to a solitary plaque represent- fied—had been submitted but were excluded from this ing unilesional MF. In 5 of 15 patients (33%), skin le- study because of their primary extracutaneous origin. sions were hyperpigmented (Figure 2). At the time of The clinical data, therapy, and outcome are pre- diagnosis, 13 of 15 (87%) were in stage I or II according sented in Table 1. Table 2 displays the histopatho- to the TNM staging system.14 First symptoms of the dis- logical, immunophenotypical, and genotypic features. ease had been reported to be present years or decades (median, 11 years; range, 1-15 years) before the diagnosis of GROUP 1: GMF GMF was established. Four patients had developed other types of lymphoid or myeloid neoplasms before or after Clinical Features the occurrence of GMF: Two patients had had nodal Hodg- kin lymphoma, nodular sclerosing type, 20 years before This group consisted of 15 patients, 9 men and 6 women, and 4 years after the occurrence of GMF. In the third pa- resulting in a male to female ratio of 1.5:1. Median age at tient, nodal CD30ϩ anaplastic large-cell lymphoma devel-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 3. Granulomatous mycosis fungoides showing dense nodular lymphocytic infiltrates throughout the entire dermis. Note the grenz zone and the absence of epidermotropism (hematoxylin-eosin, original magnification ϫ25).

served in 5 (33%) with involvement of lymph nodes, liver, and bone marrow (Table 1). In 3 of 15 patients (20%), transformation into CD30ϩ large-cell phenotype was observed. Six of 15 patients (40%), including the 3 patients with transformation into a CD30ϩ large-cell phenotype, died of lym- Figure 1. Granulomatous mycosis fungoides showing erythematous patches and plaques. Note that clinical features are not suggestive of granulomatous phoma after a median follow-up of 5.3 years (range, 1-20 histologic findings. years) after diagnosis and 16 years (range, 2-54 years) after onset of the disease, ie, the appearance of first symptoms. Disease-specific 5-year survival rate in GMF was 66%.

Histologic Features

The infiltrate was diffuse in 6 of 15 cases (40%), nodular in 4 (27%) (Figure 3), and perivascular or periadnexal in 5 (33%), and it extended throughout the entire dermis in 8 cases (53%) and into the subcutis in 5 (33%). Epi- dermotropism of lymphocytes was a prominent feature in only 4 cases (27%) and was subtle with only a few lymphocytes in another 4. In the remaining 7 biopsy specimens (47%), epidermotropism of lymphocytes could not Figure 2. Granulomatous mycosis fungoides showing hyperpigmented be detected. The lymphocytic component of the infiltrate patches. consisted of small lymphocytes without significant nuclear atypia in 4 cases (27%), whereas small lymphocytes with oped 4 years before the diagnosis of GMF, and the fourth cerebriform nuclei were found in 5 (33%). In 6 cases (40%), patient had had myeloid leukemia in childhood 21 years tumor cells were small to medium-sized with pleomor- before the diagnosis of GMF. In all 4 patients, complete phic nuclei, and in 1 of these cases large pleomorphic lym- remission from nodal non-Hodgkin lymphomas or my- phocytes were intermingled with the predominant small eloid leukemia was observed. to medium-sized tumor cells. Eosinophils were present and Treatment of GMF was heterogeneous, involving com- readily identifiable in 9 of 15 cases (60%) (Figure 4). Clus- bined treatment with psoralen–UV-A and interferon alfa ters of plasma cells, which were not related to overlying in 7 patients. Three patients received chemotherapy with ulceration, were observed in 2 (13%) of the biopsy speci- the CHOP regimen (cyclophosphamide, doxorubicin, vin- mens. Granuloma formation with aggregations of histio- cristine sulfate, and prednisolone acetate), whereas 2 pa- cytes was found in 13 of 15 cases (87%), and multinucle- tients were treated with single-agent chemotherapy. Ra- ated histiocytic giant cells were present in 8 biopsy diation was applied in 7 of 15 patients. Other treatment specimens (53%) (Figure 4 and Figure 5). In all cases modalities included topical corticosteroids, imiquimod, and with granuloma formation, there was a sarcoid-like pat- systemic retinoids. Complete tumor regression was ob- tern of granulomas (Figure 4), whereas a granuloma an- served in only 3 of 15 patients (20%), but recurrence de- nulare–like pattern could not be found in any of the speci- veloped within 2 years in 1 patient. In both patients with mens. Granulomas were absent in 2 specimens, but complete remission, the remission followed treatment with numerous multinucleated giant cells were scattered in a interferon alfa. Progression of the disease was observed in diffuse lymphocytic infiltrate in those 2 cases (Figure 6 6 of 15 patients (40%), and extracutaneous spread was ob- and Figure 7). In 4 cases (27%), infiltration of dermal or

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Figure 6. Granulomatous mycosis fungoides showing diffuse lymphocytic infiltrate covering all dermal layers (hematoxylin-eosin, original magnification ϫ25).

Figure 7. Granulomatous mycosis fungoides showing scattered multinucleated giant cells and absence of granuloma formation (hematoxylin-eosin, original magnification ϫ20). Inset, Note the scattered multinucleated giant cells with phagocytosis of small lymphocytes (hematoxylin-eosin, original magnification ϫ100).

Figure 4. Granulomatous mycosis fungoides. A, Infiltrate of small lymphocytes and granuloma formation (hematoxylin-eosin, original subcutaneous vessels by lymphocytes was found and, in 2 magnification ϫ40). B, The lymphocytes exhibit nuclear atypia. Note of these 4 cases, numerous multinucleated giant cells were admixed eosinophils (hematoxylin-eosin, original magnification ϫ200). observed around and within the walls of large veins in the subcutis (Figure 8). Elastica staining was available in 12 cases. Loss of elastic fibers throughout the infiltrated areas was found in all 12 biopsy specimens, but elastophagocytosis was found in only 1 of 12 specimens (8%).

Immunophenotype and Genotype

The lymphocytes expressed a CD3ϩ, CD4ϩ, CD8− phenotype in 12 of 15 cases (80%). One of those cases showed expression of TIA-1 by CD4ϩ lymphocytes. Three cases (20%) exhibited a CD3ϩ, CD4−, CD8ϩ cytotoxic phenotype. Clonal rearrangement of T-cell receptor ␥ genes was detected by polymerase chain reaction in 13 (87%) of the biopsy specimens.

GROUP 2: GSS

Clinical Features Figure 5. Granulomatous mycosis fungoides showing infiltrate with histiocytic multinucleated giant cells (hematoxylin-eosin, original The GSS group included 2 men and 2 women. Median age magnification ϫ100). at diagnosis was 46 years (range, 22-71 years). All 4 pa-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 8. Infiltration of a large subcutaneous vein by the infiltrate containing multinucleated giant cells (hematoxylin-eosin, original magnification ϫ20).

Figure 10. Granulomatous slack skin showing dense lymphocytic infiltrate throughout the entire dermis (hematoxylin-eosin, original magnification ϫ25).

Figure 9. Granulomatous slack skin showing bulky skin folds in the right axilla.

tients showed poikilodermatous patches and plaques in the intertriginous areas (axillae and groins) with the development of characteristic bulky skin folds (Figure 9). In 1 patient who had additional skin lesions on nonintertrigi- nous areas of the trunk, only the lesions in the axillae and groin underwent cutis laxa–like changes, whereas skin lesions at other sites did not evolve in a similar way. All patients experienced an indolent, slowly progressive course without extracutaneous spread and were alive with disease after a median follow-up of 17 years. One patient developed a second lymphoid neoplasia (CD30ϩ lymphoproliferative disorder of the skin) after the occurrence of Figure 11. Granulomatous slack skin showing numerous multinucleated GSS. Partial remission was achieved in 2 patients by pso- giant cells but lack of granuloma formation (hematoxylin-eosin, original ralen–UV-A or topical carmustine. However, none of the magnification ϫ100). other therapies, including surgical excision, topical corti- costeroid, and mechlorethamine hydrochloride, or systemic therapies such as interferon alfa, in combination with tire dermis and the upper parts of the subcutis with nu- retinoids, was effective, and in none of the patients was com- merous scattered multinucleated giant cells displaying plete tumor regression observed. All patients were alive af- more than 10 nuclei per cell (Figure 10 and Figure 11). ter a median follow-up of 17 years (range, 10-28 years), In addition, granuloma formation was identified in 1 of resulting in a 5-year survival rate of 100%. 4 cases. One biopsy specimen exhibited a lichenoid infiltrate of small to medium-sized lymphocytes mostly in Histologic Features the upper and mid-dermis with sarcoid-like granuloma and a few giant cells. This pattern was not related to ini- Five biopsy specimens of the 4 patients were available tial disease manifestation because this biopsy specimen for histologic evaluation. In 4 of the 5 specimens there was obtained from established lesions with hanging skin was a diffuse lymphocytic infiltrate throughout the en- folds. Epidermotropism of lymphocytes was present in

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 only 1 case, but absent or very subtle with only a few scat- In contrast, all patients with GSS were still alive after tered intraepidermal lymphocytes in the remaining 3 cases. a median follow-up of 17 years despite the fact that GSS The lymphocytes were small without nuclear atypia in was therapy resistant and complete remission could not 2 cases and small to medium-sized pleomorphic cells in be achieved in any of the patients. Recently, response of the remaining 2 cases. Eosinophils could be found in all GSS to topical mechlorethamine was observed in 2 pa- specimens, and mostly scattered plasma cells were pres- tients,24 but definitive therapy for GSS has yet to be es- ent in 3 of 4 cases. In 2 cases, infiltration of large veins tablished. Extracutaneous spread is exceedingly rare in in the subcutis by multinucleated giant cells and lym- GSS and did not occur in our series of patients with GSS. phocytes was observed. Elastica staining demonstrated Patients with GMF and GSS are known to be at risk for loss of elastic fibers in the infiltrated area in all cases. Elas- the development of second lymphoid neoplasias. In our tophagocytosis was subtle and found in only 2 of 4 cases. series, 4 of 19 patients (21%) with GMF or GSS had experienced a second lymphoma before or after occurrence Immunophenotype and Genotype of granulomatous CTCLs, and an additional patient had had myeloid leukemia. This prevalence is lower than that In 3 of 4 patients, lymphocytes displayed a CD3ϩ CD4ϩ reported in the literature, with 48% of the patients with CD8− phenotype. In contrast, 1 case showed a CD3ϩ CD4− GSS having second lymphoid neoplasias.10,25,26 These pa- CD8ϩ phenotype. Monoclonal rearrangement of T-cell tients may be overrepresented in the literature because of receptor ␥ genes could be demonstrated by polymerase the development of a second lymphoma and, eventually, chain reaction in all cases. In addition, monoclonal re- misinterpretation of large-cell transformation as develop- arrangement of T-cell receptor ␤ genes was demon- ment of a second anaplastic large-cell lymphoma unre- strated by Southern blot technique in 1 of the cases. lated to GSS. Hodgkin lymphoma is the most common second neoplasia in patients with granulomatous CTCLs in the literature as well as in our series.10,25,26 The interval be- COMMENT tween lymphoid neoplasias and GMF or GSS may be years or even decades, as seen in 1 patient in our series who de- In our series, GMF was the most common disorder, ac- veloped nodal Hodgkin lymphoma 20 years before onset counting for 79% of the analyzed cases. Patients affected of GMF. Thus, lifelong observation of patients with GMF by GMF and GSS were on average diagnosed in their fifth and GSS is required. decade of life, with a male predominance in GMF. In both Histologically, a diffuse infiltrate of lymphocytes ex- disorders, the disease extent and distribution of skin le- tending throughout the entire dermis and the subcutis was sions at diagnosis corresponded to TNM stage Ia in the the most common growth pattern (Figure 4). Granulo- majority of patients (11 of 19 [58%]), with the trunk rep- mas were sarcoid-like in all biopsy specimens (Figure 6). resenting the predilection site (Figure 1). The clinical pre- Other patterns of granulomatous reactions, such as granu- sentation of skin lesions in GMF was not indicative of the loma annulare–like, palisaded, or necrobiotic granuloma, histologically detected granulomatous features (Figure 1). as reported in the literature,27-30 were not found in our se- One-third of the patients with GMF manifested hyperpig- ries. In 70% of the CTCL cases, the infiltrates contained mented skin lesions (Figure 2). Hyperpigmented MF has histiocytic giant cells displaying 10 or more nuclei been reported as a common feature in CD8ϩ MF,17 but none (Figure 11). Remarkably, infiltration of the vessel walls of of the cases with hyperpigmented skin lesions in our se- large veins by small lymphocytes and even by large mul- ries displayed a CD8ϩ cytotoxic T-cell phenotype. tinucleated histiocytic giant cells was observed in a third Psoralen–UV-A and/or interferon alfa in addition to of the cases (Figure 8). This is more common than re- radiotherapy were the most commonly used treatment ported in the literature.4,5 Epidermotropism of lympho- modalities. Complete tumor regression could be achieved cytes was previously reported as a common finding in granu- in only 3 of 15 patients (20%) with GMF. In half of the lomatous CTCLs and considered to be a useful histologic patients, the disease showed a slowly progressive course. feature for discrimination of granulomatous CTCLs from Extracutaneous spread was observed in a third of pa- reactive granulomatous disorders.5 In our series, how- tients with GMF and was associated with transforma- ever, epidermotropism was absent in almost half of the cases, tion into CD30ϩ anaplastic large-cell lymphoma in 20% limiting its value as a diagnostic marker in GMF and GSS. of the patients. Six of 15 patients (40%) with GMF, in- Although classic MF commonly displays epidermotro- cluding the 3 patients with large-cell transformation, died pism, this histologic feature is not a prerequisite for MF of the disease. The percentage of patients with unfavor- according to the WHO-EORTC classification. Thus, lack able outcome is identical to that in the study by Chen et of epidermotropism does not exclude the diagnosis of MF. al,13 who reported death due to the disease in 40% of pa- In those cases, diagnosis of MF relies on the characteristic tients with GMF. Whereas the occurrence of granulo- clinical presentation with patches and plaques. mas in MF has been considered to be associated with a Diagnosis in granulomatous CTCLs is often delayed, favorable prognosis by some authors,6,18 other investiga- with a latency of years to decades after the onset of initial tors could not confirm this observation.19-21 These and symptoms. Diagnosis is particularly challenging in cases our findings demonstrate that GMF is not associated with with predominant granuloma formation in the absence of a better prognosis than classic, nongranulomatous MF. nuclear atypia or epidermotropism of tumor cells. Detec- In fact, the 5-year survival rate of GMF (66%) is worse tion of a neoplastic T-cell clone, which was present in nearly than that of classic MF and similar to that of folliculo- all cases, may thus be a useful diagnostic adjunct in granu- tropic MF.22,23 lomatous CTCLs.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 The histologic features of GSS have been reported as Chimenti), Semmelweis Medical School, Budapest, Hun- pathognomonic, with a diffuse lymphocytic infiltrate har- gary (Dr Marschalko), Necker-Enfants Malades Hopital, boring numerous scattered multinucleated giant cells5,31 Paris, France (Dr Fraitag), and Hopital Tarnier Cochin, (Figures 6 and 7), but identical histologic features can Paris, France (Dr Carlotti); Departments of Pathology, Uni- also be observed in GMF.32 Remarkably, this pattern was versity of Pavia, Pavia, Italy (Drs Paulli and Lucioni), Hoˆ- also found in 2 of the 15 GMF cases in our series (Figures 6 pital Henri Mondor, Creteil, France (Dr Wechsler), Luit- and 7) and is therefore not pathognomonic for GSS. These pold Hospital, Würzburg, Germany (Dr Rüdiger), Vrije observations demonstrate that GMF and GSS differ clini- Universiteit Medical Center, Amsterdam, the Nether- cally but show overlapping histologic findings and there- lands (Dr Meijer), University Hospital, Djion, France (Drs fore cannot be discriminated by histologic examination Petrella and Courville), and Cantonal Hospital, Aarau, Swit- alone. It should be recalled that both diseases are con- zerland (Dr Laeng); Department of Human Pathology and sidered variants of a single disease,33 which implies that Oncology, University of Florence Medical School, Flo- GSS may be listed in future classifications for cutaneous rence, Italy (Dr Santucci); Hautklinik Linden, Hannover, lymphomas as another variant and not a subtype of MF. Germany (Dr Hallermann); Skin Tumour Unit, St John’s As emphasized by Scarabello and coworkers,4 diagnosis Institute of Dermatology, St Thomas’ Hospital, London, of GSS should rest on clinical grounds and be restricted England (Dr Robson); Sikl’s Department of Pathology, to patients presenting clinically with characteristic bulky Charles University, Medical Faculty Hospital, Pilsen, Czech skin lesions. Republic (Dr Kazakov); and Division of Special and En- The classic pathogenetic concept links the develop- vironmental Dermatology, Department of Dermatology, ment of hanging skin folds in GSS to destruction of elas- Vienna, Austria (Dr Knobler). tic fibers due to elastophagocytosis by histiocytic giant Correspondence: Werner Kempf, MD, Department of cells. However, loss of elastic fibers was found in all ex- Dermatology, University Hospital Zürich, Gloriastrasse 31, amined cases. The extent of loss of elastic fibers corre- CH-8091 Zürich, Switzerland ([email protected]). lated with the extent of the granulomatous infiltrate but Author Contributions: All authors had full access to was not restricted to GSS. Moreover, only skin lesions all of the data in the study and take responsibility for in skin folds such as the axilla and the groin underwent the integrity of the data and the accuracy of the data cutis laxa–like changes, whereas skin lesions present at analysis. Study concept and design: Kempf, Burg, and other body sites did not evolve in a similar way. These Willemze. Acquisition of data: All authors. Analysis and observations suggest that development of hanging skin interpretation of data: Kempf, Ostheeren-Michaelis, folds is a location-related phenomenon and not solely the and Burg. Drafting of the manuscript: Kempf. Critical result of the destruction of elastic fibers. Hypotheti- revision of the manuscript for important intellectual con- cally, the continuous stretching of elastic fibers in the in- tent: All authors. Statistical analysis: Kempf. Study super- tertriginous body areas during physiologic movements vision: Kempf, Burg, and Willemze. may facilitate the loss of their function when these re- Financial Disclosure: None reported. gions become affected by lymphomatous infiltrates. Additional Contributions: We thank Beatrix Mueller for The pathogenetic mechanisms of granuloma forma- the excellent technical assistance. tion in lymphoid neoplasms are poorly understood. Granu- lomatous reaction has been regarded by some authors as a local tissue response to the infiltrating malignant cells REFERENCES or their antigens,34 but this hypothesis has been criticized by others on the basis of the occurrence of granulomas in 1. Sacks EL, Donaldson SS, Gordon J, Dorfman RF. 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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 10. Clarijs M, Poot F, Laka A, Pirard C, Bourlond A. Granulomatous slack skin: treat- of 525 patients with mycosis fungoides and Se´zary syndrome: clinical prognos- ment with extensive surgery and review of the literature. Dermatology. 2003; tic factors and risk for disease progression. Arch Dermatol. 2003;139(7):857- 206(4):393-397. 866. 11. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous 24. Hultgren TL, Jones D, Duvic M. Topical nitrogen mustard for the treatment of lymphomas. Blood. 2005;105(10):3768-3785. granulomatous slack skin. Am J Clin Dermatol. 2007;8(1):51-54. 12. Burg G, Jaffe ES, Kempf W, et al. WHO/EORTC classification of cutaneous 25. Noto G, Pravata G, Miceli S, Arico M. Granulomatous slack skin: report of a case lymphomas. In: LeBoit P, Burg G, Weedon D, Sarasin A, eds. WHO Books: Tu- associated with Hodgkin’s disease and a review of the literature. Br J Dermatol. mors of the Skin. Lyon, France: WHO IARC; 2005. 1994;131(2):275-279. 13. Chen KR, Tanaka M, Miyakawa S. Granulomatous mycosis fungoides with small 26. van Haselen CW, Toonstra J, van der Putte SJ, van Dongen JJ, van Hees CL, van intestinal involvement and a fatal outcome. Br J Dermatol. 1998;138(3):522- Vloten WA. Granulomatous slack skin: report of three patients with an updated 525. review of the literature. Dermatology. 1998;196(4):382-391. 14. International Union Against Cancer. TNM Classification of Malignant Tumors. 6th 27. Barksdale SK, Perniciaro C, Halling KC, Strickler JG. Granuloma annulare in pa- ed. New York, NY: Wiley-Liss; 2002. tients with malignant lymphoma: clinicopathologic study of thirteen new cases. 15. Whittaker SJ, Smith NP, Jones RR, Luzzatto L. Analysis of beta, gamma, and J Am Acad Dermatol. 1994;31(1):42-48. delta T-cell receptor genes in mycosis fungoides and Se´zary syndrome. Cancer. 28. Garrie SA, Hirsch P, Levan N. Granuloma annulare–like pattern in mycosis fungoides. 1991;68(7):1572-1582. Arch Dermatol. 1972;105(5):717-719. 16. Wood GS, Tung RM, Haeffner AC, et al. Detection of clonal T-cell receptor gamma 29. Miyamoto T, Mihara M. Subcutaneous granuloma annulare with Hodgkin’s disease. gene rearrangements in early mycosis fungoides/Se´zary syndrome by polymer- J Dermatol. 1996;23(6):405-407. ase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). 30. Rongioletti F, Cerroni L, Massone C, Basso M, Ciambellotti A, Rebora A. Differ- J Invest Dermatol. 1994;103(1):34-41. ent histologic patterns of cutaneous granulomas in systemic lymphoma. JAm 17. Dummer R, Kamarashev J, Kempf W, Haffner AC, Hess-Schmid M, Burg G. Acad Dermatol. 2004;51(4):600-605. Junctional CD8ϩ cutaneous lymphomas with nonaggressive clinical behavior: a 31. LeBoit PE. Granulomatous slack skin. Dermatol Clin. 1994;12(2):375-389. CD8ϩ variant of mycosis fungoides? Arch Dermatol. 2002;138(2):199-203. 32. Metzler G, Schlagenhauff B, Krober SM, Kaiserling E, Schaumburg-Lever G, Lischka 18. Schwartz RA, Burgess GH, Holtermann OA. Mycosis fungoides associated with G. Granulomatous mycosis fungoides: report of a case with some histopatho- florid sarcoid reactions. J Surg Oncol. 1980;14(4):347-357. logic features of granulomatous slack skin. Am J Dermatopathol. 1999;21(2): 19. Schewach-Millet M, Azizi E, Semah D, Bubis JJ, Chaitchuk S. Cutaneous T-cell 156-160. lymphoma first presenting at the tumor stage: a clinicopathologic study. Int J 33. Topar G, Zelger B, Schmuth M, Romani N, Thaler J, Sepp N. Granulomatous slack Dermatol. 1984;23(4):275-278. skin: a distinct disorder or a variant of mycosis fungoides? Acta Derm Venereol. 20. Dabski K, Stoll HJ. Granulomatous reactions in mycosis fungoides. J Surg Oncol. 2001;81(1):42-44. 1987;34(4):217-229. 34. Kahn LB, Gordon W, Camp R. Florid sarcoid reaction associated with lymphoma 21. Papadavid E, Yu RC, Bunker C, Scoones D, Chu AC. Tumour progression in a of the skin. Cancer. 1974;33(4):1117-1122. patient with granulomatous mycosis fungoides. Br J Dermatol. 1996;134(4): 35. Anderson R, Geraint James D, Peters PM, Thomson AD. Local sarcoid-tissue 740-743. reactions. Lancet. 1962;1(7241):1211-1213. 22. Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous 36. Ruiz-de-Casas A, Carrizosa-Esquivel A, Herrera-Saval A, Rios-Martı´n JJ, Cama- lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the Eu- cho F. Se´zary syndrome associated with granulomatous lesions during treat- ropean Organization for Research and Treatment of Cancer. Blood. 1997;90 ment with bexarotene. Br J Dermatol. 2006;154(2):372-374. (1):354-371. 37. Ikonomou IM, Aamot HV, Heim S, Fossa A, Delabie J. Granulomatous slack skin 23. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome with a translocation t(3;9)(q12;p24). Am J Surg Pathol. 2007;31(5):803-806.

Archives Web Quiz Winner

ongratulations to the winner of our September C quiz, Rajesh Chhetia, MD, Dermatology Consul- tant, Sanchaiti Hospital, Kandivali, Mumbai, India. The correct answer to our September challenge was lipoid pro- teinosis. For a complete discussion of this case, see the Off-Center Fold section in the October Archives (Cole JA, Novosel TA, Williams JV. Pocklike scarring and sub- lingual papules in a child. Arch Dermatol. 2008;144[10]: 1383-1388). Be sure to visit the Archives of Dermatology Web site (http://www.archdermatol.com) to try your hand at the interactive quiz. We invite visitors to make a diagnosis based on selected information from a case report or other feature scheduled to be published in the following month’s print edition of the Archives. The first visitor to e-mail our Web editors with the correct answer will be recog- nized in the print journal and on our Web site and will also receive a free copy of The Art of JAMA II.

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