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Reticulohistiocytoma of the dorsum
Clinical a n d l a b o r a t o r u s t u d i e s III II
II
I
I
I
I
I
_
III II II
Reticulohistiocytoma of the dorsum Emilio Berti, M.D.,* Elvio Alessi, M.D.,* Ruggero Caputo, M.D.,* Raffaele Gianotti, M.D.,* Domenico Delia, M.D.,** and Paolo Vezzoni, M.D.*** Milan, Italy To clarify the nature of reticulohistiocytoma of the dorsum, 19 cases, including three of the seven original cases described by Crosti, were evaluated clinically, histologically, and immunologically. In seven cases gene rearrangement analysis was also performed. Results indicate that reticulohistiocytoma of the dorsum must be considered a primary cutaneous B cell lymphoma of follicular center cell origin. This localized skin disease has a very slowly progressive course, with many patients showing no systemic involvement even after prolonged follow-up. (J AM ACADDERMATOL1988;19:259-72.)
In 1951 Crosti* used the term "reticulohistiocytoma of the dorsum" to define seven cases characterized by figurate erythematous patches and by firm nodules often merging into mammillated plaques that developed on the back and the lateral portion of the thorax in adult life. On histologic examination the lesions showed a dense infiltrate o f lymphocytes and large atyical histiocytic-like cells around the vessels and adnexa of the dermis, with rare mitotic figures. The course of the disease was very slow, with possible involvement of lymph nodes and viscera years later. The lesions w e r e markedly sensitive to radiation therapy. Crosti considered reticulohistiocytoma of the dorsum to be a new clinicopathologic entity that
had to be differentiated from mycosis fungoides d'emblde, Hodgkin's disease, and pseudolymphomas. Up to 1987, 42 cases of Crosti's reticulohistiocytoma of the dorsum had been reported as such (Table I), and I 1 other similar cases had been described under different names (Table II). Crosti's reticulohistiocytoma of the dorsum was considered to be a histiocytic disorder by some authors 4'6's'9 and a T cell lymphoma by others,~~ t,. but recently its striking similarities with primary cutaneous germinal center cell lymphomas have been underlined.22,23,t The purpose of our study was to clarify the nature of this entity by immunologic investigations and gene rearrangement analysis. PATIENTS AND METHODS
From The First Clinic of Dermatology, University of Milan,* the National Cancer Institute,** and the Department of General Pathology, University of Milan.*** Carried out within the framework of Italian National Research Council Project No. 44. Presented in part as a poster at the Forty-fifth Annual Meeting of the American Academy of Dermatology, New Orleans, LA, Dee, 611, 1986; presented as an advanced lecture at the Eighth International Dermatopathology Colloquium, Barcelona, Spain, Oct. 8-10, 1987. Accepted for publication Nov. 12, 1987. Reprint requests to: Dr. Elvio Alessi, Clinica Dermatologica I ~ Via Pace 9, 20122 Milan, Italy. *Crosti A. Micosi fungoide e reticoloistioeitomi cutanei maligni. Minerva Dermat 1951 ;26:3-11.
Sixteen of our patients meeting the clinical and histologic requirements suggested by Crosti and three of the seven original cases described by Crosti entered the study. Histologic and immunologic investigations on specimens fixed in Bouin's solution and embedded in paraffin were carried out in all cases, while ultrastructBonvalet D, Civatte J, Jeanmougin M, Renaud-Vilmer C. Lymphome T h type de rdticulose de Crosti. Joumdes Dermatologiques de Paris, March 12-14, 1981; abstract book, p. 13. SWillemze R, Meijer CJLM, Sentis HI, et al. Crosti's reticulohistioeytoma: a cutaneous B-cell lymphoma of follicular center cell origin, ln: Caputo R, ed. Immunodermatology. Milan: CIC Edizioni Intemazionali, 1988.
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T a b l e I, C a s e s o f r e t i c u l o h i s t i o c y t o m a o f the d o r s u m reported up to 1987
Author(s)
Crosti*
Marchini~: Cainelli t Monacelli 2 Cerutti et al. 3
Laugier et al. 4 Rimbaud et al. ~ G a m b y et al. ~
Cainelli et al. 7
Forestier et al. s Zala et al. 9
Bonvalet et al.{} Toonstra et al. Jo Payne et al." Willemze et al.II
Case No.
1 2 3 4 5 6]" 7 1 1 1 1 2 3 4 1 1 1 2 3 1 2 3 1 1 2 3 4 1 1 2 1 1 2 3 4 5 6 7 8 9 10 11
Sex
Age (yr)
M M M M M M F F M M M M M M M M F F M M F M F M
54 49 59 48 54 59 39 25 65 65 47 52 48 41 56 45 48 48 81 63 48 54 79
M M M F M M M F F M M M M M M M M M
40-60 55 53 56 68
Initial location
Scapula Back Scapula Back Back Scapula Back Back Back Back Back Back Scapula Scapula Back Back Scapula Back Back Back Scapula Back Back
Subsequent location
Trunk, lymph node Axilla, bones Back, lumbar region Lymph node Back Back Lymph node Back, axilla Back Back Back Scapula, back Back -Back Back Lymph node, scapula -----
3 back, 1 axilla Back Scapula Scapula Thorax, neck
Back, thorax Neck, thorax, arm, back Back Thorax, abdomen, back
6 back, 5 chest or abdomen
1 lymph node, 1 systemic, 1 skin relapse
Pharm., Pharmacologic. *Crosti A. Micosi fungoide e retieuloistiocitomi cutanei maligni. Minerva Dermat 1951; 26:3-11. tCases included in our study. :~Marchini E. Su di un case di Retieuloistiocitoma del dorso dell'adulto. Ann Ital Derm sir 1954;9:49-90. w D, Civatte J, Jeanmougin M, Renaud-Vilmer C. LymphomeT ~ttype de r6ticulose de Crosti. Joum~es Dermatologlgues de Paris, March 12-14, 1981; abstract book, p 13. [IWillemze R, Meijer CILM, Sentis HJ, et al. Crosti's reticulohistiocytoma: a cutaneous B-cell lymphoma of follicular center cell origin. In: Caputo R, ed. lmmunodermatology. Milan: CIC Edizioni Internazlonali, 1988,
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Reticuloh&tiocytoma of dorsum
Duration at last examination Treatment
1~, Pharm. Pharm. 1~, Pharm. Pharm.
1~, Pharm. Pharm., surgical
(yr) 13 4 2 5 3 1 5.5 10 2.5 30 2.5 2 5 3 10.5 8 20 7 6 3
261
Status at last examination
Died Died Relapse Relapse Relapse Well Well Well Well Well Relapse Well Well Well Well Died other cause Well
Fig. 1. Case 13. Large mammillated plaque and nodules of the back.
1
3 1
Well Well
1-21
Pharm., 1~
7I~, 2 Pharm., 1 1~ and pharm. 1 surgery and Pharm.
30 10 3.5 27.5
Well Well Well Well
1 died, 10 well
tural studies were made in six of 16 patients, immunologic studies on frozen sections were done in 12, immunologic studies on cell suspension were done in four, and studies of immunoglobulin heavy chain gene rearrangement were done in seven. Histologic prepa-
rations were stained with hematoxylin-eosin, Giemsa, periodic acid-Schiff, Gomori's, and Weigert-van Gieson stains. Biopsy specimens for electron microscopy were cut into small cubes and immediately fixed in ice-cold phosphate-buffered osmic acid for 3 hours? 4 Tissue samples were then dehydrated in alcohol and embedded in epoxy resin. 25The tissue was sectioned, stained with uranyl acetate and lead citrate, 26 and examined with an electron microscope. Immunologic investigations on specimens fixed in Bouin's solution and embedded in paraffin were carried out with the monoclonal antibodies reported in Table III. For immunologic studies on fresh material, skin biopsy specimens were snap frozen in liquid nitrogen and stored at - 8 0 ~ C. Cryostat sections 5 p, thick were air dried for 12 to 24 hours. Immediately before staining, the slides were fixed for 10 minutes in acetone at room temperature and air dried. An immunoalkaline phosphatase method 27 was then used to stain frozen and deparaffinized sections with the monoclonal antibodies reported in Table IV. A fluorescence-activated cell sorter analyzer from Becton, Dickinson & Co. was used to study cell suspensions. Cell suspensions were stained with the reagents against B-associated antigens, T-lymphocytes,
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T a b l e I I . Cases similar to Crosti's reticulohistiocytoma o f the dorsum described under different d e n o m i n a t i o n s
Author(s)
Sex
(yr)
S6zary et al.*
M
45
Thorax
Thiers et al. 1~ Woringer et a1.13 Beurey et al. ~4
M M F
49 51 30
Pierard and Kint ~5 Thiers et al. ~ Temime et al.~7
M ? F
42 56 48
Thorax Back Back, mammary gland Back Back Shoulder
Renkin t8 De Graciansky and Leclercq ~9 Temime et al. 2~
F M F
44 65 48
Scapula Scapula Back
Beurey et al. zl
F
37
Back
Initial location
Duration at last examination Treatment
(yr)
Status at last examination
Thorax, leg Neck
Radium therapy Surgical Surgical
4
Relapse
0.5 1.5 0.5
Relapse Well Unknown
Back
1~ Pharm. 1~
11 6 8
Well Well Relapse
1 15
Unknown Relapse Unknown
Subsequent location
Back, scapula Back
I~ Pharmacol Surgical, Pharm.
7
Relapse
Pharm., Pharmacologic. *S6zary A, Bolgert M, Boulenger P. Reticulomatose cutan6e ~t 6volution lente. Bull Soc Fr Derrn Syph. 1941;48:704-14.
monocyte-macrophages reported in Table IV, and fluorescein- or rhodamine-conjugated goat antimouse IgG or IgM. The gene rearrangement study was carried out according to the following procedure. High-molecularweight deoxyribonucleic acid (DNA) was lysed from the tissue with sodium dodecyl sulfate and digested with pronase (200/xg/ml). After sequential extraction with buffered phenol and chloroform, nucleic acids were precipitated with ethanol. DNA was further purified by digestion with ribonuclease A (50 ~g/ml) and proteinase K (100 ixg/ml), chloroform extraction, and ethanol precipitation. DNA samples, resuspended in trisethylene buffer (10 m m o l / L Tris-HCl, 1 m m o l / L ethylene diamine tetraacetic acid pH 7.5), were digested to completion with restriction endonuclease Barn HI, Eco RI, or Hind llI under the conditions recommended by the manufacturer (Boehringer Mannheim, Mannhelm, West Germany). Restriction fragments were fractionated on 0.8% agarose gels and transferred to nitrocellulose filters as previously described? 8 Baked filters were prehybridized for 6 hours at 42 ~ C in 50% formamide, 5 concentrated standard sodium citrate solution, 1 concentrated Denhardt's solution, 50 mmol/L sodium phosphate buffer at pH 6.5, 1% glycine, 100 p.g/ml denatured salmon sperm DNA, and 100 ~g/ml transfer ribonucleic acid. Hybridization with 32P-labeled
DNA probes (3 to 5 x 106 cpm/ml) was for 24 hours at 42 ~ C in the above buffer containing 10% dextran sulfate. Filters were washed three times at room temperature for 5 minutes in 2 concentrated standard sodium citrate solution, 0.1% sodium dodecyl sulfate, and twice at 42 ~ C in 0.1 concentrated standard sodium citrate solution, 0.1% sodium dodecyl sulfate for 20 minutes, and then autoradiographed for various periods of time at - 70 ~ C with intensifying screens. The probe used to study immunoglobulin heavy chain gene rearrangements was a Bam HI/Hind III fragment of a clone (JH) specific for the J region, z9 The fragment sequences by electroelution were nick translated to a specific activity of 109 cpm/Ixg according to manufacturer's specifications (Amersham International, Amersham, United Kingdom) ? ~ RESULTS Clinical findings are reported in Table V. At the first examination, patients' ages varied f r o m 39 to 75 years. The duration of the lesions f r o m onset ranged from a few months to 19 years. T h e disease manifested with one or more plaques and nodules in all patients. T h e most typical clinical feature, observed in 11 cases, was a large plaque with a mammillated smooth sur-
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Reticulohistiocytoma of dorsum 263
Table IIl. Antibodies used on paraffin sections
Name
1 Origin
IaDR (910/D7)* PD7 / 26-2B 1It F8-11-13:~ UCHLIw C3bt Lysozymet
Mouse Mouse Mouse Mouse Mouse Rabbit
ct-Antitrypsint Ki-M6* S 100t Kappall Lambdall
Rabbit Mouse Rabbit Mouse Mouse
Specificity MHC class II Pan leukocytes Pan B Pan T DRC Macrophages, PMN Macrophages Macrophages Langerhans cells Light chain kappa Light chain lambda
DRC, Dendritic reticulum cell; MHC, major histiocompatibility complex; PMN, polymorphonuclear leukocytes. *From Behring Pharmaceuticals, Berlin, West Germany. tFrom Dako Corp., Santa Barbara, CA. SFrom Dr. Dalchau, Queen Victoria Hospital, Grinstead, Sussex, UK. w P. Beverley, University College Medical School, London, UK. I[From Cappel Laboratories, Malvem, PA.
face surrounded by figurate erythematous patches (Fig. 1). The hemogram and chest x-ray films showed normal findings in all patients. Abdominal computer tomography, lymphography, and bone marrow biopsy, performed in 10 cases, showed normal findings. The patients were treated successfully with x-ray therapy. Sixteen cases were followed for 6 months to 13 years and relapses were observed in 12 cases (75%). In one patient the new lesions enlarged to cover most of the back (Fig. 2), and one patient showed lymph node involvement 3 years after the onset of the disease. Relapses were treated predominantly with x-ray therapy. Surgery was used to remove the lymph node in patient 5 and the nodules in patients 6 and 9. Chemotherapy produced complete remission in patient 4. At the last examination, seven patients were free of lesions, while eight had relapses. One of the original patients of Crosti's was followed until death, which occurred 4 years after the onset of the disease and resulted from lymphomatous bone involvement.
Fig. 2. Case 7. Nodules, plaques, and erythematous edematous lesions of the back.
Histopathology and electron microscopy Histologic examination of specimens from nine of 19 patients revealed a perivascular and periadnexal infiltration of small lymphocytes associated with coalescent nodular lymphoid masses within the reticular dermis (Fig. 3). A massive infiltration with destruction of adnexal structures, starting from the papillary dermis and extending into the subcutaneous tissues, was present in the remaining patients. In all specimens, a zone of normal collagen separated the heavy dermal lymphoid infiltrate from the normal epidermis. The central portion of the nodules and the diffuse infiltrative areas were composed of large central follicular-type lymphocytes (Fig. 4). Mitoses were frequent and, sometimes, atypical. At the periphery of the large cell masses, there was a rim of small, well-differentiated lymphocytes. Small lymphocytes were also present around the vessels within the heavily infiltrated areas. Eosinophils were absent, while some plasma-
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Table IV. Antibodies used on cryostat sections Name
I
Specificity
HLA-DRt IgA, IgG, IgM, IgD~: B1 and B4,w TO15,t BAlll
MHC class II Surface Ig Pan B lymphocytes
B2,w M.HM682
B lymphocyte subsets, DRC Plasma cells Pan T lymphocytes
PCA- 1# Leu-1 and Leu-4,~: T l l , w RFT2 and Rb-T12** Leu-3al: Leu-2a~: DRCI ,t Ki-M4?I" Leu-M5,~: MO1 ,w UCHM 1,:~: Leu-M3$ RFD7, RFD9** Leu-6$ K i - l , t interleukin 25 Transferrin-R,$ Ki-67t Kappaw167 Lambdaw167
T helper T suppressor/cytotoxic DRC Monocyte-macrophage Macrophages Langerhans cells, cortical thymocytes Activation antigens Proliferating cells Light chain kappa Light chain lambda
Cluster defined*
CD20, CD19, CD22, CD24 CD21, CD23 CD5, CD3, CD2, CD7, CD6 CD4 CD8 CD1 lc, CDllb, CD14a, CD14b CDIa CD30, CD25
MHC, Majorhistocompatibilityindex;DRC, dendriticreticulnmcell.
*Clusters were definedon the basis of biochemicalanalysisand tissuedistributionof the moleculesrecognizedfrommonoclonalantibodiesas reported at the first, second, and third InternationalWorkshopson LeucocyteDifferentiationAntigens. tFrom Dako Corp., Santa Barbara, CA. ~.FromBectonDickinson and Co., Paramus,NL wFromCoulterElectronics,Hialeah, FI. I[FromHybritech,San Diego, CA. 82 A.J. MclV[ichael,NuffieldDepartmentof Medicine,John RoadcliffeHospital,Heedington,Oxford,UK. #From E.L Reinherz,Laboratoryof Immunology,DanaFarberCancerInstitute,Boston,MA. **From G. Janossy,Departmentof Immunology,RoyalFree HospitalSchoolof Medicine,London,UK. ttFrom BehringPharmaceuticals. :~:~FromBeverleyChemicalEngineering,Ltd., WestSussex, UnitedKingdom. w167 FromCappelLaboratories,Malvern,PA.
cytic cells were scattered within the large lymphoid cells. Cellular debris was abundant in some specimens. Table VI reports the subdivision of our cases according to the working formulation of the National Cancer Institute 31 and the Kiel classification) 2 Under electron microscopic examination (six cases), no monomorphous patterns similar to the ones described in lymph nodes were observed. Cells of the infiltrate were clustered into groups and centrocytic cells with nuclear indentation, binucleated centroblastic cells, plasmacytic cells, ceils with cerebriform nuclei, cells with lysosomerich cytoplasm, and cellular debris were observed.
Cell membranes were frequently villous and intertwined. Mitoses were observed.
Immunologic and gene rearrangement studies Results of immunologic investigations on paraffin sections (19 cases) are reported in Table VII, while Table VIII summarizes those on cryostat sections (12 cases). The large proliferating lymphoid cells showed expression of major histocompatibility complex class II antigens and reactivity with B cell-associated monoclonal antisera in all cases (Fig. 5). On cryostat sections, they also showed a monoclonal staining pattern for surface immunoglobulins. Nine cases expressed kappa
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Reticulohistiocytoma of dorsum 265
Fig. 3. Case 15. Multiple coalescent nodules of large lymphoid cells are visible in the reticular dermis.
Fig. 4. Case 14. At high magnification there are pleomorphic cells of a germinal center type.
clonality (kappa:lambda ratio 10: 1), while three cases expressed lambda clonality (lambda:kappa ratio 6: 1). The number of Ki-67-positive B cells was high in the diffuse areas, as in the nodules, revealing a high proliferation rate. Transferrin receptor positivity confirmed these results. The small lymphocytes at the periphery of and within the large cell masses showed expression o f T cell-associated antigens (Fig. 6). T4:T8 ra-
fios varied from 1:2 to 2:1. Dendritic reticulum cells were absent or few in the diffuse areas, while in nodular areas they were irregularly distributed (Fig. 7). A sparse pattern of positivity was detected for macrophages. Langerhans cells were found only in the epidermis and not within the neoplastic B cell infiltrates. The data yielded by fluorescence-activated cell sorter analysis o f cell suspensions (four cases)
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T a b l e V . Clinical findings Initial location
Duration from onset
(yr)
First treatment
Follow-up duration (yr)
Case
Sex
(yr)
Initial lesion(s)
1 2 3 4 5
M M M F F
56 39 42 62 51
Plaque Haque Plaque Nodule Nodules
Back Back Scapula Back Back
3 3 0.5 18 5
1~ /} I~ l~ I~
1.5 1.5 Lost 2 4
6 7
M M
51 75
Back Back
6 19
tt 1~
4 5.5
8 9 10 I1 12 13 14 15 16 17' 18" 19'
F M M M M M M M M M M M
72 55 68 42 38 63 37 50 77 49 59 59
Plaque Plaque Nodules Nodules Nodules Plaque Nodules Plaque Plaque Plaque Plaque Nodules Plaque Plaques Nodules
Scapula Back Scapula Back Back Scapula Scapula Back Back Back Scapula Scapula
16 15 9 4 5 13 1 19 1 0.5 1 0.5
I~ 1~ 1~ ~ 1~ ~ I~ 1~ 1~ /~ I~ 1~
2 2 4 Lost 2.5 13 Lost 9 1 3.5 1 0.5
Age
*Cases originallydescribedby Crosti.
T a b l e V I . Histologic findings Kiel Classificationt
Working Formulation* Case
Type
Malignancy~
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
FM DM DM DM DL FM DSC DM FM FM FM FM DM DM FM FM DM DM FM
LG IG IG IG IG LG IG IG LG LG LG LG IG IG LG LG IG IG IG
Type
Cb / Cc follicular Cb / Cc diffuse Cb / Cc diffuse Cb / Cc diffuse Cb diffuse Cb/Cc follicular Cc small cells Cb / Cc diffuse Cb / CC follicular Cb/Cc follicular Cb / Cc follicular Cb/Cc follicular Cb / Cc diffuse Cb / Cc diffuse Cb/Cc follicular Cb/Cc follicular Cb/Cc diffuse Cb / Cc diffuse Cb/Cc follicular
Malignancy:~
___ diffuse
__+ diffuse
_ --_ -_-
diffuse diffuse diffuse diffuse
- diffuse -+- diffuse - diffuse
LG LG LG LG HG LG LG LG LG LG LG LG LG LG LG LG LG LG LG
*Workingformulationof the National CancerInstitute: FM, Follicular,mixed small cleavedand large cell; DM, diffuse, mixed small and large cells; DL, diffuse large cell; DSC, diffuse small cleaved cells. tKiel classification:CbCe, Centroblasticcentrocytlc(small eentrocytic);Cb, centroblastic;Cc, centrocytic(small cell). ~.LG, Low grade; 1G, intermediategrade; HG, high grade.
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Reticulohistioeytoma of dorsum 267
Subsequent treatment
Relapses during follow-up
Status at last examination
Plaque, back Plaque, back
1~ 1~
Relapse Relapse
Nodule, mammary Nodule, back, lymph node Nodules, back Plaques, nodules, back
Chemotherapy 1~ Surgery Surgery 1~
Well Relapse
Nodule, back Plaque, back
Surgery 1~
Nodules, back
1~
Nodule, axilla, bones Plaque, back Plaque, back
Relapse Relapse Well Well Relapse Well Well Well Well Dead Relapse Relapse
showed the presence of 30% to 40% of B cells (CD 19, CD20, and CD22 positive) presenting surface immunoglobulins (IgA, IgG, and IgM) with a monoclonal pattern (kappa in three cases, lambda in one case). Only in one of seven cases did molecular analysis for the immunoglobulin heavy chain region show a well-defined band, indicating that a large number of cells from a single clone were present (Fig. 8). Nevertheless, with a different technique used at the National Cancer Institute of Milan, all seven patients showed clonality for immunoglobulin heavy chain of the B cells.* DISCUSSION
Our series, including three of the seven original cases reported by Crosti, makes it possible to better define the nature of reticulohistiocytoma of the dorsum. In fact, our histologic, immunologic, and gene rearrangement studies suggest that Crosti's *Delia D, Biassoni D, Borrello MG, et al. Primary cutaneous B-ceil lymphomas. A molecular study. Presented at the Third international Conference on Malignant Lymphornas. Lugano, Switzerland, June 1987.
reticulohistiocytoma of the dorsum is a B cell lymphoma of follicular center cell origin. At present, the histiocytic nature of this disease can be ruled out despite studies that had led several authors to put forward such a hypothesis. In the first reports 13,* the identification of the proliferating cells was based purely on histologic findings. In one of the more recent publications, Laugier et al. 4 did not use monoclonal antibodies to define the cellular line. Gamby et al. 6 based their statement on ultrastructural findings of one case. Fotestier et al. ~ did not use monoclonal antibodies for the B cell line, and Zala et al. 9 suggested a histiocytic nature despite the lambda monoclonality of the infiltrate. Even if the existence of histiocytic lymphomas marked by lymph nodes and visceral involvement has been supported 33 and true histiocytic lymphomas of non-Crosti type involving only the skin have been described, 34 many lymphomas previously regarded as being of histiocytic type are presently considered large B cell lymphomas that produce immunoglobulins. 35-38 The T cell nature of Crosti's reticulohistiocytoma of the dorsum can also be ruled out. In the case of Bonvalet et al. ,~ no immunologic studies on frozen sections were done, and identification of the proliferating cells was based only on cell suspension analysis. Toonstra et al.'s patients ~~ showed multilobated cells, similar to the large cleaved cells of our patients, and a slow course as in B cell low-grade lymphomas; no amplification systems were used to detect surface immunoglobulins on tissue sections? 9 Finally, immunologic data were defective in the case of Payne et al. it Clinically, histologically, and immunologically, our cases are comparable to those of Willemze et a1.,22':[: who also stated that Crosti's reticulohistiocytoma of the dorsum is a primary cutaneous B cell lymphoma of follicular center cell origin. *Crosti A. Mieosi fungoide e reticuloistiocitomi cutauei maligrti. Minerva Dermat 1951;26:3-11. l"Bonvalet D, Civatte ], Jeanmougin M, Renaud-Vilmer C. Lymphome T ~ type de rrticulose de Crosti. Journres Dermatologlques de Paris, March 12-14, 1981; abstract book, p. 13. ~:WiUemze R, Meijer CJLM, Sentis HI, et al. Crosti's reticulohistioeytoma: a cutaneous B-cell lymphoma of follieular center cell origin. In: Caputo R, ed. Immunodermatology. Milan: CIC Edlzioni Internazionali, 1988.
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Table VII. Immunohistochemical findings in paraffin sections Antibodies
I
laDR (9 i0 / D7) PD7 / 26-2B 11 F8-11-13 UCHL1 C3b Lysozyme oL~-Antitrypsin Ki-M6 $100 Kappa Lambda
Labeled cells
Labeling patterns
Large lymphoid cells, Langerhans cells Small and large mononucleated cells Large lymphoid cells Small lymphoid ceils Dendritic cells Histiocytic-Iike cells Histiocytic-like cells Histiocytic-like cells Dendritic cells Large lymphoid cells Large Iymphoid ceils
>70% of the large lymphoid cells, intraepidermal Langerhans cells >70% of all cells of the infiltrate >70% of large lymphoid cells >70% of small lymphoid cells Only some cells scattered within the nodules Cells scattered within the infiltrate Cells scattered within the infiltrate Cells scattered within the infiltrate Intraepidermal Langerhans cells Plasma cells scattered within the infiltrate Plasma cells scattered within the infiltrate
Table VIII. Immunohistochemical findings in cryostat sections Antibodies [ Labeled cells [ HLA-DR IgA, IgG, IgM, IgD B1, B4, T015, BA1 B2, MHM6 PCA- 1 Leu-1, Leu-4, T l l , RFT2, RFT12 Leu-3a Leu-2a DRC1, Ki-M4 Leu-M5, M01, UCHM 1, Leu-M3 RFD7, RFD9 Leu-6 Ki- 1, interleukin 2 Transferrin-R, Ki-67 Kappa Lambda
Large lymphoid cells, Langerhans cells Large lymphoid cells Large lymphoid cells Large lymphoid cells, dendritic reticulum cells Plasmacytic cells Small lymphoid cells
Labeling patterns
>70% of large lymphoid cells, intraepidermal Langerhans cells 10% to 70% of large lymphoid cells >70% of large lymphoid cells >70% of large lymphoid cells in cases 7 and 4, 10% in other cases; dendritic reticulum cells Cells scattered within the infiltrate >70% of small lymphoid cells
Small lymphoid cells Small lymphoid cells Dendritic cells Histiocytic-like cells
T4: T8 ratios 2:1 or 1 :2 T4: T8 ratios 2: 1 or 1 : 2 Only some cells within the nodules 10% to 30% of cells scattered within the infiltrate
Histiocytic-like cells Dendritic cells Large lymphoid cells Large lymphoid cells
<10% of cells scattered within the infiltrate Intraepidermal Langerhans cells Few cells scattered within the infiltrate 10% to 30% of the large lymphoid cells
Large tymphoid cells Large lymphoid cells
Kappa monoclonality in nine cases Lambda monoclonality in three cases
The rearrangement of the immunoglobulin heavy chain in all the seven cases we studied strongly supports the lymphomatous nature of the disease. It must be pointed out that primary lymphomas with identical histologic and immunologic features, but with different involvement sites and, sometimes, with a worse prognosis, may be ob-
served in the skin. 4~ Secondary cutaneous follicular lymphomas have also been described. 62 With regard to differential diagnosis, pseudolymphoma of B cell type and large cell lymphocytoma 63 can raise problems. Crosti' s reticulohistiocytoma of the dorsum may be misdiagnosed as pseudolymphoma o f B cell
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Reticulohistioeytoma of dorsum 269
Fig. 5. Case 7. Strong reactivity of large proliferating cells with B cell-associated monoclonal antiserum To-15 (CD22).
Fig. 6. Case 16. Positivity of the peripheral lymphocytes with Pan T Leu-4 (CD3). type in its early stage. The criteria that we consider useful for differentiating these two entities are listed in Table IX. The large cell lymphocytoma is characterized by single or multiple nodules involving mainly the head and the limbs, has a long course, and is as sensitive to radiation as the reticulohistiocytoma of the dorsum. On histologic examination, lesions typically show nodular collections of pleomorphic large lymphoid cells, similar to the proliferating
cells of the germinative centers, surrounded by a thin rim of small lymphocytes. Recently, Winkelmann and Dabski 64 reported B cell predominance in three immunologically studied cases and kappa clonality in one of them. They suggested the benign nature of the disease purely on the basis of histologic findings and follow-up. They also suggested that some cases of Crosti's reticulohistiocytoma of the dorsum are probably large cell lymphocytoma.
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T a b l e I X . Criteria for differentiating Crosti's reticulohistiocytoma of the d o r s u m f r o m p s e u d o l y m p h o m a o f B cell t y p e Reticuiohistiocytoma of the dorsum
Clinical findings Age of onset Cutaneous lesions Preferential sites Course Histologic findings Infiltrate Germinative centers Eosinophils Mitoses Immunohistochemical findings B lymphocytes T lymphocytes Mantle zone B lymphocytes Dendritic reticulum cells of the follicle
Pseudolymphoma of B cell type
Adults Usually multiple nodules or plaques Back Slow progression, possible extracutaneous involvement
Children, adults Usually single nodule Face, ear lobes, scrotum Frequently resolved spontaneously
Massed cells Absent; if present, abnormal Absent Often atypical
Cells separated by edema Present, sometimes abnormal Often present Usually typical
Monoclonal Variable at the periphery Usually disappear
Polyclonal Abundant Usually present
Absent or irregularly distributed
Always present
We think that these t w o entities are v e r y similar and that the c o n t r o v e r s y a b o u t their b e n i g n or m a lignant nature will b e s o l v e d in the future by the use of n e w techniques o f m o l e c u l a r analysis. REFERENCES
1. Cainelli T. Reticolo-istiocitoma del dorso dell'adulto di Crosti. G Ital Derm 1964;105:505-12. 2. Monaeelli M. Reticolodermie, micosi fungoide e reticoloistiocitomi di Crosti. G Ital Derm 1966;107:100918. 3. Cerutti P, Santoianni P. A relatively benign reticulosis: Crosti's "reticulohistiocytoma of the back." Int J Dermatol 1973; 12:35-40. 4. Laugier P, Hunziker N, Olmos L. R~ticulo-histiocytome du dos de 1' adulte. R6ticulose cutan6e circonscrite ~tevolution lente. Dermatologica 1974;i49:350-8. 5. Rimbaud P, Meynadier J, Guilhou JJ, et al. R6ticulose cutan6e circonscrite h 6volution lente (r6ticulohistiocytome de Crosti). Bull Soc Fr Dermatol Syph 1976;83:132. 6. Gamby Th, Chandon JP, Dor JF, et al. La r6ticulose de Crosti. A propos de 3 cas dont un avec Etude ultrastructurelle. Ann Dermatol Venereol 1978;105:821-30. 7. Cainelli T, Alessi E, Prandi G. Reticoloistiocitoma del dorso di Crosti. G Ital Derm-Minerva Derm 1978; 113:796-8. 8. Forestier JY, Schmitt D, Thivolet J. Histiocytosarcome cutan6: aspects eliniques, immunohistochimiques et ultrastmcturaux: difficult6s d'6tude et probl~mes nosologiques. Ann Dermatol Venereol 1980;158:7-19. 9. Zala L, Zimmermann A, Armagni C, Krebs A. Morbus
10.
1l. 12.
13. 14. 15. 16. 17. 18. 19. 20.
Crosti. (Retikuloistiozytom Typ Crosti). Hautarzt 1981; 32:499-504. Toonstra J, Van der Putte SCJ, KaIsbeek GL. Multilobated Cutaneous T-cell lymphoma. Report of two cases resembling Crosti's reticulosis. Dermatologica 1983; 166:128-35. Rowland Payne CME, Meyrick Thomas RH, Black MM, Crosti indolent lymphoma and persistent superficial dermatitis. Clin Exp Dermatol 1984;9:303-8. Thiers H, Colomb D, Fayolle J, Arcadio F, NoveJosserand R. R6ticulose histiomonocytaire ~t plaque unique. Recidive malgr6 ablation ehirurgicale pr6coce large. Bull Soc Fr Dermatol Syph 1959;66:214-5. Woringer F, Alt J, Levy JF. Rdticulose cutan6e localis6e. Traitement chirurgical. Bull Soc Fr Derrnatol Syph 1962;69:368. Beurey J, Mougeolle JM, Vadot J, Bermont A. R6ticulose dorsale. Bull Soc Fr Dermatol Syph 1964;71:628. Pifrard J, Kint A. R6ticulosarcome. Arch Belg Dermatol Syph 1964;20:230. Thiers H, Fayolle J, Deidier C. R6ticulose en placard du dos trait6e par la seule histioth6rapie. Bull Soc Fr Dermatol Syph 1968;75:512-3. Temime P, Privat Y, Coulier L, Marchand JP, Costes A. Lymphoreticulopathie cutan6e lentement 6volutive. Bull Soc Fr Dermatol Syph 1969;76:421-2. Renkin A. R6ticulose histioeytaire maligne. Arch Belg Dermatol Syph 1969;25:380. De Graciansky P, Leclercq R. R6ticulose. Evolution au cours de quinze ann6es. Bull Soc Fr Dermatol Syph 1969;76:279-80. Temime P, Privat Y, Haik A, Marchand JP. R6ticulose cutande du dos ~ tumeur unique. Bull Soc Fr Dermatol Syph 1972;79:294.
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Fig. 7. Case 9. Paraffin-embedded tissue. Irregularly distributed dendritic reticulum cells, stained with C3b monoclonal antibody, are present within coalescent nodular masses.
21. Beurey J, Weber M, Mougeolle JM, Delrous JL, Thanry MJ. R6ticulose cutan6e. Recidive 7 ans apr6s ex6rese. Bull Soc Fr Dermatol Syph 1972;79:189-90. 22. Willemze R, Meijer CJLM, Sentis HJ, et al. Primary cutaneous large cell lymphomas of follicular center cell origin. J AM ACADDEr~MATOL1987;16:518-26. 23. Berti E, Caputo R, Alessi E, Gianotti R, VezzoniP. Adult reticulohistiocytoma of the back (Morbus Crosti) [abstract]. J Invest Dermatol 1986;87:129. 24. Millonig G. Advantage of a phosphate buffer Os04 solution in fixation. J Appl Physiol 1961;32:1637. 25. Luft JH. Improvements in epoxy resin embedding methods. J Biophys Biochem Cytol 1961;9:409-14. 26. Reinotds ES. The use of lead citrate at high pH levels on electron opaque stain in electron microscopy. J Cell Biol 1973;t7:208-12. 27. Cordell JL, Folini B, Erber WN, Stein H, Mason DY. Immunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal antialkaline phosphatase (APAAP complexes). J Histochem Cytochem 1984;32:219. 28. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 1975;98:503-17. 29. Korsmeyer SJ, Arnold A, Bakhishi A, et al. Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias of T cell and B cell precursor origin. J Clin Invest 1983;71:30113. 30. Rigby PWJ, Dieckmann M, Rhoses C, Berg P. Heterogeneity of T cell beta chain gene rearrangements in human leukemias and lymphomas. EMBO J 1985; 4:2217-24. 31. NCI sponsored study of classifications of non-Hodgkin's lymphomas. Summary and description of a working formulation for clinical usage. Cancer 1982;49:211235.
Fig. 8. Twenty micrograms of high-molecular-weight DNA from peripheral blood lymphocytes (1), our~case 5 (2), T-lymphoma (3), and placenta (4) were digested with Eco RI, subjected to electrophoresis on 0.8% agarose gei, transferred to a nitrocellulose filter, and hybridized with JH-specific probe as described by Southern. 28 All samples show the germline band of 19 Kb. Two clonality rearranged bands are present (arrow) only in sample 2. 32. G6rard-Marchand R, Hamlin I, Lennert K, Rilke F, Stansfeld AG, Van Unnick JAM. Classification of non Hodgkin's lymphomas. Lancet 1974;2:406-8. 33. Isaacson P, Wright DH, Jones DB. Malignant lymph0ma
272
34. 35. 36.
37.
38. 39.
40. 41.
42. 43.
44. 45. 46. 47.
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of true histiocytic (monocyte/macmphage) origin. Cancer 1983;51:80-91. Gall EA, Mallory TB. Malignant lymphoma: elinicopathologic survey of 618 cases. Am J Pathol 1942; 18:381-429. Stein H, Kaiserling E, Lennert K. Evidence for B cell origin of reticfllum cell sarcoma. Virchows Arch [Pathol Anat] 1974;364:51-67. Lennert K. Follicular lymphoma: A tumor of the germinal centers. In: Akazaki K, Rappaport H, Berard CW, Bennet JM, Ishikawa MY, eds. Malignant diseases of the hematopoietic system. GANN Monograph on Cancer Research No. 15. Tokyo: University of Tokyo, 1973: 217-31. Lukes RJ, Collins RD. New observations in follicular lymphoma. In: Akazaki K, Rappaport H, Berard CW, Bennet JM, Ishikawa MY, eds. Malignant diseases of the hematopoietic system. GANN Monograph on Cancer Research No. 15. Tokyo: University of Tokyo, 1973: 209-15. Grody WW, Weiss LM, Warnke RA, Magdison JG. Gastrointestinal lymphomas: Immunohistochemical studies on the cell of origin. Am J Surg Pathol 1985;9:328-37. Van Der Putte SCJ, Schuurman HJ, Toonstra J. Cutaneous T-cell lymphoma, multilobated type expressing membrane differentiation antigens of precursor T-lymphoeytes. Br l Dermatol 1982;107:293-300. Joulia P, Le Coulant P. R6ticulose histiomonocytaire du front. R6gression spontan6e apr~s biopsie. Bull Soe Fr Dermatol Syph 1955;62:399-400. Degos R, Lortat-Jaeob E, Ossipowski B, Civatte J, Touraine R. R6ticulose histiocytaire g plaque unique. Passage du stade hyperplasique au stade dysplasique. Bull Soc Fr Dermatol Syph 1957;64:12-4. Lapiere S. Quelque eas de r6ticuloses cutan6es histiomonocytaires lentement 6volutives et de r6tieulomatoses. Bull Soc Fr Dermatol Syph 1957;64:21-9. Degos R, Lortat-Jacob E, Ossipowski B, Civatte J, Touraine R, Repess6 G. R6ticulose maligne cutan6e et gastrique: stade pr6alable de r6ficulose hyperplasique sempie pendant 30 ans. Bull Soc Fr Dermatol Syph 1957;64:9-11. Canizares O. Reticulum cell sarcoma. Arch Dermatol 1958;78:529-30. Obermayer ME, MacDonald I. Lymphoblastoma localized on the scalp for thirty years. Arch Dermatol 1958;78:775-7. Wolf M. Reticulum cell carcinoma. Arch Dermatol 1959;80:246-7. Bureau Y, Gouin JL, Barriere H. R6ticulose maligne
48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58.
59. 60. 61. 62. 63. 64.
localisation tumorale unique, trait6e par ablation et greffe libre. Bon 6tat apr~s un recul de 7 tools. Bull Soc Fr Dermatol Syph 1959;66:775-6. Dupont A. R6tieulose localis6e de l'oreille. Traitement radioth6rapique suivi de greffe. Arch Belg Dermatol Syph 1965;21:159-60. Temime P, Privat Y, Benne M, Vivier MAF. Lymphor6ticulose cutan6e. Bull Soc Fr Dermatol Syph 1965; 72:744. Tramier G, Mathieu J. R6ticulose cutan6e. Bull Soc Fr Dermatol Syph 1965;72:693. Fivet H, Reginster JP. R6ticulose du cuir ehevelu. Arch Belg Dermatol Syph 1967;23:137. Grosshans E, Alt J, Basset A. R6ticulose histiomonocytaire d'6volution ehronique (35 ans). Bull Soc Fr Dermatol Syph 1968;75:126-7. Elalouf C, Grupper C. R6tieulose maligne loealis6e am6liorfe par le chloraminoph~ne. Bull Soc Fr Dermatol Syph 1969;76:787-8. Bolgert M, Fisher RM. R6ticulose cutan6e 6volutive anterieurement traitfe par ablation et autogreffe (2~me pr6sentation). Bull Soc Fr Dermatol Syph 1968;75:429-30. Former JL. Reticulum cell lymphoma. Arch Dermatol 1970;102:124-5. Bazex A, Dupre A, Debarre M. R6ticulose histiocytaire hyperplastique en placard infiltr6 unique 6voluant depuis 12 ans. Bull Soc Fr Dermatol Syph 1970;77:146-8. Texier L, Delaunay M. Electronth6rapie d'une r6ticulose maligne. R6sultat favorable. Bull Soc Fr Dermatol Syph 1975;82:442-3. Brittinger G, Bartles H, Bremer K, et al. KlinJk der rnalignen non Hodgkin Lymphome entsprechend der Kiel Klassifikation: zentrocytisches Lymphom, zentroblastisch-zentrocytisches Lymphom. Hematol Blutlransfus 1976;18:211-23. Beeker H. Maligne non Hodgkin Lymphoma: pathomorfophologische Grundlagen. Hautarzt 1978;29:21-9. Orfanos CE, Lammer D. Retikulohistiozytare Tumore der Haut. Hautarzt 1980;31:297-307. Kerl H, Kresbach H. Germinal center cell-derived lymphomas of the skin. J Dermatol Surg Oncol 1984;10: 291-5. GareiaCF, Weiss LM, Warnke RA, WoodGS. Cutaneous follicular lymphoma. Am J Surg Pathol 1986;10:454-63. Duncan SC, Evans HL, Winkelmann RK. Large cell lymphocytoma. Arch Dermatol 1980;116:1142-6. Winkelmann RK, Dabski K. Large cell lymphocytoma: follow-up, immunopathology studies, and comparison to cutaneous follicular and Crosti lymphoma. Arch Dermatol Res 1987;279:$81-7.
II
I
I
I
I
I
_
III II II
Reticulohistiocytoma of the dorsum Emilio Berti, M.D.,* Elvio Alessi, M.D.,* Ruggero Caputo, M.D.,* Raffaele Gianotti, M.D.,* Domenico Delia, M.D.,** and Paolo Vezzoni, M.D.*** Milan, Italy To clarify the nature of reticulohistiocytoma of the dorsum, 19 cases, including three of the seven original cases described by Crosti, were evaluated clinically, histologically, and immunologically. In seven cases gene rearrangement analysis was also performed. Results indicate that reticulohistiocytoma of the dorsum must be considered a primary cutaneous B cell lymphoma of follicular center cell origin. This localized skin disease has a very slowly progressive course, with many patients showing no systemic involvement even after prolonged follow-up. (J AM ACADDERMATOL1988;19:259-72.)
In 1951 Crosti* used the term "reticulohistiocytoma of the dorsum" to define seven cases characterized by figurate erythematous patches and by firm nodules often merging into mammillated plaques that developed on the back and the lateral portion of the thorax in adult life. On histologic examination the lesions showed a dense infiltrate o f lymphocytes and large atyical histiocytic-like cells around the vessels and adnexa of the dermis, with rare mitotic figures. The course of the disease was very slow, with possible involvement of lymph nodes and viscera years later. The lesions w e r e markedly sensitive to radiation therapy. Crosti considered reticulohistiocytoma of the dorsum to be a new clinicopathologic entity that
had to be differentiated from mycosis fungoides d'emblde, Hodgkin's disease, and pseudolymphomas. Up to 1987, 42 cases of Crosti's reticulohistiocytoma of the dorsum had been reported as such (Table I), and I 1 other similar cases had been described under different names (Table II). Crosti's reticulohistiocytoma of the dorsum was considered to be a histiocytic disorder by some authors 4'6's'9 and a T cell lymphoma by others,~~ t,. but recently its striking similarities with primary cutaneous germinal center cell lymphomas have been underlined.22,23,t The purpose of our study was to clarify the nature of this entity by immunologic investigations and gene rearrangement analysis. PATIENTS AND METHODS
From The First Clinic of Dermatology, University of Milan,* the National Cancer Institute,** and the Department of General Pathology, University of Milan.*** Carried out within the framework of Italian National Research Council Project No. 44. Presented in part as a poster at the Forty-fifth Annual Meeting of the American Academy of Dermatology, New Orleans, LA, Dee, 611, 1986; presented as an advanced lecture at the Eighth International Dermatopathology Colloquium, Barcelona, Spain, Oct. 8-10, 1987. Accepted for publication Nov. 12, 1987. Reprint requests to: Dr. Elvio Alessi, Clinica Dermatologica I ~ Via Pace 9, 20122 Milan, Italy. *Crosti A. Micosi fungoide e reticoloistioeitomi cutanei maligni. Minerva Dermat 1951 ;26:3-11.
Sixteen of our patients meeting the clinical and histologic requirements suggested by Crosti and three of the seven original cases described by Crosti entered the study. Histologic and immunologic investigations on specimens fixed in Bouin's solution and embedded in paraffin were carried out in all cases, while ultrastructBonvalet D, Civatte J, Jeanmougin M, Renaud-Vilmer C. Lymphome T h type de rdticulose de Crosti. Joumdes Dermatologiques de Paris, March 12-14, 1981; abstract book, p. 13. SWillemze R, Meijer CJLM, Sentis HI, et al. Crosti's reticulohistioeytoma: a cutaneous B-cell lymphoma of follicular center cell origin, ln: Caputo R, ed. Immunodermatology. Milan: CIC Edizioni Intemazionali, 1988.
259
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T a b l e I, C a s e s o f r e t i c u l o h i s t i o c y t o m a o f the d o r s u m reported up to 1987
Author(s)
Crosti*
Marchini~: Cainelli t Monacelli 2 Cerutti et al. 3
Laugier et al. 4 Rimbaud et al. ~ G a m b y et al. ~
Cainelli et al. 7
Forestier et al. s Zala et al. 9
Bonvalet et al.{} Toonstra et al. Jo Payne et al." Willemze et al.II
Case No.
1 2 3 4 5 6]" 7 1 1 1 1 2 3 4 1 1 1 2 3 1 2 3 1 1 2 3 4 1 1 2 1 1 2 3 4 5 6 7 8 9 10 11
Sex
Age (yr)
M M M M M M F F M M M M M M M M F F M M F M F M
54 49 59 48 54 59 39 25 65 65 47 52 48 41 56 45 48 48 81 63 48 54 79
M M M F M M M F F M M M M M M M M M
40-60 55 53 56 68
Initial location
Scapula Back Scapula Back Back Scapula Back Back Back Back Back Back Scapula Scapula Back Back Scapula Back Back Back Scapula Back Back
Subsequent location
Trunk, lymph node Axilla, bones Back, lumbar region Lymph node Back Back Lymph node Back, axilla Back Back Back Scapula, back Back -Back Back Lymph node, scapula -----
3 back, 1 axilla Back Scapula Scapula Thorax, neck
Back, thorax Neck, thorax, arm, back Back Thorax, abdomen, back
6 back, 5 chest or abdomen
1 lymph node, 1 systemic, 1 skin relapse
Pharm., Pharmacologic. *Crosti A. Micosi fungoide e retieuloistiocitomi cutanei maligni. Minerva Dermat 1951; 26:3-11. tCases included in our study. :~Marchini E. Su di un case di Retieuloistiocitoma del dorso dell'adulto. Ann Ital Derm sir 1954;9:49-90. w D, Civatte J, Jeanmougin M, Renaud-Vilmer C. LymphomeT ~ttype de r6ticulose de Crosti. Joum~es Dermatologlgues de Paris, March 12-14, 1981; abstract book, p 13. [IWillemze R, Meijer CILM, Sentis HJ, et al. Crosti's reticulohistiocytoma: a cutaneous B-cell lymphoma of follicular center cell origin. In: Caputo R, ed. lmmunodermatology. Milan: CIC Edizioni Internazlonali, 1988,
Volume 19 Number 2, Part 1 August 1988
Reticuloh&tiocytoma of dorsum
Duration at last examination Treatment
1~, Pharm. Pharm. 1~, Pharm. Pharm.
1~, Pharm. Pharm., surgical
(yr) 13 4 2 5 3 1 5.5 10 2.5 30 2.5 2 5 3 10.5 8 20 7 6 3
261
Status at last examination
Died Died Relapse Relapse Relapse Well Well Well Well Well Relapse Well Well Well Well Died other cause Well
Fig. 1. Case 13. Large mammillated plaque and nodules of the back.
1
3 1
Well Well
1-21
Pharm., 1~
7I~, 2 Pharm., 1 1~ and pharm. 1 surgery and Pharm.
30 10 3.5 27.5
Well Well Well Well
1 died, 10 well
tural studies were made in six of 16 patients, immunologic studies on frozen sections were done in 12, immunologic studies on cell suspension were done in four, and studies of immunoglobulin heavy chain gene rearrangement were done in seven. Histologic prepa-
rations were stained with hematoxylin-eosin, Giemsa, periodic acid-Schiff, Gomori's, and Weigert-van Gieson stains. Biopsy specimens for electron microscopy were cut into small cubes and immediately fixed in ice-cold phosphate-buffered osmic acid for 3 hours? 4 Tissue samples were then dehydrated in alcohol and embedded in epoxy resin. 25The tissue was sectioned, stained with uranyl acetate and lead citrate, 26 and examined with an electron microscope. Immunologic investigations on specimens fixed in Bouin's solution and embedded in paraffin were carried out with the monoclonal antibodies reported in Table III. For immunologic studies on fresh material, skin biopsy specimens were snap frozen in liquid nitrogen and stored at - 8 0 ~ C. Cryostat sections 5 p, thick were air dried for 12 to 24 hours. Immediately before staining, the slides were fixed for 10 minutes in acetone at room temperature and air dried. An immunoalkaline phosphatase method 27 was then used to stain frozen and deparaffinized sections with the monoclonal antibodies reported in Table IV. A fluorescence-activated cell sorter analyzer from Becton, Dickinson & Co. was used to study cell suspensions. Cell suspensions were stained with the reagents against B-associated antigens, T-lymphocytes,
262
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T a b l e I I . Cases similar to Crosti's reticulohistiocytoma o f the dorsum described under different d e n o m i n a t i o n s
Author(s)
Sex
(yr)
S6zary et al.*
M
45
Thorax
Thiers et al. 1~ Woringer et a1.13 Beurey et al. ~4
M M F
49 51 30
Pierard and Kint ~5 Thiers et al. ~ Temime et al.~7
M ? F
42 56 48
Thorax Back Back, mammary gland Back Back Shoulder
Renkin t8 De Graciansky and Leclercq ~9 Temime et al. 2~
F M F
44 65 48
Scapula Scapula Back
Beurey et al. zl
F
37
Back
Initial location
Duration at last examination Treatment
(yr)
Status at last examination
Thorax, leg Neck
Radium therapy Surgical Surgical
4
Relapse
0.5 1.5 0.5
Relapse Well Unknown
Back
1~ Pharm. 1~
11 6 8
Well Well Relapse
1 15
Unknown Relapse Unknown
Subsequent location
Back, scapula Back
I~ Pharmacol Surgical, Pharm.
7
Relapse
Pharm., Pharmacologic. *S6zary A, Bolgert M, Boulenger P. Reticulomatose cutan6e ~t 6volution lente. Bull Soc Fr Derrn Syph. 1941;48:704-14.
monocyte-macrophages reported in Table IV, and fluorescein- or rhodamine-conjugated goat antimouse IgG or IgM. The gene rearrangement study was carried out according to the following procedure. High-molecularweight deoxyribonucleic acid (DNA) was lysed from the tissue with sodium dodecyl sulfate and digested with pronase (200/xg/ml). After sequential extraction with buffered phenol and chloroform, nucleic acids were precipitated with ethanol. DNA was further purified by digestion with ribonuclease A (50 ~g/ml) and proteinase K (100 ixg/ml), chloroform extraction, and ethanol precipitation. DNA samples, resuspended in trisethylene buffer (10 m m o l / L Tris-HCl, 1 m m o l / L ethylene diamine tetraacetic acid pH 7.5), were digested to completion with restriction endonuclease Barn HI, Eco RI, or Hind llI under the conditions recommended by the manufacturer (Boehringer Mannheim, Mannhelm, West Germany). Restriction fragments were fractionated on 0.8% agarose gels and transferred to nitrocellulose filters as previously described? 8 Baked filters were prehybridized for 6 hours at 42 ~ C in 50% formamide, 5 concentrated standard sodium citrate solution, 1 concentrated Denhardt's solution, 50 mmol/L sodium phosphate buffer at pH 6.5, 1% glycine, 100 p.g/ml denatured salmon sperm DNA, and 100 ~g/ml transfer ribonucleic acid. Hybridization with 32P-labeled
DNA probes (3 to 5 x 106 cpm/ml) was for 24 hours at 42 ~ C in the above buffer containing 10% dextran sulfate. Filters were washed three times at room temperature for 5 minutes in 2 concentrated standard sodium citrate solution, 0.1% sodium dodecyl sulfate, and twice at 42 ~ C in 0.1 concentrated standard sodium citrate solution, 0.1% sodium dodecyl sulfate for 20 minutes, and then autoradiographed for various periods of time at - 70 ~ C with intensifying screens. The probe used to study immunoglobulin heavy chain gene rearrangements was a Bam HI/Hind III fragment of a clone (JH) specific for the J region, z9 The fragment sequences by electroelution were nick translated to a specific activity of 109 cpm/Ixg according to manufacturer's specifications (Amersham International, Amersham, United Kingdom) ? ~ RESULTS Clinical findings are reported in Table V. At the first examination, patients' ages varied f r o m 39 to 75 years. The duration of the lesions f r o m onset ranged from a few months to 19 years. T h e disease manifested with one or more plaques and nodules in all patients. T h e most typical clinical feature, observed in 11 cases, was a large plaque with a mammillated smooth sur-
Volume 19 Number 2, Part 1 August 1988
Reticulohistiocytoma of dorsum 263
Table IIl. Antibodies used on paraffin sections
Name
1 Origin
IaDR (910/D7)* PD7 / 26-2B 1It F8-11-13:~ UCHLIw C3bt Lysozymet
Mouse Mouse Mouse Mouse Mouse Rabbit
ct-Antitrypsint Ki-M6* S 100t Kappall Lambdall
Rabbit Mouse Rabbit Mouse Mouse
Specificity MHC class II Pan leukocytes Pan B Pan T DRC Macrophages, PMN Macrophages Macrophages Langerhans cells Light chain kappa Light chain lambda
DRC, Dendritic reticulum cell; MHC, major histiocompatibility complex; PMN, polymorphonuclear leukocytes. *From Behring Pharmaceuticals, Berlin, West Germany. tFrom Dako Corp., Santa Barbara, CA. SFrom Dr. Dalchau, Queen Victoria Hospital, Grinstead, Sussex, UK. w P. Beverley, University College Medical School, London, UK. I[From Cappel Laboratories, Malvem, PA.
face surrounded by figurate erythematous patches (Fig. 1). The hemogram and chest x-ray films showed normal findings in all patients. Abdominal computer tomography, lymphography, and bone marrow biopsy, performed in 10 cases, showed normal findings. The patients were treated successfully with x-ray therapy. Sixteen cases were followed for 6 months to 13 years and relapses were observed in 12 cases (75%). In one patient the new lesions enlarged to cover most of the back (Fig. 2), and one patient showed lymph node involvement 3 years after the onset of the disease. Relapses were treated predominantly with x-ray therapy. Surgery was used to remove the lymph node in patient 5 and the nodules in patients 6 and 9. Chemotherapy produced complete remission in patient 4. At the last examination, seven patients were free of lesions, while eight had relapses. One of the original patients of Crosti's was followed until death, which occurred 4 years after the onset of the disease and resulted from lymphomatous bone involvement.
Fig. 2. Case 7. Nodules, plaques, and erythematous edematous lesions of the back.
Histopathology and electron microscopy Histologic examination of specimens from nine of 19 patients revealed a perivascular and periadnexal infiltration of small lymphocytes associated with coalescent nodular lymphoid masses within the reticular dermis (Fig. 3). A massive infiltration with destruction of adnexal structures, starting from the papillary dermis and extending into the subcutaneous tissues, was present in the remaining patients. In all specimens, a zone of normal collagen separated the heavy dermal lymphoid infiltrate from the normal epidermis. The central portion of the nodules and the diffuse infiltrative areas were composed of large central follicular-type lymphocytes (Fig. 4). Mitoses were frequent and, sometimes, atypical. At the periphery of the large cell masses, there was a rim of small, well-differentiated lymphocytes. Small lymphocytes were also present around the vessels within the heavily infiltrated areas. Eosinophils were absent, while some plasma-
264
Journal of the American Academy of Dermatology
Berti et aL
Table IV. Antibodies used on cryostat sections Name
I
Specificity
HLA-DRt IgA, IgG, IgM, IgD~: B1 and B4,w TO15,t BAlll
MHC class II Surface Ig Pan B lymphocytes
B2,w M.HM682
B lymphocyte subsets, DRC Plasma cells Pan T lymphocytes
PCA- 1# Leu-1 and Leu-4,~: T l l , w RFT2 and Rb-T12** Leu-3al: Leu-2a~: DRCI ,t Ki-M4?I" Leu-M5,~: MO1 ,w UCHM 1,:~: Leu-M3$ RFD7, RFD9** Leu-6$ K i - l , t interleukin 25 Transferrin-R,$ Ki-67t Kappaw167 Lambdaw167
T helper T suppressor/cytotoxic DRC Monocyte-macrophage Macrophages Langerhans cells, cortical thymocytes Activation antigens Proliferating cells Light chain kappa Light chain lambda
Cluster defined*
CD20, CD19, CD22, CD24 CD21, CD23 CD5, CD3, CD2, CD7, CD6 CD4 CD8 CD1 lc, CDllb, CD14a, CD14b CDIa CD30, CD25
MHC, Majorhistocompatibilityindex;DRC, dendriticreticulnmcell.
*Clusters were definedon the basis of biochemicalanalysisand tissuedistributionof the moleculesrecognizedfrommonoclonalantibodiesas reported at the first, second, and third InternationalWorkshopson LeucocyteDifferentiationAntigens. tFrom Dako Corp., Santa Barbara, CA. ~.FromBectonDickinson and Co., Paramus,NL wFromCoulterElectronics,Hialeah, FI. I[FromHybritech,San Diego, CA. 82 A.J. MclV[ichael,NuffieldDepartmentof Medicine,John RoadcliffeHospital,Heedington,Oxford,UK. #From E.L Reinherz,Laboratoryof Immunology,DanaFarberCancerInstitute,Boston,MA. **From G. Janossy,Departmentof Immunology,RoyalFree HospitalSchoolof Medicine,London,UK. ttFrom BehringPharmaceuticals. :~:~FromBeverleyChemicalEngineering,Ltd., WestSussex, UnitedKingdom. w167 FromCappelLaboratories,Malvern,PA.
cytic cells were scattered within the large lymphoid cells. Cellular debris was abundant in some specimens. Table VI reports the subdivision of our cases according to the working formulation of the National Cancer Institute 31 and the Kiel classification) 2 Under electron microscopic examination (six cases), no monomorphous patterns similar to the ones described in lymph nodes were observed. Cells of the infiltrate were clustered into groups and centrocytic cells with nuclear indentation, binucleated centroblastic cells, plasmacytic cells, ceils with cerebriform nuclei, cells with lysosomerich cytoplasm, and cellular debris were observed.
Cell membranes were frequently villous and intertwined. Mitoses were observed.
Immunologic and gene rearrangement studies Results of immunologic investigations on paraffin sections (19 cases) are reported in Table VII, while Table VIII summarizes those on cryostat sections (12 cases). The large proliferating lymphoid cells showed expression of major histocompatibility complex class II antigens and reactivity with B cell-associated monoclonal antisera in all cases (Fig. 5). On cryostat sections, they also showed a monoclonal staining pattern for surface immunoglobulins. Nine cases expressed kappa
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Reticulohistiocytoma of dorsum 265
Fig. 3. Case 15. Multiple coalescent nodules of large lymphoid cells are visible in the reticular dermis.
Fig. 4. Case 14. At high magnification there are pleomorphic cells of a germinal center type.
clonality (kappa:lambda ratio 10: 1), while three cases expressed lambda clonality (lambda:kappa ratio 6: 1). The number of Ki-67-positive B cells was high in the diffuse areas, as in the nodules, revealing a high proliferation rate. Transferrin receptor positivity confirmed these results. The small lymphocytes at the periphery of and within the large cell masses showed expression o f T cell-associated antigens (Fig. 6). T4:T8 ra-
fios varied from 1:2 to 2:1. Dendritic reticulum cells were absent or few in the diffuse areas, while in nodular areas they were irregularly distributed (Fig. 7). A sparse pattern of positivity was detected for macrophages. Langerhans cells were found only in the epidermis and not within the neoplastic B cell infiltrates. The data yielded by fluorescence-activated cell sorter analysis o f cell suspensions (four cases)
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T a b l e V . Clinical findings Initial location
Duration from onset
(yr)
First treatment
Follow-up duration (yr)
Case
Sex
(yr)
Initial lesion(s)
1 2 3 4 5
M M M F F
56 39 42 62 51
Plaque Haque Plaque Nodule Nodules
Back Back Scapula Back Back
3 3 0.5 18 5
1~ /} I~ l~ I~
1.5 1.5 Lost 2 4
6 7
M M
51 75
Back Back
6 19
tt 1~
4 5.5
8 9 10 I1 12 13 14 15 16 17' 18" 19'
F M M M M M M M M M M M
72 55 68 42 38 63 37 50 77 49 59 59
Plaque Plaque Nodules Nodules Nodules Plaque Nodules Plaque Plaque Plaque Plaque Nodules Plaque Plaques Nodules
Scapula Back Scapula Back Back Scapula Scapula Back Back Back Scapula Scapula
16 15 9 4 5 13 1 19 1 0.5 1 0.5
I~ 1~ 1~ ~ 1~ ~ I~ 1~ 1~ /~ I~ 1~
2 2 4 Lost 2.5 13 Lost 9 1 3.5 1 0.5
Age
*Cases originallydescribedby Crosti.
T a b l e V I . Histologic findings Kiel Classificationt
Working Formulation* Case
Type
Malignancy~
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
FM DM DM DM DL FM DSC DM FM FM FM FM DM DM FM FM DM DM FM
LG IG IG IG IG LG IG IG LG LG LG LG IG IG LG LG IG IG IG
Type
Cb / Cc follicular Cb / Cc diffuse Cb / Cc diffuse Cb / Cc diffuse Cb diffuse Cb/Cc follicular Cc small cells Cb / Cc diffuse Cb / CC follicular Cb/Cc follicular Cb / Cc follicular Cb/Cc follicular Cb / Cc diffuse Cb / Cc diffuse Cb/Cc follicular Cb/Cc follicular Cb/Cc diffuse Cb / Cc diffuse Cb/Cc follicular
Malignancy:~
___ diffuse
__+ diffuse
_ --_ -_-
diffuse diffuse diffuse diffuse
- diffuse -+- diffuse - diffuse
LG LG LG LG HG LG LG LG LG LG LG LG LG LG LG LG LG LG LG
*Workingformulationof the National CancerInstitute: FM, Follicular,mixed small cleavedand large cell; DM, diffuse, mixed small and large cells; DL, diffuse large cell; DSC, diffuse small cleaved cells. tKiel classification:CbCe, Centroblasticcentrocytlc(small eentrocytic);Cb, centroblastic;Cc, centrocytic(small cell). ~.LG, Low grade; 1G, intermediategrade; HG, high grade.
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Reticulohistioeytoma of dorsum 267
Subsequent treatment
Relapses during follow-up
Status at last examination
Plaque, back Plaque, back
1~ 1~
Relapse Relapse
Nodule, mammary Nodule, back, lymph node Nodules, back Plaques, nodules, back
Chemotherapy 1~ Surgery Surgery 1~
Well Relapse
Nodule, back Plaque, back
Surgery 1~
Nodules, back
1~
Nodule, axilla, bones Plaque, back Plaque, back
Relapse Relapse Well Well Relapse Well Well Well Well Dead Relapse Relapse
showed the presence of 30% to 40% of B cells (CD 19, CD20, and CD22 positive) presenting surface immunoglobulins (IgA, IgG, and IgM) with a monoclonal pattern (kappa in three cases, lambda in one case). Only in one of seven cases did molecular analysis for the immunoglobulin heavy chain region show a well-defined band, indicating that a large number of cells from a single clone were present (Fig. 8). Nevertheless, with a different technique used at the National Cancer Institute of Milan, all seven patients showed clonality for immunoglobulin heavy chain of the B cells.* DISCUSSION
Our series, including three of the seven original cases reported by Crosti, makes it possible to better define the nature of reticulohistiocytoma of the dorsum. In fact, our histologic, immunologic, and gene rearrangement studies suggest that Crosti's *Delia D, Biassoni D, Borrello MG, et al. Primary cutaneous B-ceil lymphomas. A molecular study. Presented at the Third international Conference on Malignant Lymphornas. Lugano, Switzerland, June 1987.
reticulohistiocytoma of the dorsum is a B cell lymphoma of follicular center cell origin. At present, the histiocytic nature of this disease can be ruled out despite studies that had led several authors to put forward such a hypothesis. In the first reports 13,* the identification of the proliferating cells was based purely on histologic findings. In one of the more recent publications, Laugier et al. 4 did not use monoclonal antibodies to define the cellular line. Gamby et al. 6 based their statement on ultrastructural findings of one case. Fotestier et al. ~ did not use monoclonal antibodies for the B cell line, and Zala et al. 9 suggested a histiocytic nature despite the lambda monoclonality of the infiltrate. Even if the existence of histiocytic lymphomas marked by lymph nodes and visceral involvement has been supported 33 and true histiocytic lymphomas of non-Crosti type involving only the skin have been described, 34 many lymphomas previously regarded as being of histiocytic type are presently considered large B cell lymphomas that produce immunoglobulins. 35-38 The T cell nature of Crosti's reticulohistiocytoma of the dorsum can also be ruled out. In the case of Bonvalet et al. ,~ no immunologic studies on frozen sections were done, and identification of the proliferating cells was based only on cell suspension analysis. Toonstra et al.'s patients ~~ showed multilobated cells, similar to the large cleaved cells of our patients, and a slow course as in B cell low-grade lymphomas; no amplification systems were used to detect surface immunoglobulins on tissue sections? 9 Finally, immunologic data were defective in the case of Payne et al. it Clinically, histologically, and immunologically, our cases are comparable to those of Willemze et a1.,22':[: who also stated that Crosti's reticulohistiocytoma of the dorsum is a primary cutaneous B cell lymphoma of follicular center cell origin. *Crosti A. Mieosi fungoide e reticuloistiocitomi cutauei maligrti. Minerva Dermat 1951;26:3-11. l"Bonvalet D, Civatte ], Jeanmougin M, Renaud-Vilmer C. Lymphome T ~ type de rrticulose de Crosti. Journres Dermatologlques de Paris, March 12-14, 1981; abstract book, p. 13. ~:WiUemze R, Meijer CJLM, Sentis HI, et al. Crosti's reticulohistioeytoma: a cutaneous B-cell lymphoma of follieular center cell origin. In: Caputo R, ed. Immunodermatology. Milan: CIC Edlzioni Internazionali, 1988.
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Table VII. Immunohistochemical findings in paraffin sections Antibodies
I
laDR (9 i0 / D7) PD7 / 26-2B 11 F8-11-13 UCHL1 C3b Lysozyme oL~-Antitrypsin Ki-M6 $100 Kappa Lambda
Labeled cells
Labeling patterns
Large lymphoid cells, Langerhans cells Small and large mononucleated cells Large lymphoid cells Small lymphoid ceils Dendritic cells Histiocytic-Iike cells Histiocytic-like cells Histiocytic-like cells Dendritic cells Large lymphoid cells Large Iymphoid ceils
>70% of the large lymphoid cells, intraepidermal Langerhans cells >70% of all cells of the infiltrate >70% of large lymphoid cells >70% of small lymphoid cells Only some cells scattered within the nodules Cells scattered within the infiltrate Cells scattered within the infiltrate Cells scattered within the infiltrate Intraepidermal Langerhans cells Plasma cells scattered within the infiltrate Plasma cells scattered within the infiltrate
Table VIII. Immunohistochemical findings in cryostat sections Antibodies [ Labeled cells [ HLA-DR IgA, IgG, IgM, IgD B1, B4, T015, BA1 B2, MHM6 PCA- 1 Leu-1, Leu-4, T l l , RFT2, RFT12 Leu-3a Leu-2a DRC1, Ki-M4 Leu-M5, M01, UCHM 1, Leu-M3 RFD7, RFD9 Leu-6 Ki- 1, interleukin 2 Transferrin-R, Ki-67 Kappa Lambda
Large lymphoid cells, Langerhans cells Large lymphoid cells Large lymphoid cells Large lymphoid cells, dendritic reticulum cells Plasmacytic cells Small lymphoid cells
Labeling patterns
>70% of large lymphoid cells, intraepidermal Langerhans cells 10% to 70% of large lymphoid cells >70% of large lymphoid cells >70% of large lymphoid cells in cases 7 and 4, 10% in other cases; dendritic reticulum cells Cells scattered within the infiltrate >70% of small lymphoid cells
Small lymphoid cells Small lymphoid cells Dendritic cells Histiocytic-like cells
T4: T8 ratios 2:1 or 1 :2 T4: T8 ratios 2: 1 or 1 : 2 Only some cells within the nodules 10% to 30% of cells scattered within the infiltrate
Histiocytic-like cells Dendritic cells Large lymphoid cells Large lymphoid cells
<10% of cells scattered within the infiltrate Intraepidermal Langerhans cells Few cells scattered within the infiltrate 10% to 30% of the large lymphoid cells
Large tymphoid cells Large lymphoid cells
Kappa monoclonality in nine cases Lambda monoclonality in three cases
The rearrangement of the immunoglobulin heavy chain in all the seven cases we studied strongly supports the lymphomatous nature of the disease. It must be pointed out that primary lymphomas with identical histologic and immunologic features, but with different involvement sites and, sometimes, with a worse prognosis, may be ob-
served in the skin. 4~ Secondary cutaneous follicular lymphomas have also been described. 62 With regard to differential diagnosis, pseudolymphoma of B cell type and large cell lymphocytoma 63 can raise problems. Crosti' s reticulohistiocytoma of the dorsum may be misdiagnosed as pseudolymphoma o f B cell
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Reticulohistioeytoma of dorsum 269
Fig. 5. Case 7. Strong reactivity of large proliferating cells with B cell-associated monoclonal antiserum To-15 (CD22).
Fig. 6. Case 16. Positivity of the peripheral lymphocytes with Pan T Leu-4 (CD3). type in its early stage. The criteria that we consider useful for differentiating these two entities are listed in Table IX. The large cell lymphocytoma is characterized by single or multiple nodules involving mainly the head and the limbs, has a long course, and is as sensitive to radiation as the reticulohistiocytoma of the dorsum. On histologic examination, lesions typically show nodular collections of pleomorphic large lymphoid cells, similar to the proliferating
cells of the germinative centers, surrounded by a thin rim of small lymphocytes. Recently, Winkelmann and Dabski 64 reported B cell predominance in three immunologically studied cases and kappa clonality in one of them. They suggested the benign nature of the disease purely on the basis of histologic findings and follow-up. They also suggested that some cases of Crosti's reticulohistiocytoma of the dorsum are probably large cell lymphocytoma.
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Journal of the American Academy of Dermatology
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T a b l e I X . Criteria for differentiating Crosti's reticulohistiocytoma of the d o r s u m f r o m p s e u d o l y m p h o m a o f B cell t y p e Reticuiohistiocytoma of the dorsum
Clinical findings Age of onset Cutaneous lesions Preferential sites Course Histologic findings Infiltrate Germinative centers Eosinophils Mitoses Immunohistochemical findings B lymphocytes T lymphocytes Mantle zone B lymphocytes Dendritic reticulum cells of the follicle
Pseudolymphoma of B cell type
Adults Usually multiple nodules or plaques Back Slow progression, possible extracutaneous involvement
Children, adults Usually single nodule Face, ear lobes, scrotum Frequently resolved spontaneously
Massed cells Absent; if present, abnormal Absent Often atypical
Cells separated by edema Present, sometimes abnormal Often present Usually typical
Monoclonal Variable at the periphery Usually disappear
Polyclonal Abundant Usually present
Absent or irregularly distributed
Always present
We think that these t w o entities are v e r y similar and that the c o n t r o v e r s y a b o u t their b e n i g n or m a lignant nature will b e s o l v e d in the future by the use of n e w techniques o f m o l e c u l a r analysis. REFERENCES
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Fig. 7. Case 9. Paraffin-embedded tissue. Irregularly distributed dendritic reticulum cells, stained with C3b monoclonal antibody, are present within coalescent nodular masses.
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