Partecipa al sondaggio su oncoinfo.it
Banner Recenti Progressi in oncologia - Letteratura, Casi clinici, Opinioni chiave
Banner Vip Mieloma - Terapia del Mieloma Multiplo - Tutta la letteratura - Very Important Papers
Link al Pdf della rivista Tumori: Exemestane nella terapia adiuvante del carcinoma mammario risultati dallo studio ies
 
Società Italiana di Cancerologia

Associazione Italiana di Radioterapia Oncologica

Associazione Italiana di Oncologia Medica

Società Italiana di Chirurgia Oncologica
 
 
Home Page About the Journal Editorial Board Subscriptions Publisher Instructions to Authors Advertising and Reprints


  Volume 96
Numero 3
maggio-giugno 2010 		I documenti sono in formato PDF, consultabili utilizzando Acrobat Reader
 
B-cell lymphofollicular infiltrates in mycosis fungoides

Gerardo Ferrara, Concetta Chiarelli, Stefano Simonetti
1Pathologic Anatomy Unit, Gaetano Rummo General Hospital, Benevento; 2Pathologic Anatomy Unit, San Martino Hospital, Belluno; 3Department of Dermatology, University of Perugia, Perugia, Italy

Key words: B-cell, lymphofollicular infiltrates, mycosis fungoides.

abstract

Aims and background. The histopathological picture of mycosis fungoides can be characterized by heavy reactive infiltrates. These are rarely composed of B lymphocytes with formation of reactive follicles.
Methods and study design. We collected three cases of mycosis fungoides with a reactive B-cell lymphofollicular reaction at the bottom of the epidermotropic infiltrate. 
Results. Case 1 showed flat lesions (patches) with a CD4+ neoplastic phenotype; case 2 presented infiltrated lesions (plaques) with a CD8+ immonophenotype; case 3 was characterized by nodular lesions (tumors) with a CD4+ neoplastic component. In all three cases, no clonal gene rearrangement was found with the polymerase chain reaction technique.
Conclusions. Among the protean clinicopathological features which mycosis fungoides can show, we underline that a B-cell lymphofollicular component can be encountered at the base of the epidermotropic infiltrate even in clinically flat (“patchy”) lesions. Free full text available at www.tumorionline.it

Introduction
Granulomatous mycosis fungoides1 and granulomatous slack skin2 are well-recognized clinicopathological subtypes of mycosis fungoides (MF) that may harbor a reactive infiltrate mainly composed of epithelioid histiocytes with or without giant cells. Interstitial mycosis fungoides may also show a histiocytic component accounting for up to 30% of the dermal infiltrate3. Folliculotropic mycosis fungoides may be associated with marked eosinophilic and/or plasmacellular infiltration4. Cutaneous lymphomas other than MF may also show a reactive granulomatous infiltrate5; other cutaneous lymphoproliferative disorders including type A lymphomatoid papulosis6, marginal zone B-cell lymphoma7, and T-cell-rich B-cell lymphoma8 are characterized by a more or less heavy reactive infiltrate within which only a minority of neoplastic cells are found.
In 1999 van der Putte et al.9 reported an unusual variant of MF characterized by a heavy B-cell infiltrate, even with immunohistochemical evidence of immunoglobulin light chain restriction. Since then, this unusual accompanying feature of MF has been rarely investigated10,11.
We describe 3 additional such cases, which point to the possibility that even “patchy” (non-infiltrated) lesions of MF can host a heavy reactive B-cell lymphofollicular infiltrate.

Case reports

Case 1
A 59-year-old woman was seen for flat, erythematous and scaling lesions of the trunk and limbs involving less than 10% of the skin surface (Figure 1, A-B). A biopsy specimen from the axilla revealed a superficial and deep infiltrate with marked formation of follicles with pale centers (Figure 1C). Within the superficial dermis, the infiltrate showed a perivascular and interstitial distribution, with a tendency to fill the dermal papillae and align along the basal layer of the epidermis (Figure 1D). The deep infiltrate showed reactive-appearing germinal centers and some mono- and multinucleated histiocytes (Figure 1D), even with ill-formed epithelioid granulomas. No elastophagic giant cells were found.



Immunohistochemically, CD3 +, CD4+ (Figure 1E), CD5+, CD7+, CD8-, and CD56- T lymphocytes were the prevailing cell population within the superficial dermis, as well as within the epidermis, whereas CD20+ and CD79α+ B lymphocytes with some bcl6-positive aggregates prevailed within the deep dermis; the cell cycle-related protein Ki67 was prevailingly expressed within the germinal centers with evidence of polarization (Figure 1F) (see Table 1 for the list of the antibodies used in the present study). The anti-kappa and the anti-lambda antibodies showed few positive cells. Only sparse cells stained with the anti-CD30 antibody. No clonal IgH and TCR gene rearrangements were found with the polymerase chain reaction performed on the paraffin-embedded tissue sample according to the previously described technique 12.
Staging procedures performed according to a standard protocol13 proved negative for extracutaneous involvement (Stage IA; T1 N0 M0).

Table 1 - List of primary antibodies used in the present study

Target cell antigen

Clone

Source

 

 

 

CD3ε

F7.2.38

DakoCytomation, Glostrup, DK

CD4

4B12

LabVision, Fremont, CA, USA

CD5

CD5/54/F6

DakoCytomation, Glostrup, DK

CD7

DK24

DakoCytomation, Glostrup, DK

CD8

4B12

LabVision, Fremont, CA, USA

CD20

L26

DakoCytomation, Glostrup, DK

CD30

BerH2

DakoCytomation, Glostrup, DK

CD56/NCAM

1B6

Novocastra Labs, Newcastle-

 

 

  upon-Tyne, UK

CD79α

JCB117

DakoCytomation, Glostrup, DK

Ki67

MIB1

DakoCytomation, Glostrup, DK

bcl6

P1F6 + PG-B6p

LabVision, Fremont, CA, USA

kappa light chains

Polyclonal

DakoCytomation, Glostrup, DK

lambda light chains

Polyclonal

DakoCytomation, Glostrup, DK




Case 2
A 68-year-old man was seen for long-standing plaques of the trunk involving 20% of the skin surface (Figure 2, A-B). Histology showed an extremely thinned epidermis with a heavy subepidermal infiltrate (Figure 2C) of small to medium-sized atypical lymphocytes (Figure 2D) admixed with a few large cells. The deep portion of the infiltrate was mainly composed of variously sized lymphoid cells with well formed germinal centers (Figure 2, C-D). Immunohistochemically, most subepidermal lymphocytes were CD3+, CD4-, CD5+, CD7+, CD8+ (Figure 2E), and CD56-; conversely, the majority of the deep lymphocytes were CD20+ (Figure 2F) and CD79α+ with nodular aggregates which were highly proliferating as shown by the anti-Ki67 antibody. Only occasional cells were found to be CD30+. No appreciable plasma-cell component was detected with the anti-kappa and anti-lambda antibodies. No clonal gene rearrangement was found with the PCR technique. Staging procedures were negative for extracutaneous involvement (Stage IB; T2 N0 M0)




Case 3
A 55-year-old man had a 3-year history of infiltrated plaques and nodules on the buttocks and thighs (Figure 3, A-B). Histopathologically, there was a dense lymphoid infiltrate involving the entire dermis (Figure 3C). The superficial portion of the infiltrate was predominantly composed of small lymphocytes with irregular nuclear contours; some collections of lymphocytes were also seen within the epidermis (Figure 3D). The deeper portion of the infiltrate mainly showed well formed germinal centers with a reactive architecture. Sparse histiocytic giant cells were seen as well. Immunohistochemistry showed that the subepidermal, intraepidermal, and some of the deep dermal component was mostly composed of CD3 +, CD4+ (Figure 3E), CD5+, CD7+, CD8-, and CD56- cells, while the B-cell antigens CD20 and CD79α were prevailing within the cell population of the reticular dermis. The anti-blc6 antibody highlighted the germinal center component (Figure 3F) with no appreciable staining of cells in the diffuse areas; the germinal centers showed a large fraction of Ki67+ cells. Only sparse CD30+ blasts were found within the dermis. The anti-kappa and anti-lambda antibodies stained a small population of plasma cells with no evidence of clonal restriction. T-cell receptor and IgH genes were not clonally rearranged. The inguinal nodes were enlarged, but histopathologically negative (Stage IIB; T3 N1 M0).




Discussion
The present cases draw the attention to an unusual histopathological pitfall of MF, namely, the presence of a heavy B-cell lymphofollicular reaction at the bottom of the epidermotropic infiltrate. We interpret this finding as a peculiar host response to the tumor; its prognostic significance is still unknown due to the limited number of cases reported so far. Interestingly, we found that this feature can be present even at an early (“patch”) stage of MF, which is quite unexpected on clinical grounds. The cases we have described above show an undoubtedly intriguing histopathological picture that leaves space for numerous differential diagnoses. In short, we think that the main diagnostic clues of our cases are i) the clinical picture; ii) the striking compartmental distribution of the infiltrate; iii) the more or less pronounced epidermotropism. 
Clinicopathological correlation is crucial for the diagnosis of MF in each of its stages and each of its diverse clinicopathological presentations. Several inflammatory dermatoses, such as psoriasis, dermatophytosis, chronic eczema, erythema multiforme, pityriasis rubra pilaris, drug eruption, secondary syphilis, scleroderma, etc.14,15, are notoriously hard to be differentiated from MF, particularly in its early or “patch” stage. Our cases 2 and 3 showed long-standing infiltrated lesions involving large areas of the body, a picture which was not consistent with an inflammatory dermatosis. Only case 1 could clinically recall an inflammatory dermatosis, but its histopathological picture, albeit highly unusual, allowed us to exclude virtually all the inflammatory dermatoses that enter the classical differential diagnosis of patch-stage MF 14,15.
The term cutaneous pseudolymphoma is a “working clinicopathological diagnosis” which – from time to time – is applied to benign mimickers of lymphoma, low-grade lymphomas, and/or lymphoid infiltrates with a favorable prognosis. The clinical picture is highly variable, depending on the etiology. Histopathologically, a pseudolymphoma can be either band-like (e.g., lymphomatoid allergic contact dermatitis, lymphomatoid drug eruption) or nodular/diffuse (e.g., insect bite)16-18, with the latter more typically showing an admixture of T and B lymphocytes. Histopathological clues for nodular/diffuse pseudolymphoma are the prevailingly superficial (“top-heavy”) distribution of the infiltrate; the preservation of epidermal and adnexal structures; the lack of involvement of the subcutis; the presence of reactive components (eosinophils, polyclonal plasma cells, highly proliferating polarized germinal centers, vertically oriented thick-walled vessels, edematous and fibrotic areas) 16-18. With the remarkable exception of the germinal center cell component, virtually none of these features of pseudolymphomas was present in our cases. Moreover, the striking compartmental distribution of the infiltrate, with most T lymphocytes close to the epidermis and most B lymphocytes in the deeper portion, also argued against a pseudolymphoma, whose lymphocytic components are classically intermingled.
Cutaneous follicle center cell lymphoma19 and cutaneous marginal zone lymphoma7 are low-grade B-cell malignancies which can harbor more or less well-formed germinal centers as well as a more or less conspicuous reactive T-cell component. Clinically, these neoplasms are characterized by sparse or grouped papulonodular lesions; the flat (patchy) erythematous areas found in our cases 1 and 2 are usually not found in these B-cell malignancies. Histopathologically, the differential diagnosis of these B-cell lymphomas from a nodular/diffuse pseudolymphoma can prove difficult; in follicle center cell lymphoma, germinal centers are neoplastic, and this can be documented by the absence of tingible-body macrophages, the absence of polarization, and the low proliferation rate 19; in marginal zone lymphoma, the germinal centers are reactive but they are surrounded by sheets of small to medium-sized lymphocytes with irregular nuclei and relatively abundant, pale cytoplasm, often associated with monotypic plasma cells7. None of these entities commonly show epidermotropic T lymphocytes, as found in our cases. 
Epidermotropic T lymphocytes are also found in primary cutaneous aggressive epidermotropic CD8-positive lymphoma, in cutaneous/subcutaneous gamma/delta T-cell lymphoma, and in nasal-type extranodal NK/T-cell lymphoma20. These malignancies are clinically very aggressive and rapidly progressive; histopathologically, they never show an appreciable reactive B-cell infiltrate; immonohistochemically, neoplastic lymphocytes express one or more cytotoxic antigens, namely, CD56, TIA1, and perforin20. We suggest the use of at least one of these cytotoxic markers when typifying cutaneous lymphoid infiltrates, with the caveat that even primarily non-cytotoxic lymphomas, including classical MF, can express cytotoxic molecules15,20.
All the above-described entities can be differentiated also by means of biomolecular techniques, the most popular being PCR-DGGE on paraffin-embedded tissues for the rearrangement of the IgH and TCR genes. However, it must be underlined that a clonal rearrangement is found in roughly 75% of lymphomas and that cases of “clonal dermatitis” have been reported as well21,22.
In conclusion, the cases we have described are a good example of the polymorphic clinicopathological features MF may show. A B-cell lymphofollicular infiltrate can be present even in clinically flat (patchy) lesions of MF, a finding that is quite surprising from a clinicopathological point of view. The need for a continuing dialogue between clinicians and histopathologists must be underlined to make sure deceptive cases of MF with a polymorphic morphology and immunopathology will not be missed.

References
 1. Argenyi ZB, Goeken JA, Piette WW, Madison KC: Granulomatous mycosis fungoides: Clinicopathologic study of two cases. Am J Dermatopathol, 14: 200-210, 1992.
 2. Le Boit PE: Granulomatous slack skin. Dermatol Clin, 12: 375-389, 1994.
 3. Su LD, Kim YH, LeBoit PE, Swetter SM, Kohler S: Interstitial mycosis fungoides, a variant of mycosis fungoides resembling granuloma annulare and inflammatory morphea. J Cutan Pathol, 29: 135-141, 2002.
 4. Gerami P, Guitart J: The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides. Am J Surg Pathol, 31: 1430-1438, 2007.
 5. Scarabello A, Leinweber B, Ardigò M, Ruetten A, Feller AC, Kerl H, Cerroni L: Cutaneous lymphomas with prominent granulomatous reaction. A potential pitfall in the histopathologic diagnosis of cutaneous T- and B-cell lymphomas. Am J Surg Pathol, 26: 1259-1268, 2002.
 6. El Shabrawi-Caelen L, Kerl H, Cerroni L: Lymphomatoid papulosis: reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C. Arch Dermatol, 140: 441-447, 2004.
 7. Takino H, Li C, Hu S, Kuo TT, Geissinger E, Muller-Hermelink HK, Kim B, Swerdlow SH, Inagaki H: Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathological study of cases from Asia, Germany, and the United States. Mod Pathol, 21: 1517-1526, 2008.
 8. Sander CA, Kaudewitz P, Kutzner H, Simon M, Schirren CG, Sioutos N, Cossman J, Plewig G, Kind J, Jaffe ES: T-cell-rich B-cell lymphoma presenting in skin. A clinicopathologic analysis of six cases. J Cutan Pathol, 23: 101-108, 1996.
 9. van der Putte SCJ, Toonstra J, van Wichen DF: B cells and plasma cells in mycosis fungoides. A study including cases with B cell follicle formation or a monotypic plasma cell component. Am J Dermatopathol, 1: 509-516, 1989.
10. Weedon D: Cutaneous infiltrates – non-lymphoid. In: Skin pathology, 2nd edition, Weedon D (Ed), pp 1073-1074, Churchill Livingstone, Edinburgh 2002.
11. Tan SH, Sim CS, Ong B, Sander CA: Follicular mycosis fungoides mimicking a cutaneous B-cell lymphoproliferative disorder. Australas J Dermatol, 45: 188-191, 2004.
12. Tok J, Szabolcs MJ, Silvers DN, Zhong J, Matsushima AY: Detection of clonal T-cell receptor gamma chain gene rearrangements by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE) in archival specimens from patients with early cutaneous T-cell lymphoma: correlation of histologic findings with PCR/DGGE. J Am Acad Dermatol, 38: 453-460, 1998.
13. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, Burg G, Cerroni L, Dreno B, Glusac E, Guitart J, Heald PW, Kempf W, Knobler R, Lessin S, Sander C, Smoller B, Telang G, Whittaker S, Iwatsuki K, Oitz E, Takigawa M, Turner ML, Wood GS: Defining early mycosis fungoides. J Am Acad Dermatol, 53: 1053-1063, 2005.
14. Kim YH, Liu HL, Mraz-Gerhard S, Varghese A, Hoppe RT: Long-term outcome of 525 patients with mycosis fungoides and Sézary’s syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol, 139: 857-866, 2003.
15. Ferrara G, Di Blasi A, Zalaudek I, Argenziano G, Cerroni L: Regarding the algorithm for the diagnosis of early mycosis fungoides proposed by the International Society for Cutaneous Lymphomas: suggestions from routine histopathology practice. J Cutan Pathol, 35: 549-553, 2008.
16. Gilliam AC, Wood GS: Cutaneous lymphoid hyperplasias. Semin Cutan Med Surg, 19: 133-141, 2000.
17. Kazakov DV, Burg G, Dummer R, Kempf W: Cutaneous lymphomas and pseudolymphomas: newly described entities. Recent Results Cancer Res, 160: 283-293, 2002.
18. Arai E, Shimizu M, Hirose T: A review of 55 cases of cutaneous lymphoid hyperplasia: reassessment of the histopathologic findings leading to reclassification of 4 lesions as cutaneous marginal zone lymphoma and 19 as pseudolymphomatous folliculitis. Hum Pathol, 36: 505-511, 2005.
19. Kim BK, Surti U, Pandya A, Cohen J, Rabkin MS, Swerdlow SH: Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas. Am J Surg Pathol, 29: 69-82, 2005.
20. Assaf C, Gellrich S, Whittaker S, Robson A, Cerroni L, Massone C, Kerl H, Rose C, Chott A, Chimenti S, Hallermann C, Petrella T, Wechsler J, Bagot M, Hummel M, Bullani-Kerl K, Bekkenk MW, Kempf W, Meijer CJ, Willemze R, Sterry W: CD56-positive haematological neoplasms of the skin: a multicentre study of the Cutaneous Lymphoma Project Group of the European Organisation for Research and Treatment of Cancer. J Clin Pathol, 60: 981-989, 2007.
21. Sandberg Y, Heule F, Lam K, Lugtenburg PJ, Wolvers-Tettero IL, van Dongen JJ, Langerak AW: Molecular immunoglobulin/T cell receptor clonality analysis in cutaneous lymphoproliferations. Experience with the IOMED-2 standardized polymerase chain reaction protocol. Haematologica, 88: 659-670, 2003.
22. Morales AV, Arber DA, Seo K, Kohler S, Kim YH, Sundram UN: Evaluation of B-cell clonality using the BIOMED-2 PCR method effectively distinguishes cutaneous B-cell lymphoma from benign lymphoid infiltrates. Am J Dermatopathol, 30: 425-430, 2008.
 
  Search by title |?|

Enter title words or phrases

Search by author |?|

Enter author name

Search by keywords

You can select more that one keyword by holding down the CTRL key; to obtain meaningful results it is recommended not to select more than two.
 
Abbonati alla nostra newsletter!
È semplice: clicca sul pulsante e compila il modulo.

Abbonati a Va' Pensiero
 
    Credits    Contatti     ISSN online: 2038-2529      Riproduzione e diritti riservati