Primary Cutaneous Composite Lymphomas.
PRIMARY CUTANEOUS CL
The early series of CLs were predominantly nodal/systemic disease, (3,6,7) and most cases included 2 types of B-cell neoplasms. However, cases with B- and T-cell components have been reported. (7,10,12-24) Cutaneous CLs, although rare, include secondary involvement of the skin by systemic/nodal lymphomas, (7,11,14,25,26) or a mixture of primary and secondary cutaneous lymphomas. (14,21,27-32) More recently, primary cutaneous CLs in which both lymphoma components are primary cutaneous lymphomas have been described (reviewed in the Table; see Figures 1 and 2). (19-22,24,33) Although only a handful of these cases have been described, the reported cases are CLs composed of B-cell/T-cell lymphomas. Moreover, most cases are composed of mycosis fungoides (MF) along with a low-grade B-cell lymphoma (Figures 1 through 3; Table).
Since its first description, CL has been recognized as a challenge for pathologists. (2,3) As stated by Kim et al (3): "The differential diagnosis of these lesions depends, of course, on the particular combination of lymphomas being considered." Differential diagnostic considerations are consequently quite broad, include differentials for 2 separate lymphomas, and are based on the particular features of the case being considered. (34) Cutaneous lesions are especially difficult because skin biopsies are often small and crushed, and many processes within the skin include a mixed population of B cells and T cells. Specifically, reactive lymphoid hyperplasia (pseudolymphoma), primary cutaneous [CD4.sup.+] small/medium T-cell lymphoproliferative disorders, primary cutaneous marginal zone lymphoma, and primary cutaneous follicle center lymphoma all characteristically include a mixed population of B cells and T cells (reviewed by Lan et al (35)). Accurate diagnosis often requires a combination of clinical, histopathologic, immunophenotypic, and genetic features. (36,37) To complicate matters even more, B-cell lymphomas may display a clonal T-cell receptor gene rearrangement and vice versa. (22,37) Some suggest that CLs are really a single lymphoma with an associated atypical, reactive lymphoid hyperplasia, (14,22) and others have questioned whether the term CL provides any utility. (11)
Regardless of terminology, recognition of both components of a CL is important for determining prognosis and therapy, and for facilitating interpretation of multiple lesions. (3,5,7,34) Indeed, in CL, prognosis and treatment are determined by the most aggressive component, (3,7,11,34) although consideration of both components is important for the overall treatment strategy. (34) Both components should also be considered in the case of recurrent disease, and staging is often very difficult to determine with certainty, because either or both lymphomas may be present throughout the body. (34) In cases of MF with an associated tumor-forming primary cutaneous B-cell lymphoma, as seen in Figure 1, close clinical-pathologic correlation and follow-up are required to determine whether the patient has tumor-stage MF.
Given the rarity of CLs and the variability in definition, their incidence is difficult to determine with certainty. It has been estimated at approximately 1% to 5% of systemic/nodal lymphomas, (3,7,34) but it may be closer to 10%. (22,37) In 1 study of MF and B-cell malignancies, of 398 cases of MF, 11 patients (3%) had an associated B-cell malignancy and 2 patients had a CL (1%). (21) Only 1 of these patients had a CL composed of 2 primary cutaneous lymphomas. (21)
The pathogenesis of CLs is not well understood, and it likely varies depending on the case and types of lymphomas involved. (34) Hypotheses include a coincidence, (3,6,10,24,27,34,36) exposure, such as to a virus or carcinogen, (3,10,20,23,24,27,28,34,36) genetic predisposition to lymphoma development, (27,34,36) interactions between lymphoma cells and surrounding lymphocytes, (10,17,24,27,34,36) immunodeficiency or immune dysregulation, (3,16,17,24,27,28,34) or as biphenotypic manifestations of the same neoplastic clone. (6,7,17,27,34,36,38) Regarding the latter proposal, CLs lent early support to the hypothesis that Hodgkin lymphoma is a B-cell neoplasm. (6,11,34,39,40)
Composite lymphomas are rarely encountered, but they offer a diagnostic challenge to pathologists. Primary cutaneous CLs are a rare subset of CLs that can be difficult to recognize. Nonetheless, accurate characterization of all CLs, including primary cutaneous CLs, is important for staging, prognosis, and treatment.
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Stephanie Chen, MD; Daniel Boyer, MD; Alexandra C. Hristov, MD
Accepted for publication June 4, 2018.
From the Department of Pathology, University of Iowa Health Care, Iowa City (Dr Chen); and the Departments of Pathology (Drs Boyer and Hristov) and Dermatology (Dr Hristov), University of Michigan Medical Center, Ann Arbor.
The authors have no relevant financial interest in the products or companies described in this article.
Presented in part at the New Frontiers in Pathology meeting; October 19-21, 2017;Ann Arbor, Michigan.
Corresponding author: Alexandra C. Hristov, MD, Department of Pathology, Michigan Medicine, 3261 Med Sci I, 1301 Catherine Street, Ann Arbor, MI 48109-5602 (email: email@example.com. edu).
Caption: Figure 1. A 49-year-old woman had a 4-year history of patches and plaques. Biopsy demonstrated mycosis fungoides. There were cytologically atypical lymphoid cells that displayed epidermotropism, Pautrier microabscesses, and a bandlike dermal distribution (A). Immunohistochemical studies showed that these lymphoid cells expressed CD3 (B), with significant loss of CD7 (C) (hematoxylin-eosin, original magnification X200 [A]; original magnification X200 [B and C]).
Caption: Figure 2. Four years later, the patient described in Figure 1 developed a forehead mass that enlarged during 4 months. She had no evidence of systemic disease. Biopsy revealed a dense dermal lymphoid infiltrate (A) with 2 populations of cells: medium-sized cells with rounded nuclei, vesicular chromatin, and visible nucleoli (B), and a population of smaller lymphoid cells with irregular nuclear contours and clumped chromatin (C) (hematoxylin-eosin, original magnifications X40 [A] and X600 [B and C]).
Caption: Figure 3. Immunohistochemical studies performed on the biopsy in Figure 2 revealed that the larger lymphoid cells were positive for CD3 (A) and CD4 (B) but showed loss of CD2 (C) and CD7 (D). The smaller lymphoid cells were highlighted by CD20 (E) but did not express CD10, BCL6, cyclin D1, CD43, or CD5. Plasma cells were almost exclusively k positive (F), with a few K-positive cells intermixed (G). T-cell and B-cell gene rearrangement studies revealed clonal T-cell and B-cell populations, and the patient received a diagnosis of a composite lymphoma: mycosis fungoides and a lowgrade B-cell lymphoma with plasmacytic differentiation (immunohistochemistry, original magnifications X20 [A through E] and X400 [F and G]).
Summary of Reported Primary Cutaneous Composite Lymphomas (CLs) Report of Primary Cutaneous CL: Clinical Features CL Components Source, y Barzilai et Man age 70 y with a Papular MF and PCMZL al, (21) 2006 10-y history of papular MF (stage IB) developed a subcutaneous nodule on his right arm that showed a primary cutaneous CL Huwait et Woman age 67 y with Iatrogenic al, (22) 2010 RA treated for 6 y immunodeficiency- with MTX and variably associated LPD: MF, with prednisone had a tumor stage with 2-y history of large cell plaques. Biopsies of transformation, and chin, leg, and PCFCL auricle revealed CL Whitling et Man age 73 y with a MF, patch-plaque, and al, (20) 2013 2/y history of patch/ primary cutaneous, plaque MF developed [CD5.sup.+] small plaquelike to nodular B-cell lymphoma lesions on his scalp (up to 1.2 cm). Biopsy confirmed a CL Yang et Woman age 65 y with PCPTCL and al, (19) 2011 diabetes mellitus, [EBV.sup.+] large hypertension, and B-cell lymphoma hyperlipidemia developed a plaque on her left leg. Biopsy showed a CL Wang et Man age 70 y with Erythrodermic MF and al, (24) 2014 multiple patch/ primary cutaneous plaque/nodules on his [CD5.sup.+] arm, trunk, and small B-cell lymphoma Jullie et Man age 50 y with MF, tumor stage, and al, (22) 2013 patches and tumors. PCFCL Biopsy revealed a CL scalp. Biopsies of arm and leg lesions revealed CL Jullie et Man age 67 y with MF, tumor stage, and al, (22) 2013 patches and tumors. PCFCL Biopsy revealed a CL Report of Primary Cutaneous CL: Additional Features Source, y Barzilai et Indolent course al, (21) 2006 Huwait et T-cell and B-cell gene al, (22) 2010 rearrangements with the same amplicon size were identified in the chin and leg Disease progression to tumors and large cell transformation despite systemic chemotherapy (cyclophosphamide, vincristine, and prednisone with concurrent rituximab) Whitling et Flow cytometry of both the al, (20) 2013 peripheral blood and lymph node revealed a small [CD5.sup.+] B-cell population with X bias Yang et Per the authors, this case al, (19) 2011 could also be considered an "atypical [EBV.sup.+] lymphoproliferative disorder." Complete regression occurred Wang et T-cell and B-cell gene al, (24) 2014 rearrangements of the same amplicon size were identified in the arm and leg Flow cytometry revealed 0.7% clonal, [CD5.sup.+] B cells in the bone marrow Jullie et Treated with systemic al, (22) 2013 chemotherapy, including rituximab, then allogenic stem cell transplantation. Although the B-cell lymphoma underwent complete remission, the MF relapsed 4 mo later Jullie et Patient developed lymph node al, (22) 2013 and brain involvement (not biopsied) and died Abbreviations: EBV, Epstein-Barr virus; LPD, lymphoproliferative disorder, MF, mycosis fungoides; MTX, methotrexate; PCFCL, primary cutaneous follicle center lymphoma; PCMZL, primary cutaneous marginal zone lymphoma; PCPTCL, primary cutaneous peripheral T-cell lymphoma; RA, rheumatoid arthritis.
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|Author:||Chen, Stephanie; Boyer, Daniel; Hristov, Alexandra C.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Nov 1, 2018|
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