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Primary Cutaneous Composite Lymphomas.

In 1948, Custer and Bernhard described "combined lesions" in which lymphomas with distinct histopathologic appearances were identified in a single patient, either at different anatomic sites or in separate areas of a single lymph node. (1) In 1954, Custer designated these cases as "composite" lymphomas. (2) In 1977, Kim et al (3) refined the definition of composite lymphoma (CL), limiting it to the presence of 2 distinct and well-defined varieties of lymphoma at a single anatomic site. In 1982, the working formulation of non-Hodgkin lymphomas sponsored by the National Cancer Institute continued the definition of CL provided by Kim et al, (3) describing CL as the presence of 2 distinct lymphomas within a single organ or tissue. (4) This definition of CL was based solely on morphology. (4,5) The advent of immunophenotypic and genetic techniques revealed that some lymphomas included as CLs actually represent 2 morphologic manifestations or stages of the same neoplastic clone (eg, follicular lymphoma transforming to diffuse large B-cell lymphoma). (5-9) Some authors excluded these latter cases from the term CL, emphasizing the coexistence of 2 "separate and distinct lymphomas" with different cells of origin. (9-11) This later definition has gained more support with time.


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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(15.) Strickler JG, Amsden TW, Kurtin PJ. Small B-cell lymphoid neoplasms with coexisting T-cell lymphomas. Am J Clin Pathol. 1992;98(4):424-429.

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(20.) Whitling NA, Shanesmith RP, Jacob L, et al. Composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient. Hum Pathol. 2013;44(4):670-675.

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(22.) Huwait H, Wang B, Shustik C, Michel RP. Composite cutaneous lymphoma in a patient with rheumatoid arthritis treated with methotrexate. Am J Dermatopathol. 2010;32(1):65-70.

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(26.) Balague O, Martinez A, Colomo L, et al. Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: a phenomenon with distinctive clinicopathologic features. Am J Surg Pathol. 2007; 31(9):1310-1322.

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(38.) Kikuchi A, Anzai H, Kosuge H, Naka W, Nishikawa T. Aggressive B-cell lymphoma induced by Epstein-Barr virus infection in erythrodermic cutaneous T-cell lymphoma. Br J Dermatol. 1997;136(1):124-128.

(39.) Jaffe ES, Zarate-Osorno A, Medeiros LJ. The interrelationship of Hodgkin's disease and non-Hodgkin's lymphomas-lessons learned from composite and sequential malignancies. Semin Diagn Pathol. 1992;9(4):297-303.

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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: ahristov@med.umich. 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
                      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

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
                    Disease progression to
                      tumors and large cell
                      transformation despite
                      systemic chemotherapy
                      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.+]
                      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
Article Type:Report
Date:Nov 1, 2018
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