BRIEF REPORT
Composite Mantle Cell and Primary Cutaneous Anaplastic Large Cell Lymphoma: Case Report and Review of the Literature Charles Leduc, MD,* Ivan I. P. Blandino, MD, PhD,* Abdulmohsen Alhejaily, PhD,* Tara Baetz, MD,† David J. Good, MD,* Patricia L. Farmer, MD,* Jeremy A. Squire, PhD,* and David P. LeBrun, MD*
Abstract: We describe the first reported occurrence of a composite cutaneous lymphoma involving a mantle cell lymphoma (MCL) and primary cutaneous anaplastic large cell lymphoma. The lesion occurred in a 76-year-old man with longstanding MCL who developed nodular skin lesions on his trunk and extremities. Biopsy revealed a CD30-positive lymphoma with pathological features characteristic of cutaneous anaplastic large cell lymphoma in the superficial dermis and a subjacent deposit of MCL in the deep dermis and subcutaneous adipose tissue. Immunophenotyping demonstrated T versus B lymphoid origin, respectively, for the 2 neoplasms, and fluorescence in situ hybridization demonstrated an 11;14 chromosomal translocation exclusively in the MCL. These results argue that the lymphomas represented clonally distinct neoplasms. Our case illustrates the extreme diversity associated with the cutaneous manifestations of lymphoid neoplasia and in particular of composite lymphomas, which present diagnostic challenges for clinicians and pathologists alike. Key Words: composite lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, cutaneous lymphoma, primary cutaneous CD30+ lymphoproliferative disorders (Am J Dermatopathol 2015;37:232–236)
INTRODUCTION
The term “composite lymphoma” (CL) describes the simultaneous occurrence of 2 distinct and well-delineated varieties of lymphomas occurring at a single anatomic site.1,2 The concept excludes cases that appear to arise through the progression and transformation of an indolent to a more aggressive lymphoma as occurs, for example, when chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/ SLL) progresses to diffuse large B-cell or Hodgkin lymphoma (HL). Although the literature describes a wide variety of combinations, most CLs involve the co-occurrence of a B From the *Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada; and †Department of Oncology, Queens University and Cancer Centre of Southeastern Ontario, Kingston General Hospital, Kingston, Ontario, Canada. T. Baetz provides consultancy for Lundbeck, Roche, and Bristol Myers Squibb. The remaining authors declare no conflicts of interest. Reprints: Charles Leduc, MD, Department of Pathology and Molecular Medicine, Queen’s University, Richardson Laboratory, 88 Stuart Street, Kingston, Ontario, Canada K7L 3N6 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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lineage non-HL with HL.3 CLs composed of lymphomas of different cell lineages are rare; when they occur, such cases most often combine diffuse large B-cell lymphoma and mycosis fungoides (MF).4 Here we report the first occurrence, to our knowledge, of a CL composed of mantle cell lymphoma (MCL) and primary cutaneous anaplastic large cell lymphoma (C-ALCL).
CASE REPORT A 76-year-old man presented in November 2006 with shortness of breath and unintentional weight loss. He had mild cervical lymphadenopathy and normocytic anemia. Endoscopy and random duodenal biopsies revealed MCL involving the duodenal mucosa. Computed tomography revealed wall thickening of the small bowel and distal colon and extensive intra-abdominal and axillary lymphadenopathy. Six cycles of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone completed in June 2007 produced a good response with substantial reduction of lymphadenopathy. One year later, computed tomography demonstrated progression of abdominal lymphadenopathy, which responded well to chlorambucil treatment. However, approximately 2 months into treatment, a pruritic maculopapular rash appeared on the trunk and extremities. Repeat imaging studies indicated progressing intra-abdominal lymphadenopathy. The peripheral lymphocyte count and lactate dehydrogenase and liver transaminase levels were within normal limits. Third-line therapy with intravenous cyclophosphamide, vincristine, and prednisone produced no clinical response in either the lymphadenopathy or the rash. The rash remained relatively unchanged over several months and eventually progressed into several separate raised nodules, which became painful and ulcerated (Fig. 1). An excisional biopsy of one of the skin lesions was performed, and the patient was started on oral prednisone. The patient was then lost to follow-up before expiring in September 2010. Macroscopically, the skin ellipse exhibited a central ulcer and was markedly indurated. Histologic examination showed 2 distinct infiltrative cell populations within the dermis and subcutaneous tissue separated by a mildly fibrotic “demarcation zone” (Fig. 2). The deeper component infiltrated the deeper portions of the reticular dermis and subcutaneous fat. These neoplastic cells were arranged in a vaguely nodular pattern and consisted of small lymphoid cells with somewhat irregular nuclear contours and dense chromatin (Fig. 3). Immunostains demonstrated expression by the lesional cells of CD45, CD20, CD43, CD5, PAX5, CD79a, and cyclin D1 but not CD2, CD3, CD4, CD10, CD23, CD15, CD30, T1A1, ALK, cytokeratin, or S100 protein. These findings identified the deeper component as cutaneous and subcutaneous involvement by MCL. In contrast, the more superficial process consisted of diffuse infiltration by mostly large, pleomorphic, prominently nucleolated Am J Dermatopathol Volume 37, Number 3, March 2015
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FIGURE 1. Clinical photograph showing a representative skin nodule from the right arm. cells with obvious mitotic activity (Fig. 3). Hallmark cells were readily identified. Reactive eosinophils, neutrophils, and lymphocytes were present in relatively small numbers. Immunostains demonstrated strong expression of CD30 and CD43 in virtually all neoplastic cells; lesional cells also expressed CD45, CD2, TIA1, and, focally, CD15. There was no expression of CD3, CD4, CD8, CD5, CD10, CD20, CD23, ALK, cyclin D1, PAX5, CD79a, cytokeratin, EMA, or S100 protein. Immunohistochemistry failed to demonstrate expression of the Epstein–Barr virus (EBV)–associated latent membrane protein 1, nor was the transcription of EBVencoding region (EBER) demonstrable by in situ hybridization (ISH). The clinical and pathological features were considered diagnostic of C-ALCL. To investigate the clonal interrelationship between the 2 lymphoid neoplasms, fluorescence ISH (FISH) was performed using the fusion probe set for t(11;14)(q13;q32) that juxtaposes CCND1 with a portion of IGH. FISH detected a t(11;14) that was restricted to the MCL component (Fig. 4), thereby confirming the presence of genetically distinct populations corresponding to the MCL and C-ALCL components. More generally, our pathological findings document the simultaneous presence of 2 distinct lymphoma types within a single skin lesion and justify the diagnosis of CL.
MATERIALS AND METHODS Histologic and Immunohistochemical Assessments
The specimens were fixed in 10% neutral buffered formalin and embedded in paraffin. Histologic assessment was performed by light microscopy on 5-mm-thick sections stained with hematoxylin phloxine saffron. Immunohistochemistry was performed using an automated immunostainer
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Composite MCL and Primary C-ALCL
FIGURE 2. A low-power view of the skin and subcutaneous tissue showing 2 distinct infiltrative processes. A, Superficial diffuse infiltrate expanding the papillary and reticular dermis; (B) darker staining small cell infiltrate in the deep dermis and subcutaneous adipose tissue (hematoxylin phloxine saffron stain, original magnification, ·20).
(Ventana Medical Systems, Tucson, AZ). The antibodies used were as follows: ALK (clone DF 5F3; Cell Signaling Technology, Danvers, MA), BCL2 (clone 124; Ventana Medical Systems), BCL6 (clone PIF6; Vector Laboratories, Burlingame, CA), CD3 (clone 2GV6; Ventana Medical Systems), CD4 (clone BC/1F6; Abcam, Cambridge, MA), CD5 (clone 4C7; Vector Laboratories), CD8 (clone SP57; Ventana Medical Systems), CD10 (clone 56C6; Cell Marque, Rocklin, CA), CD15 (clone MMA; Ventana Medical Systems), CD20 (clone L26; Ventana Medical Systems), CD23 (clone SP23; Ventana Medical Systems), CD30 (clone BER-H2; Ventana Medical Systems), CD43 (clone L60; Ventana Medical Systems), CD45 (clone RP2/18; Ventana Medical Systems), CD79a (clone SP34; Ventana Medical Systems), cyclin D1 (clone SP4; Medicorp, Montreal, Quebec, Canada), cytokeratin AE1/AE3 (clone AE1/AE3; Cell Marque), EBV (CS 1-4 cocktail; DAKO, Carpinteria, CA), EMA (clone E29; DAKO), PAX5 (clone SP34; Ventana Medical Systems), S100 (rabbit polyclonal; DAKO), and TIA1 (clone TIA-1; Abcam). An external positive control was run with each antibody, and a negative control was run with each stain.
Chromogenic ISH and FISH Chromogenic ISH for EBV was performed on a formalin-fixed paraffin-embedded section. The assay was conducted using an automated staining instrument (BenchMark autostainer) and the ISH iVIEW Blue Detection Kit with the INFORM EBER probe (Ventana Medical Systems). The manufacturer’s instructions were used with no modifications. www.amjdermatopathology.com |
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FIGURE 3. Higher power photomicrographs demonstrating the presence of both C-ALCL (left column) and MCL (right column) in the biopsy sample, as defined by distinctive morphological and immunophenotypic features. The arrows indicate hallmark cells (hematoxylin phloxine saffron stain and CD2 immunostain, original magnification, ·400; PAX5, CD30, and cyclin D1immunostains, original magnification, ·200).
Briefly, after cell block sections were deparaffinized and enzymatically digested with ISH-PROTEASE-1, hybridization solution, INFORM EBER probe, was applied to the sections, warmed up, and incubated. Hybridization was completed using iVIEW BLUE SA-AP. The slides were then counterstained with Nuclear Fast Red and coverslipped. A known EBV-positive tissue was used as a positive control, and hybridization without a probe was carried out as a negative control. Positive staining was identified as blue nuclear dots. Any definitive nuclear staining in the lesional cells was considered positive, and the absence of such staining in the nuclei of lesional cells was considered to be negative.
FISH was carried out with the commercial Vysis LSI IGH/CCND1 dual color/dual fusion probe, with CCND1 labeled with Spectrum Orange and IGH labeled with Spectrum Green (Abbott Molecular, IL). Briefly, 5-mm-thick formalin-fixed paraffin-embedded sections were placed in a dry oven at 658C for 24 hours, deparaffinized with xylene, and dehydrated in 100% ethanol. Air-dried slides were first incubated in 10 mM sodium citrate [saline sodium citrate (SSC)], pH 6.4, at 808C for 50 minutes and rinsed sequentially in SSC and distilled water (dH2O). The slides were then digested with 750 U/mL pepsin in 0.01 N HCl solution at 378C for 18 minutes followed by dH2O at room temperature
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FIGURE 4. FISH demonstrates IGH–CCND1 fusion in the MCL (B) but not the ALCL (A) component. Red signal, CCND1 probe; green signal, IGH probe. The arrows indicate fusion signals.
for 10 minutes and dehydration in an ascending ethanol series. Each probe was added, and the slides were coverslipped and sealed with rubber cement. Co-denaturation was carried out at 808C for 10 minutes in a microprocessor-controlled system (HYBrite; Abbot Molecular), and then the sections were hybridized at 378C overnight. Post-hybridization washes consisted of 2-fold concentrated SSC (·2 SSC) buffer, pH 7.0, containing 0.3% octylphenyl-polyethylene glycol (IGEPAL) for 2 minutes at 728C followed by 2 minutes in ·2 SSC, pH 7.0, at room temperature. After rinsing in dH2O, the slides were air-dried in a dark chamber and then counterstained with 40 ,6-diamidino-2-phenylindole (Vector Laboratories). The slides were analyzed under a ·60 oil immersion objective using an Olympus BX-51 fluorescence microscope equipped with appropriate filters. A cell was considered positive for t(11;14) if it contained at least one fused (yellow) signal, and the tumor was considered to be harboring the t(11;14) translocation if at least 10% of cells were positive for the translocation.5–7 Image acquisition was performed using the Isis FISH imaging system (MetaSystems Group Inc, Boston, MA).
DISCUSSION The available evidence supports our conclusion that the more superficial process in this biopsy represents an example of primary CD30+ cutaneous T lymphoproliferative disorder, with no evidence of systemic T-cell lymphoma. The main diagnostic entities considered were large cell transformation Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Composite MCL and Primary C-ALCL
of MF and the primary CD30+ cutaneous T lymphoproliferative disorders, which include C-ALCL, lymphomatoid papulosis (LyP), and borderline cases. Involvement of the skin by systemic ALCL cannot be ruled out entirely based on the available information. However, this caveat almost always attaches to the pathological diagnosis of a lymphoma considered as primarily cutaneous, and the available imaging results provide no evidence of systemic ALCL. Arguing against a diagnosis of large cell transformation of MF, there were no cerebriform cells or evidence of epidermotropism, and CD30 was expressed in nearly all lesional cells.8,9 Perhaps more importantly, there was no history of MF. Differentiating C-ALCL from LyP can be challenging and is often based largely on clinical presentation.10,11 Although our case could conceivably represent an instance of type C LyP or a borderline case, C-ALCL is more likely because of the nongrouped nature of some skin nodules (Fig. 1) and the lack of resolution of the skin lesions over a period of at least 1 year. In contrast, LyP tends to present as grouped or disseminated lesions that, by definition, undergo spontaneous regression within weeks to months.8,10,12–14 Although we did not attempt to demonstrate clonal rearrangement of a T-cell receptor genetic locus, neither T-cell receptor rearrangement is universally present in C-ALCL nor is it required for the diagnosis.15 T-cell lineage is supported in our case especially by the expression of CD2 and TIA1 but not PAX5. PAX5 is an extremely sensitive and specific marker of B lymphoid differentiation in human neoplasms; its complete absence in the C-ALCL component in our case argues strongly against a B lineage lymphoma, such as MCL or classical HL.16 At least 26 cases of CL involving MCL have been reported, with the most frequent partners being follicular lymphoma, SLL, and classical HL.17 Other lymphomas found in CLs with MCL include plasma cell neoplasms, marginal zone lymphoma, plasmablastic lymphoma, and Burkitt lymphoma. To our knowledge, there have been no reports of a CL involving MCL and a non-B lineage lymphoma, such as C-ALCL. Reports of CLs involving ALCL are exceedingly rare; our review yielded only 4 cases.18–21 In most of these, the diagnosis was made in an elderly patient with a long history of CLL/SLL. Although little evidence exists to elucidate the pathogenesis of CLs with both B and T lineage components, hypotheses invoke immunodeficiency, autoimmune disorders, chemotherapy, EBV-induced transformation, and genetic instability of the initial lymphoma with clonal divergence.17,22 An emerging body of research on CLs suggests that most cases are not clonally distinct but instead develop from common lymphoma-initiating cells.23 In our case, however, the distinct cell lineages of the 2 lymphomas and the presence of t(11;14) in the apparently preexisting MCL but not the C-ALCL suggest, but do not prove, that the 2 lymphomas arose from separate neoplastic clones. We can only speculate as to why the MCL and C-ALCL infiltrates were juxtaposed sufficiently intimately as to be sampled together in a single skin nodule. Random chance cannot be discounted, especially in a patient with widely disseminated MCL. Loss of L-selectin and gain of E-selectin have been documented to promote homing of malignant lymphocytes to the skin.24–26 Although we did not ascertain selectin expression in our case, such a mechanism www.amjdermatopathology.com |
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Leduc et al
could have been operative. Immunocompromise because of relatively advanced age, MCL, and chemotherapy might have predisposed to the subsequent development of C-ALCL. Finally, the local proliferation of C-ALCL might have been induced or promoted by local effects of the MCL deposits mediated either by cytokines or through direct interactions. Indeed, the occurrence of T-cell neoplasia in patients with B lineage SLL/CLL is well documented, and evidence suggests the possibility that the T lineage neoplasms might have arisen, in part, because of chronic immunological stimulation by the B lineage neoplasm.27–29 In conclusion, this report describes a rare case of CL involving MCL and C-ALCL in the skin of an elderly man. Although much has been learned about the genetic and phenotypic plasticity of neoplastic lymphocytes and the potential role this plays in the development of CLs, our knowledge about the required inciting factors and the role of the tumor microenvironment remains limited. This case illustrates the extreme diversity associated with manifestations of lymphoid neoplasia, which continue to present diagnostic challenges for clinicians and pathologists alike.
11. 12. 13. 14.
15. 16. 17. 18. 19.
REFERENCES 1. Hicks EB, Rappaport H, Winter WJ. Follicular lymphoma. A reevaluation of its position in the scheme of malignant lymphoma, based on a survey of 253 cases. Cancer. 1956;9:792–821. 2. Kim H, Hendrickson R, Dorfman RF. Composite lymphoma. Cancer. 1977;40:959–976. 3. Thirumala S, Esposito M, Fuchs A. An unusual variant of composite lymphoma: a short case report and review of the literature. Arch Pathol Lab Med. 2000;124:1376–1378. 4. Yang SF, Chang WY, Lan CC, et al. Composite primary cutaneous peripheral T-cell lymphoma and Epstein-Barr virus-positive large B-cell lymphoma. Leuk Lymphoma. 2011;52:2027–2030. 5. Li JY, Gaillard F, Moreau A, et al. Detection of translocation t(11;14) (q13;q32) in mantle cell lymphoma by fluorescence in situ hybridization. Am J Pathol. 1999;154:1449–1452. 6. Ondrejka SL, Lai R, Smith SD, et al. Indolent mantle cell leukemia: a clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica. 2011;96:1121–1127. 7. Sun T, Nordberg ML, Cotelingam JD, et al. Fluorescence in situ hybridization: method of choice for a definitive diagnosis of mantle cell lymphoma. Am J Hematol. 2003;74:78–84. 8. Kadin ME, Hughey LC, Wood GS. Large-cell transformation of mycosis fungoides-differential diagnosis with implications for clinical management: a consensus statement of the US Cutaneous Lymphoma Consortium. J Am Acad Dermatol. 2014;70:374–376. 9. Song SX, Willemze R, Swerdlow SH, et al. Mycosis fungoides: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop. Am J Clin Pathol. 2013;139:466–490. 10. Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis
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20. 21. 22. 23. 24. 25. 26. 27. 28.
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and primary cutaneous anaplastic large-cell lymphoma. Blood. 2011; 118:4024–4035. Swerdllow S, Campo E, Harris NL. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. Drews R, Samel A, Kadin ME. Lymphomatoid papulosis and anaplastic large cell lymphomas of the skin. Semin Cutan Med Surg. 2000;19: 109–117. Macaulay WL. Lymphomatoid papulosis. A continuing self-healing eruption, clinically benign–histologically malignant. Arch Dermatol. 1968;97:23–30. Quintanilla-Martinez L, Jansen PM, Kinney MC, et al. Non-mycosis fungoides cutaneous T-cell lymphomas: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop. Am J Clin Pathol. 2013;139:491–514. Pileri SA, Agostinelli C, Sabattini E, et al. Lymphoma classification: the quiet after the storm. Semin Diagn Pathol. 2011;28:113–123. Desouki MM, Post GR, Cherry D, et al. PAX-5: a valuable immunohistochemical marker in the differential diagnosis of lymphoid neoplasms. Clin Med Res. 2010;8:84–88. Papathomas TG, Venizelos I, Dunphy CH, et al. Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications. Hum Pathol. 2012;43:467–480. Liu T, He M, Carlson DL, et al. ALK-positive anaplastic large cell lymphoma in a patient with chronic lymphocytic leukemia. Int J Surg Pathol. 2010;18:424–428. Marschalko M, Csomor J, Eros N, et al. Coexistence of primary cutaneous anaplastic large cell lymphoma and mycosis fungoides in a patient with B-cell chronic lymphocytic leukaemia. Br J Dermatol. 2007;157: 1291–1293. van den Berg A, Maggio E, Rust R, et al. Clonal relation in a case of CLL, ALCL, and Hodgkin composite lymphoma. Blood. 2002;100: 1425–1429. Persad P, Pang CS. Composite ALK-negative anaplastic large cell lymphoma and small lymphocytic lymphoma involving the right inguinal lymph node. Pathol Res Pract. 2014;210:127–129. Mokhtar NM. Review article composite lymphoma. J Egypt Natl Canc Inst. 2007;19:171–175. Martinez-Climent JA, Fontan L, Gascoyne RD, et al. Lymphoma stem cells: enough evidence to support their existence? Haematologica. 2010; 95:293–302. Drillenburg P, Pals ST. Cell adhesion receptors in lymphoma dissemination. Blood. 2000;95:1900–1910. Campbell JJ, Clark RA, Watanabe R, et al. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood. 2010;116:767–771. Abel EA, Wood GS, Hoppe RT, et al. Expression of Leu-8 antigen, a majority T-cell marker, is uncommon in mycosis fungoides. J Invest Dermatol. 1985;85:199–202. Boyer DF, Lindeman NI, Harris NL, et al. Peripheral T-cell lymphomas with cytotoxic phenotype in patients with chronic lymphocytic leukemia/ small lymphocytic lymphoma. Am J Surg Pathol. 2014;38:279–288. Alomari A, Hui P, Xu M. Composite peripheral T-cell lymphoma not otherwise specified, and B-cell small lymphocytic lymphoma presenting with hemophagocytic lymphohistiocytosis. Int J Surg Pathol. 2013;21: 303–308. Martinez A, Pittaluga S, Villamor N, et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am J Surg Pathol. 2004;28:849–858.
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Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Composite Mantle Cell and Primary Cutaneous Anaplastic Large Cell Lymphoma: Case Report and Review of the Literature Charles Leduc, MD,* Ivan I. P. Blandino, MD, PhD,* Abdulmohsen Alhejaily, PhD,* Tara Baetz, MD,† David J. Good, MD,* Patricia L. Farmer, MD,* Jeremy A. Squire, PhD,* and David P. LeBrun, MD*
Abstract: We describe the first reported occurrence of a composite cutaneous lymphoma involving a mantle cell lymphoma (MCL) and primary cutaneous anaplastic large cell lymphoma. The lesion occurred in a 76-year-old man with longstanding MCL who developed nodular skin lesions on his trunk and extremities. Biopsy revealed a CD30-positive lymphoma with pathological features characteristic of cutaneous anaplastic large cell lymphoma in the superficial dermis and a subjacent deposit of MCL in the deep dermis and subcutaneous adipose tissue. Immunophenotyping demonstrated T versus B lymphoid origin, respectively, for the 2 neoplasms, and fluorescence in situ hybridization demonstrated an 11;14 chromosomal translocation exclusively in the MCL. These results argue that the lymphomas represented clonally distinct neoplasms. Our case illustrates the extreme diversity associated with the cutaneous manifestations of lymphoid neoplasia and in particular of composite lymphomas, which present diagnostic challenges for clinicians and pathologists alike. Key Words: composite lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, cutaneous lymphoma, primary cutaneous CD30+ lymphoproliferative disorders (Am J Dermatopathol 2015;37:232–236)
INTRODUCTION
The term “composite lymphoma” (CL) describes the simultaneous occurrence of 2 distinct and well-delineated varieties of lymphomas occurring at a single anatomic site.1,2 The concept excludes cases that appear to arise through the progression and transformation of an indolent to a more aggressive lymphoma as occurs, for example, when chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/ SLL) progresses to diffuse large B-cell or Hodgkin lymphoma (HL). Although the literature describes a wide variety of combinations, most CLs involve the co-occurrence of a B From the *Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada; and †Department of Oncology, Queens University and Cancer Centre of Southeastern Ontario, Kingston General Hospital, Kingston, Ontario, Canada. T. Baetz provides consultancy for Lundbeck, Roche, and Bristol Myers Squibb. The remaining authors declare no conflicts of interest. Reprints: Charles Leduc, MD, Department of Pathology and Molecular Medicine, Queen’s University, Richardson Laboratory, 88 Stuart Street, Kingston, Ontario, Canada K7L 3N6 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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lineage non-HL with HL.3 CLs composed of lymphomas of different cell lineages are rare; when they occur, such cases most often combine diffuse large B-cell lymphoma and mycosis fungoides (MF).4 Here we report the first occurrence, to our knowledge, of a CL composed of mantle cell lymphoma (MCL) and primary cutaneous anaplastic large cell lymphoma (C-ALCL).
CASE REPORT A 76-year-old man presented in November 2006 with shortness of breath and unintentional weight loss. He had mild cervical lymphadenopathy and normocytic anemia. Endoscopy and random duodenal biopsies revealed MCL involving the duodenal mucosa. Computed tomography revealed wall thickening of the small bowel and distal colon and extensive intra-abdominal and axillary lymphadenopathy. Six cycles of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone completed in June 2007 produced a good response with substantial reduction of lymphadenopathy. One year later, computed tomography demonstrated progression of abdominal lymphadenopathy, which responded well to chlorambucil treatment. However, approximately 2 months into treatment, a pruritic maculopapular rash appeared on the trunk and extremities. Repeat imaging studies indicated progressing intra-abdominal lymphadenopathy. The peripheral lymphocyte count and lactate dehydrogenase and liver transaminase levels were within normal limits. Third-line therapy with intravenous cyclophosphamide, vincristine, and prednisone produced no clinical response in either the lymphadenopathy or the rash. The rash remained relatively unchanged over several months and eventually progressed into several separate raised nodules, which became painful and ulcerated (Fig. 1). An excisional biopsy of one of the skin lesions was performed, and the patient was started on oral prednisone. The patient was then lost to follow-up before expiring in September 2010. Macroscopically, the skin ellipse exhibited a central ulcer and was markedly indurated. Histologic examination showed 2 distinct infiltrative cell populations within the dermis and subcutaneous tissue separated by a mildly fibrotic “demarcation zone” (Fig. 2). The deeper component infiltrated the deeper portions of the reticular dermis and subcutaneous fat. These neoplastic cells were arranged in a vaguely nodular pattern and consisted of small lymphoid cells with somewhat irregular nuclear contours and dense chromatin (Fig. 3). Immunostains demonstrated expression by the lesional cells of CD45, CD20, CD43, CD5, PAX5, CD79a, and cyclin D1 but not CD2, CD3, CD4, CD10, CD23, CD15, CD30, T1A1, ALK, cytokeratin, or S100 protein. These findings identified the deeper component as cutaneous and subcutaneous involvement by MCL. In contrast, the more superficial process consisted of diffuse infiltration by mostly large, pleomorphic, prominently nucleolated Am J Dermatopathol Volume 37, Number 3, March 2015
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Am J Dermatopathol Volume 37, Number 3, March 2015
FIGURE 1. Clinical photograph showing a representative skin nodule from the right arm. cells with obvious mitotic activity (Fig. 3). Hallmark cells were readily identified. Reactive eosinophils, neutrophils, and lymphocytes were present in relatively small numbers. Immunostains demonstrated strong expression of CD30 and CD43 in virtually all neoplastic cells; lesional cells also expressed CD45, CD2, TIA1, and, focally, CD15. There was no expression of CD3, CD4, CD8, CD5, CD10, CD20, CD23, ALK, cyclin D1, PAX5, CD79a, cytokeratin, EMA, or S100 protein. Immunohistochemistry failed to demonstrate expression of the Epstein–Barr virus (EBV)–associated latent membrane protein 1, nor was the transcription of EBVencoding region (EBER) demonstrable by in situ hybridization (ISH). The clinical and pathological features were considered diagnostic of C-ALCL. To investigate the clonal interrelationship between the 2 lymphoid neoplasms, fluorescence ISH (FISH) was performed using the fusion probe set for t(11;14)(q13;q32) that juxtaposes CCND1 with a portion of IGH. FISH detected a t(11;14) that was restricted to the MCL component (Fig. 4), thereby confirming the presence of genetically distinct populations corresponding to the MCL and C-ALCL components. More generally, our pathological findings document the simultaneous presence of 2 distinct lymphoma types within a single skin lesion and justify the diagnosis of CL.
MATERIALS AND METHODS Histologic and Immunohistochemical Assessments
The specimens were fixed in 10% neutral buffered formalin and embedded in paraffin. Histologic assessment was performed by light microscopy on 5-mm-thick sections stained with hematoxylin phloxine saffron. Immunohistochemistry was performed using an automated immunostainer
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Composite MCL and Primary C-ALCL
FIGURE 2. A low-power view of the skin and subcutaneous tissue showing 2 distinct infiltrative processes. A, Superficial diffuse infiltrate expanding the papillary and reticular dermis; (B) darker staining small cell infiltrate in the deep dermis and subcutaneous adipose tissue (hematoxylin phloxine saffron stain, original magnification, ·20).
(Ventana Medical Systems, Tucson, AZ). The antibodies used were as follows: ALK (clone DF 5F3; Cell Signaling Technology, Danvers, MA), BCL2 (clone 124; Ventana Medical Systems), BCL6 (clone PIF6; Vector Laboratories, Burlingame, CA), CD3 (clone 2GV6; Ventana Medical Systems), CD4 (clone BC/1F6; Abcam, Cambridge, MA), CD5 (clone 4C7; Vector Laboratories), CD8 (clone SP57; Ventana Medical Systems), CD10 (clone 56C6; Cell Marque, Rocklin, CA), CD15 (clone MMA; Ventana Medical Systems), CD20 (clone L26; Ventana Medical Systems), CD23 (clone SP23; Ventana Medical Systems), CD30 (clone BER-H2; Ventana Medical Systems), CD43 (clone L60; Ventana Medical Systems), CD45 (clone RP2/18; Ventana Medical Systems), CD79a (clone SP34; Ventana Medical Systems), cyclin D1 (clone SP4; Medicorp, Montreal, Quebec, Canada), cytokeratin AE1/AE3 (clone AE1/AE3; Cell Marque), EBV (CS 1-4 cocktail; DAKO, Carpinteria, CA), EMA (clone E29; DAKO), PAX5 (clone SP34; Ventana Medical Systems), S100 (rabbit polyclonal; DAKO), and TIA1 (clone TIA-1; Abcam). An external positive control was run with each antibody, and a negative control was run with each stain.
Chromogenic ISH and FISH Chromogenic ISH for EBV was performed on a formalin-fixed paraffin-embedded section. The assay was conducted using an automated staining instrument (BenchMark autostainer) and the ISH iVIEW Blue Detection Kit with the INFORM EBER probe (Ventana Medical Systems). The manufacturer’s instructions were used with no modifications. www.amjdermatopathology.com |
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FIGURE 3. Higher power photomicrographs demonstrating the presence of both C-ALCL (left column) and MCL (right column) in the biopsy sample, as defined by distinctive morphological and immunophenotypic features. The arrows indicate hallmark cells (hematoxylin phloxine saffron stain and CD2 immunostain, original magnification, ·400; PAX5, CD30, and cyclin D1immunostains, original magnification, ·200).
Briefly, after cell block sections were deparaffinized and enzymatically digested with ISH-PROTEASE-1, hybridization solution, INFORM EBER probe, was applied to the sections, warmed up, and incubated. Hybridization was completed using iVIEW BLUE SA-AP. The slides were then counterstained with Nuclear Fast Red and coverslipped. A known EBV-positive tissue was used as a positive control, and hybridization without a probe was carried out as a negative control. Positive staining was identified as blue nuclear dots. Any definitive nuclear staining in the lesional cells was considered positive, and the absence of such staining in the nuclei of lesional cells was considered to be negative.
FISH was carried out with the commercial Vysis LSI IGH/CCND1 dual color/dual fusion probe, with CCND1 labeled with Spectrum Orange and IGH labeled with Spectrum Green (Abbott Molecular, IL). Briefly, 5-mm-thick formalin-fixed paraffin-embedded sections were placed in a dry oven at 658C for 24 hours, deparaffinized with xylene, and dehydrated in 100% ethanol. Air-dried slides were first incubated in 10 mM sodium citrate [saline sodium citrate (SSC)], pH 6.4, at 808C for 50 minutes and rinsed sequentially in SSC and distilled water (dH2O). The slides were then digested with 750 U/mL pepsin in 0.01 N HCl solution at 378C for 18 minutes followed by dH2O at room temperature
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FIGURE 4. FISH demonstrates IGH–CCND1 fusion in the MCL (B) but not the ALCL (A) component. Red signal, CCND1 probe; green signal, IGH probe. The arrows indicate fusion signals.
for 10 minutes and dehydration in an ascending ethanol series. Each probe was added, and the slides were coverslipped and sealed with rubber cement. Co-denaturation was carried out at 808C for 10 minutes in a microprocessor-controlled system (HYBrite; Abbot Molecular), and then the sections were hybridized at 378C overnight. Post-hybridization washes consisted of 2-fold concentrated SSC (·2 SSC) buffer, pH 7.0, containing 0.3% octylphenyl-polyethylene glycol (IGEPAL) for 2 minutes at 728C followed by 2 minutes in ·2 SSC, pH 7.0, at room temperature. After rinsing in dH2O, the slides were air-dried in a dark chamber and then counterstained with 40 ,6-diamidino-2-phenylindole (Vector Laboratories). The slides were analyzed under a ·60 oil immersion objective using an Olympus BX-51 fluorescence microscope equipped with appropriate filters. A cell was considered positive for t(11;14) if it contained at least one fused (yellow) signal, and the tumor was considered to be harboring the t(11;14) translocation if at least 10% of cells were positive for the translocation.5–7 Image acquisition was performed using the Isis FISH imaging system (MetaSystems Group Inc, Boston, MA).
DISCUSSION The available evidence supports our conclusion that the more superficial process in this biopsy represents an example of primary CD30+ cutaneous T lymphoproliferative disorder, with no evidence of systemic T-cell lymphoma. The main diagnostic entities considered were large cell transformation Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Composite MCL and Primary C-ALCL
of MF and the primary CD30+ cutaneous T lymphoproliferative disorders, which include C-ALCL, lymphomatoid papulosis (LyP), and borderline cases. Involvement of the skin by systemic ALCL cannot be ruled out entirely based on the available information. However, this caveat almost always attaches to the pathological diagnosis of a lymphoma considered as primarily cutaneous, and the available imaging results provide no evidence of systemic ALCL. Arguing against a diagnosis of large cell transformation of MF, there were no cerebriform cells or evidence of epidermotropism, and CD30 was expressed in nearly all lesional cells.8,9 Perhaps more importantly, there was no history of MF. Differentiating C-ALCL from LyP can be challenging and is often based largely on clinical presentation.10,11 Although our case could conceivably represent an instance of type C LyP or a borderline case, C-ALCL is more likely because of the nongrouped nature of some skin nodules (Fig. 1) and the lack of resolution of the skin lesions over a period of at least 1 year. In contrast, LyP tends to present as grouped or disseminated lesions that, by definition, undergo spontaneous regression within weeks to months.8,10,12–14 Although we did not attempt to demonstrate clonal rearrangement of a T-cell receptor genetic locus, neither T-cell receptor rearrangement is universally present in C-ALCL nor is it required for the diagnosis.15 T-cell lineage is supported in our case especially by the expression of CD2 and TIA1 but not PAX5. PAX5 is an extremely sensitive and specific marker of B lymphoid differentiation in human neoplasms; its complete absence in the C-ALCL component in our case argues strongly against a B lineage lymphoma, such as MCL or classical HL.16 At least 26 cases of CL involving MCL have been reported, with the most frequent partners being follicular lymphoma, SLL, and classical HL.17 Other lymphomas found in CLs with MCL include plasma cell neoplasms, marginal zone lymphoma, plasmablastic lymphoma, and Burkitt lymphoma. To our knowledge, there have been no reports of a CL involving MCL and a non-B lineage lymphoma, such as C-ALCL. Reports of CLs involving ALCL are exceedingly rare; our review yielded only 4 cases.18–21 In most of these, the diagnosis was made in an elderly patient with a long history of CLL/SLL. Although little evidence exists to elucidate the pathogenesis of CLs with both B and T lineage components, hypotheses invoke immunodeficiency, autoimmune disorders, chemotherapy, EBV-induced transformation, and genetic instability of the initial lymphoma with clonal divergence.17,22 An emerging body of research on CLs suggests that most cases are not clonally distinct but instead develop from common lymphoma-initiating cells.23 In our case, however, the distinct cell lineages of the 2 lymphomas and the presence of t(11;14) in the apparently preexisting MCL but not the C-ALCL suggest, but do not prove, that the 2 lymphomas arose from separate neoplastic clones. We can only speculate as to why the MCL and C-ALCL infiltrates were juxtaposed sufficiently intimately as to be sampled together in a single skin nodule. Random chance cannot be discounted, especially in a patient with widely disseminated MCL. Loss of L-selectin and gain of E-selectin have been documented to promote homing of malignant lymphocytes to the skin.24–26 Although we did not ascertain selectin expression in our case, such a mechanism www.amjdermatopathology.com |
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Am J Dermatopathol Volume 37, Number 3, March 2015
Leduc et al
could have been operative. Immunocompromise because of relatively advanced age, MCL, and chemotherapy might have predisposed to the subsequent development of C-ALCL. Finally, the local proliferation of C-ALCL might have been induced or promoted by local effects of the MCL deposits mediated either by cytokines or through direct interactions. Indeed, the occurrence of T-cell neoplasia in patients with B lineage SLL/CLL is well documented, and evidence suggests the possibility that the T lineage neoplasms might have arisen, in part, because of chronic immunological stimulation by the B lineage neoplasm.27–29 In conclusion, this report describes a rare case of CL involving MCL and C-ALCL in the skin of an elderly man. Although much has been learned about the genetic and phenotypic plasticity of neoplastic lymphocytes and the potential role this plays in the development of CLs, our knowledge about the required inciting factors and the role of the tumor microenvironment remains limited. This case illustrates the extreme diversity associated with manifestations of lymphoid neoplasia, which continue to present diagnostic challenges for clinicians and pathologists alike.
11. 12. 13. 14.
15. 16. 17. 18. 19.
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