Primary cutaneous marginal zone lymphoma (MZL) is a common B-cell lymphoma of skin and is characterized by an infiltrate of neoplastic marginal zone B cells typically within the marginal zones of reactive lymphoid follicles and the interfollicular region. However, in our experience, many cases have underemphasized features such as marked plasmacytic differentiation and/or a prominent T-cell component, which may obscure the neoplastic B cells and lead to misdiagnosis. We wanted to draw attention to these features and have studied 15 cases of MZL with marked plasmacytic differentiation, 10 of which had numerous T cells, some with cytologic atypia, and few B cells in the interfollicular region. Plasma cells were monotypic in all cases by in situ hybridization. By polymerase chain reaction, 6 of 8 T cell–rich cases had an IGH gene rearrangement, and none were clonal for T-cell receptor gene. We discuss the terminology, morphologic features, molecular profile, behavior, and differential diagnosis of cutaneous MZL.
Primary cutaneous marginal zone B-cell lymphoma (MZL) is a recently described entity that can present diag-nostic difficulty. MZL has been historically diagnosed as “primary cutaneous immunocytoma” or “primary cutaneous plasmacytoma” if the lesion was considered malignant and as “lymphocytoma cutis” if the lesion was considered benign. These terms persist in medical and pathology literature and contribute to confusion regarding this diagnostic entity. Primary cutaneous plasmacytoma was first described in the English literature by Agarwal in 1956.1 A first series of cuta-neous lymphoplasmacytic lymphomas has been published by Rijlaarsdam et al2 in 1993 under the name of immunocy-toma. The term immunocytoma was subsequently used in the updated Kiel classification and in the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group classification.3,4 At the same time, similar lesions were being diagnosed as MZL by other groups, who argued that their morphologic features were analogous to those of lymphoma of mucosa-associated lymphoid tissue (MALT) at other extranodal sites and noted that some cases of cutaneous lymphoma were concurrent with MALT lympho-mas at extracutaneous sites.5-10 Following consensus meet-ings of the World Health Organization (WHO) and EORTC, the term primary cutaneous MZL has been accepted as the favored diagnostic term, incorporating the entities of primary cutaneous immunocytoma and primary cutaneous plasmacy-toma.11,12 This change has been reflected in the latest WHO classification of skin tumors.13
Primary cutaneous MZL is defined as lymphoma com-posed of small B cells, including marginal zone (centrocyte-like) or monocytoid cells, lymphoplasmacytoid cells, and
Upon completion of this activity you will be able to:• define the current classification criteria for primary cutaneous
marginal zone lymphoma.• describe the morphologic and immunohistochemical features of
marginal zone lymphoma of skin, including the unusual variants.• analyze the advantages and pitfalls of molecular clonality testing.
The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.
The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.
Questions appear on p 162. Exam is located at www.ascp.org/ajcpcme.
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
plasma cells. It is considered to be part of the broad group of extranodal MALT lymphomas.14 The monotypic lym-phoplasmacytoid and plasma cells are usually located at the periphery of the infiltrates, while central areas of the infiltrates may contain variable numbers of reactive B and T cells with reactive lymphoid follicles.4 These definitions allow for a relatively straightforward recognition of classic cases of cutaneous MZL. However, atypical cases may be quite challenging for a pathologist owing to their rarity and the confusing terminology.
We recently encountered an unusual case with a promi-nent component of monotypic plasma cells, numerous T cells, and few extrafollicular B cells. We searched our files for pri-mary cutaneous MZLs with similar features.
Materials and Methods
A computer-assisted search of the pathology files of the Massachusetts General Hospital, Boston, and review of identified cases disclosed 15 patients with primary cutaneous MZL characterized by marked plasmacytic differentiation, defined as focal solid aggregates of plasma cells occupying at least one ×20 power field on an excision specimen or a ×40 power field on a small biopsy specimen as determined by histologic and light chain restriction studies. Lymphomas were defined as primary if there was no evidence of extracu-taneous involvement at the time of diagnosis and completion of initial staging evaluation, based on the WHO-EORTC classification.11
The total number of cases diagnosed as primary cutane-ous MZL was 33. Cases had been classified according to the criteria of the WHO classification of skin tumors using a combination of morphologic and immunophenotypic crite-ria.13 The remaining 18 cases not described in this report were typical cutaneous MZL as described.11-13 Of 15 cases, 2 were retrieved from the department of pathology archive and 13 from the consultation files of two of us (J.A.F. and N.L.H.).
Immunohistochemical analysis and in situ hybridiza-tion were performed on paraffin-embedded tissue as part of the diagnostic evaluation, including immunostaining for pan–B and pan–T antigens (CD20, DAKO, Carpinteria, CA; CD3, Novocastra, Newcastle upon Tyne, England), CD21 (Novocastra), CD23 (Novocastra), bcl-2 (DAKO), bcl-6 (DAKO), CD10 (DAKO), CD5 (Novocastra), CD2 (Novocastra), CD4 (Novocastra), CD8 (Novocastra), CD7 (Novocastra), CD138 (Serotec, Raleigh, NC), MUM-1 (DAKO), CD79a (DAKO), and immunoglobulin heavy chains α (BioGenex, San Ramon, CA), γ (BioGenex), μ (DAKO), δ (DAKO) and assessment of in situ hybridization for κ and λ immunoglobulin light chains (Becton Dickinson, Mountain View, CA).
Based on immunohistochemical analysis of B- and T-cell markers, cases were further subdivided in 2 groups: a T cell–rich group (10 cases) with rare extrafollicular B cells and numerous extrafollicular T cells (B cells < T cells, using a semiquantitative analysis) and a B cell–rich group (5 cases) with conspicuous extrafollicular B cells, equal in number or more frequent than the T cells (B = T or B > T cells).
Cases from the T cell–rich group were analyzed for immunoglobulin heavy chain (IGH) and T-cell receptor γ chain (TCR) rearrangements. DNA was isolated from deparaffinized tissue using QIAGEN QIamp DNA micro kits (QIAGEN, Valencia, CA). The B- and T-cell clonal-ity assays were performed using polymerase chain reaction (PCR) according to the manufacturer’s instructions with reagents purchased from InVivoScribe Technologies, San Diego, CA (IgH Gene Clonality Assay and TCRG Gene Clonality Assay for ABI Fluorescence Detection). The kits use the primer sequences published by BIOMED-2,15,16 and had all the necessary reagents except for sample DNA and Taq polymerase (AmpliTAQ Gold, Applied Biosystems, Foster City, CA). PCR products were analyzed by capillary gel electrophoresis (3100xl, Applied Biosystems).
Clinical information was available in all cases through the pathology report, the electronic medical record, or by contact-ing the referring physician. Institutional review board approval was obtained from Partners Healthcare System, Boston.
Results
Clinical FindingsThe clinical features are summarized in ❚Table 1❚.
Overall, 11 patients were men and 4 were women with a median age of 55 years (range, 20-83 years).
T Cell–Rich GroupThere were 8 men and 2 women with a median age of 55
years (range, 20-74 years). All patients had solitary cutaneous nodules involving the leg (4 cases), trunk (2 cases), shoulder (2 cases), arm (1 case), and scalp (1 case).
Two patients had a history of lymphoma. Case 1 first manifested 17 years earlier with a lesion on the left upper arm, diagnosed at the time as lymphocytoma cutis (original mate-rial not available for review). Thirteen years later, the patient had a new skin lesion on the right upper thigh diagnosed as cutaneous MZL and treated with local radiation. He devel-oped a recurrence in the right buttocks area 6 months later, was again treated with electron beam radiation therapy, and is currently free of disease.
Case 7 first manifested with a solitary scalp lesion 15 years earlier, diagnosed as “granulomatous mycosis fungoides,”
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
based on numerous atypical-appearing T cells and rare aggre-gates of cytologically benign B cells. Fourteen years later, the patient developed a new, morphologically similar-appearing scalp lesion, consistent with MZL owing to evidence of clonal plasma cells by in situ hybridization and PCR. TCR-γ gene analysis showed a polyclonal pattern. The patient received external beam radiation to a total dose of 30 Gy and is cur-rently doing well.
The remaining patients had no significant history. Three patients had 1 relapse, and 1 patient had 2 relapses occurring 3 months to 16 years (mean, 96 months) after the initial presen-tation. In 2 of 4 patients, the recurrent skin lesions appeared at a different site, whereas the other 2 patients had local recur-rence at the same location.
B Cell–Rich GroupThere were 3 men and 2 women with a median age of 54
years (range, 28-83 years). Patients had solitary skin lesions involving trunk (2 cases), shoulder and upper arm (2 cases), and neck (1 case).
Two patients had a history of lymphoma or atypical lymphoid proliferation. Case 12 manifested 5 years earlier with skin lesions on the chest and left arm, diagnosed at the time as atypical lymphoid infiltrate, “suspicious” of but not diagnostic for lymphoma. After 2 years, he developed a new lesion on the back, which was diagnostic for cutaneous MZL with marked plasmacytic differentiation. On review, the prior biopsy specimens had similar morphologic features except for a much less conspicuous presence of plasma cells.
Case 12 had a history of “diffuse small cleaved cell lymphoma” present in lymph nodes and in paratrabecular bone marrow diagnosed 19 years earlier and subsequently of diffuse large B-cell lymphoma of the stomach. Fourteen years later, she developed an isolated nodule on the right shoulder, diagnosed as cutaneous MZL, most likely unrelated to the prior lymphoma.
The remaining patients had no significant history. One patient developed a local recurrence 2 months after the initial diagnosis, followed by a distant recurrence after 6 months.
Pathologic FindingsThe cases with numerous T cells and few B cells were
indistinguishable from those with many B cells by light microscopy. Relevant findings are summarized in ❚Table 2❚. Thirteen lesions were excised, and two were biopsied (shave, 1; punch, 1). Tumor size ranged from 0.4 to 2 cm (mean, 1.2 cm) based on the clinical description and the glass slide mea-surement, with the caveat that most specimens had at least 1 positive margin. Examined sections showed skin and super-ficial subcutaneous tissue with a dense lymphoid infiltrate composed of multiple small and large, superficial and deep dermal, perivascular, and periadnexal aggregates of lympho-plasmacytic cells, focally extending into the subcutaneous fat ❚Image 1A❚ and ❚Image 2A❚. All cases had a prominent com-ponent of plasma cells, located predominantly in the super-ficial dermis and between the lymphoid aggregates ❚Image 1B❚ and ❚Image 2B❚. The plasma cells at least focally formed sheets and aggregates. Three cases had prominent Russell
❚Table 1❚Clinical Features of Patients With Cutaneous MZL With Plasmacytic Differentiation
Site of Examined Treatment AfterCase No./Sex/Age (y) Skin Lesion* Additional Lesions* Excision Follow-up*
T cell–rich MZL 1/M/55 Right thigh (13 y) Left arm†; right buttock (16 y) RT ANED (17 y) 2/M/72 Left knee Left knee (10 mo) RT ANED (12 mo) 3/M/41 Left shoulder Left upper back (3 mo) RT ANED (11 mo) 4/M/20 Right lower leg None RT ANED (45 mo) 5/F/29 Right breast None RT ANED (26 mo) 6/F/72 Back None None ANED (26 mo) 7/M/60 Scalp (15 y) Scalp† RT ANED (16 y) 8/M/74 Right arm None RT ANED (3 mo) 9/M/67 Right thigh None None ANED (3 mo) 10/M/70 Right shoulder None None AWD (2 mo)B cell–rich MZL 11/M/44 Back Back ×3 (2 mo); right arm (6 mo) RT ANED (12 mo) 12/M/28 Back (3 y) Chest and left arm† None ANED (48 mo) 13/F/83 Right shoulder SCL lymph node; DLBCL stomach‡ None AWD (15 mo) 14/F/53 Left neck None None ANED (5 mo) 15/M/61 Right upper arm None None ANED (2 mo)
ANED, alive with no evidence of disease (lymphoma); AWD, alive with disease (lymphoma); DLBCL, diffuse large B-cell lymphoma; MZL, marginal zone lymphoma; RT, radiation therapy; SCL, “small cleaved cell–type” lymphoma.
* Values in parentheses are the time after initial diagnosis.† Site of initial presentation.‡ The DLBCL occurred 14 years before the skin lesion; the SCL occurred 17 years before the skin lesion (slides not available for review).
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
bodies (Image 1B). Small lymphoid cells with irregular nuclei resembling marginal zone B cells were present in all cases (Image 2B). Lymphoid follicles were small and compact or expanded and infiltrated by atypical lymphocytes and plasma cells. The epidermis was uninvolved in all cases. Prominent lymphoepithelial lesions were not present.
Immunohistochemical StudiesT Cell–Rich Group
CD20+ B cells were predominantly confined to the centers of lymphoid aggregates, while the vast majority of the lymphoid cells surrounding the follicles and in diffuse
areas were CD3+ T cells, including 3 cases with conspicu-ous atypical-appearing lymphocytes with irregular nuclear contours and clear cytoplasm morphologically resembling marginal zone cells (cases 1, 2, and 7) ❚Image 3A❚, ❚Image 3B❚, ❚Image 3C❚, and ❚Image 3D❚. In cases in which lym-phoid follicles were not identified, the B cells were scattered throughout the infiltrate, predominantly in the most super-ficial portion. B cells in follicle centers were bcl-2– and bcl-6+. The extrafollicular B cells were negative for CD10 in all cases. CD3+ T cells commonly surrounded the B-cell aggregates and expressed CD2, CD5, CD7, and CD43. Of 10 cases, 6 had small, compact, nodular meshworks of CD21+
A B
❚Image 1❚ (Case 1) T cell–rich cutaneous marginal zone lymphoma with marked plasmacytic differentiation. A, Dense, deep nodular lymphoid infiltrate (H&E, ×4). B, Numerous plasma cells with Russell bodies are present in the superficial dermis (H&E, ×40).
❚Table 2❚Morphologic and Immunophenotypic Features of Cutaneous MZL With Plasmacytic Differentiation
T-Cell MZL-like Reactive FDC Plasma Cell Plasma Cell Follicular Cell CD4/CD8Case No. Predominance Cells Follicles Meshworks Light Chains Heavy Chains Heavy Chains Ratio
1 Yes 3+ Yes C κ IgG IgM, IgD High2 Yes 3+ No C κ None IgM, IgD ND3 Yes 1+ No C κ IgA IgM, IgD ND4 Yes 1+ No C κ IgG IgM, IgD ND5 Yes 1+ No No/min κ ND ND ND6 Yes 1+ Yes C κ ND ND ND7 Yes 3+ No E λ IgG IgM, IgD High8 Yes 1+ No No/min κ ND ND ND9 Yes 1+ No C λ ND ND ND10 Yes 3+ Yes E κ ND ND High11 No 1+ Yes E κ ND ND ND12 No 3+ Yes E λ ND ND ND13 No 3+ Yes E κ ND ND ND14 No 1+ No No κ ND ND ND15 No 3+ No No/min κ IgG IgM, IgD ND
C, compact follicles; E, expanded follicles; FDC, follicular dendritic cells; MZL, marginal zone lymphoma; ND, staining not done; No/min, none or minimal; 1+, rare MZL-like cells; 3+, numerous MZL-like cells.
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
and CD23+ follicular dendritic cells confined to the B-cell aggregates without evidence of expansion or disruption. Two cases had expanded and irregular follicular dendritic cell meshworks, and in 2 cases, there was minimal and focal staining with CD21 and CD23. CD79a immunostain expres-sion mirrored the distribution of CD20+ B cells and also highlighted the increase in plasma cells, further confirmed by the CD138 and immunoglobulin stains ❚Image 3E❚ and ❚Image 3F❚. Both CD20 and CD79a immunostains showed that the B-cell population was decreased in relationship to the T-cell population. CD4 and CD8 stains were performed on 3 cases and showed a predominance of CD4+ T cells with few scattered CD8+ T cells. All cases showed monotypic plasma cells with immunostains or in situ hybridization for κ and λ; 8 cases showed monotypic κ expression, and 2 cases showed monotypic λ expression ❚Image 3G❚, ❚Image 3H❚, ❚Image 3I❚, and ❚Image 3J❚.
B Cell–Rich GroupCD20+ B cells were present in the centers of the lym-
phoid aggregates and in the extrafollicular region and were equal to or more numerous than CD3+ T cells ❚Image 4A❚, ❚Image 4B❚, ❚Image 4C❚, and ❚Image 4D❚. Of 5 cases, 3 had expanded nodular meshworks of follicular dendritic cells ❚Image 4E❚. The remaining 2 cases had minimal to no stain-ing with CD21 and CD23. CD79a immunostain highlighted B cells and plasma cells. All cases showed monotypic plasma cells with immunostains or in situ hybridization for κ and λ; 4 cases showed monotypic κ expression and 1 case had mono-typic λ expression ❚Image 4F❚.
Molecular Analysis
In 8 of the 10 T cell–rich cases, material was available for IGH and TCR-γ gene rearrangement analysis ❚Table 3❚. Of 8 examined cases (including patients with numerous atypical-appearing lymphocytes), 7 had a polyclonal pat-tern of TCR-γ chain. One case had suboptimal DNA quality and showed minimal TCR amplification. Of 8 cases, 6 had evidence of a clonal rearrangement of IGH: 4 of 8 showed IGH VH-JH rearrangement (frameworks 1 and 2 with a poly-clonal framework 3 pattern), while the 2 remaining cases were polyclonal with VH-JH PCR analysis but showed a clonal PCR product with the IgH DH-JH (BIOMED-2 tube D) fluorescent-labeled primer.
A B
❚Image 2❚ (Case 11) B cell–rich cutaneous marginal zone lymphoma with numerous plasma cells. A, Deep nodular lymphoid infiltrate (H&E, ×4). B, Numerous atypical marginal zone cells admixed with lymphoplasmacytoid cells and sheets of plasma cells (H&E, ×40).
❚Table 3❚Molecular Profile of T Cell–Rich Cutaneous Marginal Zone Lymphoma
the diagnostic possibility of plasmacytoma. Extraosseous plasmacytoma is a neoplasm of plasma cells in patients with-out histologic and radiologic evidence of bone marrow plasma cell myeloma. It constitutes 3% to 5% of all plasma cell neo-plasms, with 80% occurring in the upper respiratory tract.14 Solitary plasmacytoma of the skin is unusual, with approxi-mately 35 reported cases.17-23 The clinical course in most cases was indolent with or without local recurrences, although a few patients subsequently developed overt plasma cell myeloma and died of disease. Our experience, in conjunction with the indolent behavior of many of the previously reported cases, suggests that many of them may be examples of MZL
Discussion
Plasmacytic differentiation is a common feature in MZL in the skin and in extracutaneous locations and likely represents a recapitulation of normal MALT, with reactive lymphoid follicles surrounded by neoplastic marginal zone cells and interfollicular plasma cells. The observation of a mixture of small lymphoid cells, marginal zone cells, and monotypic plasma cells is an extremely helpful feature in diagnosing MALT lymphomas. However, as our study illus-trates, occasionally the plasma cells are unusually prominent with arrangement in monotonous sheets or nodules, raising
G H
I J
❚Image 3❚ (Case 1) Immunohistochemical profile of T cell–rich cutaneous marginal zone lymphoma with numerous plasma cells. A and B, CD20+ B cells are a minor population mostly confined to the lymphoid follicles (×4 and ×20, respectively). C and D, CD3+ T cells predominate (C, ×4) and include the atypical cells that morphologically resemble marginal zone cells (D, ×20). E, CD138 highlights the plasma cells (×4). F, CD79a staining pattern is similar to that of CD20 (×4). G, H, I, and J, Monotypic expression of κ light chain in neoplastic plasma cells (G, ×4; H, ×40) with very rare λ+ cells (I, ×4; J, ×40).
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
❚Image 4❚ (Case 9) Immunohistochemical profile of a B cell–rich cutaneous marginal zone lymphoma with numerous plasma cells. A and B, Abundant CD20+ B cells in nodular aggregates (×4 and ×20, respectively). C and D, Numerous CD3+ T cells surrounding and infiltrating the lymphoid follicles (×4 and ×20, respectively). E, Expanded and colonized lymphoid follicles highlighted by CD21 immunostain (×20). F, Monotypic expression of κ light chain in neoplastic plasma cells (×20).
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
To address this differential diagnosis, we performed IGH and TCR PCR on all cases with abundant T cells. No cases showed TCR-γ gene rearrangements, and 6 (75%) of 8 had clonal IGH. This finding is similar to that previously reported (64% in a study of 22 cutaneous MZLs).24 All of our clonal cases showed a polyclonal pattern with framework 3 primers, as may be seen with postsomatic hypermutation, and supports the use of BIOMED-2 primers for frameworks 1, 2, and 3, as opposed to older studies that typically used framework 3 analysis only.24 In addition, we found that additional testing with IGH DH-JH primers increases PCR sensitivity even further. Thus, based on our findings, D-tube analysis appears to be of added value in clonality assessment of MZL.
The abundance of reactive T cells in cutaneous B-cell lymphomas may be indicative of an as yet unknown patho-genic environmental insult affecting the skin. Borrelia burgdorferi infection has been linked to occasional cases of MZL in European patients34,35; however, these find-ings have not been confirmed in other series.36 Extranodal MZLs typically arise in a background of Th1-type chronic inflammation, related to infection (Helicobacter pylori) or autoimmune disease (Sjögren syndrome). In contrast, most primary cutaneous MZLs appear to be associated with a Th2-type cytokine environment,37 making them somewhat unique among extranodal MZLs. In this context, primary cutaneous MZLs also undergo class-switch, as confirmed in our series, with expression of IgG and IgA by the neo-plastic plasma cells, as opposed to the non–class-switched IgM+ extranodal MZLs.37 In short, although the cause of the inflammation that may lead to cutaneous MZLs is not known in most cases, it is possible that the initiating agent may be responsible for eliciting a Th2-type cytokine environment and numerous admixed T cells in some cases.
According to the literature, MZL of the skin affects mid-dle-aged men and women.7,24,26 Cutaneous lesions most com-monly involve upper extremities, trunk, and head and neck. The rate of recurrence ranges from 30% to 70% and appears independent of the treatment modality used.5,10,24,26 In our study, patients in the T cell–rich group were comparable to patients from the B cell–rich group and the literature in terms of age, sex, and location of the lesions. Clinical course was also similar, with relapsing disease present in 4 (40%) of 10 patients in the T cell–rich group and 2 (40%) of 5 patients in the B cell–rich group. These results indicate that the T cell–rich variant of MZL has no prognostic implications.
We have found that cutaneous MZLs often show marked plasmacytic differentiation (about half of the cases) with sheets and aggregates of neoplastic plasma cells. In addition, two thirds of such cases are associated with a predominance of T cells. These 2 features may cause diagnostic difficulty and lead to misdiagnosis of plasmacytoma or cutaneous T-cell
with marked plasmacytic differentiation, while rare cases may be cutaneous presentations of plasma cell myeloma. In the absence of history of plasma cell myeloma, the diagnosis of cutaneous plasmacytoma should be made with great caution. The presence of any lymphoid follicles, B cells, or follicular dendritic cells would tend to exclude plasmacytoma.
We also observed that two thirds of the cases with prominent plasma cells had numerous T cells and few extrafollicular marginal zone B cells. The B cells that were present were mostly confined to reactive germinal centers. In addition, 3 of these cases appeared to have numerous atypical small lymphocytes, resembling the marginal zone B cells; however, by immunohistochemical analysis, most if not all of these cells were expressing T-cell markers. It has been previously described that lesions in some patients may have a significant number of reactive T cells,24-27 des-ignated by Magro et al25 as T cell–rich plasmacytic MZL. This phenomenon is not particular to MZL, as, in general, cutaneous B-cell lymphomas tend to have many admixed T cells.27 This may cause diagnostic difficulty, as illustrated by case 7 that was probably initially misdiagnosed as mycosis fungoides based on the paucity of B cells and the presence of numerous atypical-appearing T cells.
Another entity that needs to be distinguished from MZL is primary cutaneous small-medium CD4+ T-cell lym-phoma. Similar to MZL, it presents with nodular or diffuse infiltrate of dermis and subcutaneous tissue and contains atypical small to medium-sized lymphoid cells admixed with small reactive lymphocytes and histiocytes. Faced with this differential diagnosis, heavy chain and light chain analysis should be performed to evaluate clonality of the marginal zone cells and plasma cells. Molecular study of IGH gene and TCR-γ gene rearrangements may be warranted to con-firm the results.
Conversely, peripheral T-cell lymphomas (PTCLs), in particular angioimmunoblastic T-cell lymphoma, may have an extensive nonneoplastic component, including a prominent B-cell proliferation.28-30 The expansion of B cells ranges from small clusters of large activated B cells to focally confluent B cells, which may obscure the T-cell proliferation.31 In 1 study, up to 40% of these cases demonstrated oligoclonal and clonal B-cell rearrangements.28 The majority of B-cell prolif-erations have been attributed to expansion of an Epstein-Barr virus–positive B cell population.30,32,33 However, cases with Epstein-Barr virus–negative clonal B-cell proliferations coex-isting with PTCL have also been reported, some with large sheets of monotypic plasma cells that displaced the PTCL component.28 The distinction between a primary B-cell cuta-neous lymphoma and a T-cell cutaneous lymphoma is clini-cally relevant because the latter overall has a poor prognosis and requires more aggressive treatment compared with the indolent nature of MZL.
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
15. McClure RF, Kaur P, Pagel E, et al. Validation of immuno-globulin gene rearrangement detection by PCR using commercially available BIOMED-2 primers. Leukemia. 2006;20:176-179.
16. van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17:2257-2317.
17. Johnson WH Jr, Taylor BG. Solitary extramedullary plasmacytoma of the skin: a review of the world literature and the report of an additional case. Cancer. 1970;26:65-68.
18. Kazakov DV, Belousova IE, Muller B, et al. Primary cutaneous plasmacytoma: a clinicopathological study of two cases with a long-term follow-up and review of the literature. J Cutan Pathol. 2002;29:244-248.
19. Wong KF, Chan JK, Li LP, et al. Primary cutaneous plasmacytoma: report of two cases and review of the literature. Am J Dermatopathol. 1994;16:392-397.
20. LaPerriere RJ, Wolf JE, Gellin GA. Primary cutaneous plasmacytoma. Arch Dermatol. 1973;107:99-100.
21. Mikhail GR. Primary cutaneous plasmacytoma. Arch Dermatol. 1973;107:917.
22. Kwong YL, Ng WK. Different guises of plasmacytoma: from skin to bone. J Clin Pathol. 1994;47:951-953.
24. Servitje O, Gallardo F, Estrach T, et al. Primary cutaneous marginal zone B-cell lymphoma: a clinical, histopathological, immunophenotypic and molecular genetic study of 22 cases. Br J Dermatol. 2002;147:1147-1158.
25. Magro CM, Porcu P, Ahmad N, et al. Cutaneous immunocytoma: a clinical, histologic, and phenotypic study of 11 cases. Appl Immunohistochem Mol Morphol. 2004;12:216-224.
26. Cerroni L, Signoretti S, Hofler G, et al. Primary cutaneous marginal zone B-cell lymphoma: a recently described entity of low-grade malignant cutaneous B-cell lymphoma. Am J Surg Pathol. 1997;21:1307-1315.
27. Sander CA, Kaudewitz P, Kutzner H, et al. T-cell–rich B-cell lymphoma presenting in skin: a clinicopathologic analysis of six cases. J Cutan Pathol. 1996;23:101-108.
28. 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;31:1310-1322.
29. Geissinger E, Bonzheim I, Krenacs L, et al. Identification of the tumor cells in peripheral T-cell lymphomas by combined polymerase chain reaction–based T cell receptor beta spectratyping and immunohistological detection with T-cell receptor beta chain variable region segment-specific antibodies. J Mol Diagn. 2005;7:455-464.
30. Tan BT, Warnke RA, Arber DA. The frequency of B- and T-cell gene rearrangements and Epstein-Barr virus in T-cell lymphomas: a comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations. J Mol Diagn. 2006;8:466-475.
31. Higgins JP, van de Rijn M, Jones CD, et al. Peripheral T-cell lymphoma complicated by a proliferation of large B cells. Am J Clin Pathol. 2000;114:236-247.
lymphoma. However, these features are not associated with clinical or prognostic differences.
From the Departments of Pathology, 1Massachusetts General Hospital and 2Brigham and Women’s Hospital, Boston, MA.
Address reprint requests to Dr Zukerberg: Pathology Department (Warren 2), Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114.
* Dr Flotte is now with the Mayo Clinic, Rochester, MN.
References
1. Agarwal MD. Extramedullary plasmacytoma: report of a case. AMA Arch Derm. 1956;74:679-801.
2. Rijlaarsdam JU, van der Putte S, Berti E, et al. Cutaneous immunocytoma; a clinicopathologic study of 26 cases. Histopathology. 1993;23:117-125.
3. Stansfeld AG, Diebold J, Noel H, et al. Updated Kiel classification for lymphomas [letter; published correction appears in Lancet. 1988;1:372]. Lancet. 1988;1:292-293.
4. Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. 1997;90:354-371.
5. Bailey E, Ferry J, Harris N, et al. Marginal zone lymphoma (low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type) of skin and subcutaneous tissue: a study of 15 patients. Am J Surg Pathol. 1996;20:1011-1023.
6. Baldassano MF, Bailey E, Ferry J, et al. Cutaneous lymphoid hyperplasia and cutaneous marginal zone lymphoma: comparison of morphologic and immunophenotypic features. Am J Surg Pathol. 1999;23:88-96.
7. de Leval L, Harris NL, Longtine J, et al. Cutaneous B-cell lymphomas of follicular and marginal zone types. Am J Surg Pathol. 2001;25:732-741.
8. Dierlamm J, Pittaluga S, Wlodarska I, et al. Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features. Blood. 1996;87:299-307.
9. Duncan L, LeBoit P. Are primary cutaneous immunocytoma and marginal zone lymphoma the same disease? Am J Surg Pathol. 1997;21:1368-1372.
10. Tomaszewski MM, Abbondanzo SL, Lupton GP. Extranodal marginal zone B-cell lymphoma of the skin: a morphologic and immunophenotypic study of 11 cases. Am J Dermatopathol. 2000;22:205-211.
11. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785.
12. Slater DN. The new World Health Organization–European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol. 2005;153:874-880.
13. LeBoit P, Burg G, Weedon D, et al, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Skin Tumours. Lyon, France: IARC Press; 2006.
14. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008.
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
36. Takino H, Li C, Hu S, et al. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathological study of cases from Asia, Germany, and the United States. Mod Pathol. 2008;21:1517-1526.
37. van Maldegem F, van Dijk R, Wormhoudt TAM, et al. The majority of cutaneous marginal zone B-cell lymphomas expresses class-switched immunoglobulins and develops in a T-helper type 2 inflammatory environment. Blood. 2008;112:3355-3361.
32. Lome-Maldonado C, Canioni D, Hermine O, et al. Angioimmunoblastic T-cell lymphoma (AILD-TC) rich in large B cells and associated with Epstein-Barr virus infection: a different subtype of AILD-TL? Leukemia. 2002;16:2134-2141.
33. Zettl A, Lee SS, Rudiger T, et al. Epstein-Barr virus–associated B-cell lymphoproliferative disorders in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Am J Clin Pathol. 2002;117:368-379.
34. Cerroni L, Zochling N, Putz B, et al. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol. 1997;24:457-461.
35. Goodlad JR, Davidson MM, Hollowood K, et al. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland. Am J Surg Pathol. 2000;24:1279-1285.
by guest on February 8, 2016http://ajcp.oxfordjournals.org/
