REVIEW ARTICLE

Pitfalls in the Diagnosis of Cutaneous Lymphoma Meenakshi Batrani, MD and Jag Bhawan, MD

Abstract: Cutaneous lymphomas are primarily classified as cutaneous T-cell/natural killer (NK) cell lymphomas and B-cell lymphomas; their classification being of utmost importance for prognostic and therapeutic purposes. Despite certain distinguishing attributes related to both these categories of lymphomas, considerable overlaps and deviations from the usual features exist and can lead to misclassification. The objective of this review is to discuss the various pitfalls involving morphology, immunohistochemistry, and gene rearrangement studies, all of which pose challenges in classifying cutaneous lymphomas as either the T-cell/natural killer cell or B-cell type. Key Words: cutaneous lymphomas, T cell lymphoma, B cell lymphoma, classification (Am J Dermatopathol 2014;36:90–100)

INTRODUCTION The classification of lymphomas based on lineage as either T-cell/natural killer (NK) cell or B-cell type is the major criteria in World Health Organization (WHO)–European Organization For Research and Treatment of Cancer lymphoma classification1,2 (Table 1). Diagnosing cutaneous lymphomas is challenging and requires an integrated approach based on morphology, immunohistochemistry (IHC), and gene rearrangement studies. However, considerable overlaps and pitfalls exist with each of these 3 modalities. It is of utmost importance to delineate the lineage of lymphomas as either T cell/NK cell or B cell for both therapeutic and prognostic purposes. This review is not intended to describe the diagnostic features of each cutaneous lymphoma category; rather, it is an attempt to discuss the difficulties encountered in the basic classification of non–Hodgkin cutaneous lymphomas into the T-cell/NK-cell type or B-cell type.

MORPHOLOGY Traditionally, patterns of cutaneous involvement by B-cell lymphoma and T-cell lymphoma are considered distinctive with epidermal involvement as a T-cell feature and dermal infiltrates separated from the epidermis by a grenz zone as a B-cell feature.3 Since the conception of cutaneous From the Department of Dermatology, Dermatopathology Section, Boston University School of Medicine, Boston, MA. Disclosures: The authors no conflicts of interest. Reprints: Jag Bhawan, MD, Department of Dermatology, Dermatopathology Section, Boston University School of Medicine, 609 Albany Street, Boston, MA 02118 (e-mail: [email protected]). © 2013 Lippincott Williams & Wilkins

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lymphomas as an entity, epidermotropism has been synonymous with cutaneous T-cell lymphoma (CTCL). As the classification of cutaneous lymphomas evolved over the past few decades, wherein many different categories of lymphomas were being recognized, the morphological spectrum also extended to include angioinvasion/angiodestruction, subcutaneous involvement, and intravascular patterns, all as the prototype patterns for specific T-cell/NK-cell and B-cell lymphomas.2,4,5 These patterns are helpful in the initial assessment to determine the cell lineage; however, no single histological pattern can be used to reliably classify cutaneous lymphomas.

Epidermotropism Epidermotropism is considered as the hallmark histological feature of mycosis fungoides (MF), which is the most common type of CTCL.6–8 Pagetoid reticulosis, a subtype of MF, is also characterized by extensive epidermotropism.9 However, not all cases of MF show epidermotropism, including the tumor stage of MF where epidermotropism may be lost,6 folliculotropic MF, in which epidermotropism of the overlying epidermis is not a feature,10,11 a proportion of cases of syringotropic MF,12 granulomatous MF, and granulomatous slack skin.13 Additionally, rare cases of classical MF (4% in 1 series)8 do not exhibit epidermotropism (Table 2). In non–MF CTCL, epidermotropism is a distinctive feature of primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma.21–23 It is also present in the majority of cases of early stage adult T-cell leukemia/lymphoma (ATLL)31,32 and type B lymphomatoid papulosis (LYP).16 However, epidermotropism is either absent or variably seen in other non–MF CTCLs included in WHO classification14,15,17–20,24–30,33 (Table 2). In 2 different studies, epidermotropism was absent in 60% and 79% of non–MF CTCL cases.3,34 Although the presence of epidermotropism points toward CTCL, its absence cannot necessarily be equated with lymphoma of B-cell origin. Presumably, epidermotropism suggests the process to be of T-cell origin; nevertheless, B-cell lymphoma cannot be entirely excluded based solely on the presence of epidermotropism. Epidermotropism of B cells has been demonstrated in murine models.35 Isolated reports of B-cell lymphomas exhibiting epidermotropism and mimicking MF have been cited in literature.3,36–45 In 8 of these epidermotropic B-cell lymphomas, the neoplastic B cells involved the epidermis as demonstrated by IHC (Table 3),3,36–41 whereas in 2 of them, the type of epidermotropic cells was not specified.42,43 In 5 cases, the intraepidermal cells were reactive T cells in an otherwise B-cell lymphoma, giving the false impression of T-cell morphology.3,44,45 Regardless of the lineage of intraepidermal lymphocytes, some of these B-cell lymphomas histologically and clinically mimic MF in the form of a pruritic Am J Dermatopathol  Volume 36, Number 1, January 2014

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TABLE 1. From Third Edition 2006 WHO Pathology and Genetics of Skin Tumors and Modifications in Fourth Edition 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues1,2 Mature T-cell and NK-cell neoplasms MF MF subtypes Pagetoid reticulosis (localized disease) Follicular MF Granulomatous slack skin Sezary syndrome CD30+ T-cell lymphoproliferative disorders of the skin LYP Primary cutaneous ALCL SPTCL* Primary cutaneous PTL-U Rare Subtypes of PTL Primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphoma (Provisional) Cutaneous gamma/delta-positive T-cell lymphoma Primary cutaneous small/medium CD4+ T-cell lymphoma (Provisional) Extranodal NK/T-cell lymphoma, nasal type Hydroa vacciniformia-like lymphoma (variant) Adult T-cell leukemia/lymphoma† Angioimmunoblastic T-cell lymphoma† Mature B-cell neoplasms Cutaneous marginal zone B-cell lymphoma (MALT-type) Cutaneous follicle centre lymphoma Cutaneous DLBCL-leg type DLBCL, not otherwise specified Intravascular large B-cell lymphoma† LYG† Chronic lymphocytic leukemia† MCL† Burkitt lymphoma† Immature hematopoietic malignancies Blastic Plasmacytoid dendritic cell neoplasm Precursor lymphoblastic leukemia/lymphoma T-lymphoblasic leukemia† T-lymphoblastic lymphoma† B-lymphoblastic leukemia† B-lymphoblastic lymphoma† Myeloid and monocytic leukemias† Hodgkin lymphoma† MALT, mucosa associated lymphoid tissue. *Definition is restricted to lymphomas of alpha/beta T-cell origin. †Extracutaneous lymphomas frequently involving the skin as a secondary site.

rash as the primary clinical presentation.3,36,37,45 Amongst the 8 cases, where true B-cell epidermotropism was seen, 4 had systemic involvement and 4 of the 8 were marginal zone lymphomas (MZLs)3,36–41 (Table 3). Involvement of pilosebaceous unit epithelium and/or epidermis was seen in 4 cases in a series of 15 cases of cutaneous B-cell MZL. The epitheliotropic cells morphologically resembled marginal zone cells, and CD20 positivity of epitheliotropic cells was demonstrated by IHC only in 1 case with pilosebaceous unit involvement.46 Ó 2013 Lippincott Williams & Wilkins

Cutaneous Lymphomas

TABLE 2. Epidermotropism in Mature Cutaneous T-Cell Lymphomas Mature T-Cell Neoplasm

Epidermotropism

MF MF

Absent in rare cases (not seen in 4% cases in 1 series),8 may be lost in tumor satge6

MF variants and subtypes Pagetoid reticulosis Follicular MF Syringotropic MF* Granulomatous MF* Granulomatous slack skin Non–MF CTCL Sezary syndrome

Present9 Absent in majority (not seen in 46/51 and 20/34 cases in 2 series)10,11 Present in most (seen in 65% biopsies in 1 series)12 Present in about half of the cases (seen in 8/15 cases in 1 series)13 Rarely present (seen in 1/4 cases in 1 series)13

Absent in majority (not seen in 62% biopsies and absent to minimal in 61% cases in 2 series, respectively)14,15 CD30+ T-cell lymphoproliferative disorder of skin LYP Present in many cases especially type B16 Primary cutaneous Present in some cases (seen in 45% ALCL cases in 1 series)17 SPTCL Absent,18 except in rare case (present in 2/63 cases in a series)19 Primary cutaneous PTL, Absent in most cases1,20 unspecified Rare subtypes of PTL Primary cutaneous Present,21,22 rare exception23 epidermotropic CD8 + cytotoxic T-cell lymphoma Cutaneous gd T-cell Present in many cases19,23,24 lymphoma Primary cutaneous small/ Absent,25,26 in rare case minimally medium CD4+ T-cell present25,27 lymphoma Extranodal NK/T-cell Variable (seen in 24%–50% cases)23,28–30 lymphoma, nasal type Adult T-cell leukemia/ Present in many cases in early stages31,32 lymphoma Angioimmunoblastic T-cell Absent33 lymphoma *Not considered as distinct entity in lymphoma classification.

ANGIOINVASION AND ANGIOCENTRICITY The other T-cell pattern is angiocentricity and angioinvasion, characteristic morphological features for extranodal NK/T-cell lymphoma,28–30 including the Hydroa vacciniformia–like lymphoma variant.47 This pattern is also variably seen with other T-cell lymphomas like LYP,16,48 anaplastic large cell lymphoma (ALCL),17,49 subcutaneous panniculitislike T-cell lymphoma (SPTCL),18,23 ATLL,50 peripheral T-cell lymphoma, unspecified (PTL-U),20 and its variants, that is, aggressive epidermotropic CD8+ T-cell lymphoma21–23 and cutaneous gd T-cell lymphoma.19,23 However, this morphological pattern is not restricted to CTCL as lymphomatoid www.amjdermatopathology.com |

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TABLE 3. Summary of IHC-Proven Reported Cases of B-Cell Lymphomas With Epidermotropism of Neoplastic B Cells Case No.

Authors

Clinical Features

B-Cell Lymphoma Type

Systemic Involvement

1

Glusac et al3

Nonhealing focally eroded plaque on leg

Large B-cell lymphoma

Not provided

2

Wilkel and GrantKels36

Pruritic eczematous eruption which progressed to indurated erythematous plaques Involving trunk and extremities

High-grade B-cell lymphoma with some features suggestive of Mantle zone lymphoma

Lymph node involvement

3

Chui et al37

Extranodal MZL

Bone marrow involvement

4

Pavlovic et al38

Pruritic scaly patches and atrophic plaques involving trunk and proximal extremities Disseminated pruritic erythematous papules, plaques, and hyperpigmented macules with a waxing waning course

Primary cutaneous MZL

Absent

5

Chiang et al39

Pruritic erythematous papules on chest, abdomen, and thighs

Extranodal MZL

Bone marrow, peripheral blood, spleen, and splenic lymph node involvement

6

Erythematous violaceous plaques and nodules

Splenic MZL

Spleen, bone marrow, and peripheral blood involvement

7

Gómez-de la Fuente et al40 Plaza et al41

Not available

Primary cutaneous DLBCL-leg type

Absent

8

Plaza et al41

Not available

Primary cutaneous DLBCL-leg type

Absent

granulomatosis (LYG), a B-cell disorder, shows an angiocentric and angiodestructive pattern similar to NK/T-cell lymphoma. LYG is primarily a pulmonary disease, but skin involvement is seen in 40%–50% of cases. Furthermore, skin involvement may precede the diagnostic pulmonary involvement in 16% of cases, and cutaneous involvement may be the primary manifestation of the disease in up to one third of the patients.51 Rarely, the angiocentric/angioinvasive pattern has been documented in other cutaneous B-cell lymphomas such as diffuse large B-cell lymphoma, leg type (DLBCLleg type), diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS),41 methotrexate-induced cutaneous

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Histological Features Intraepidermal, superficial and deep dermal atypical lymphoid infiltrate, acanthosis, and focal spongiosis Intraepidermal hyperchromatic mononuclear cells, epidermal hyperplasia, spongiosis, follicular mucinosis, superficial, and deep perivascular periappendageal and interstitial infiltrate Dense band like infiltrate of atypical lymphocytes and focal prominent epidermotropism without spongiosis Upper dermal band like infiltrate with focal epidermotropism and mid-deep dermal perivascular nodular infiltrate of small-sized to medium-sized lymphocytes Dense band like infiltrate of monomorphous lymphocytes in upper dermis abutting dermoepidermal junction, basal layer vacuolization with rare intraepidermal lymphocytes Pandermal epidermotropic infiltrate Prominent infiltration of epidermis by neoplastic B cells Prominent infiltration of epidermis by neoplastic B cells

DLBCL,52 primary cutaneous T-cell–rich B-cell lymphoma (TCRBCL).53

SUBCUTANEOUS INVOLVEMENT WITH RIMMING OF ADIPOCYTES Another pattern in cutaneous lymphoma is subcutaneous involvement with rimming of adipocytes by lymphoid cells, a pattern initially thought to be diagnostic of SPTCL, which is considered to be the prototype of this pattern. This pattern was later shown to be present in other T-cell and B-cell lymphomas as well.54 Nevertheless, most of these T-cell and B-cell Ó 2013 Lippincott Williams & Wilkins

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lymphomas involve the dermis and extend to the subcutaneous tissue. Exclusive involvement of lymphoma cells to the subcutis is characteristic of SPTCL.19 Less commonly, prominent subcutaneous involvement is seen with various other T-cell lymphomas55,56 like gd T-cell lymphoma,19,24,55 CD8+ epidermotropic T-cell lymphoma,22,23 tumor stage mycosis fungoides,55,57 extranodal NK/T-cell lymphoma,23,55,58 ATLL,31,55 ALCL,17,55,56,59–62 and PTL-U.55,63 Similar to other T-cell patterns, this pattern is also not confined to T-cell lymphoma, as some cases of B-cell lymphoma may show the predominant subcutaneous involvement. Matsuoka64 described for the first time a panniculitis-like involvement by a systemic B-cell lymphoma. Most often, a subcutaneous infiltrate is seen in secondary or concurrent skin involvement by extracutaneous B-cell lymphomas.46,65 In a series of 15 cases of cutaneous MZL, only 1 of 7 primary cases showed subcutaneous involvement as opposed to 6 of 8 cases of concurrent/secondary MZL.46 Massone et al55 reported 4 cases of secondary nodal B-cell lymphomas (3 diffuse large cell and 1 lymphoplasmacytic lymphoma) predominantly involving subcutaneous fat. This pattern is rarely seen in primary cutaneous B-cell lymphomas. Some of these rare cases of primary cutaneous B-cell lymphoma with predominant subcutaneous involvement cited in literature include primary subcutaneous Follicular centre lymphoma (FCL),66 primary subcutaneous mantle cell lymphoma (MCL),67 primary subcutaneous CD5+ DLBCL,68,69 primary subcutaneous B-cell lymphoma,65 primary MZL,46 primary cutaneous immunocytoma70 (considered as a variant of MZL in WHO classification)1 and primary cutaneous DLBCL-leg type.71

INTRAVASCULAR LYMPHOMA Intravascular lymphoma, formerly known as angioendotheliomatosis proliferans systemisata, was demonstrated to be the proliferation of neoplastic lymphoid cells within vascular lumina by Bhawan et al.72,73 It is now distinctly categorized as “intravascular large B-cell lymphoma” in WHO classification.1,73 These lymphomas have a predilection for skin and brain involvement.73 More recently, intravascular lymphomas of T-cell/NK-cell origin are increasingly being recognized and constitute 10%–15% of all intravascular lymphomas.74 There are 26 reported cases of T-cell/NK-cell intravascular lymphoma involving skin.75–80 In many reported cases of T-cell or NK-cell intravascular lymphomas, complete IHC profiles were not available to delineate T-cell and NKcell lineage separately.75 Amongst 14 of the 25 cases of intravascular lymphomas involving skin, where an IHC profile was available to delineate the lineage, 7 were of NK-cell origin and seven were of T-cell origin.75–80

IMMUNOHISTOCHEMISTRY IHC plays a key role in classification and subclassification of lymphomas by detection of lineage-specific antigens. Nevertheless, this technique is not exempt from pitfalls, which may lead to difficulties in terms of delineating lineage. It is important to use a panel of IHC markers in conjunction with morphology and gene rearrangement studies to reach a conclusive diagnosis. Ó 2013 Lippincott Williams & Wilkins

Cutaneous Lymphomas

ABSENCE/LOSS OF PAN B–CELL AND PAN T–CELL ANTIGENS It is a common practice in the diagnosis of lymphoma to begin with pan T–cell and pan B–cell IHC markers and in a sequential manner perform further markers for subclassification. CD45RO, CD3, CD2, CD5, and CD7 are considered the T-cell lineage markers; and CD79a, CD20, CD19, PAX5, and OCT.2 are considered the markers for B-cell lineage. The most commonly used among these are CD20 for B cells and CD3 for T cells.81–83 Although these markers help in specifically delineating lineage, some exceptions to the rules exist. In precursor B-cell and T-cell lymphomas, which may secondarily involve the skin, the expression of pan T–cell and pan B–cell markers is variable. Precursor T-cell leukemia/ lymphoma shows a variable CD3 expression.1 In precursor B-cell lymphoma/leukemia, the expression of CD20 is variable; however, CD79a, CD19, and PAX5 are usually positive.1,83 Extranodal NK/T-cell lymphoma of true NK-cell origin is characterized by the absence of surface CD3, whereas cytoplasmic CD3 and or CD3e may be positive or negative.23,28–30 Cases of T-cell origin are less frequent and show surface CD3 positivity23 and very rarely show CD3 negativity; the latter may be due to aberrant loss or due to derivation from natural killer T (NKT) or (NK 1.1) lymphocytes.84 Additionally, primary cutaneous ALCL shows CD3 negativity in many cases (71% in 1 series).85 Rarely, CD3 loss has been seen in Sezary syndrome,86 ATLL,87 SPTCL, epidermotropic CD8+ lymphoma, gd T-cell lymphoma, and ab pleomorphic T-cell lymphoma.23 CD3 loss also occurs in MF especially with disease progression.4,6 Therefore, use of other pan T–cell markers like CD45RO, CD2, CD5, CD7 and specific markers such as CD4 (helper) and CD8 (suppressor) should be used in conjunction with CD3 to confirm T-cell origin.81 As far as pan B–cell lineage markers are concerned, CD20 is absent in plasmablastic B-cell lymphoma, a subtype of DLBCL,88,89 which rarely occurs as primary cutaneous lymphoma.88 Studies evaluating expression of other pan B–cell markers in cutaneous and in extracutaneous plasmablastic lymphomas have found some positivity for other pan B–cell markers like CD79a (1/6,89 1/12,90 and 0/383), PAX5 (2/9,89 0/383) and OCT.2 (3/3).83 Some cases of cutaneous immunocytoma70 (considered a variant of MZL in WHO classification)1 and rare cases of MZLs may also show absence of CD20.46 Another potential pitfall is the loss of CD20 expression in relapses of CD20-positive lymphomas including cutaneous B-cell lymphomas treated with Rituximab, an anti-CD20 immunoglobulin increasingly being used for the treatment of CD20-positive B-cell lymphomas.91 However, CD79a, PAX5, and OCT.2 remain positive in most of these cases.83,91 Because CD20 is the most extensively used pan B–cell marker, it is important to recognize the above-mentioned fallacies in its use as the only marker for B-cell recognition. Therefore, the use of other pan B–cell markers in difficult cases may be of help to designate a lymphoma to be of B-cell origin. www.amjdermatopathology.com |

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REACTIVE CELL POPULATION OF OTHER LINEAGE Reactive populations of T cells in B-cell lymphoma or reactive B cells in T-cell lymphoma may be misleading while assessing the immunophenotype. TCRBCL is a rare but distinct category of B-cell lymphoma, which may present as primary cutaneous lymphoma or may involve skin secondarily in nodal TCRBCL. It is characterized by pleomorphic CD20-positive large atypical B-cells, which constitute less than 10% of cellularity, whereas the majority of cells are CD3-positive small T lymphocytes and may be misdiagnosed as peripheral T-cell lymphoma (PTL).92 Henceforth, it is important not to rely just on the proportion of CD3-positive and CD20-positive cells as reactive T cells outnumber the neoplastic, large, pleomorphic B cells which are sparse. Two other B-cell lymphomas, LYG and MZL, are associated with a large proportion of reactive CD3-positive T-cell populations in many cases.51,93–95 Apart from these, other B-cell lymphoma types such as FCL and rare case of DLBCL show significant proportions of reactive T cells.94–96 In a series of 10 cases of CD30-positive primary cutaneous B-cell lymphomas, 7 cases showed a significant population of reactive T cells.97 In 2 separate case reports of B-cell leukemia cutis and DLBCL, epidermotropic reactive T cells were present, thus making these B-cell lymphomas simulate MF histologically.44,45 A reactive population of B cells in T-cell lymphomas is also seen. The B cells form the major population in angioimmunoblastic T-cell lymphoma, a rare lymphoma to involve skin secondarily.33,98 A significant proportion of reactive B cells has also been documented in many cases of small/medium CD4+ T-cell lymphoma25,26,98 and few cases of PTL-U.98,99 Mattoch et al99 studied 16 cases of cutaneous PTL having significant B-cell proliferations including 2 cases with systemic involvement and a subset of cases representing small/medium CD4+ T-cell lymphoma. They found a reactive B-cell component comprising 20%–50% of the cells and 3 cases initially misdiagnosed as B-cell lymphoma. Occasional cases of MF may show a reactive B-cell population.100,101 A case of follicular MF that showed reactive B cells in the absence of epidermotropism, a common feature of follicular MF, was initially misdiagnosed as B-cell lymphoma.102 In a series of MF cases transformed to large cell lymphoma, 45% had reactive B cells.103 Yagi et al104 reported a case of CTCL with a massive B-cell infiltrate.

ABERRANT ANTIGEN EXPRESSION Aberrant expression or coexpression of IHC markers implies immunohistochemical expression of T-cell lineage antigens in B-cell lymphoma or B-cell lineage antigens in T-cell lymphoma.105,106 This is well known in precursor T-cell acute lymphoblastic leukemia/lymphoma, 40%–52% of which are CD79a positive,107 and in low-grade B-cell lymphomas such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma and MCL, where the expression of the CD5 and CD43 T-cell–associated markers is diagnostic.105 Aberrant expression outside of these situations is

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infrequent. Nevertheless, these phenotypic variations should always be kept in mind to avoid misdiagnosis. Aberrant expression of CD20 in various T-cell lymphomas/leukemia, though well recognized, is rare and fewer than 40 cases have been reported.108 Rarely, expression of other pan B–cell markers such as CD79a, CD19, PAX5, and OCT.2 has been demonstrated in T-cell lymphomas.106–113 The majority of these T-cell lymphomas with aberrant expression are PTL-U.106,114 Only 11 cases of CTCLs with aberrant expression of CD20 are known in literature. Of these 11 cases, 6 were PTL-U, 4 were MF, and 1 case was of small/medium CD4+ T-cell lymphoma.108,114 (Table 4) In addition, Vergier et al103 in their series of MF cases transformed to large cell lymphoma found CD20-positive reactive B-cells in 18 of 40 cases, many of which also expressed CD20 antigen on transformed large neoplastic T cells as well. Coexpression of CD3 and CD20 was also demonstrated on these large cells in some of these cases (number not specified). Sun et al123 reported a case of nodal T-cell lymphoma with skin involvement where aberrant CD20 expression was seen in nodal lymphoma but was absent in skin lesions. This may represent instability of expression of aberrant markers. Though exceptions are known, the majority of T-cell lymphomas show expression of only 1 of these aberrant markers and, therefore, diagnostic errors can be avoided by using a panel of B-cell markers such as CD20, CD19, CD79a, and PAX5 in challenging cases. Blakolmer et al124 found that aberrant expression of CD20 and CD79a is mutually exclusive. However, occasional cases of T-cell lymphomas positive for both markers have been documented including 1 case of cutaneous PTL-U.106,108,109 Rarely, coexpression of other pan B–cell markers, such as T-cell acute lymphoblastic leukemia with CD19 and CD79a positivity,107 a case of nodal PTL-U with CD20, CD19, and CD79a positivity,106 and a case of PTL-U involving periscapular soft tissue with CD19 and PAX5 positivity, have been reported.111 In cutaneous lymphomas, a case of LYP transforming to ALCL has been cited where both initial LYP and transformed ALCL showed positive for PAX5, CD79a, and OCT.2.113 On the other hand, 2 B-cell neoplasms, CLL and MCL, are characterized by expression of the T-cell markers CD43 and CD5.105 Moreover, the expression of other T-cell markers like CD2, CD3, CD4, CD7, CD8, and CD45RO is often cited for CLL, and rare cases of MCL expressing CD8 have been reported.105,125 Both of these lymphomas involve skin secondarily. Cutaneous involvement is the primary manifestation of the disease in 16.7% cases of CLL126 and occasionally in MCL.115 Rare cases of primary cutaneous MCL have also been reported.115,127 The aberrant expression is known to occur in B-cell lymphomas other than CLL and MCL, albeit less frequently.105,125,128 The various types of cutaneous B-cell lymphomas other than CLL and MCL documented with aberrant expression include CD5-positive DLBCL,68,69,117 intravascular B-cell lymphoma with CD5 expression,120 CD5-positive unclassifiable primary cutaneous B-cell lymphoma,121 nodal DLBCL with skin involvement having CD7 expression,118 cutaneous MZL, and immunocytoma with aberrant CD43 expression,39,46,70 CD43-positive FCL,96 and plasmablastic lymphoma with CD3 expression.119 A case of HIV-associated B-cell lymphoma with Ó 2013 Lippincott Williams & Wilkins

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TABLE 4. Reported Cases of Aberrant Antigen Expression in Cutaneous Lymphomas Authors

No. Cases

Cutaneous T-cell lymphoma Blakolmer et al124 Magro et al132 Oshima et al140 Balmer et al141 Lee et al108 Martin et al114 Martin et al114 Sen et al115 Rahemtullah et al106 Garcia-Herrera et al25

Aberrant Marker

Systemic Involvement

1

PTL-U PTL-U PTL-U PTL-U PTL-U PTL-U MF MF MF Primary cutaneous small/ medium CD4+ T-cell lymphoma MF transformed to large cell lymphoma LYP transforming to ALCL

Hagiwara et al113 Hagiwara et al113 Cutaneous B-cell lymphoma Yamaguchi et al69

1 1

LYP ALCL

PAX5, CD79a, OCT.2 (positive in both Lyp and ALCL PAX5 PAX5

6

DLBCL

CD5

Takahashi et al68 Dargent et al117

1 1

CD5 CD5

Inaba et al118 Bergman et al96 Chiang et al39

1 2

DLBCL DLBCL (arising in chronic limb lymphedema) DLBCL Primary cutaneous FCL MZL

Bailey et al46

3

LeBoit et al70 Sun et al119 Khalidi et al120

1

Yang et al121 Aboulafia et al122

1 1

Vergier et al103 Hagiwara et al113

1 1 1 1 1 1 1 1 2 1

Type of Lymphoma

Not documented

1

MZL (Two primary cutaneous and 1 secondary cutaenous) Immunocytoma Plasmablastic lymphoma Intravascular large B-cell lymphoma PCBCL-U HIV associated B-cell lymphoma

CD20 CD20 CD20 CD20 CD20, CD79a CD20 CD20 CD20 CD20 CD20

Absent Absent Absent Absent Neck lymph node involvement Absent Absent Inguinal lymph node involvement Absent Absent

CD20

Not provided Absent in LYP, spleen and axillary lymph node involvement in ALCL

CD7 CD43 CD43

Absent Lymph node involvement

Lymph node involvement in 1 out of 5 cases Absent Absent

CD43

Lymph node involvement Absent Bone marrow, peripheral blood, spleen and splenic lymph node involvement Not available

CD43 CD3 CD5

Absent Absent Absent

CD5 CD45RO

Absent Lymph node involvement

PCBCL-U, primary cutaneous B-cell lymphoma, unclassifiable.

aberrant expression of CD45RO has also been reported which is not surprising given the fact that AIDS-related lymphomas are known to have unusual immunoprofiles122 (Table 4). IHC is integral for diagnostic workup of lymphomas; however, this same technique may lead to misdiagnosis if exceptional phenotypic variations such as aberrant antigenic expression are not considered.

GENE REARRANGEMENT STUDIES With the advent of molecular diagnostics, T-cell receptor (TCR) and immunoglobulin heavy chain (IgH) gene rearrangement studies for clonality have become important tools for the Ó 2013 Lippincott Williams & Wilkins

diagnosis and for the characterization of lymphomas as either Tcell or B-cell type. To complicate the matter further, TCR or IgH gene rearrangements are not always markers of T-cell or Bcell lineage, respectively, as dual genotypes (rearrangement of both TCR and IgH) can exist, making it difficult to assign the lineage. Dual genotype has been found to be present in 60% of precursor lymphoid malignancies and 5%–29% of mature T-cell and B-cell lymphomas.116 This dual genotype occurs either because of lineage infidelity (a single clone of cells exhibiting both rearrangements) or occurrence of 2 distinct clones in the same lymphoma (first, phenotypically neoplastic cells of particular lineage and second, an oligo or monoclonal clone of reactive cells of other lineage)116,129 (Table 5). www.amjdermatopathology.com |

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TABLE 5. Dual Genotype in Cutaneous Lymphoma Dual Genotype (Rearrangement of Both TCR and IgH Genes in a Single Lymphoma of Either T-Cell or B-Cell Type) Lineage Infidelity (Single Clone of Neoplastic Cells Exhibiting Gene Rearrangement for its Own Lineage and of Other Lineage)

Uncertain (Either Due to Lineage Infidelity or Due to Dual Clones)

Dual Clones (Two Distinct Clones One of Phenotypically Neoplastic Cells and Second Clone of Oligo or Monoclonal Clone of Reactive Cells of Other Lineage)

Reported Cases of Cutaneous Lymphoma With Lineage Infidelity Authors

Type of Lymphoma 116

Vergier et al Berger et al130 Toro et al24 Magro et al132

Gallardo et al133

Sezary syndrome Sezary syndorme Cutaneous gd T-cell lymphoma CD20+CD10+CD8+ cutaneous T-cell lymphoma

Reported Cases of Cutaneous Lymphoma With Dual Clones Authors

Type of Lymphoma 129

Kazakov et al

Vergier et al Ho et al131 Mattoch et al99

Angioimmunoblastic T-cell lymphoma MF (EBV+) EBV+ secondary cutaneous PTL

TCRBCL

Balagué et al98

Primary cutaneous small/medium CD4+ T-cell lymphoma Primary cutaneous PTL-U Secondary cutaneous PTL TCRBCL

Primary cutaneous MZL

LINEAGE INFIDELITY The studies which have found a high dual genotype prevalence in Sezary syndrome of 20% and 50% using T-cell enrichment on peripheral blood and single-cell microdissection in skin biopsies, respectively, demonstrated that the IgH gene rearrangement involves the T cells in cases of Sezary syndrome.116,130 Toro et al24 reported a case of cutaneous gd T-cell lymphoma with IgH rearrangement interpreted as lineage infidelity involving the T cells based on a strong IgH band on gel electrophoresis and the fact that the B-cell population was less than 1%. Similarly, Magro et al132 reported an interesting case of dual CD8-positive CTCL which also was positive for CD20, a B-cell marker. As the cell population was phenotypically homogenous, the author concluded that the IgH rearrangement involved the T cells. In such cases, where an immunophenotype is aberrant along with the dual genotype, the diagnosis may be very challenging. On the contrary, if the phenotypic population is not homogenous and is comprised of both T and B cells, then techniques such as laser microdissection can be of help as exemplified by Gallardo et al,133 who reported a case of primary cutaneous MZL with a prominent T-cell component, a common feature for MZL. The gene rearrangement study showed the presence of both TCR and IgH clonality in microdissected B cells, whereas microdissected T cells showed no clonality, confirming the diagnosis of B-cell lymphoma with lineage infedility.133 | www.amjdermatopathology.com

Type of Lymphoma

116

DLBCL-leg type DLBCL-NOS MZL

Despite a high prevalence of 50% (2 of 4)116 and 20% (4 of 13)130 of dual genotypes in Sezary syndrome found in 2 studies, very few cases of bigenotypic cutaneous lymphomas have been cited in literature. In a large series by Kazakov et al,129 the dual genotype was seen in only 1% of primary cutaneous lymphomas. However, the authors indicated that the bigenotypic lymphomas may be underestimated as it is a common practice to carry out either of the 2 (TCR or IgH gene rearrangement) depending on phenotype.

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DUAL CLONES Monoclonal or oligoclonal B-cell clones have been demonstrated in T-cell lymphomas, especially those associated with EBV,134 and less commonly in non–EBV-associated PTL.98 Amongst CTCLs, IgH clonality involving the reactive B cells has been demonstrated by single-cell microdissection in angioimmunoblastic lymphoma with concomitant skin involvement.116 A case of MF (EBV positive) showed a faint clonal band of IgH over a background genotype and was therefore regarded as a clonal B-cell population associated with neoplastic T cells.131 In a case of EBV-positive secondary cutaneous PTL, the authors argued in favor of T-cell lymphoma with a clonal population of B cells based on the presence of cytologically atypical T cells and the fact that oligo/monoclonal B cells are not unusual in T-cell lymphomas, whereas vice versa is not true.99 Balagué et al98 in their series had a clonal B-cell proliferation with IgH rearrangement associated with primary cutaneous small/medium CD4+ T-cell lymphoma, and cutaneous PTL-U, both primary and secondary. In one of the cases in their series, they could demonstrate that a plasma cell proliferation showed different IgH rearrangement in biopsies from the skin and lung and a different light chain restriction in sequential biopsies, whereas TCR rearrangement showed similar peaks in different biopsies. Although clonal T cells in B-cell lymphomas are uncommon, Gogstetter et al53 reported a case of TCRBCL where 90% of the cell population was T cells and TCR clonality was present in the initial biopsy. The large atypical cells being B cells and the subsequent biopsies showing a T-cell population reduced to 40% with loss of TCR clonality confirmed the case to be a TCRBCL. In a series of cutaneous lymphomas, clonal TCR and IgH rearrangement was found in DLBCL-leg type, DLBCL, DLBCL-NOS, MZL, TCRBCL, and LYP. However, as all of these lymphomas had admixed reactive cells of other lineage and no further studies were done to see if the rearrangement was present in reactive cell populations or in neoplastic cells, it cannot be ascertained whether these cases represent dual clones or lineage indifelity.129 Ó 2013 Lippincott Williams & Wilkins

Am J Dermatopathol  Volume 36, Number 1, January 2014

TABLE 6. Composite Cutaneous Lymphomas Composite Lymphoma (Simultaneous Occurrence of 2 Morphologically and Immunophenotypically Distinct Lymphomas at the Same Anatomic Location) Reported Cases of Cutaneous Composite T-Cell and B-Cell Lymphomas Authors Barzilai et al136 Huwait et al137 Papalas et al138 Kazakov et al129 Lazzi et al139

Type of Composite Lymphoma MF + CLL/small lymphocytic lymphoma MF + MZL MF + follicular centre lymphoma (methotrexate associated) PTL + DLBCL (EBV associated) T-cell lymphoma + B-cell lymphoma (unclassifiable) T-cell lymphoma + B-cell lymphoma (unclassifiable)

COMPOSITE LYMPHOMAS A composite lymphoma is the simultaneous occurrence of 2 morphologically and immunophenotypically distinct lymphomas at the same anatomic location.135 Rare cases of composite cutaneous B-cell and T-cell lymphomas cited in literature include MF with CLL/small lymphocytic lymphoma,136 MF with MZL,136 methotrexate-associated composite lymphoma of MF with FCL,137 and EBV-associated DLBCL with PTL.138 Two cases of primary cutaneous composite T-cell and B-cell lymphomas with morphological atypical populations of both lineages, but not classifiable in distinct subtypes, have been reported129,139 (Table 6). It is important that a composite lymphoma of B cell and T-cell is to be distinguished from the dual genotype in a single lymphoma.

CONCLUSIONS Cutaneous lymphomas follow the law of averages with majority of the cases demonstrating the defined conventional criteria; however, the exceptions discussed above impose challenges (Fig. 1). An integrated approach of clinicopathological correlation, histomorphology, immunoprofiling using a panel of markers, and gene rearrangement studies is important. It cannot be overemphasized to interpret various results in conjunction and to avoid relying solely on one feature.

FIGURE 1. Pitfalls in the diagnosis of cutaneous lymphomas. Ó 2013 Lippincott Williams & Wilkins

Cutaneous Lymphomas

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