VI.	Malignant Lymphomas that Mimic Other Lymphomas of a Different Type with Very Different Clinical Implications (continued) Marsha Kinney, James Cook and Steven Swerdlow

Case 12 Diagnosis: Primary cutaneous follicle center lymphoma with spindle-cell features Case history: 62 year old male who underwent two biopsies of a right upper scalp tumor. As far as can be determined, he was treated only with radiation therapy. Except for cardiac problems, he is alive and well with a PET/CT scan performed about 1 ½ years following his diagnosis showing no evidence of lymphoma (as of 5/05) and no mention of lymphoma in December, 2007 (~4 years s/p diagnosis). Histopathology : The histologic sections of the skin demonstrate a dense lymphoid infiltrate that extends from the superficial to deeper dermis. The infiltrate appears denser more superficially and focally surrounds hair follicles. Although admixed small lymphocytes are also present, many of the cells in these areas are relatively large and include cells with dispersed chromatin and prominent nucleoli as well as others with angulated nuclear contours and without distinct nucleoli. Particularly the deeper portions of the biopsy show a very spindled and sclerotic infiltrate. Some similar appearing cells are also seen superficially. Flow cytometric immunophenotypic studies: Not performed. Paraffin section immunohistochemistry: Pan-keratin – Only highlights normal epithelium. S100 and Melan A – Negative. LCA/CD45 – Numerous positive cells throughout dermis. CD3 – moderate number of positive cells in aggregates and scattered throughout. Majority of cells are negative. CD20 – Numerous positive cells, both lymphocytes and spindled cells, throughout entire biopsy. CD10 – Although somewhat difficult to interpret, many lymphocytes and spindled cells appear positive. CD5 – B-cells negative. Bcl-6 – Many positive lymphocytes and spindled cells. Bcl-2 – Numerous positive cells. CD21 – Negative. Ki-67 – Moderately numerous positive cells including both plumper cells and spindled cells. Genotypic & Cytogenetic studies: None performed. Diagnostic pathway: This case demonstrated an extensive dermal infiltrate that included the more obvious lymphoid portion and an extensive spindle cell infiltrate with a broad differential diagnosis. The diagnosis that this represented some type of B cell lymphoma required appropriate immunohistochemical stains that demonstrated an extensive B cell infiltrate which, together with the histopathology, would be unacceptable for a reactive process. Further classification of this case was complicated by the fact that it fulfilled the criteria for a diffuse large B-cell lymphoma with spindle cell features, using the basic criteria of the 2001 WHO classification, but, assuming that there was no extracutaneous disease, also had features consistent with what is now known as cutaneous follicle centre lymphoma in the 2005 WHO/EORTC consensus classification of primary cutaneous lymphomas and the 2008 WHO classification. The more detailed phenotype further supported that this was a neoplastic infiltrate and, even if not specific, was helpful in further classifying this lymphoma. This case illustrates the following: Cutaneous B-cell lymphomas can be very spindled raising the differential diagnosis of other spindle cell neoplasms. In one of the reported cases, the original pathologist initially would not accept the consultant's diagnosis of lymphoma because of complete disbelief. [1] Immunophenotypic studies are critical in the assessment of cutaneous lymphoid infiltrates. Appropriate classification of this lymphoma with its attendant prognostic and therapeutic implications requires knowledge of the WHO/EORTC classification of primary cutaneous lymphomas or the 2008 WHO classification. Classification of cutaneous lymphomas is very dependent on knowing whether or not there is extracutaneous disease since, in contrast to other extranodal lymphomas, the presence of extracutaneous disease completely excludes the diagnosis of a primary cutaneous lymphoma. Therefore, if primary, cases such as this, get a diagnosis associated with a good prognosis and generally require only local therapies. In contrast, if this represented secondary involvement of the skin, a different diagnosis requiring systemic therapy would be required. Spindle cell B cell lymphomas of the skin: Cutaneous B cell lymphomas with a marked spindle cell component are uncommon but well described. [1, 2, 3] These cases are distinguished from other lymphomas that may appear spindled solely because of prominent sclerosis. [1] They have generally been considered to be a type of large B-cell lymphoma with a reported variable behavior. Apparently extensive Ki-67 positivity, as seen in this case is well described. [1, 3] It is important to recognize that more than one type of B cell lymphoma may have spindle cell features. Some have suggested that they are of follicle center origin with admixed centrocytes and centroblasts, but others have suggested that they are not. [1, 2] Immunohistochemical stains are the key to diagnosing these cases, most of which have had only restricted phenotypic analyses. One must be aware that some cases have been reported to be muscle specific actin positive, although many others are reportedly negative. [1, 3, 4] More details about these cases can be obtained from the references. These cutaneous lymphomas may be related to a larger group of "spindle cell variant of diffuse large B-cell lymphoma", an entity that was found to have genotypic and phenotypic markers of a germinal center B-cell origin, involve extranodal sites (with or without lymph node involvement) and which responds well to therapy. [5] Classification of cutaneous lymphomas: Up until 2005, there were two major ways in which cutaneous lymphomas were being classified. The EORTC (European Organisation for Research and Treatment of Cancer) classification of cutaneous lymphomas, published in 1997, emphasized the need for a classification specifically for primary cutaneous lymphomas. [6] The WHO classification of tumours of hematopoietic and lymphoid tissues published in 2001 covers all lymphomas and does include some skin-specific categories/variants such as "cutaneous follicle centre lymphoma." [7] 2005, however, saw the publication of a WHO-EORTC consensus classification of cutaneous lymphomas. [8] This consensus classification, to be used for primary cutaneous lymphomas, resulted from the planning for the new WHO classification of skin tumors which was published in late, 2005. Discussions that led to the final classification were held at the editorial consensus conference for the WHO skin tumor blue book in September, 2003 in Lyon, France and additional discussions to resolve remaining issues with some of the B-cell lymphomas were held in Zurich, Switzerland in January, 2004 hosted by G. Burg, the editor responsible for the section on cutaneous lymphomas. These discussions included individuals who were intimately involved in the WHO classification of lymphoid tumors as well as others who were intimately involved in the EORTC classification. The official new classification is published in the WHO Classification of Skin Tumors monograph. [8] The topic has also been covered in two publications. [9, 10] The major categories are also incorporated into the 2008 WHO classification. [11] The classification of primary cutaneous lymphomas (and one entity formerly included among the lymphomas – blastic plasmacytoid dendritic cell neoplasm, formerly known as blastic NK-cell lymphoma) is on the following page. Remember that "primary" cutaneous lymphomas means those without any extracutaneous disease at diagnosis. Note that this is different than the usual definition of a primary extranodal lymphoma at other sites. No one has a problem diagnosing, for example, a stage IV gastric lymphoma. By definition, however, you cannot have a primary cutaneous lymphoma that is stage IV. This obviously introduces biases into the description of cutaneous lymphomas since any that are prone to early extracutaneous dissemination are summarily excluded from being a primary cutaneous lymphoma. The prior criterion that no extracutaneous disease could be present for six months following the diagnosis has been dropped. Primary cutaneous haematopoietic/lymphoid neoplasms in the 2008 WHO classification* [11] ACUTE MYELOID LEUKAEMIA AND RELATED PRECURSOR NEOPLASMS Blastic plasmacytoid dendritic cell neoplasm MATURE B-CELL NEOPLASMS Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Primary cutaneous follicle centre lymphoma Diffuse large B-cell lymphoma (DLBCL), NOS Primary cutaneous DLBCL, leg type MATURE T-CELL AND NK-CELL NEOPLASMS Hydroa vacciniforme-like lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30 positive T-cell lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous CD4 positive small/medium T-cell lymphoma Peripheral T-cell lymphoma, NOS *The inclusion of entities in this unofficial table is somewhat arbitrary as there are other entities that may involve the skin primarily (or secondarily), the two "not otherwise specified" categories mostly include cases that are not primary in the skin and the MALT lymphoma category does not distinguish different types of MALT lymphomas based on site whereas the 2005 WHO-EORTC classification identifies cutaneous marginal zone B-cell lymphoma as a specific entity. The lymphomas in italics represent provisional entities. Mature B-cell neoplasms: We will briefly discuss the primary cutaneous mature B-cell neoplasms that were included in the WHO/EORTC classification but we will not cover the T cell, natural killer cell or other hematopoetic/lymphoid neoplasms. Compared to the WHO/EORTC classification, cutaneous MALT lymphomas are not segregated in the 2008 WHO classification, primary cutaneous diffuse large B-cell lymphoma, leg type is considered a subtype of DLBCL, not otherwise specified and what was known as DLBCL, other would just be incorporated in the appropriate DLBCL category used for extra-cutaneous cases. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) – WHO/EORTC "Cutaneous marginal zone B-cell lymphoma (MALT-type)": Primary cutaneous MALT lymphomas are not a controversial entity at the moment and there are no major changes to deal with. This category does include cases previously diagnosed as "immunocytoma" as well as non-myelomatous "plasmacytomas" of skin. It should be noted that in the 2008 WHO classification MALT lymphomas from different sites are not considered different entities even though they may have distinctive clinical and biologic features. Arriving at a classification for the more contentious B-cell lymphomas: In arriving at the 2005 WHO-EORTC classification of the cutaneous lymphomas, there were lengthy discussions about the remaining mature primary cutaneous B-cell lymphomas which engendered a second consensus conference held in Zurich. WHO and EORTC oriented individuals reviewed slides of follicular/follicle center cell and diffuse large B-cell lymphomas together with all available clinical data, follow-up, and a variety of ancillary studies. The major question was how to reconcile the 2001 WHO categories of follicular lymphoma (including cutaneous follicle centre lymphoma) and diffuse large B-cell lymphoma with the EORTC-defined categories of follicle center lymphoma and DLBCL of the leg. The ultimate conclusion and resultant consensus classification rested upon the clinical aspects of these neoplasms being critical in what would be grouped and what segregated, with biologic features also important. With relatively minor exceptions, the WHO-EORTC classification was incorporated into the 2008 WHO classification. Specifically, the questions that had to be answered in developing a consensus classification of the primary cutaneous mature B-cell lymphomas other than those of MALT type included: What defines a cutaneous lymphoma of follicular or follicle center (cell) type? Some definitions are very broad and others much more restricted. It had to be determined whether to follow guidelines similar to those for lymph nodes or something different. In the former instance, growth pattern and the number of centroblasts are clinically very important. When should a lymphoma, that might even be of follicular center origin, be called a diffuse large B-cell lymphoma (DLBCL)? Discussion of this topic included concern that many primary cutaneous "DBLCL" do well with local therapies [12] and, use of the term DLBCL puts these patients at risk for being overtreated. [6] Are DLBCL of the leg something unique that should be segregated from other DLBCL? The following three categories were agreed upon, together with the criteria for each. Cutaneous follicle centre lymphoma Cutaneous diffuse large B-cell lymphoma, leg type (now considered a subtype of DLBCL, NOS in the 2008 WHO classification) Cutaneous diffuse large B-cell lymphoma, other (now included in varied categories in the 2008 WHO classification depending on the precise features in each case, still realizing that there may be situations where the cutaneous location is of clinical importance). In brief, one can think of these categories as being recognized because the first defines an indolent lymphoma believed to be composed of neoplastic follicular center cells. In contrast, the leg type DLBLC are aggressive and also a relatively homogeneous group of cases from a cytologic/phenotypic perspective. The third category was there because it was felt that there were lymphomas that did not fall into either of the other two categories but which needed to be diagnosed as a DLBCL. However, it was never considered to be a uniform entity and therefore those cases are not segregated into one group in the 2008 WHO classification. Cutaneous follicle centre lymphoma Clinical features: Primary cutaneous follicle centre lymphoma usually presents with solitary or grouped plaques or tumors, mostly on the head and neck or trunk regions (rare on legs). The prognosis is excellent, without evidence that the category should be further subdivided in any way (5 year survival >95%). [9] Most cases are treated with radiation therapy including cutaneous relapses. Rituximab might also have a role to play. Problems interpreting the literature: The complexity of this area is emphasized by the fact that this is the only entity in the Blood, 2005 paper to have a "comment" section because there is so much variation between what has been found in different studies. [9] Possible reasons for the variation include geographic differences (European studies are often different than American ones), the possible inclusion of secondary cases due to incomplete staging and technical or interpretive differences with the ancillary studies. Definition and histopathology: Cutaneous follicle centre lymphoma (CFCL) is defined as a lymphoma composed of neoplastic follicular center cells -- centrocytes with variable numbers of centroblasts. CFCL can have a follicular, follicular and diffuse or diffuse growth pattern. The growth pattern is not considered to be of any clinical significance. The only difference the cytologic composition would make is if there were pure sheets of centroblasts growing diffusely in which case one of the types of DLBCL would have to be diagnosed. In other words, these lymphomas are not graded, in contrast to follicular lymphomas occurring at any other site. The cases that are totally diffuse often do have many large centrocytes and, in part because of this, and in part because there can be a moderate number of centroblasts present, a significant subset of these cases would fulfill the criteria for a DLBCL at other sites. It is important, however, to also remember that CFCL is not just a default diagnosis to make when one has a B-cell lymphoma that is not on the leg and not a marginal zone lymphoma! It remains critical to exclude other primary or secondary cutaneous lymphomas. One does not want to end up diagnosing a secondary DLBCL as a CFCL and having the patient undertreated. Phenotype/genotype: The description of CFCL includes the following phenotypic/genotypic characteristics: Monoclonal B-cells although they may lack surface immunoglobulin CD10 often positive incases with a follicular growth pattern and generally negative in diffuse cases Bcl-6 positive MUM-1 negative BCL2 protein negative or faint staining in a minority of cells in one set of studies, others report a significant proportion of cases with a follicular growth pattern to be positive (see below) BCL2 translocation absent in one set of studies, but present in a minority of cases in others (see below) Although the reasons for the variability in the literature regarding BCL2 protein expression and BCL2 translocations in primary cutaneous follicle center lymphomas, and specifically those with a follicular growth pattern, remain uncertain, the issues are clearly discussed both the Blood paper that presented the WHO-EORTC classification and the 2008 WHO monograph. [9, 13] BCL2 protein expression is reported in up to 86% of primary cutaneous FL, with its presence more common in cases with fewer centroblasts. [14] IGH@/BCL2 translocations are reported in 10 - 41% of primary cutaneous FL, with its presence more common in cases with fewer centroblasts (reviewed in Kim, et al [14] ). Although beyond the scope of this discussion, the literature remains confusing with one study finding BCL2 translocations using cytogenetic FISH analysis but not being able to confirm the findings by PCR studies, while others show well-documented translocations using PCR analyses. [15, 16] One must remember that FCL is a broader category than FL so that these studies do not reflect the proportions of cases one would find using the WHO-EORTC or 2008 WHO criteria for the former type of lymphoma. In general, more CD10 and BCL2 staining and more frequent BCL2 translocations will be found in the PCFCL that have a follicular growth pattern and a higher proportion of centrocytes (cleaved cells). These observations and comparisons to secondary and nodal FL do mean that because BCL2 abnormalities are found more often in the former types of FL compared to the primary cutaneous cases, their presence should at least raise more suspicion that the lesion is not primary or, if diffuse, that the lymphoma is not a FCL at all. Their presence in a primary cutaneous FL is not supposed to be of clinical significance. One must be cautious, however, because once you are dealing with a primary cutaneous large B-cell lymphoma (including diffuse CFCL), BCL2 protein expression (>50% of cells) is an adverse prognostic indicator. [17] Primary cutaneous diffuse large B-cell lymphomas, more than one kind: The primary cutaneous diffuse large B-cell lymphomas are divided into those of "leg type" and others. The latter was considered a second although heterogeneous type of primary cutaneous DLBCL in the WHO-EORTC classification, but these cases are not segregated in the 2008 WHO classification. Again, the literature can be very confusing and some report more cases of the "other" type. Primary cutaneous DLBCL, leg type: Primary cutaneous DLBCL, leg type is defined as an aggressive B-cell lymphoma that usually but not always presents on the (lower) leg and is composed of a generally monotonous proliferation of immunoblasts or, perhaps less often, centroblast-like transformed cells with few admixed reactive cells. [18, 19, 20] The leg type DLBCL reportedly make up most non-FCL diffuse B-cell lymphomas composed of large cells (at least according to some authors). They occur mostly in elderly females who present with rapidly growing tumors on one or both legs; however, as noted, some are located at other sites. In contrast to CFCL, they are more likely to disseminate to extracutaneous sites (50%). [19] They are aggressive with a 5 year survival of 55% and usually require treatment with combination chemotherapy (perhaps with the exception of single small lesions where radiation therapy might be sufficient). [9] The presence of multiple lesions is an adverse prognostic indicator. [19] Anatomic/histologic/phenotypic features: Recognition of the leg type DLBCL is based on a number of different parameters. Site is an important clue but not pathognomonic and one must be able to diagnose these at non-leg sites. Histologically, one should see sheets of transformed B-cells with few admixed reactive elements. Immunophenotypic studies show the following: Strong bcl-2 expression (versus little in diffuse CFCL) – may be negative however. Bcl-6+ but CD10- in most cases (some exceptions especially re bcl-6) MUM-1/IRF4+ (versus absent in CFCL) – may be negative however. Genotypic/cytogenetic features: Based on the above, not surprisingly the leg-type DLBCL have an activated B-cell gene expression profile. [21] One cytogenetic FISH study demonstrated MYC translocation (6) or BCL6 (5) translocations in 11/14 large B-cell lymphomas of the leg. [22] IGH@/BCL2 translocations are not present. There are some reported conflicting results which I cannot reconcile with the above findings. [23] Other abnormalities including BCL2 gene amplification are also reported. [20] Primary cutaneous DLBCL, other types: There are rare other diffuse large B-cell lymphomas not of PCFCL or DLBCL, leg type. Some of these cases fall into subcategories that are already well known and well defined, including the following entities: T-cell/histiocyte rich large B-cell lymphoma (believed to be more indolent than its nodal "counterpart") [24] Cutaneous plasmablastic lymphoma [25] These cases should be diagnosed according to these already well defined entities. Other cases, however, may need to just be included in the DLBCL, NOS category. References : Cerroni L, El-Shabrawi-Caelen L, Fink-Puches R, et al. Cutaneous spindle-cell B-cell lymphoma: a morphologic variant of cutaneous large B-cell lymphoma. Am J Dermatopathol 22: 299-304., 2000. Ferrara G, Bevilacqua M, Argenziano G. Cutaneous spindle B-cell lymphoma: a reappraisal. Am J Dermatopathol 24: 526-527; author reply 527-528, 2002. Nozawa Y, Wang J, Weiss LM, et al. Diffuse large B-cell lymphoma with spindle cell features. Histopathology 38: 177-178, 2001. Fung CH, Antar S, Yonan T, et al. Actin-positive spindle cell lymphoma. 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Molecular cytogenetic evidence of t(14;18)(IGH;BCL2) in a substantial proportion of primary cutaneous follicle center lymphomas. Am J Surg Pathol 30: 529-536, 2006. Mirza I, Macpherson N, Paproski S, et al. Primary cutaneous follicular lymphoma: an assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol 20: 647-655., 2002. Grange F, Petrella T, Beylot-Barry M, et al. Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas. Blood 103: 3662-3668, 2004. Goodlad JR, Krajewski AS, Batstone PJ, et al. Primary cutaneous diffuse large B-cell lymphoma: prognostic significance of clinicopathological subtypes. Am J Surg Pathol 27: 1538-1545, 2003. Grange F, Bekkenk MW, Wechsler J, et al. Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J Clin Oncol 19: 3602-3610., 2001. Meijer CJLM, Vergier B, Duncan LM, et al., Primary cutaneous DLBCL, leg type. in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Swerdlow SH, Campo E, Harris NL, et al., [Eds.] IARC: Lyon. 2008, 242. Hoefnagel JJ, Dijkman R, Basso K, et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood, 2004. Hallermann C, Kaune KM, Gesk S, et al. Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas. J Invest Dermatol 123: 213-219, 2004. Wiesner T, Streubel B, Huber D, et al. Genetic Aberrations in Primary Cutaneous Large B-Cell Lymphoma: A Fluorescence In Situ Hybridization Study of 25 Cases. Am J Surg Pathol 29: 666-673, 2005. Li S, Griffin CA, Mann RB, et al. Primary cutaneous T-cell-rich B-cell lymphoma: clinically distinct from its nodal counterpart? Mod Pathol 14: 10-13, 2001. Hausermann P, Khanna N, Buess M, et al. Cutaneous plasmablastic lymphoma in an HIV-positive male: an unrecognized cutaneous manifestation. Dermatology 208: 287-290, 2004.