Extramedullary plasmacytoma (EMP) are poorly characterized tumours that typically arise in the upper aerodigestive tract but rarely progress to multiple myeloma. These latter observations have led some investigators to suggest that EMP are not part of the spectrum of plasma cell disorders but represent a form of extranodal marginal zone lymphoma showing extreme plasma cell differentiation (Hussong et al, 1999). Here we report a detailed clinico-pathological assessment of a cohort of patients with EMP which we believe adds further insight into this disorder. 26 patients were included in this analysis (16 male, 10 female; median age 65 years) and sites of presentation were as follows: nasopharynx (n = 9), lymph node (n = 7), GI tract (n = 6), skin (n = 2) and other (n = 2). All cases fulfilled the International Myeloma Working Group (2003) criteria for EMP as there was no evidence of local bone destruction or generalized myeloma. Surgical biopsies were obtained in all cases and standard immunohistochemical methods were used to assess the expression of the following antigens: CD138, MUM1/IRF4, PAX5, CD20, CD56, CD117, CD27 and cyclin D1. In cases with sufficient material available, fluorescence in situ hybridization (FISH) was used to evaluate for chromosome 13 loss, IGH and MALT1 rearrangements. Cases with IGH rearrangements were further investigated with IGH/FGFR3, IGH/MAF, IGH/CCND1 dual colour dual fusion probe combinations and a PAX5 break-apart probe set. Multiparameter flow cytometry was also used to assess iliac crest-derived bone marrow aspirate samples for the presence of aberrant phenotype plasma cells indicative of occult bone marrow disease. In this series all cases were characterized by a monomorphic plasma cell infiltrate showing strong uniform expression of both CD138 and MUM1/IRF4. There was no obvious B-cell component identified either by morphology or immunohistochemistry. Two cases did express CD20 but they both lacked PAX5 expression. With respect to the antigens aberrantly expressed in myeloma plasma cells; CD56 and CD117 expression was documented in 58% (15/26) and 29% (5/17) of cases respectively while loss of CD27 was documented in 63% (12/19). Aberrant expression of at least one of these antigens was demonstrable in 92% of assessable cases (22/24). Monosomy 13 was evident in 6 of 18 (33%) cases and IGH rearrangements in 9 of 17 (53%) cases but no MALT1 rearrangements were encountered. Cases with IGH rearrangements were further investigated and a single case was shown to have a t(11;14)(q13;q32) which was further clarified by demonstrating cyclin D1 protein expression by immunohistochemistry. This case has been reported previously and was characterized by an aggressive clinical course (Parkins et al, 2010). There was however no evidence of translocations involving FGFR3, MAF or PAX5 in the remaining cases with IGH rearrangements. Multiparameter flow cytometry utilizing European Myeloma Network (EMN) consensus methodology (Rawstron et al, 2008) was used to accurately enumerate and phenotype the plasma cells present in staging bone marrow aspirate samples in 18 cases. In all cases plasma cells comprised <5% of cells by routine morphological assessment. By flow cytometry, plasma cells comprised a median of 0·36% (range 0·14–2·06%) of bone marrow leucocytes. Aberrant phenotype plasma cells (defined by the absence of CD19 and/or presence of CD56) were evident in 10 of 18 (56%) cases. When present, aberrant phenotype plasma cells comprised a median of 58% of plasma cells and 0·3% of bone marrow leucocytes (range 0·05–1·26%). We believe that this data along with other recently published studies strongly suggest that EMP should be considered part of the spectrum of plasma cell disorders rather than lymphoma. The immunophenotypic profile of myeloma plasma cells differs considerably from that of their normal counterparts and this includes loss of CD19, CD45 and CD27 along with aberrant expression of CD56, CD117, CD20 and cyclin D1 (Rawstron et al, 2008). In our series we have demonstrated aberrant expression of CD56, CD117, CD27 and CD20 while CD56 and cyclin D1 expression (Table I) has also been demonstrated by other investigators although the overall incidence may be lower than that typically seen in myeloma (Kremer et al, 2005; Kojima et al, 2009). Similarly the high incidence of chromosome 13 loss and IGH rearrangements along with absence of MALT1 and PAX5 rearrangements strongly argues in favour of considering EMP as true plasma cell disorders rather than lymphoma. This is also supported by two further cytogenetic studies. Aalto et al (1999) demonstrated chromosome 13 loss in 8/9 EMP cases assessed by comparative genomic hybridization. Similarly Bink et al (2008) found a high incidence of 13q loss (40%) and IGH rearrangements (37%) amongst 38 cases assessed by FISH-based assays. Interestingly they demonstrated a relatively high incidence of the t(4;14)(p16;q32) but no cases with the t(11;14)(q13;q32). They also demonstrated a high incidence of chromosome gains (82%) but no evidence of rearrangements of MALT1, BCL6 or FOXP1 (Bink et al, 2008). An additional novel finding in this study is the demonstration of aberrant phenotype plasma cells in the staging marrow of a significant proportion of patients. This is highly suggestive of occult bone marrow disease although definitive proof will require the demonstration of clonal identity through immunoglobulin gene sequencing. This to our knowledge has not been previously demonstrated in EMP. We have previously demonstrated (by flow cytometry) that aberrant phenotype plasma cells are also present at distant bone marrow sites in 67% of patients with solitary plasmacytoma of bone. In this context they comprised a median of 70% of bone marrow plasma cells and 0·52% of bone marrow leucocytes and their presence was predictive of progression (Hill et al, 2007). We would conclude that the available data suggests that EMP are characterized by a similar range of immunophenotypic and genotypic abnormalities to those encountered in standard myeloma. The available data suggests there may be subtle differences, such as a lower incidence of CD56 expression and the t(11;14) in EMP but this should not lead to the mistaken assessment that such cases represent lymphoma. Variations in immunophenotypic and genotypic profiles are well recognized amongst distinct plasma cell clinical syndromes exemplified, for example, by the high incidence of the t(11;14)(q13;q32) in non-secretory and IgM myeloma and primary AL amyloidosis (Avet-Loiseau et al, 2003). The clinical behaviour of EMP is however distinct from that of myeloma and the underlying mechanisms for this remain unclear.
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