To the Editor:
According to WHO, mastocytosis represents a heterogenous group of diseases, which is characterized by an increased number of mast cells in different organs. Skin and bone marrow are most often affected. WHO subclassifies mastocytosis based on clinical and laboratory features and the involved organs.1 The majority of patients with systemic mastocytosis exhibit a KIT-D816V mutation.2 Histologically, mast cells in the skin can be easily identified in Giemsa or Toluidine blue stains. More than 15 mast cells arranged in clusters, or scattered mast cells exceeding 20 cells per microscopic high-power field argues for the diagnosis of a cutaneous mastocytosis.3 Additional helpful immunohistochemical markers are CD2, CD117, and CD25, the latter exclusively expressed on mast cells in the context of mastocytosis. The aberrant expression of CD30 on mast cells has been detected in different forms of systemic mastocytosis, whereas some investigators supposed it to be associated rather with the aggressive forms of the disease. Sotlar et al investigated the bone marrow of 3 patients with cutaneous mastocytosis. They found no CD30 expression in the bone marrow, however, no cutaneous biopsy was performed.4 Van Anrooij reported about another study (Arredondo AR, Jennings CD, Shier L, et al CD30 expression in Mastocytosis. Lab Invest. 2011; 91:285A–286A), in which 12 patients with cutaneous mastocytosis were investigated and 6 showed an aberrant expression of CD30 using a cut-off value of >5%. Whether skin biopsies or only bone marrow biopsies were taken is, unfortunately, not possible to elicit because, despite all our efforts, more details of the article could not be identified. On the contrary, Morgado et al5 could not confirm the association between an aberrant expression of CD30 and the aggressiveness of mastocytosis, although they observed an up-regulated aberrant expression of CD30 in most forms of indolent and aggressive mastocytosis. Concerning the expression of CD4 on mast cells, only a single report exists, and CD30 expression was not investigated.6
We report a case of a 50-year-old white male, who recently developed slightly pruritic papules on the trunk (Fig. 1A) and extremities, and suffered from recurrent diarrhea. The suspected diagnosis of the clinician was lymphomatoid papulosis. Histologically, a subepidermal infiltrate predominantly consisting of spindle-shaped cells with fine granules was observed (Figs. 1B, C). These cells were both positive for CD4 (clone SP 35; dilution 1:50, Zytomed, Berlin, Germany) (Fig. 1E) and CD30 (BerH2; dilution 1:50, Medac, Germany) (Fig. 1F), while negative for CD3 (rabbit polyclonal; dilution 1:100, DAKO, Germany), CD68 (PG-M1; DAKO, dilution 1:100, Germany), CD1a (3PM30; dilution 1:25, Leica, Germany), and S100-protein (polyclonal rabbit; DAKO, Germany). Moreover, the cells expressed CD117 (rabbit polyclonal; dilution 1:100) (Fig. 1D). A large number of eosinophils were also found (Fig. 1C). Further examination of the patient revealed raised serum tryptase levels (44 μg/L), an infiltration of the bone marrow by mast cells (15%–20%), and osteopenia were also noted. The other assays did not show any abnormalities related to mastocytosis, especially, no gastrointestinal pathology, despite the reported diarrhea. No activating point mutations in the 9 (the membrane-proximal immunoglobulin-like domain), 11 (juxta/near-membrane domain), 13, and 17 exons (tyrosine kinase domains) of the KIT-Gene were found. The diagnosis of an indolent systemic mastocytosis with an aberrant CD4 and CD30 coexpression was made.
Mast cells in mastocytosis may express aberrant immunophenotypical features, thus leading to a misdiagnosis of other hematological diseases.7 The aberrant expression of CD30 is not that uncommon in all forms of systemic mastocytosis. Some authors supposed that CD30 expression might be an additional helpful tool in distinguishing between an indolent and an aggressive mastocytosis,5 but this is still controversially discussed in the literature.
CD30 is a member of the tumor necrosis factor receptor superfamily.8 An interaction between CD30 and its ligand (CD30L), and the following downstream signaling leads to the activation of nuclear factor kappa B and mitogen-activated protein kinases. Under physiologic conditions, activated lymphocytes and leukocytes can express CD30. In neoplastic diseases, CD30 is typically expressed in different subtypes of non-Hodgkin lymphoma (anaplastic large-cell lymphoma, lymphomatoid papulosis), and Hodgkin lymphoma.9 The aberrant expression is not only used as a diagnostic factor but also the binding to its ligand results in proliferation and increased survival of pathological cells.10–13 It is supposed that the CD30 signaling also plays a role in the regulation of eosinophils.14,15 This might also be the case in our patient, because the number of eosinophils was unusually high. Remarkably, the aberrant expression of CD30 also allows the application of targeted immunotherapy with specific monoclonal antibodies.16
In our case, a simultaneous aberrant expression of CD30 and CD4 by mast cells was noted. Soilleux et al6 reported a case of aberrant expression of CD4 in patients with mastocytosis, however, the expression of CD30 was not documented. The aberrant of expression of CD4 by mast cells is not widely investigated. It has been shown that CD4 is a receptor for Interleukin 16. Soilleux et al6 speculate that it probably plays an important role in recruiting mast cells in mastocytosis via Interleukin 16, which is a chemotactic factor for mast cells. It is interesting to note that mast cells, both in cutaneous and systemic mastocytosis, may express also other T-cell antigens such as CD2 and CD25.17 In our case, the coexpression of CD4 and CD30 of mast cells is a unique finding, to the best of our knowledge, not yet reported in the literature. The aberrant expression of those markers, and in some cases the subtle morphological features of mast cells, could lead, in non-typical cases of cutaneous mastocytosis, to a misdiagnosis, especially when the clinician has suspected a lymphoproliferative disease, as in our case.
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