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Aberrant Expression of CD30 in Neoplastic Mast Cells in High-Grade Mastocytosis

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Aberrant Expression of CD30 in Neoplastic Mast Cells in High-Grade Mastocytosis Modern Pathology (2011) 24, 585–595 & 2011 USCAP, Inc. All rights reserved 0893-3952/11 $32.00 585 Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis Karl Sotlar1, Sabine Cerny-Reiterer2, Karina Petat-Dutter1, Harald Hessel1, Sabina Berezowska1, Leonhard Mu¨ llauer3, Peter Valent2,4 and Hans-Peter Horny5 1Institute of Pathology, University of Munich, Munich, Germany; 2Division of Hematology and Hemostaseology, Department of Internal Medicine I, Vienna, Austria; 3Institute of Pathology, Medical University of Vienna, Vienna, Austria; 4Ludwig-Boltzmann Cluster Oncology, Vienna, Austria and 5Institute of Pathology of Ansbach, Ansbach, Germany Systemic mastocytosis either presents as aggressive neoplasm with short survival time or indolent systemic mastocytosis with normal life expectancy. In both instances, neoplastic mast cells usually harbor the D816V- mutated variant of KIT. Phenotypically, mast cells in systemic mastocytosis usually express CD25. However, no robust marker that discriminates between aggressive and indolent variants of systemic mastocytosis has been identified yet. We here report that CD30, also known as Ki-1 antigen, is expressed in neoplastic mast cells in a majority of patients with advanced systemic mastocytosis (11/13, 85%), whereas in most patients with indolent systemic mastocytosis (12/45, 27%; Po0.001), only a few if any mast cells stained positive for CD30. These results could be confirmed by TissueFAXS analysis in subsets of patients with indolent systemic mastocytosis (n ¼ 7) and advanced systemic mastocytosis (n ¼ 4; P ¼ 0.008). The mast cell leukemia cell line HMC-1, derived from a patient with aggressive systemic mastocytosis also expressed the CD30 protein. In addition, we were able to detect CD30 mRNA in HMC-1 cells as well as in bone marrow biopsy samples in patients with systemic mastocytosis. In contrast, CD30 transcripts could not be detected in bone marrow biopsies in cases of reactive mast cell hyperplasia and in various other myeloid neoplasms. In conclusion, CD30 is preferentially expressed in neoplastic mast cells in advanced mast cell neoplasms. Upregulated expression of CD30 in advanced systemic mastocytosis may thus be employed as a potential marker for grading systemic mastocytosis in hematopathology. Modern Pathology (2011) 24, 585–595; doi:10.1038/modpathol.2010.224; published online 24 December 2010 Keywords: CD30; grading; immunohistochemistry; mast cell leukemia; RT-PCR; systemic mastocytosis Systemic mastocytosis is a myeloid neoplasm 4200 ng/ml; organomegaly) and signs of a spread characterized by abnormal growth and accumula- of the disease into myeloid lineages (dysmyelopoi- tion of neoplastic mast cells in one or more organ esis; KITD816V in other myeloid lineages). In the systems.1–3 Indolent and aggressive variants of presence of two B findings, a smouldering systemic systemic mastocytosis occur.4,5 mastocytosis is diagnosed. The absence of B and C So-called B and C findings have been defined findings usually indicates an indolent course. Mast to sub-classify systemic mastocytosis.4 The latter cell leukemia, per definition, is diagnosed when include organopathies especially of bone marrow, neoplastic mast cells exceed 20% of nucleated cells liver, and bone because of mast cell infiltration and in the bone marrow smear and/or 10% of nucleated is indicative of aggressive systemic mastocytosis. cells in the peripheral blood.6,7 Patients with The former include a high mast cell burden (420% indolent systemic mastocytosis are either asympto- mast cells in the bone marrow; serum tryptase matic or suffer from skin lesions, mediator-related symptoms, or osteoporosis. Indolent systemic mas- tocytosis patients with a silent clinical course have a Correspondence: Professor K Sotlar, MD, Institute of Pathology, normal or near-normal life expectancy.1–3,5,8-10 In Ludwig Maximilians University of Munich, Thalkirchner Strabe contrast, patients with aggressive systemic masto- 36, D-80337 Munich, Germany. cytosis or mast cell leukemia have a less favorable E-mail: [email protected] Received 21 April 2010; revised 22 September 2010; accepted 12 prognosis and show a poor response to conventional October 2010; published online 24 December 2010 cytostatic drugs.5,8,11 These patients are therefore www.modernpathology.org CD30 in advanced mastocytosis 586 K Sotlar et al candidates for experimental therapy11–14 and several single cases of myeloid sarcoma, CD30 expression attempts have been made to identify novel thera- has not been reported in the context of myeloid peutic targets in neoplastic mast cells.5,8,12–14 neoplasms so far. We here report that CD30 is In most patients with systemic mastocytosis, expressed by neoplastic mast cells in certain including both those with aggressive systemic patients with systemic mastocytosis. CD30 expres- mastocytosis/mast cell leukemia and those with sion was found to correlate with the subtype of indolent systemic mastocytosis, the transforming systemic mastocytosis in that in most patients with KIT mutation D816V can be detected.5,8,15–20 This high-grade systemic mastocytosis (aggressive sys- mutation is associated with autonomous activation temic mastocytosis or mast cell leukemia) the of the KIT receptor and is therefore considered to majority of mast cells were CD30-positive, whereas contribute to abnormal growth and survival of in most patients with indolent systemic mastocyto- neoplastic mast cells in systemic mastocytosis.21 sis, the great majority of mast cells were found to be As KITD816V is detectable not only in aggressive CD30-negative. systemic mastocytosis and mast cell leukemia but also in indolent systemic mastocytosis,15,19,20 it is thought that additional pro-oncogenic pathways and Patients and methods markers trigger and are indicative of the aggressive Patients and Diagnoses disease variants, that is, aggressive systemic masto- cytosis and mast cell leukemia. Unfortunately, such Immunohistochemical evaluation of CD30 expres- additional molecular markers and pathways have sion in tryptase-positive mast cells was performed not yet been identified. on bone marrow biopsies from a total of 61 patients An important diagnostic approach in systemic with mastocytosis (45 patients with typical indolent mastocytosis is the immunophenotyping of neoplas- systemic mastocytosis, 2 with smouldering systemic tic mast cells by flow cytometry and/or immuno- mastocytosis, 5 with aggressive systemic mastocy- histochemistry.22–24 In contrast to other myeloid tosis, 6 with mast cell leukemia, 3 with cutaneous cells, mast cells co-express tryptase and KIT and mastocytosis) and 1 patient with monoclonal mast can thus be detected easily in bone marrow sections cell activation syndrome. Serum tryptase levels by immunostaining.22,25 A key marker of mast cells were available for about half of these patients in systemic mastocytosis is CD25 (Escribano et al22; (indolent systemic mastocytosis, n ¼ 26; smoulder- Sotlar et al24), which is expressed by neoplastic mast ing systemic mastocytosis, n ¼ 2; aggressive sys- cells in almost all patients with systemic masto- temic mastocytosis, n ¼ 2; mast cell leukemia, cytosis, whereas normal and reactive mast cells n ¼ 2, cutaneous mastocytosis, n ¼ 3; monoclonal in non-mastocytic hematopoietic and non-hemato- mast cell activation syndrome, n ¼ 1; Table 1). The poietic disorders are usually CD25-negative.24 The control group consisted of 15 patients with bone expression of CD25 has also been proposed as a marrow mast cell hyperplasia, 15 with various minor diagnostic criterion for systemic mastocyto- myelogenous neoplasms other than systemic masto- sis.6 However, CD25 expression in systemic masto- cytosis (chronic myeloid leukemia, n ¼ 2; primary cytosis is independent of the aggressiveness of the myelofibrosis, n ¼ 4; polycytemia vera, n ¼ 1; myelo- neoplasm and is thus not related to the systemic dysplastic syndrome, n ¼ 4; chronic myelomonocy- mastocytosis subtype. A number of other mast cell tic leukemia, n ¼ 1; acute myeloid leukemia, n ¼ 3), markers, such as CD9, CD63, CD68, and pSTAT5, are 3 with Hodgkin lymphoma (2 patients with nodal also expressed on and/or in neoplastic mast cells involvement and 1 patient with medullary involve- independent of the disease variant.26,27 Some of ment), and 3 with testicular germ cell tumors (2 with these markers may be expressed by mast cells at embryonal carcinoma, 1 with seminoma). slightly higher or lower levels in aggressive systemic Molecular analysis for the assessment of CD30 mastocytosis or mast cell leukemia compared with mRNA expression was performed in 9 patients with indolent systemic mastocytosis.28 However, so far no systemic mastocytosis (indolent systemic mastocy- robust immunological marker that would discrimi- tosis, n ¼ 5; aggressive systemic mastocytosis, n ¼ 3; nate between the indolent and aggressive variants of mast cell leukemia, n ¼ 1) and 13 patients without systemic mastocytosis has been identified. The mastocytosis, 3 of which showed a marked increase CD30 antigen, also known as Ki-1 antigen, is a in bone marrow mast cells. The latter included two member of the tumor necrosis factor receptor super- patients with an unclassifiable myeloproliferative family.29,30 A number of studies have shown that neoplasm with eosinophilia and one patient with a CD30 is expressed by neoplastic cells in a small and tumor-free bone marrow in Hodgkin lymphoma. distinct spectrum of human neoplasms, including Unfortunately,
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