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Leukemia Research 36 (2012) 799– 801

Contents lists available at SciVerse ScienceDirect

Leukemia Research

jo ur nal homep age: www.elsev ier .com/ locate / leukres

ase of the Month

dvanced systemic mastocytosis as a mimicker of metastatic clear cell renalell carcinoma

hristoph Walza, Marion Subkleweb, Hans-Peter Hornyc, Michael Flaigd, Andreas Reitere,homas Kirchnera, Karl Sotlara,∗

Pathologisches Institut, Ludwig-Maximilians-Universität, München, GermanyMedizinische Klinik und Poliklinik III, Ludwig-Maximilians-Universität, München, GermanyInstitut für Pathologie Ansbach, Ansbach, GermanyKlinik für Dermatologie, Ludwig-Maximilians-Universität, München, GermanyIII. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany

r t i c l e i n f o

rticle history:eceived 16 December 2011

vailable online 28 March 2012

eywords:ystemic mastocytosislear cell renal cell carcinomaitd816V

ast cell leukemia

. Case report

A 63-year-old male patient with a history of a right-sidedenal cell carcinoma eight years ago presented with palpa-le splenomegaly, flush, diarrhea, vertigo and fatigue. Bloodounts revealed thrombocytopenia (88 × 109/L) and transfusion-ependent anemia (8.4 g/dL). In addition to hepato-/splenomegaly,scites and marked lymphadenopathy of the mesenteric, paraaor-al and gastral regions was found. Ultrasound revealed a tumorf 2.3 cm in maximum diameter in the left kidney which wasemoved by partial left-sided nephrectomy. Histopathologic anal-sis revealed a clear cell renal cell carcinoma (CCRCC; pT1a, G2, Nx,0; Fig. 1A).

A lymph node biopsy showed diffuse infiltration by neoplasticlear cells (Fig. 1C). Considering the underlying disease in com-ination with the histomorphologic presentation, a lymph nodeetastasis originating from the CCRCC appeared to be the most

ikely diagnosis. However, the clear cells did not express CD10, RCC

r pancytokeratins (LU5 and KL1), all of which were demonstratedo be positive in the primary tumor, thus excluding metastasis ofCRCC.

∗ Corresponding author at: Pathologisches Institut Ludwig-Maximilians-niversität, Thalkirchner Strasse 36, 80337 München, Germany.el.: +49 89 2180 73606; fax: +49 89 2180 73604.

E-mail address: karl.sotlar@med.uni-muenchen.de (K. Sotlar).

145-2126/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.oi:10.1016/j.leukres.2012.02.031

Immunohistochemical analysis was extended and the clearcells were found to co-express tryptase, CD117 and CD25(Fig. 1D) which all are typical markers of neoplastic mastcells. Markers of lymphomas were negative (not shown). Muta-tional analysis of the lymph node tissue demonstrated thepresence of the activating KITD816V point mutation whichis frequently found in neoplastic mast cells in systemicmastocytosis.

Bone marrow histology displayed marked hypercellularity withfocal fibrosis and ostesclerosis. The morphologic picture was dom-inated by disseminated, partly confluating compact infiltrates ofpartly round, partly spindle-shaped mast cells mainly located peri-trabecularly and occupying up to 35% of the marrow space (Fig. 1E).These cells also co-expressed tryptase, CD117 and CD25 (Fig. 1F).Bone marrow smears showed an abundance of atypical hypogranu-lated round mast cells. Neutrophilic granulopoiesis was left-shiftedexhibiting mild signs of dysplasia. There was no increase in CD34+progenitors or blast cells and no significant increase in CD14+monocytoid cells.

Additional careful staging disclosed evidence of microscopicmast cell infiltrates in the gastric cardia, colon and skin (Fig. 1Gand H). Moreover, immunohistochemical examination of the left-sided nephrectomy specimen demonstrated aggregates of tryptase,

CD117 and CD25-expressing mast cells around the pseudo-capsuleof the tumor (Fig. 1B), but some loosely scattered mast cells werealso detected within the CCRCC. In addition, a serum tryptase levelof 350 �g/L (normal <11.4) was measured.

800 C. Walz et al. / Leukemia Research 36 (2012) 799– 801

Fig. 1. Organ manifestations by aggressive SM. Right sided CCRCC (A, right) with adjacent normal renal tissue (A, left). Diffuse and compact mast cell infiltrates aroundthe CCRCC (B, CD117). Clear cell infiltrates within a lymph node biopsy (C, Giemsa) emerging as neoplastic mast cells by immunohistochemistry (D, CD117). Extremelyhypercellular bone marrow with fibrosis and extensive infiltrates of partly round clear cells (E, H&E) again emerging as neoplastic mast cells (F, tryptase). In addition,m D25).

onh

astocytosis infiltrates could be demonstrated in the colonic mucosa (G, H&E; H, C

Based on these results, the final patho-anatomical diagnosisf an aleukemic mast cell leukemia with infiltration of lymphodes, skin and gastrointestinal mucosa and consecutive cytopenia,ypoalbuminemia and ascites was established.

2. Discussion

Diagnosis of mastocytosis is frequently missed by clini-cians and pathologists because it represents a rare disease,

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xhibiting highly variable clinical features [1,2]. Skin involvements a key feature in indolent SM but is often absent in aggressiveM and mast cell leukemia. The broad range of clinical symp-oms is due to mediator-related systemic events (e.g., anaphylaxis,ush, diarrhea) and variable organ involvement. However, therean be organ involvement in SM without major dysfunction. SMay also be associated with other clonal hematologic non-mast

ell lineage disorders (SM-AHNMD) such as chronic myelomono-ytic leukemia (CMML), hypereosinophilic syndrome (chronicosinophilic leukemia (HES/CEL), or acute myeloid leukemia (AML)nd mastocytosis may even be obscured by these neoplasms [3].

However, once SM is taken into consideration, a straightfor-ard panel of immunohistochemical markers (tryptase, CD117 andD25) in combination with molecular analysis (KITD816V) and lab-ratory parameters (i.e., serum tryptase) will readily confirm orxclude the diagnosis [4]. Hence, if SM is suspected, a careful work-p of the WHO criteria should be performed in order to achieve anal diagnosis and subclassification. In addition, new markers suchs the recently described aberrant expression of CD30 can be useful5]. Correct subclassification of SM is of relevant clinical impor-ance for selection of symptomatic or cytoreductive treatment withnterferon, cladribin or targeted treatment with a tyrosine kinasenhibitor, e.g. midostaurin (PKC412) [6,7].

Here, we present a case of a 63-year-old male patient withCRCC and lymphadenopathy associated with bicytopenia. Theffected lymph nodes displayed neoplastic clear-cell infiltrates,hich were morphologically suspicious for metastases of theCRCC but in fact represented infiltrates of KITD816V-positiveast cell leukemia. Of interest, mast cell infiltrates were not only

etected in the bone marrow, gastrointestinal mucosa and skin butlso in and around the CCRCC. To the best of our knowledge, renalanifestation of SM has not yet been reported. However, we are

ware of an additional case of SM with renal involvement. This find-ng was initially misinterpreted as reactive histiocytosis because of

physiological) CD68 positivity of mast cells (not shown).

We summarize that SM is a rare disease presenting with highlyariable clinical features and sometimes presenting with clear-cellnfiltrates thus mimicking other, more frequently observed reactive

[

rch 36 (2012) 799– 801 801

or neoplastic conditions. However, to achieve the correct diagnosisis crucial since the course of the disease can be fatal and effectivetargeted therapies are available.

Role of the funding source

None.

Conflict of Interest

There is no conflict of interests.

Acknowledgments

None.Authors’ contributions: CW, KS, TK and HPH designed research

and wrote the paper. MS, MF and AR provided vital specimens anddata.

References

1] Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al.Standards and standardization in mastocytosis:consensus statements on diag-nostics, treatment recommendations and response criteria. Eur J Clin Invest2007;37(6):435–53.

2] Arock M, Valent P. Pathogenesis, classification and treatment of mastocy-tosis:state of the art in 2010 and future perspectives. Expert Rev Hematol2010;3(4):497–516.

3] Bernd HW, Sotlar K, Lorenzen J, Osieka R, Fabry U, Valent P, et al. Acutemyeloid leukaemia with t(8,21) associated with “occult” mastocytosis reportof an unusual case and review of the literature. J Clin Pathol 2004;57(3):324–8.

4] Horny HP, Sotlar K, Valent P. Differential diagnoses of systemic mastocytosisin routinely processed bone marrow biopsy specimens:a review. Pathobiology2010;77(4):169–80.

5] Sotlar K, Cerny-Reiterer S, Petat-Dutter K, Hessel H, Berezowska S, Mullauer L,et al. Aberrant expression of CD30 in neoplastic mast cells in high-grade masto-cytosis. Mod Pathol 2011;24(4):585–95.

6] Gotlib J, DeAngelo DJ, George TI, Corless CL, Linder A, Langford C, et al. KIT

inhibitor midostaurin exhibits a high rate of clinically meaningful and durableresponses in advanced systemic mastocytosis: report of a fully accrued phase IItrial. Blood 2010:116–316. ASH Annual Meeting Abstracts.

7] Pardanani A. Systemic mastocytosis in adults: 2011 update on diagnosis, riskstratification, and management. Am J Hematol 2011;86(4):362–71.