mitotically active deep juvenile xanthogranuloma active deep... · mitotically active deep juvenile...

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Cytologic-Pathologic Correlations Mitotically active deep juvenile xanthogranuloma Jan Koren, MD, PhD a, , Ludovit Matecek, MD b , Michal Zamecnik, MD c a Cytopathos s.r.o., 830 07, Bratislava, Slovak Republic b Histocyt s.r.o., Private Diagnostic Center, 974 11, Banska Bystrica, Slovak Republic c Histamed s.r.o., Cytological and Bioptic Center, 911 71, Trencin, Slovak Republik Abstract Juvenile xanthogranuloma is a relatively rare cutaneous tumor of histiocytic origin, occurring mainly in neonates, children, and young people in the first 2 decades of life. An occurrence in adults is rare. Very rare is also a deepsubcutaneous and intramuscular localization of this tumor that is called in such case as deep juvenile xanthogranuloma.A very uncommon variant of this tumor is the so-called mitotically active xanthogranuloma, which was described in the literature only in a single case. We present an interesting case of the mitotically active intramuscular juvenile xanthogranuloma of the upper arm in a 28-year-old woman. Before surgical excision, the tumor was examined by fine-needle aspiration biopsy. A diagnosis of deep malignant melanoma or alveolar rhabdomyosarcoma was considered. One year after the total excision, the patient is free of disease. In the presented case, we emphasize cytologic-histologic correlation. In the differential diagnosis, we considered especially an atypical diffuse giant cell tumor of tendon sheaths and joints (extra-articular pigmented villonodular synovitis) and some rare types of soft tissue leiomyosarcoma, such as epitheloid leiomyosarcoma and leiomyosarcoma with prominent osteoclast-like giant cells. © 2010 Elsevier Inc. All rights reserved. Keywords: Deep juvenile xanthogranuloma; Desmin; Mitotically active juvenile xanthogranuloma; Cytologic-histologic correlation; Atypical diffuse giant cell tumor of tendon sheaths and joints; Epitheloid leiomyosarcoma; Leiomyosarcoma with osteoclast-like cells 1. Introduction Juvenile xanthogranuloma (JXG) is a relatively rare benign histiocytic cutaneous tumor that occurs typically in young patients in the first 2 decades of life [1-9]. Juvenile xanthogranuloma rarely affects adults [1-7,9]. A less common is subcutaneous and intramuscular localization of this tumor, that is, so-called deep JXG [1-7,9]. A very rare is a mitotically active deep JXG, of which only a single case was reported by Miguélez et al [5] in 2002. Here we report an interesting case of mitotically active intramuscular JXG of the left upper arm in a 28-year-old woman. The tumor was of nonlipidized type. It was examined before the surgical excision by fine-needle aspiration (FNA) biopsy. One year after the complete excision, the patient is free of disease. To our knowledge, only 2 well-documented JXGs examined by FNA were described [6,10], and only one case of deep JXG was verified histologically after the cytologic examination and surgical excision [10]. 2. Materials and methods The tumor was examined before the surgical excision by FNA, using a standard method with a special pistol. The smears were fixed by air and were stained by May-Giemsa- Grunwald stain. The tissue was fixed in 4% formalin and processed routinely. All tumor tissues were paraffin- embedded. The sections were stained with hematoxylin and eosin stain and Pearl's histochemical stain for iron. Immunohistochemical studies were performed on for- malin-fixed, paraffin-embedded sections using the follow- ing antibodies: α-musclespecific actin (HHF-35, 1:50), Available online at www.sciencedirect.com Annals of Diagnostic Pathology 14 (2010) 36 40 Corresponding author. Tel.: +421 917 211 764; fax: +421 259 543 481. E-mail address: [email protected] (J. Koren). 1092-9134/$ see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2009.09.004

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Page 1: Mitotically active deep juvenile xanthogranuloma active deep... · Mitotically active deep juvenile xanthogranuloma ... Abstract Juvenile xanthogranuloma is a relatively rare cutaneous

Available online at www.sciencedirect.com

Annals of Diagnostic Pathology 14 (2010) 36–40

Cytologic-Pathologic Correlations

Mitotically active deep juvenile xanthogranulomaJan Koren, MD, PhDa,⁎, Ludovit Matecek, MDb, Michal Zamecnik, MDc

aCytopathos s.r.o., 830 07, Bratislava, Slovak RepublicbHistocyt s.r.o., Private Diagnostic Center, 974 11, Banska Bystrica, Slovak RepubliccHistamed s.r.o., Cytological and Bioptic Center, 911 71, Trencin, Slovak Republik

Abstract Juvenile xanthogranuloma is a relatively rare cutaneous tumor of histiocytic origin, occurring

⁎ Corresponding aE-mail address: k

1092-9134/$ – see frodoi:10.1016/j.anndiag

mainly in neonates, children, and young people in the first 2 decades of life. An occurrence inadults is rare. Very rare is also a “deep“ subcutaneous and intramuscular localization of this tumorthat is called in such case as “deep juvenile xanthogranuloma.” A very uncommon variant of thistumor is the so-called mitotically active xanthogranuloma, which was described in the literatureonly in a single case. We present an interesting case of the mitotically active intramuscularjuvenile xanthogranuloma of the upper arm in a 28-year-old woman. Before surgical excision, thetumor was examined by fine-needle aspiration biopsy. A diagnosis of deep malignant melanomaor alveolar rhabdomyosarcoma was considered. One year after the total excision, the patient isfree of disease. In the presented case, we emphasize cytologic-histologic correlation. In thedifferential diagnosis, we considered especially an atypical diffuse giant cell tumor of tendonsheaths and joints (extra-articular pigmented villonodular synovitis) and some rare types of softtissue leiomyosarcoma, such as epitheloid leiomyosarcoma and leiomyosarcoma with prominentosteoclast-like giant cells.

© 2010 Elsevier Inc. All rights reserved.

Keywords: Deep juvenile xanthogranuloma; Desmin; Mitotically active juvenile xanthogranuloma; Cytologic-histologiccorrelation; Atypical diffuse giant cell tumor of tendon sheaths and joints; Epitheloid leiomyosarcoma;Leiomyosarcoma with osteoclast-like cells

1. Introduction

Juvenile xanthogranuloma (JXG) is a relatively rarebenign histiocytic cutaneous tumor that occurs typically inyoung patients in the first 2 decades of life [1-9]. Juvenilexanthogranuloma rarely affects adults [1-7,9]. A lesscommon is subcutaneous and intramuscular localization ofthis tumor, that is, so-called deep JXG [1-7,9]. A very rare isa mitotically active deep JXG, of which only a single casewas reported byMiguélez et al [5] in 2002. Here we report aninteresting case of mitotically active intramuscular JXG ofthe left upper arm in a 28-year-old woman. The tumor was ofnonlipidized type. It was examined before the surgicalexcision by fine-needle aspiration (FNA) biopsy. One yearafter the complete excision, the patient is free of disease. To

uthor. Tel.: +421 917 211 764; fax: +421 259 543 [email protected] (J. Koren).

nt matter © 2010 Elsevier Inc. All rights reserved.path.2009.09.004

our knowledge, only 2 well-documented JXGs examined byFNA were described [6,10], and only one case of deep JXGwas verified histologically after the cytologic examinationand surgical excision [10].

2. Materials and methods

The tumor was examined before the surgical excision byFNA, using a standard method with a special pistol. Thesmears were fixed by air and were stained by May-Giemsa-Grunwald stain. The tissue was fixed in 4% formalin andprocessed routinely. All tumor tissues were paraffin-embedded. The sections were stained with hematoxylinand eosin stain and Pearl's histochemical stain for iron.

Immunohistochemical studies were performed on for-malin-fixed, paraffin-embedded sections using the follow-ing antibodies: α-muscle–specific actin (HHF-35, 1:50),

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37J. Koren et al. / Annals of Diagnostic Pathology 14 (2010) 36–40

α-smooth muscle actin (1A4, 1:100), CD68 (KP1, 1:100),vimentin (3B4, 1:200), myogenin (F5F1, 1:5), h-caldesmon(h-CD, 1:400), desmin (D33, 1:100), S-100 protein(Z0311, 1:400), cytokeratins (AE1-3, 1:100), EMA (E29, 1:100), HMB-45 (HMB-45, 1:100), CD34 (QBEND19, 1:50), CD117 (polyclonal, kit CD117, 1:600), Ki-67(MIB1, 1:100) (all from Dako, Glostrup, Denmark).Immunostaining was performed according to standardprotocols using streptavidin-biotin complex labeled withperoxidase (Dako). Appropriate positive and negativecontrols were applied.

3. Results

A 28-year-old and otherwise healthy woman presentedwith 2-month slowly growing painless mass of the leftupper arm. Ultrasonography showed intramuscular tumor inthe distal part of the biceps brachii muscle. The lesion wasexamined by FNA biopsy, and, 2 days after the cytologicdiagnosis of malignancy, a wide tumor excision wasperformed. The resected intramuscular tumor measured2.5 cm in diameter, and had a soft consistency and strongyellow and homogenous cut surface. Fibrous capsule wasnot seen, but the tumor was circumscribed and did not showgrossly visible infiltration of adjacent muscle tissue. Apatient is free of disease 1 year after the surgery.

The smears obtained by FNA biopsy were very cellular.They contained mainly numerous epitheloid cells ofintermediate size, with eccentric nuclei devoid of nuclearpleomorphism. Numerous nuclei had inconspicuous nucle-oli, and some of them also showed less conspicuousintranuclear inclusions of cytoplasm. The cytoplasm wasabundant, and it was of more dense appearance in the centralparts of cells. Some mononuclear histiocytes and scatteredgiant multinuclear cells were found in the smears (Fig. 1). A

Fig. 1. Cellular smear by FNA biopsy mimicking primary epithelioidmalignant tumor (May-Giemsa-Grünwald stain).

Fig. 2. Mitotically active deep juvenile xanthogranuloma. (A) Tumor withwell-circumscribed margin, without infiltration into surrounding skeletalmuscle (hematoxylin and eosin). (B) The tumor consists of numerousmononucleated epitheloid cells, foamy macrophages, and multinucleatedgiant cells of Touton type (hematoxylin and eosin). (C) High cellularity andnumerous typical mitoses.

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38 J. Koren et al. / Annals of Diagnostic Pathology 14 (2010) 36–40

peritheliomatous growth pattern was focally well visible. Acytologic diagnosis of primary epitheloid malignant tumor,most probably of epitheloid melanoma or alveolar rhabdo-myosarcoma, was suggested.

Histologic examination revealed intramuscular, well-circumscribed, non-encapsulated, very cellular and solidtumor, with minimal formation of intercellular matrix/fibers(Fig. 2A). The tumor consisted of numerous mononuclearepitheloid cells with abundant and strongly eosinophiliccytoplasm, with some intranuclear inclusions of thecytoplasm. In this dominant epitheloid cell population,less numerous, smaller, round to ovoid synovial-like cellswith paler nuclei were scattered. In addition, sheets ofvoluminous foamy macrophages with intracytoplasmaticgranulations and some multinucleated giant cells of bothosteoclast-like and Touton type were seen through the tumor(Fig. 2B). Mitotic rate varied from 15 to 20 typical mitoticfigures per 10 high-power field (HPF) (Fig. 2C). The tumor

Fig. 3. Immunohistochemical results. (A) Diffuse positivity for desmin. (B)Immunohistochemical stain for Ki-67 (MIB1) demonstrates relatively highproliferation of the tumor cells (hematoxylin and eosin, streptavidin-biotincomplex method [SABC] technique).

contained no necrosis, and it was sharply demarcated froman adjacent muscle tissue. Histochemical Pearl's stain foriron was negative in the tumor. Immunohistochemically,mononucleated epitheloid cells were diffusely positive fordesmin (Fig. 3A) and focally positive for vimentin. Foamymacrophages were positive for CD68. Tumor cells werenegative for cytokeratins, EMA, HMB-45, CD34, CD117,S-100 protein, actins, h-caldesmon, and myogenin. Positiv-ity for Ki-67 was seen in 15% of the tumor cells (Fig. 3B). Adiagnosis of mitotically active intramuscular (deep) juvenilexanthogranuloma was rendered.

4. Discussion

Juvenile xanthogranuloma, described originally byAdamson et al in 1905 [1], is a relatively rare histiocytictumor of the skin. It occurs typically in the first 2 decades oflife, and predominantly in male patients [1-9]. Occurrenceof JXG in adults (so-called adult type of JXG) is rare[4,9,11]. Juvenile xanthogranuloma is usually solitary andlocated in the head and neck region (so-called superficialJXG). Solitary JXG was rarely observed in subcutaneousand/or skeletal muscle tissue, and such form was labeled as“deep JXG” [1-12]. Deep JXG is typically located in thetrunk and extremities [2-4,7,11,13]. A less frequent form ofJXG is so-called systemic JXG with multiple cutaneous,subcutaneous, and visceral lesions and with various clinicalsymptoms [1,2,4,7,14]. In our case, a higher age of thepatient and a deep localization of the tumor representrelatively unusual clinical features, and, therefore, thediagnosis of JXG was understandably not suggested byclinical examination.

Regarding cytologic features of JXG, we are aware ofonly 2 well-documented cases of JXG examined by FNAbiopsy before surgical excision [6,10]. In the report ofBarroca et al [10], a congenital, deep intramuscular JXG waslocated in the neck region of the newborn. The smears werevery cellular and contained granulomatous clusters ofnumerous isolated isokaryotic histiocytes and sporadicmultinuclear cells. Polynuclears and necrotic debris wereseen in a background. Histologic examination confirmed so-called deep JXG. Mohindroo and Sharma [6] described acase of superficial JXG that had been located in the shoulderof a 3-year-old girl. However, the tumor was not excised andverified histologically because it regressed spontaneously.The smears contained numerous histiocytes with eosinophil-ic vacuolated cytoplasm, less numerous spindle-shapedfibroblasts, and giant multinucleated Touton-type cells.Numerous interspersed lymphocytes, eosinophils, and poly-nuclear leukocytes were seen in the background of thesmears [6]. Thus, the cytologic features in both cases weresimilar to those seen in the present tumor. In regard todistinction from any malignant epitheloid tumor by cytologicexamination, we think that most valuable features arerepresented by the absence of “true” nuclear atypia and by

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39J. Koren et al. / Annals of Diagnostic Pathology 14 (2010) 36–40

the finding of mixture of uninucleated histiocytoid cells andmultinucleated cells. High cellularity of the smears shouldnot be interpreted as a malignant feature. Histiocyte-like and/or multinucleated cytomorphology are commonly seen bycytologic examination of various malignant tumors. How-ever, malignant tumors with such malignant histiocytoma-like morphology are usually of higher grade, and thus theyshow well-visible and (well-interpretable) nuclear atypia andpleomorphism. Among benign tumors composed of histio-cytoid uni- and multinucleated cells, cytologic featuressimilar to those of JXG are seen especially in giant cell tumorof tendon sheaths and joints (GCTJS). In the cases of GCTJSexamined by FNA biopsy [14,15], the smears were verycellular and contained numerous mononuclear round toovoid histiocytes. These cells were isolated or arranged insmall solid clusters in a dirty background. In addition, lessnumerous isolated giant multinucleated cells with pigmentedcytoplasm were found. Mononucleated cells showed roundnuclei, inconspicuous nucleoli, and moderately eosinophilicor pigmented cytoplasm. The smears in our case showedvery similar features. However, the cells were not pigmentedin contrast with the cells of typical GCTJS.

Histologically, typical cutaneous JXG consists of mono-nuclear cells, foamy macrophages, multinucleated Touton-type cells, and spindle-shaped fibroblasts. Among thesecells, a few eosinophils, lymphocytes, and sometimes alsoplasmocytes are scattered. The mitotic rate ranges from 0 to 2typical mitoses per 10 HPF. More numerous mitoses in JXGare not common [1-7,10,16]. Rarely, JXG is devoid ofmononucleated cells and contains only nonlipidized mono-nucleated cells, sometimes with more eosinophilic cyto-plasm. This form is called nonlipidized JXG [1-3,17] ormitotic form of JXG [9]. Nonlipidized form of JXG containsusually numerous mitoses, especially when the lesion isulcerated [5]. Immunohistochemically, superficial JXG istypically positive for vimentin, CD68 (strongly with PG-M1clone, weakly with KP-1 clone) [7], lysozyme, and α-1-antichymotrypsin [1-4,6,7,9,10]. Sometimes it expressMAC-387 [9] and factor XIII-a, and, quite rarely, expres-sions of CD31, α-1-antitrypsin [2], S-100 protein [2-4],HHF-actin [3,7,9], and, sporadically, of fascin, CD14, andCD163 [10] were described [2-4]. In typical cases, the tumoris negative for α-smooth muscle actin, S-100 protein, EMA,cytokeratins, HMB-45, and desmin [1-4,7,9,10]. Reactivityfor desmin was not described in JXG before, to ourknowledge, and it is difficult to explain it. The stainingwas diffuse and quite weak, and immunostains for actins andh-caldesmon were negative. Therefore, we think that thisdesmin reactivity does not reflect any myofibroblastic ormyoid dendritic cell differentiation. As the positivity wasmild, we suppose that it was caused probably by endogenousperoxidase activity or by cross-reactivity.

Deep form of JXG, firstly described by Janney et al in1991 [3,12], shows morphology of common JXG except thatit often lacks the multinucleated Touton-type cells [2] andthat it contains higher number of mitoses [2,3,5,7,11-13].

The tumor infiltrates commonly a skeletal muscle. Aninteresting case of deep JXG with unusually high mitoticactivity was described by Miguélez et al [5] in 2002. Thistumor occurred in the shoulder region of a 2-year-old girl.Histologically, it was non-encapsulated intradermal tumorwith focal infiltrative growth into the subcutaneous adiposetissue. The tumor consisted of epitheloid histiocytes withsome foamy macrophages and multinucleated Touton-typecells. The mitotic rate was 23 typical mitoses per 10 HPF.Thus, this tumor showed deep location, epitheloid cytomor-phology, and high mitotic activity, which were all featuressimilar to those seen in our case. Behavior of the deep ormitotically active JXG is more aggressive in comparisonwith “common” JXG [10,13].

Whereas histologic differential diagnosis of superficialJXG includes various histiocytic lesions of the skin [1,6,7,9],reported deep JXGs needed to be differentiated mainly fromdeep malignant fibrous histiocytoma and from cellularsubcutaneous neurogenic tumors, such as neurofibromaand cellular schwannoma [3]. Differential diagnosis ofsuperficial JXG includes Langerhans cell histiocytosis,papular xanthoma, spindle-cell xanthogranuloma, xanthomadisseminatum, progressive nodular histiocytosis, generalizederuptive histiocytosis, benign cephalic histiocytosis, multi-centric reticulohistiocytosis, Rosai-Dorfmann diseases, andhemorrhagic histiocytosis [1,6,7,9]. Histologic differentialdiagnosis of deep JXG includes mainly deep malignantfibrous histiocytoma and cellular subcutaneous neurogenictumors, such as neuofibromas and cellular schwannomas [3].In the differential diagnosis of our case, we consideredmainly giant cell tumor of tendon sheaths and joints(GCTSJ), especially its so-called atypical diffuse form [18-23]. Like mitotic JXG, atypical diffuse GCTSJ containsmono- and multinucleated cells with histiocytic appearanceand numerous mitoses. However, atypical diffuse GCTSJ istypically located closely to large joints, and it showsinfiltrative growth pattern. The histologic features of JXGand atypical diffuse GTSJ are quite similar, except of thepresence of the typical larger dendritic cells in atypicaldiffuse GTSJ. These cells show broad eosinophilic cyto-plasm, large vesicular nuclei, and occasional intranuclearpseudoinclusions, and, interestingly, they are positive fordesmin [23,24]. Regarding desmin positivity, it was seenalso in our case, and this feature accentuated the similaritywith GTSJ. However, the present lesion differs from GTSJby predominant Touton-type morphology of giant cells (thegiant cells in GTSJ are predominantly of osteoclast-type) andby the absence of hemosiderin, which was confirmed bynegativity of stain for iron. Desmin positivity was mild in ourcase, and it was seen in both uni- and multinucleated cellswithout dendriform cytomorphology, whereas in GTJS, thepositivity is strong and the desmin-positive cells are usuallydendriform, with long processes that interdigitated betweenadjacent desmin-negative round cells [23,24]. In addition,epitheloid leiomyosarcoma [8] and leiomyosarcoma withosteoclast-like cells [25] were included in the differential

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40 J. Koren et al. / Annals of Diagnostic Pathology 14 (2010) 36–40

diagnosis because numerous tumor cells were of epitheloidshape and the multinucleated cells were present. In contrastwith JXG, both of these leiomyosarcoma show, althoughfocally, a distinctive fascicular growth pattern of spindle-shaped cells with eosinophilic cytoplasm and with typicalcigar-shaped nuclei. Nuclear atypia is usually more strikingand some mitotic figures can by atypical. Immunophenoty-pically, JXG and leiomyosarcoma show some overlap, butleiomyosarcoma tends to express the smooth muscle markers(actins, desmin, h-caldesmon) more strongly.

In conclusion, we described an uncommon and inter-esting case of juvenile xanthogranuloma. Unusual featurescausing diagnostic difficulty were as follows: an occurrencein the adult patient, localization in skeletal muscle (deepJXG), and nonlipidized cytomorphology with high mitoticactivity. Histologically, the tumor mimicked especiallyatypical giant cell tumor of tendon sheaths and joints,epitheloid leiomyosarcoma, and leiomyosarcoma withosteoclast-like cells [8,19,23,25]. In addition, we describedcytologic finding in deep mitotically active JXG, whichwere not reported before, to our best knowledge.Pathologist should be aware of deep and mitotically activeJXG in adult, especially because the tumor can stronglymimic some malignant lesions by both cytologic andhistologic examinations.

References

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