J Cutan Pathol 2009: 36: 896900doi: 10.1111/j.1600-0560.2008.01151.xJohn Wiley & Sons. Printed in Singapore

Copyright # 2009 John Wiley & Sons A/S

Journal of

Cutaneous Pathology

Cutaneous malignant peripheral nervesheath tumors

Cutaneous malignant peripheral nerve sheath tumors (MPNSTs) arerare entities compared with their deep soft tissue counterparts. Wedescribe two cases of cutaneous MPNSTs. The first case, occurring ina 27-year-old woman with neurofibromatosis I, presented with recentgrowth of a pre-existing nodule on her back. A biopsy showeda densely cellular area within a conventional neurofibroma composedof atypical, hyperchromatic epithelioid and spindled cells with frequentmitotic figures (MFs). The second case presented in an 88-year-oldman with no stigmata of neurofibromatosis as a rapidly growingsubcutaneous tumor of the right calf. A biopsy showed a diffuseneurofibroma that abruptly transitioned to a densely cellularproliferation of hyperchromatic atypical spindled cells arranged inshort fascicles with frequent MFs. The diagnosis of MPNST wasrendered in both cases. MPNSTs of the dermis and subcutis are raresarcomas. They can occur as sporadic tumors or in the setting ofneurofibromatosis. They are often associated with pre-existingneurofibromas. Increase in size of pre-existing neurofibromas is anindication for biopsy. Recognition of the cellular atypia, increasedcellularity and mitotic activity is key to the diagnosis.

Thomas C, Somani N, Owen LG, Malone JC, Billings SD. Cutaneousmalignant peripheral nerve sheath tumors.J Cutan Pathol 2009; 36: 896900. # 2009 John Wiley & Sons A/S.

Crystal Thomas1,Najwa Somani2,3,Lafayette G. Owen4,5,Janine C. Malone4,5 andSteven D. Billings2,3

1Department of Pathology and LaboratoryMedicine, Beth Israel Medical Center,Continuum Hospitals of New York (SaintLukes Hospital and Roosevelt Hospital),New York, NY, USA,2Department of Anatomic Pathology and3Department of Dermatology, Cleveland ClinicFoundation, Cleveland, OH, USA and4Department of Dermatology and5Department of Pathology, the University ofLouisville School of Medicine, Louisville,KY, USA

Steven D. Billings, MD, Cleveland Clinic, 9500Euclid Avenue, L25, Cleveland, OH 44195, USATel: (216) 444 2826Fax: 216-445-3707e-mail: billins@ccf.org

Accepted for publication August 6, 2008

Malignant peripheral nerve sheath tumors (MPNSTs)are rare sarcomas comprising 510% of all soft tissuesarcomas and having an incidence of 0.001% in thegeneral population.1,2 MPNST is strongly associatedwith neurofibromatosis type I (NF-1). In this setting,they typically arise in association with plexiformneurofibromas but may arise in association with otherneurofibroma types. Classically, MPNSTs arise in thedeep soft tissue; however, there have been a limitednumber of case reports and small series describingcutaneous MPNST.313 We present two cases ofcutaneous MPNST and discuss the current under-standingof this entity basedona reviewof the literature.

Case report

A 27-year-old woman with a known history of NF-1presented with a rapidly enlarging left upper back

mass. Clinical examination revealed a 1-cm skin-colored nodule that clinically resembled her otherneurofibromas except for the history of rapid growth.The biopsy revealed a tumorwithin themid to deep

dermis with areas of varying cellularity (Fig. 1). Therewas an abrupt transition from the less cellularconventional neurofibroma component to a morecellular component in the deep reticular dermis(Fig. 2). The neurofibroma was composed of blandspindled cells with pale eosinophilic cytoplasm andwavy nuclei in a collagenous stroma and lackeda plexiform or diffuse growth pattern (Fig. 3). Thehypercellular areas consisted predominantly of clus-ters and sheets of epithelioid round cells (Fig. 4) ad-mixed with some fascicles of hyperchromatic spindledcells. Mitotic activity was readily apparent in this areawith six MFs per 10 high-power fields (HPFs). Nonecrosis was identified. Immunohistochemical stains

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for S100 protein showed immunoreactivity withinboth components (Fig. 5). A diagnosis of cutaneousepithelioid MPNST arising in a neurofibroma wasrendered.To our knowledge, the patient has not had a re-

excision and has been lost to follow up despitenumerous efforts to contact her.The second case presented as a subcutaneous mass

on the right calf in an 88-year-old man with a historyof numerous non-melanoma skin cancers but nohistory of neurofibromatosis. Clinically, the lesion wasconsidered a dermatofibroma. It was clinically stablefor 17 months but then underwent a period of growthwith increasing tenderness. The patient initially optedfor expectant management but subsequently decidedto have the lesion excised. At the time of excision, thelesion was a 2.5 3 3 cm firm plaque.

Fig. 1. Scanning magnification showed a spindle cell proliferation of

varying cellularity within the mid to deep dermis (hematoxylin-

eosin, 320).

Fig. 2. There was an abrupt transition from the neurofibroma area

to a hypercellular area (hematoxylin-eosin, 340).

Fig. 3. The neurofibroma component consisted of randomly

arranged bland spindled cells with wavy nuclei (hematoxylin-eosin,

3100).

Fig. 4. The hypercellular area predominantly consisted of clusters

and sheets of round epithelioid cells within a variably collagenous

stroma (hematoxylin-eosin, 3400).

Fig. 5. The neurofibroma component was diffusely positive for S100

protein. The majority of the malignant peripheral nerve sheath tumor

was also positive for S100 protein (S100 protein, 3200).

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The excision revealed a diffuse type neurofibroma(Fig. 6) that abruptly transitioned to awell-demarcatednodule in the superficial subcutis (Fig. 7) composed ofshort fascicles of atypical hyperchromatic spindledcells (Fig. 8). The mitotic rate was comparatively high(8MF/10HPF) with occasional atypicalMFs (Fig. 9).No necrosis was present.This is a recent case, and no significant follow-up

information is available.

Discussion

Cutaneous MPNST is a rare entity. A review of 230cutaneous malignant spindle cell lesions found thatcutaneousMPNSTs account for approximately 2%ofcases.3,4 By definition, cutaneous MPNSTs are pre-dominantly located in the dermis or subcutis.313

They typically arise in association with a pre-existingneurofibroma or small cutaneous nerves.Clinically, the lesions are reported to undergo

a prolonged period of slow growth, followed by rapidproliferation. In sporadic cases of cutaneousMPNST,there is no age predilection. Cases associated withneurofibromatosis typically occur in younger patients.A strong association exists between deep MPNSTsand NF-1, with approximately 50% of cases beingassociated with the syndrome.1,5 This associationseems to be less common in cutaneous MPNSTwith10/27 (37%) of the reported cases associatedwithNF-1.5 Tumors arising in the head and neck account forthe majority (56%) of cutaneousMPNSTs, but a widevariety of sites have been reported.Histomorphologically, two variants of cutaneous

MPNST are described: a conventional or spindledvariant and an epithelioid variant. Unlike their deepsoft tissue counterparts, the epithelioid morphology is

more common in cutaneous MPNST.5,14 Conven-tional MPNST is typically composed of fascicles ofhyperchromatic spindled cells often with varyingcellularity creating a marble-like effect.6 Less com-monly, a storiform or herringbone pattern may bepresent.6 Epithelioid tumors are arranged as sheets ofatypical epithelioid cells with primitive round nucleiand pale indistinct cytoplasm.6 Some mitotic activityis invariably present.Occasionalmultinucleated giantcells have been reported.12 The stroma, similar toconventional neurofibroma, may vary from collage-nous tomyxoid withmyxoid stroma predominating inapproximately one third of cases.6 Foci of necrosis,pseudocystic change and hemorrhage may be pres-ent.2 Divergent differentiation including foci ofchondrosarcoma, osteosarcoma and angiosarcoma,among other patterns, is well described in deep soft

Fig. 6. The diffuse neurofibroma component was composed of

randomly arranged spindled cells in a myxoid to collagenous stroma

that filled the dermis and extended into the subcutis (hematoxylin-

eosin, 340).

Fig. 7. There was an abrupt transition from the loosely arranged

neurofibroma component to the cellular malignant peripheral nerve

sheath component (hematoxylin-eosin, 340).

Fig. 8. The malignant peripheral nerve sheath tumor was composed

of short fascicle of hyperchromatic spindled cells (hematoxylin-

eosin, 3200).

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tissue MPNST and may also occur in superficialtumors.1,5,6,13

The histological differential diagnosis includesbenign and malignant entities. Although neuro-fibromas may rarely show significant cytologic atypiaand some increase in cellularity, mitotic activity inthese neurofibromas is typically sparse (, 1 MF per10 HPFs).15 Furthermore, atypical neurofibromas donot show the fascicular growth pattern of MPNST. Inselected cases, immunohistochemical stains for Ki-67may be helpful. Immunoreactivity for Ki-67 is usuallyseen in less than 5%of cells in atypical neurofibromas,whereas Ki-67 labeling is high in MPNST (. 30%).Schwannomas can have degenerative nuclear

atypia and rare MFs. Identification of the fibrouscapsule, the characteristic Antoni A and B areas, andthe hyalinized vessels allows for distinction fromMPNST.When a precursor neurofibroma is not recogniz-

able, desmoplastic/spindle cell melanoma and fibro-sarcomatous transformation of dermatofibrosarcomaprotuberans are the malignant entities that figuremost prominently in the differential diagnosis.Desmoplasticmelanoma frequently shows an atypicaljunctional melanocytic proliferation in the overlyingepidermis and may also show focal melanin pigmen-tation. Desmoplastic melanoma also typically hasa more packeted or clustered arrangement of thespindled cells and lymphoid aggregates within thetumor.7 Immunohistochemistry is limited in its utilityto resolve this differential diagnosis. Both desmo-plastic melanoma and cutaneous MPNST may bepositive for S100 protein, although weak or negativeimmunoreactivity would favor MPNST.5,16 Specificmelanocytic markers are typically negative in desmo-plastic melanoma. Immunoreactivity for CD57 ormyelin basic protein is potentially helpful in recog-nizing MPNSTs.17

Recognition of the conventional dermatofibrosar-coma protuberans component helps distinguishfibrosarcomatous transformation in dermatofibrosar-coma protuberans from MPNST. Positive immuno-reactivity for S100 protein is helpful in recognizingMPNST; however, both tumors may express CD34.As has been shown in other superficial sarcomas,

cutaneousMPNST tends to present as smaller lesionscompared with deep counterparts (3.5 vs. 5 cm).Given the smaller size and superficial location,cutaneous MPNST may be less aggressive thandeep-seated MPNST.14 However, this needs to beevaluated in larger numbers of patients as studies havecontrasting results with some reporting high rates oflocal recurrence (63%) and metastasis (26%) that arecomparable with those of deep soft tissue MPNST.1,5

Pulmonary, bone and soft tissue metastases were themost common locations associated with both cutane-ous and deep soft tissue MPNSTs.1,5

Wide excision is the mainstay of treatment forsuperficial MPNST.18,19 Radiotherapy may be moreimportant in deep soft tissue MPNSTs and in lesionswhere adequate surgical margins are difficult toobtain.

Conclusion

Cutaneous MPNSTs are a rare variant of MPNST.The relatively frequent lack of associated neurofibro-matosis and superficial locationwithin the dermis andsubcutis may result in this entity being overlooked.Awareness of this entity should prompt its con-sideration in the differential diagnosis of cutaneoussarcomas.

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