Journal of

Cutaneous Pathology

Histologic mimics of perineural invasion

Background: Perineural invasion (PNI) by primary cutaneouscancers is an important adverse risk factor. Certain benign conditionsmay mimic microscopic PNI. Mohs surgery is being performed morefrequently on smaller primary cutaneous malignancies. While PNImay be present in these cases, it is likely to be microscopic andasymptomatic, affecting as little as one cutaneous nerve branch.Methods: Review of the literature base regarding PNI as well ascontribution of original findings.Results: Four benign entities that could easily be confused withmicroscopic PNI are presented.Conclusion: At least four benign mimics of microscopic PNI exist,important in the differential diagnosis of microscopic PNI. Knowledgeof these entities should help dermatopathologists to correctlydistinguish them from PNI and avoid unnecessary additionaltreatment.

Martin Dunn1, Michael B.Morgan2,3, Trevor W. Beer4,Karl T. K. Chen5 and ScottM. Acker6,7

1Skin Cancer Specialist, Inc., Sarasota,FL, USA2Department of Dermatopathology, Bay AreaDermatopathology, Ameripath, Tampa,FL, USA3Department of Pathology, College ofMedicine, University of South Florida, Tampa,FL, USA4Cutaneous Pathology, Nedlands, Australia5Department of Pathology, Saint AgnesMedical Center, Fresno, CA, USA6Department of Pathology, University ofAlabama at Birmingham, Birmingham, AL,USA, and7Dermatopathology Services PC, Ameripath

Martin Dunn, Skin Cancer Specialist, Inc., 5575Marquesas Circle, Sarasota, 34233 FL, USATel: 941 323 1879Fax: 941 924 8089e-mail: mjdunnmd@hotmail.com

Accepted for publication October 15, 2008

Perineural invasion (PNI) is an important complica-tion of primary cutaneous malignancy.1–7 In thepresence of a malignancy, PNI may be diagnosed bythe observation of cytologically malignant cells in theperineural space of nerves (Figs. 1 and 2).8 PNIcomplicates almost 6% of cutaneous squamous cellcarcinomas (SCCs)9 and up to 3% of basal cellcarcinomas (BCCs).10 Less common cutaneousmalignancies such as microcystic adnexal carcinoma(MAC) display PNI more frequently.5,11

The range of cases treated by Mohs surgeons hasevolved from the description recorded by Mohs andLathrop12 in 1952, in which an inordinate number ofadvanced cancers were included. The Mohs micro-scopically controlled surgical technique has sincebeen proven to be of use in less advanced cutaneousmalignancies where as little as one nerve may beinvolved.13 A study by Kaplan et al.14 confirmed thatreferral patterns have been shifting toward thetreatment of smaller primary cancers by Mohssurgery. The expectation is that Mohs surgeons are

encountering microscopic, asymptomatic PNI morefrequently than extensive, clinical PNI. This assertionis underscored in the work of Han and Ratner15 whoproposed a stratification of PNI into microscopic andextensive. Microscopic PNI was defined as �anincidental, routine finding that may be identified insmall peripheral nerves of the reticular dermis inclinically asymptomatic patients’. Extensive PNI wasdefined as �widespread disease that is found clinically,radiologically or during surgery’. These terms arebeing used as defined throughout this article.

Because the survival rates of patients with SCCcomplicated by PNI that are cleared byMohs surgeryare better than any other treatment or combination oftreatments,16 the role of routine adjuvant radiationtherapy (XRT) in the management of microscopicPNI is being critically evaluated. However, the riskof morbidity from XRT needs to be balanced withthe risks associated with the natural course ofPNI. The most serious of possible outcomes ofa cutaneous malignancy with PNI is progression to

J Cutan Pathol 2009: 36: 937–942doi: 10.1111/j.1600-0560.2008.01197.xJohn Wiley & Sons. Printed in Singapore

Copyright © 2008 John Wiley & Sons A/S

Dunn M, Morgan MB, Beer TW, Chen KTK, Acker SM.Histologic mimics of perineural invasion.J Cutan Pathol 2009; 36: 937–942. © 2008 John Wiley & Sons A/S.

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leptomeningeal carcinomatosis and death.17,18 Morecommonly, cutaneous malignancies with PNI recurfollowing either excisional surgery or Mohs sur-gery.9,10 When treated with Mohs surgery, bothBCC and SCC with PNI require more stages toobtain clear margins and result in larger defects.9,10

Both surgeon and pathologist therefore need toaccurately diagnose malignant PNI in its earlieststages and to assure complete removal of involvedtissue. Although Mohs surgeons are aware of PNI,they are not experienced dermatopathologists. A hairfollicle transected through the dermal papilla oran arrector pili muscle surrounded by inflammationcould be confused with malignant PNI by the novice.

Pathologists are well aware that PNI is a commonlyencountered complication of neoplasms of otherorgan systems, notably the prostate,19,20 breast,21

aerodigestive tract22 and head and neck.23 Benign

mimics of PNI have been reported in a number ofscenarios. Benign proliferative breast disease canshow perineural �invasion’.24 The observation ofbenign prostate glands in the perineural space hasbeen reported many times.25–28 Chronic pancreatitissometimes displays perineural involvement.29,30 Theparotid nerve may display benign glandular inclu-sions.31 In a report of intraneural benign glandularstructures associated with a traumatic neuroma, Ideand Umemura32 reminded us that certain normalstructures of the head and neck could be confusedwith PNI. Both the juxta-oral organ of Chievitz(located in the soft tissue near the angle of themandible) and the remnants of the nasopalatine ductincorporate both glandular and neural structures.The aim of this manuscript was to illuminate fourbenign cutaneous entities that may easily be mistakenfor microscopic PNI (Figs. 1 and 2). Peritumoralfibrosis (PF) is the most common, occurring in 6% ofBCCs and 5% of SCCs.33 Epithelial sheath neuroma(ESN), although rare, shows histopathology sostriking, it is possible to have a case misdiagnosedas SCC with extensive PNI. The true incidence ofre-excision perineural invasion (RPI) and reparativeperineural proliferation is

Peritumoral fibrosis

PF, as reported by Hassanein et al.,33 refers to thepresence of concentric rings of fibrous tissue thattogether with nests of tumor cells may mimicmicroscopic PNI (Fig. 3). Strands of fibrous tissuemay be difficult to distinguish from nerve tissuewithout the aid of additional stains, such as S100. Theauthors found PF in 5%of SCCs (n ¼ 264) and in 6%of BCCs (n ¼ 606). The highest incidence of PF wasnoticed in recurrent BCC. Concurrent microscopicPNI was seen in 29% of BCCs with PF and in 50%of SCCs with PF. PF is a more sensitive marker of

Fig. 3. Peritumoral fibrosis; hematoxylin and eosin, original mag-

nification 3100.

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Fig. 1. Recurrent infiltrating basal cell carcinoma with perineuralinvasion; hematoxylin and eosin, original magnification ×200.

Fig. 2. Extensive perineural invasion by a well-differentiated squa-mous cell carcinoma; hematoxylin and eosin, original magnification×200.

unknown.

co-existing PNI than perineural inflammation. Theauthors cautioned all to perform a thorough searchfor microscopic PNI when PF was present.

Re-excision perineural invasion

Described in 1990 by Stern and Haupt,34 RPI refersto the observation of mature benign squamousepithelium in the perineural spaces of cutaneousnerves in re-excision specimens (Figs. 4 and 5). Thesquamous epithelium may form a complete cuffaround the nerve fascicle.Diagnostic criteria include the absence of peri-

neural spread beyond the immediate previous biopsysite, benign appearance of the perineural epithelialcells in contrast to the appearance of the originaltumor, absence of residual epithelial tumor in thevicinity of the involved perineurium and eccrine ductsadjacent to the involved nerve.35

Both cases reported by Stern and Haupt were re-excision specimens of melanocytic lesions. Therefore,thepresenceof perineuralmature squamous cells couldnot have been explained as an extension of the primarytumor(s). By 2000, Stern and Haupt35 reported theobservation of RPI in both SCC and BCC re-excisionspecimens. Following their strict criteria, theywere ableto render a diagnosis of RPI rather than perineuralspread from a BCC or SCC. The pathogenesis of RPIfavored by them is aberrant reactive eccrine ductregeneration into a perineural space.34,35

In 2006, Beer36 reported RPI in association with re-excision specimens of melanoma in four patients. Allcases showed a close relationship between perineuralepitheliumandeccrine glands in thedermis.Additionalexamples of RPI have been acquired by the author andsome of these have been published.37 It is likely thatRPI is more common than currently appreciated.

The pathogenesis of RPI is thought by Beer37 to bemechanical implantation of eccrine cells into theperineural space at the time of the original procedure.

Identification ofRPI in the setting of certain tumorssuch asMACwould be particularly difficult. BothRPIand PNI associated with MAC show little nuclearatypia in the perineural epithelial cells. In contrast toRPI, PNI associated with MAC is typically accom-panied by infiltrating epithelial nests, strands and cystsin adjacent desmoplastic stroma. Furthermore, theperineural epithelium in a MAC often forms tubules.Tubular or ductal spaces have been observed rarely incases of RPI by one author (T. W. B.). Immunohisto-chemistry or special stains are unlikely to be of anyassistance with this differential diagnosis.38

In 2003, Chen39 reported five cases of a similarreactive process characterized by nerve fasciclessurrounded by mature squamous epithelial sheaths.Two cases were re-excision specimens of non-melanoma skin cancers. Of the remaining three cases,two were associated with early prurigo nodularis. Onecase was consistent with folliculitis. Of interest, theauthor noted that the folliculitis case was originallydiagnosed on biopsy as �infiltrating carcinoma withPNI’. Chen explained that three of his cases were notassociated with prior excision and proposed the termreactive neuroepithelial aggregates of the skin(RNEA). Inhis cases not associatedwithprior excision,the author noted that the RNEAs were alignedperpendicular to the skin surface, suggesting that theywere distributed along the path of normal eccrineducts. Both Chen and Beer concluded that RPI andRNEA are terms for the same reactive process.

Reparative perineural proliferation

Onoccasion, regenerating nerves in a healing surgicalwound may reveal prominent proliferation of theperineurium. Histologically, concentric rings of bland

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Fig. 4. Re-excision perineural invasion; hematoxylin and eosin,original magnification ×200.

Fig. 5. Re-excision perineural invasion. The epithelial proliferationis highlighted with the cytokeratin stain MNF116.

spindle-shaped cells envelop a nerve adjacent toscarring and reparation from the prior surgery. Thisreparative process may mimic microscopic PNI,especially in the context of a previous malignancy.The nature of the condition can be confirmed byshowing negative immunohistochemical staining inthe spindle cells for S100 and cytokeratins but positivestaining with epithelial membrane antigen, as wouldbe seen in normal perineural cells (Figs. 6 and 7).

Epithelial sheath neuroma

Described in 2000 by Requena et al.,40–42 ESN isa benign, acquired lesion found on the back ofmiddle-aged or elderly women. Clinically, the lesion may bemisdiagnosed as aBCCor an inflamednevus.None ofthe lesions have recurred after biopsy.

Microscopically, ESN multifocally permeates thereticular dermis as discrete nerve complexes consisting

of enveloping perineural mantles composed ofmature,sometimes keratinizing squamous epithelium andcentral nerve trunks. The surrounding dermis showsdelicate fibroplasia containing mucin and a mildinflammatory cell infiltrate composed of lymphocyteswith few plasma cells. There is no associated in situ orinvasive carcinomaandnochanges of previous surgery.The overall effect is striking, with an obvious re-semblance to PNI by SCC (Fig. 8). The cytopathologyof ESN is indistinguishable from that of PNI in anSCC(Fig. 9). The overall architecture showing largeinvolved nerve trunks high in the reticular dermis isdiagnostic.There are several possible mechanisms involved in

the pathogenesis of ESN.43 ESN could be an unusualform of repair following injury. Metaplastic trans-formation of the perineurium in connection withperilesional inflammation could theoretically result inthe squamous epithelial sheath. ESN could alsorepresent neural crest remnants in the dermis, whichdifferentiate into both neural and squamous epithelialelements.Five cases of ESN have been described, four in the

original report by Requena et al.40 and one by Linet al.43

Discussion

The observation of PNI associated with any cutane-ous neoplasm has ominous implications for thepatient. Mohs surgery patients with microscopicPNI are likely to have more stages taken during theirsurgery and to have larger postsurgical defects.9,10

Postsurgical radiation therapymay be recommended,even with clear margins.23 For microscopic PNI,

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Fig. 6. Reparative perineural proliferation; hematoxylin and eosin,original magnification ×400.

Fig. 7. Reparative perineural proliferation; epithelial membraneantigen, original magnification ×400.

Fig. 8. Epithelial sheath neuroma; hematoxylin and eosin, originalmagnification, ×40.

assurance of clear margins offers the best hope fora cure, with or without adjuvant XRT.We have presented four cutaneous processes that

could be misinterpreted as malignant PNI. Thepathologist may be assisted in the differentiation ofthese processes by the use of immunohistochemistry.Perineural involvement inbothRPI andESNwouldbeexpected to show positivity for epithelial markers andnegative staining for S100andmelanocyticmarkers. Incontrast, reparative perineural proliferation shouldexhibit negative epithelial marker staining, except forepithelial membrane antigen positivity, and show noS100 staining. With PF, fibrous tissue mimicking nervetissue would be negative with S100 staining.It is our hope that once aware of epithelial sheath

neuroma, reparative perineural proliferation, re-excision perineural invasion and peritumoral fibrosis,we will be able to save our patients from unnecessarymorbidity. Careful documentation will also determinethe true incidence of RPI and reparative perineuralproliferation.

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