squamous cell carcinoma ( scc ) is amongst the top 3 common skin cancers , ranking behind basal cell carcinoma ( bcc ) and ahead of melanoma . it is a tumor that is locally invasive and which has the capacity to metastasize . prognostically , it also occupies an intermediate position between bcc and melanoma , with bcc being locally invasive but typically nonmetastasizing , while melanoma having the well - known capability to metastasize . however , diagnostic challenges are occasionally encountered and contributed mainly by the myriad of histopathologic mimics of scc and small biopsies that sample only part of the lesion .   for the simulators of scc , on the one hand , there are benign squamous lesions that appear to be infiltrative histopathologically . on the other hand , there are other malignant skin tumors that may display squamous differentiation or which elicit squamous proliferation that mimic scc . misdiagnosis of benign lesions as scc would result in unnecessarily extensive surgery , while delayed diagnosis of scc could lead to local tissue destruction by tumor , sometimes metastatic disease , and even death . some malignant differential diagnostic entities , for example , melanoma and merkel cell carcinoma ( mcc ) , have worse prognosis or require different surgical strategies and differ in the need for adjuvant treatment [ 3 , 4 ] . this review will present all the salient benign and malignant differential diagnoses of scc , highlight diagnostic pitfalls , and suggest strategies for clinching the appropriate diagnosis . inverted follicular keratosis is a lesion that histopathologically shows downgrowths of follicular squamous epithelium and the adjacent epidermis . it commonly occurs in middle - aged and elderly patients , presenting as a scaly papule , nodule , or plaque . in contrast to scc , it has circumscribed borders , and significant cellular atypia is not seen ( figures 1 and 2 ) . a pitfall with regard to differential diagnosis of a supposedly benign squamous keratosis histologically , attention should be turned away from the hyperkeratotic superficial horn to the underlying lesional epithelium , which may be limited in amount in the specimen ( figure 3 ) . the presence of significant atypia or abnormal maturation would raise the possibility of actinic keratosis or bowen disease or even the superficial aspect of an invasive scc . pseudoepitheliomatous hyperplasia ( peh ) is a florid proliferation of the epidermis that may occur in the setting of chronic skin ulcers , abscesses , burns , and infections . peh with neutrophilic microabscesses is typically seen in halogenodermas , infections like chromomycosis and blastomycosis , granuloma inguinale , leishmaniasis , and pemphigus vegetans . while the squamous epithelium of peh can appear infiltrative , resembling well - differentiated scc , careful attention should show that marked cellular atypia and abnormal mitotic activity are absent ( figures 4 and 5 ) . a careful search for an inciting infective process should be carried out with examination of deeper levels and use of microbiological special stains . in challenging cases , close clinical correlation and followup are required ; rare cases require repeat biopsy for evaluation . infundibulocystic hyperplasia is a distinctive follicular epithelial proliferative process with formation of dilated canals containing keratotic material . presenting clinically as a nodule or plaque , it features histologically bland lesional squamous cells and a relatively superficial noninfiltrative deep edge ( figure 6 ) . when a short clinical evolution is noted and the lesion has a crateriform architecture , the features relate more to keratoacanthoma ( vide infra ) . when marked cellular atypia or abnormal mitosis is noted , or if deeply infiltrative tongues are present , the lesion should be regarded as malignant , and an appropriate designation is infundibulocystic scc ( figure 7 ) . verrucous hyperplasia is another type of epidermal squamous proliferation typified by broad and superficial downgrowths of the epidermis ( figure 8) . this condition usually occurs in the skin within and around the external genitalia and the oral cavity , in reaction to a variety of chronic irritative etiologies . this feature can be difficult to assess in superficial or poorly oriented biopsies . nevertheless , verrucous hyperplasia is well known to occur in close proximity , or to precede verrucous carcinoma . its presence in the context of a clinically worrying lesion should prompt close followup or a deeper and wider biopsy . eccrine squamous syringometaplasia ( ess ) is a reactive process characterized by squamous metaplasia of eccrine ducts and glands [ 10 , 11 ] . it commonly occurs in the axillary and groin regions and presents as nodules and plaques . ees is most well described as an adverse drug reaction , mostly to chemotherapeutic drugs . while it should not be confused with scc clinically , it could cause some confusion histologically . the lesion features cytologically bland squamous islands in the dermis that are closely associated with eccrine lumina and conforming to a lobular configuration ( figure 9 ) . desmoplastic trichoepithelioma presents clinically as an enlarging nodule and shows cords and nests of basaloid cells with horn cyst formation , embedded within a sclerotic dermal stroma ( figures 10 and 11 ) . the hyperplastic downgrowth of the epidermis and the cords of basaloid tumor cells give a pseudoinfiltrative appearance mimicking the features of scc . the reassuring absence of significant atypia and the paucity of mitotic activity should be sought for . the cohesive tumor cells growing as cellular sheets or cord - like manner streaming within a sclerotic dermis can appear concerning . in unusual clinical contexts , benign lesions of varied nature may mimic scc both clinically and histopathologically . meningioma has been known to occasionally be located outside the intracranial location to involve the scalp . histopathologically , the syncytial sheets or whorled arrangement of tumor cells may impart a squamoid appearance ( figure 12 ) . the presence of nuclear pseudoinclusions , psammoma bodies and the absence of significant atypia , in most cases , should allow distinction from scc . immunohistochemistry is of limited value in distinguishing the entities as both meningioma and scc share expression of ema , and the former is sometimes reactive for cytokeratins as well . another form of lesional tissue that may sometimes cause diagnostic confusion is decidualized endometrial tissue occurring outside the confines of the female genital tract . the most common context of this is endometriotic deposits in the skin and soft tissue of the abdominal wall or perineum , where background therapy with progestational agents causes decidualization of the endometrial stromal component ( figure 13 ) . such decidualized cells are plump and form sheets , complete with well - defined intercellular borders , simulating scc , if not for the notable absence of nuclear atypia . ka is a well - differentiated squamoproliferative tumor , with a fairly rapidly growing clinical course ( figure 14 ) . some authorities consider it a variant of scc , while others regard it as a unique entity in view of its typically self - involuting course . histopathologically , it features a cup - shaped or crateriform architecture , containing a central keratinous plug , bounded by lobules of lesional squamous epithelial cells ( figure 15 ) . features that favor a lesion as a ka rather than being an scc include a limited pushing deep front , distinct tumour - stromal interface , and lesional squamous cells with abundant cytoplasm centrally . while there have been numerous studies investigating the differences between ka and scc of the molecules involved in the regulation of cellular proliferation , apoptosis and the cell cycle , the histomorphology , as well as consideration of the clinical tempo of the lesion are still the most practical aspects in routine diagnosis . an scc can sometimes have a crateriform architecture mimicking a ka ( ka - like scc ) . in this regard , at least part of the tumor should have marked cytologic atypia , frequent or abnormal mitoses , or infiltrative margins ( figures 7 and 16 ) . a shave biopsy that samples only the superficial part of a well - differentiated example of such a lesion could potentially lead to an underdiagnosis of an scc ( figure 16 ) . where there is diagnostic doubt about a particular lesion , a complete excision should be recommended . proliferating tricholemmal tumor ( ptt ) , also known as proliferating pilar tumor or pilar tumor , is a well - circumscribed proliferation of squamous cells [ 18 , 19 ] . it commonly occurs on the scalp or other parts of the head and neck as a gradually enlarging nodule or tumor ( figure 17 ) . histopathologically , apart from conventional squamous cells , the tumor shows cellular areas with characteristic clear cytoplasm and abrupt pilar - type keratinization ( figure 18 ) . there is a spectrum of appearances which may translate to different biologic behaviors . in a study by ye et al . those with infiltrative borders but no significant atypia , increased mitoses , or necrosis had a local recurrence rate of 15% , while tumors which were infiltrative and which displayed cellular atypia , necrosis , and abnormal mitotic activity had a 50% chance of developing recurrence or metastasis to the regional lymph nodes . the latter category could be termed as a malignant ptt and viewed as equivalent to conventional scc . pathological examination of the entire lesion is necessary to assess the borders of the tumor as well as for the possible presence of necrosis and cytologic variation . bowen disease clinically presents as a plaque in covered as well as uncovered skin areas ( figure 19 ) . histopathologically , it features full thickness dysplasia , incorporating loss of polarity of the epidermis , nuclear pleomorphism , and mitosis at all levels ( figures 3 and 20 ) . in usual cases , all three entities display single and groups of atypical cells within the epidermis . the tumor cells of paget disease generally cluster above an intact basal layer of epidermis and may be demonstrated to contain mucin . melanoma tumor cells often contain melanin although paget cells have been known to show this feature as well . immunohistochemistry helps to distinguish the entities : the tumor cells of bowen disease are p63 positive , those of paget 's disease react for p - cea , ber - ep4 , ck7 , and cam5.2 , while melanoma cells are positive for s-100 and melan - a .   not uncommonly , bowen disease shows a markedly undulating basal contour and can be associated with subjacent dermal fibroplasia , raising the possibility of whether early invasion has occurred . the neoplastic epithelium of bowen disease can also colonize eccrine ducts , potentially exaggerating the incorrect impression of invasion ( figure 20 ) . examination of deeper levels or more blocks of tissue may reveal foci of convincing invasion , characterized by single or small jagged clusters of infiltrating tumor cells within unequivocally desmoplastic dermal stroma . the typical bcc is characterized by basaloid cellular proliferation with peripheral palisading and tumor - stromal cleft formation . the infiltrating tumor cells may not uncommonly appear squamoid and raise the possibility of scc . immunohistochemistry can be helpful as bcc , and not scc , is positive for ber - ep4 and bcl-2 ( figure 21 ) . the two variants of bcc that have significant squamous components are keratotic bcc ( figure 22 ) and basosquamous carcinoma ( metatypical bcc ) , the latter having a worse prognosis than bcc in general . a careful assessment of the tumor would usually show areas of more typical bcc . the other skin cancer in the head and neck that occasionally mimics a poorly differentiated scc is sebaceous carcinoma . this tumor is disposed of in sheets and lobules of cells with bubbly cytoplasm that indent an atypical nucleus . ( ema + ve , ber - ep4 ve ) , sebaceous carcinoma ( ema + ve , ber - ep4 + ve ) , and bcc ( ema ve , ber - ep4 + ve ) . more recently , markers that have been found to be more specific for sebaceous carcinoma include adipophilin and androgen receptor , which in turn are usually negative in bcc and scc . spindle cell melanoma is one of the classic differential diagnoses for pleomorphic spindle cell tumors of the skin . while cytological features may not enable distinction from a spindle cell scc and atypical fibroxanthoma ( afx ) , the presence of a junctional component helps delineate spindle cell melanoma ( figure 23 ) . in contrast , careful examination of a spindle cell scc may reveal overlying bowen disease or actinic keratosis . by immunohistochemistry , expression of one or more of the cytokeratins helps distinguish the tumor from spindle cell melanoma which would instead express s-100 . other skin carcinomas that sometimes feature squamous differentiation include merkel cell carcinoma ( mcc ) , porocarcinoma , and sebaceous carcinoma [ 23 , 27 , 28 ] . this is likely a manifestation of divergent differentiation of the tumor or varied differentiation of tumor stem cells . careful examination of mcc would usually show up the more typical malignant small round cells of mcc as well as dot - like expression of ck20 and positivity for the neuroendocrine markers synaptophysin , neurofilament protein , and cd56 . as for porocarcinoma , the neoplastic poroid cells should be discernible with duct lumina formation decorated by ema and p - cea immunohistochemistry . an scc present in the skin may occasionally represent direct invasion from an underlying malignancy or metastatic deposit . in such situations , the importance of clinical history and correlation can not be overemphasized . the tumor tends to show a centre that is based in the dermis or subcutis ( figure 24 ) . the overlying epidermis tends to show only reactive features or be ulcerated by the growth of the subjacent tumor . anaplastic large cell lymphoma and lymphomatoid papulosis are cd30-positive lymphoproliferative disorders that have reported cases being associated with epidermal hyperplasia . while the epidermal hyperplasia is often mild in degree , it can be very florid with features of pseudoinfiltration which mimic scc , raising the possibility of a collision between the carcinoma and lymphoproliferative process ( figure 25 ) . cellular atypia of the epidermal hyperplasia , while usually absent , has sometimes been reported . mitoses of the squamous cells , if present , should be seen to be located at the basal layer of the squamous islands and not be abnormal in form . scc can sometimes coexist with other malignant skin tumors within the same tumor mass , the most likely context being collision tumors . combinations of scc with melanoma or mcc are most well known [ 30 , 31 ] . the practical importance is that on finding a prominent scc component , the coexistence of a potentially more aggressive tumor , or a tumor that may require specific adjuvant therapy , should be sought for . such a concurrence is not surprising as ultraviolet light exposure is a well known and common risk factor . another plausible etiologic factor that has emerged more recently is that of human polyomaviruses . while the merkel cell polyomavirus has been closely linked to mcc , its detection and role in scc are less consistent and clear [ 3133 ] . interestingly , the virus has been detected in two cases of combined scc and mcc . in summary , this review serves to highlight the spectrum of conditions that could mimic scc : benign , preinvasive , and malignant . being aware of the pertinent differential diagnoses provides the setting to minimize the pitfalls in the diagnosis of challenging cases which feature squamous proliferation . this , coupled with a systematic assessment for the criteria required for an scc diagnosis , helps in the rendering of a correct diagnosis . of the adjunctive studies , immunohistochemistry is the most widely used , helping to indicate the histogenesis of the lesional cells of nonsquamous mimics . in difficult cases , a detailed and relevant history of cancers of the skin and other organs should be sought for . the clinical tempo of the lesion , knowledge of the site , size , and other characteristics are all critical pieces of information to the pathologist . if a lesion is clinically concerning , but the biopsy features are benign or nonspecific , further levels on the block often prove useful . rarely , a summative assessment of inadequate material or of an atypical lesion that can not exclude malignancy may have to be given with a recommendation for complete excisional biopsy . as always , this is balanced against the factors of cosmesis and practicability . on the one hand , the final reexcision specimen provides the opportunity for further evaluation of the residual lesion for definite diagnosis . on the other hand , the repeat excision often represents the definite surgical treatment for the lesion if it indeed turns out to be malignant . such a pragmatic approach offers the rendering of a safe yet clinically useful diagnosis when diagnostically challenging cases are encountered .