Carcinoma Cuniculatum of the Scrotum

To the Editor: We read with interest the recent article entitled “Invasive cuniculatum carcinoma of the groin mimicking hidradenitis suppurativa” by Stchepinsky et al1 in the American Journal of Dermatopathology. Carcinoma cuniculatum (CC) is a rare and unique variant of well-differentiated squamous cell carcinoma (SCC). It is an architecturally distinct tumor that forms sinuses. It can be easily confused with other benign and malignant lesions. CC has been described in certain cutaneous and noncutaneous sites.2–6 To our knowledge, we are reporting the first case of scrotal CC. The patient was a 66-year-old man who complained of discharging pus from a nodular growth in the scrotum. It was a slowly progressing painless nodule, which had been treated conservatively as infected sebaceous cysts for 5 years. Recently, it became itchy and painful with smelly discharge. The patient was diabetic with a poorly controlled disease. He is a smoker, but does not drink alcohol. No history of trauma or surgery was recorded. On examination, the lesion was a sinus-forming polypoid firm nodule on the right scrotal skin near the bottom. It was described as a hard sebaceous cyst measuring 2 × 2 cm, with infected holes. It was slightly tender and oozing yellow paste-like debris material from the surface openings. The adjacent uninvolved scrotal skin was unremarkable. No other genital or cutaneous lesions were identified. Clinically, the differential diagnoses included atheroma of the scrotum and hidradenitis suppurativa. The patient requested removal of the lump because he did not benefit from the treatment and was bothered by the soaking of the clothes and bad smell. The scrotal nodule was surgically excised. The clinical course was uneventful. After 1 year of follow-up, there was no recurrence or regional nodal metastasis. Grossly, the specimen was an expanded nodular portion of the scrotum measuring 3.0 × 2.7 × 1.6 cm. The surface was intact, corrugated, and revealed scattered dips. Sectioning revealed deep keratin-filled cysts and sinus tracts connected to the surface and embedded within a thickened and fibrosed scrotal muscular stroma. Histopathologically, the lesion showed interconnected branching sinuses penetrating through the deep scrotal stroma and terminating in deep-seated keratin-filled cysts (Fig. 1). Single channels and multiple converging tunnels opened into the scrotal surface epithelium through sinus openings. The ramifying channels dissected through the scrotal dartos muscle bundles (Figs. 1, 2). Multiple levels revealed that the apparently isolated deep cysts were actually connected to the superficial openings by burrows forming a labyrinthine network of deep penetrating furrows and cystic spaces. The sinus lining epithelium was composed of hyperkeratotic acanthotic squamous epithelium with irregular expanded rete pegs. Prominent intraepithelial neutrophilic infiltration and neutrophilic microabscesses involved the tumoral squamous epithelium of the sinuses (Figs. 2, 3). The sinus cavities were filled with parakeratotic keratin debris. Focal surface erosion into the sinus lumina was present. The irregular rete pegs were composed of well-differentiated squamous epithelium; however, occasional foci of moderately differentiated infiltrative nests were seen irregularly extending from the sinus squamous epithelium into the stroma (Fig. 3). Moderate peritumoral chronic mononuclear inflammatory infiltrates and stromal fibrosis were present around the sinuses. The surface was an intact corrugated scrotal squamous epithelium. There was a sharp transition from the sinus tumoral squamous epithelium to the nontumoral surface epithelium. The surface–sinus connection holes showed hyperparakeratotic plugs and keratin debris. Scattered atrophied apocrine sweat ducts were pushed to the periphery. No hair shafts, inflamed sweat glands, or sebaceous glands were seen.FIGURE 1.: A, B, Panoramic slide views at different levels reveal irregular, deep, penetrating, branching tunnels communicating through multiple openings into the scrotal surface. The squamous epithelium lining the sinuses is markedly irregularly acanthotic in contrast to the normal surface squamous epithelium. C, Some sinuses show cyst cavities on initial levels, which seem to be disconnected from the surface (note: unfortunately, no clinical, radiologic, or macroscopic photographs were taken of the lesion).FIGURE 2.: A–D, The deep, branching, penetrating, cavitating sinuses are lined with irregular, keratotic, acanthotic squamous epithelium. The lumen is filled with keratin debris. The peritumoral stroma shows mononuclear lymphoid infiltrate and fibrosis. Intraepithelial neutrophilic infiltration and neutrophilic microabscesses are also present [hematoxylin and eosin stain (H&E), original magnification ×40, ×100].FIGURE 3.: A, B, The tumoral squamous epithelium lining the sinuses shows well-differentiated and occasionally moderately differentiated foci of squamous cell carcinoma with irregular extensions. There are focal erosions in the sinus lining epithelium, forming inflammatory keratinous debris in the luminal cavity. C, D, The well-differentiated tongues and cords of the squamous epithelium extending from the sinus lining epithelium into the stroma are heavily infiltrated by neutrophils, dismantling the epithelium into abscesses (H&E ×200).The tumoral sinus squamous epithelium was decorated with p63 and CK5/6. The scrotal dartos muscle bundles, dissected by the deep tumoral sinuses, were highlighted by smooth muscle actin (Fig. 4). Ki67 showed a low proliferation index in the tumor cells confined to the basal layer. Immunohistochemistry for p16 was negative, and p53 immunomarker showed a wild-type expression in the tumoral sinus squamous epithelium. In situ hybridization for human papillomavirus was negative.FIGURE 4.: A, B, Keratin (CK5/6) immunomarker accentuates the irregular acanthotic squamous epithelium lining the branching tunnels that converge and open into the surface through sinus holes. The scrotal surface epithelium is not involved, with a sharp transition to the tumoral squamous epithelium in the sinuses (CK5/6, ×20). C, The deep-seated cavity and cyst-like sinuses show focal irregular infiltrative borders (CK5/6, ×20). D, Smooth muscle actin (SMA) immunomarker demonstrates the scrotal stromal dartos muscle bundles, which are divided and displaced by the deep-seated sinuses and cysts (SMA, ×20 (inset: ×40).The lesion was initially misinterpreted as ruptured, inflamed epidermoid cysts, or pilonidal sinus with pseudoepitheliomatous hyperplasia. Epidermoid cysts are well-defined rounded expansile cysts lined by a benign epidermoid-type epithelium and lack branching channels. Pilonidal sinuses show hair shafts and foreign body giant cell stromal reaction. Pseudoepitheliomatous hyperplasia is characterized by reactive elongated interconnected rete pegs due to inflammation or ulceration of the surface epithelium. The lesion was also initially mistaken for verrucous carcinoma (VC). The absence of verrucous exophytic growth of the surface epithelium, and the presence of deep penetrating burrows did not support this diagnosis. The final diagnosis of CC of the scrotum was considered. CC is a rare variant of well-differentiated SCC with a unique architecture of branching and interconnected tunnels that penetrate the stroma, ending in deep-seated cystic furrows.2,3,7 The squamous epithelium lining the sinuses shows consistent features of irregular acanthosis, hyperkeratosis, dyskeratosis, focal cytologic atypia, focal koilocyte-like cells, and keratin-filled cysts and burrows.2–4 Another characteristic finding is the presence of frequent foci of intraepithelial neutrophilic infiltration with microabscesses.2–4 The deep branching anastomosing tunnels lined by well-differentiated squamous epithelium are the hallmark of CC, reflecting a unique pattern of stromal invasion by a low-grade SCC. CC is a chronic slowly progressing locally invasive lesion that has an indolent clinical course without nodal or distal metastasis.2–4 Local complete excision is curative. Similar to VC, CC is mostly a disease of elderly men that has been predominantly reported in the oroaerodigestive tract and anourogenital region, with an infrequent occurrence in miscellaneous cutaneous sites.2–5,8 To our knowledge, scrotal CC has not previously reported in the English literature. Diagnosing CC in the genital area can be challenging because it can mimic malignant lesions such as verrucous carcinoma and warty carcinoma.2,3,5–7 Verrucous carcinoma mainly exhibits an exophytic growth with an endophytic broad front of eosinophilic glassy well-differentiated acanthotic blunted nests extending in the dermis. It lacks dissociated invasive borders, and conspicuous deep sinuses ending in keratin-filled cysts (Table 1). Warty condylomatous SCC is an exophytic papillomatous growth showing papillae with fibrovascular cores and prominent diffuse koilocytic atypia. It is a human papillomavirus-dependent genital tumor expressing p16. TABLE 1. - Comparison of the Salient Pathologic Features Between Carcinoma Cuniculatum and Verrucous Carcinoma Feature Carcinoma Cuniculatum Verrucous Carcinoma Growth pattern Endophytic component only composed of downward tunneling tumoral squamous cavitating sinusesNo exophytic componentNormal surface epithelium Mainly exophytic component composed of large warty fungating massEndophytic component composed of broad blunt solid (noncavitating) pushing bordersNo burrows penetrating the deep stroma Surface epithelium No exophytic papillomatous verrucous growthNo ulcerationFlat intact nontumoral surface squamous epithelium Exophytic papillomatous warty epithelium with endophytic bulbous rete pegsSurface ulcerationEroded expanded verrucous tumoral surface squamous epitheliumPapillary hyperparakeratosis spires and deep keratin plugging and clefting Sinus surface openings Multiple holes draining single tunnels and converging sinus tractsFilled with keratin debris with/without erosion neutrophilic infiltrateSharp transition from normal surface epithelium to sinus tumoral epithelium Absent Verrucous architecture Absent on surface epitheliumPresent in the tumoral squamous epithelium lining the sinuses and cystic spaces Characteristic diagnostic prerequisite in surface tumoral epithelium Burrowing architecture Characteristic diagnostic prerequisiteRamifying labyrinthine of deep stroma-penetrating sinusesConnection to surface epitheliumSpontaneous growth pattern; unrelated to mechanical effects Absent superficial straight short hyperparakeratotic plugs/pits forming crypts/keratin-filled “sinuses” due to massive keratosis and necrosis; well-developed in plantar lesions accentuated by mechanical effects Differentiation Well-differentiated low-grade squamous epitheliumAt least focal moderately differentiated irregular infiltrative borders Well-differentiated low-grade squamous epithelium throughout tumorAbsent (if present suggests “hybrid” verrucous/or conventional squamous cell carcinoma) Inflammatory infiltrate Characteristic intraepithelial neutrophilic infiltration and neutrophilic microabscesses involving extensions from tumoral sinusesPeritumoral lymphocytic stromal infiltrate Sometimes presentUlceration-related acute inflammatory infiltrateMixed chronic inflammatory cell infiltrates in stroma This unique variant of SCC has specific diagnostic criteria that help distinguish it from similar lesions, particularly VC. Although CC shares similar clinical features and some pathologic features with VC, specific histopathologic features suggest that CC is a different variant of SCC (Table 1). Many reported cases of CC seem to describe large complicated long-standing VCs located in pressure-prone sites on the palms and soles.1,9–13 Mechanical trauma and pressure effects, complicated by inflammation and infections, of long-standing verrucous carcinomas, particularly in weightbearing and friction-prone areas, result in degenerative alterations forming crypts and depressed invaginations that may mimic sinuses.13–15 It seems there was a misconception of the original term “cuniculatum.” For example, the case reported by Stchepinsky et al in the article we are addressing in our commentary may represent a longstanding complicated VC or SCC rather than CC. Grossly and radiologically, the tumor was a large, fungating, and deeply infiltrating solid irregular mass invading the bone with lymph node metastasis.1 These features reflect an aggressive metastatic SCC. In addition, their limited skin biopsy of a portion of the mass showed features of VC with mostly an exophytic growth pattern, whereas the deep-penetrating branching sinuses and crypts characteristic of CC were not demonstrated. Some authors have suggested that many reported cases of CC are better interpreted as VC.13 Because of the overlapping clinical and pathologic features between CC and VC, some authors have suggested the terms “inverted” VC or “verruco-cystic” SCC for CC.7,15 However, other authors consider CC to have distinct histopathologic features sufficient to distinguish it from VC (Table 1).2–8,14,15 Pathologists should adhere to these diagnostic criteria. This is important for determining the true prevalence and anatomic distribution of CC compared with other variants of low-grade well-differentiated SCC. In conclusion, CC is a rare and unique variant of well-differentiated SCC with specific anatomic distribution and distinct histopathologic features. The endophytic growth pattern of ramifying tunneling sinuses reflects a distinct stromal invasion. Although both CC and VC share overlapping clinical and pathologic features, most available evidence currently considers CC a separate subtype of SCC. Strict diagnostic criteria should be applied to avoid pitfalls and accurately report well-documented CCs.