Squamous cell carcinoma in situ with adnexal extension

The depth of follicular extension of atypical squamocytes in actinic keratosis correlates directly with the depth of invasion of an associated invasive squamous cell carcinoma, according to a recently published study in the Journal of the European Academy of Dermatology and Venereology.

This finding, the authors write, has direct implications for clinical treatment and offers an explanation of why some actinic keratoses recur and progress following superficial destructive treatments, like cryotherapy.

Researchers based in Spain and the U.S. retrospectively performed a histologic review of 193 invasive squamous cell carcinoma biopsy specimens, which had associated actinic keratosis, and studied the existence and depth of follicular extension of atypical keratinocytes in actinic keratosis.

More than a quarter of cases had follicular extension, which often extended into the lower follicular segment. In 58 percent of those cases, the invasive squamous cell carcinoma was directly adjacent to the follicular basalis and correlated strongly with follicular extension depth. The correlation exists regardless of the pathway of origin, they conclude.

Invasive squamous cell carcinomas arising from the follicular basalis had a median tumor thickness of 1.75 mm, compared to 0.9 mm for those skin cancers developing in the epidermis.

“It is therefore important to note the presence and the depth of follicular extension when diagnosing an [actinic keratosis], since follicular extension likely accounts for a significant proportion of recurrent [actinic keratosis] and the development of [invasive squamous cell carcinoma] following superficial treatment modalities,” they write.

Invasive squamous cell carcinoma of the skin usually starts as an actinic keratosis, but most actinic keratoses spare the follicular and adnexal epithelium, as they are confined to the interfollicular epidermis, according to the study.

Still, there are cases in which actinic keratoses have atypical squamocyte extensions down follicular and adnexal epithelium, which could be the precursor of many squamous cell carcinomas, the authors write. Researchers focusing on follicular involvement in invasive squamous cell carcinoma have reported, among other things, that “follicular” invasive squamous cell carcinoma selectively develops in the wall of the hair follicle, although this finding is not always in the setting of actinic keratosis.

The strong suggestion that deeply invasive squamous cell carcinoma often develops from the follicular basalis and direct implications for treatment.

“If the histopathological assessment carefully notes the presence and the depth of follicular extension of an [actinic keratosis], then more aggressive treatment modalities, such as curettage, excision or the use of photosensitizers, may be employed,” they write. “Such treatment would likely limit the incidence of recurrence and the development of [invasive squamous cell carcinoma].”

The study suggests hair follicles might contribute greatly to deeply invasive squamous cell carcinoma development - a relationship which has played out in animal studies. Another important take-away from the story for dermatologists: sweat glands, were rarely involved in this study and do not appear to play a major role in invasive squamous cell carcinoma in the presence of an actinic keratosis. While sweat glands might have been involved in their most superficial portion, the skin cancer never was identified nearby.

Together, the findings support the thinking that only the hair follicle, among adnexal structures, plays a key role in invasive squamous cell carcinoma genesis.

DISCLOSURES

The study has no funding sources. Some of its authors are consultants to and speakers for Almirall, Novartis and Leo Pharma.

REFERENCES

M.T. Fernándezâ€ÂFigueras  X. Saenzâ€ÂSardà  P. Vargas, et al. "The depth of follicular extension in actinic keratosis correlates with the depth of invasion in squamous cell carcinoma: implication for clinical treatment," Journal of European Academy of Dermatology and Venereology (JEADV), March 23, 2018. https://doi.org/10.1111/jdv.14901

Cutaneous squamous cell carcinoma (SCC) exhibiting microcystic adnexal carcinoma-like differentiation is an extremely rare tumor that shows both squamous and ductal differentiation. This tumor is often misdiagnosed clinically and histologically and is confused with other malignant and benign cutaneous neoplasms. It usually occurs in middle-aged to older adults. Here, we report a case of SCC with microcystic adnexal carcinoma-like differentiation on the left chin of a 71-year-old male. The histopathological examination revealed a nodular tumor infiltrating the dermis, subcutaneous fat, and striated muscle tissue, consisting of both prominent atypical squamous differentiation and foci of duct-like structures.

© 2018 The Author(s) Published by S. Karger AG, Basel

Introduction

Cutaneous squamous cell carcinoma (SCC) is a malignant neoplasm originating in the epidermis in which the neoplastic cells show variable squamous differentiation [1]. Most cases arise on the sun-exposed skin of elderly people. Microcystic adnexal carcinoma (MAC) is a distinctive malignant appendageal tumor [2]. This neoplasm is locally aggressive and deeply infiltrating, mostly occurring on the face. Rarely, low-grade SCC shows unusual histological aspects including focal (pseudo)ductal differentiation, thus resembling MAC and causing a diagnostic challenge. Here, we present a rare case of SCC located on the chin mimicking MAC.

Case Report

A 71-year-old male was admitted to the Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Geneva, Geneva, Switzerland, with a nodular lesion that was soft in consistency and located on the left paramedian part of the chin. It had been present for over 25 years and showed recent growth (6 months), producing purulent material after being incised 1 month before. Clinical examination showed a cutaneous lesion measuring 3 x 2 cm, and the clinical differential diagnosis was infected epidermoid cyst and subcutaneous neoplasm.

The patient’s previous medical and surgical history included a cholecystectomy, and an upper gastrointestinal bleeding developed on a gastric ulcer. Laboratory examination was unremarkable. An ultrasound investigation revealed a dermal and subcutaneous, mostly well-encapsulated cystic lesion measuring 2.3 cm in its greatest dimension and 1.07 cm in thickness. The lesion showed an irregular, deep border lying in close proximity with the aponeurosis.

An incisional biopsy of the lesion was performed. Histologically, the specimen showed an atypical squamous cell proliferation arising from the epidermis and extending to the dermis, consistent with an invasive, moderately to well-differentiated SCC.

A facial magnetic resonance imaging and a neck computed tomography scan were performed to assess any eventual tumoral extension in the maxillary bone and locoregional lymph nodes. The radiological analysis revealed a suspected, poorly circumscribed, ulcerated, cutaneous, and subcutaneous lesion of the chin invading the perimaxillary striated muscle tissue without any osseous involvement. Two bilateral parotid lesions consistent with Warthin tumors were also radiologically detected.

Seventeen days after biopsy, a radical resection of the tumor followed by local reconstruction with a rhomboid graft was performed. Histologically, the excision material revealed an ulcerated squamous cell tumor consisting of some clear cells and microcystic structures filled with eosinophilic keratinous material. There were also micronodules showing some prominent ductal differentiation resembling MAC, associated with foci of calcification. The tumor invaded the whole dermis, subcutaneous fat, and striated muscle tissue in the form of atypical squamous cells, micronodules, and cords (Fig. 1). The tumoral depth was evaluated to be 1.7 cm, and the resection margins were free of tumor. There was only 1 image of perineural tumoral invasion.

Fig. 1.

a Photomicrographs of the squamous cell carcinoma at low magnification, showing a squamous cell tumor arising from the epidermis and extending to the dermis, subcutaneous fat, and striated muscle tissue. H&E. Original magnification, ×1. b High magnification showing squamous tumor cells with some clear cells forming microcystic structures and micronodules with ductal differentiation. H&E. Original magnification, ×20. c p63 immunostaining confirms the squamous nature of the tumor cells. Original magnification, ×10. d Epithelial membrane antigen immunostaining highlights the ductal differentiation. Original magnification, ×10.

The tumor cells showed diffuse immunostaining for pancytokeratins and p63. The focal ductal structures were highlighted by the expression of epithelial membrane antigen and carcinoembryogenic antigen (Fig.1). The tumor cells were negative for cytokeratin 7, cytokeratin 20, Ber-EP4 (Ep-CAM), and androgen receptor.

This histological aspect was highly reminiscent of cutaneous MAC but with areas with pure squamous differentiation consistent with an invasive SCC mimicking MAC.

There was no further treatment. A clinical and ultrasonographic surveillance were performed every 3 months. The patient was followed up at 3 and 6 months postoperatively and showed no suspected cervical lymphadenopathy. The parotid lesions remained unaltered. A squamous papilloma of the right anterior oropharyngeal pillar has been detected and biopsied at 6 months during the follow-up.

Discussion

Both cutaneous SCC and MAC are infiltrating tumors that can sometimes be difficult to be distinguished one from another clinically and histologically. MAC occurs predominantly on the head and neck, in the centrofacial region, and mainly in the white population[3]. It is a slowly growing, indurated nodule, plaque, or partially cystic lesion that has often been present for many years. Radiation therapy is a possible etiologic factor [3-5]. This tumor is usually asymptomatic without ulceration and is often unnoticed. Sometimes, symptoms such as numbness, burning, paresthesia, and tenderness appear, usually caused by the high frequency of perineural invasion [3, 4]. MAC is a locally aggressive tumor that deeply invades the adjacent tissue and rarely metastasizes [6, 7]. Histologically, MAC is composed of keratin-filled cysts, nests, and cords of bland basaloid and/or squamoid cells with the formation of ductal structures within a desmoplastic stroma. These ducts and nests can show tail-like appearances [3, 6]. There is no connection to the epidermis. In general, tumor aggregates are smaller as the tumor invades more deeply. Typically, there are no cytologic atypia, mitoses, or tumoral necrosis, but infiltrative growth and perineural invasion are a feature [6, 8].

The histologic differential diagnosis includes malignant tumors such as SCC with MAC-like differentiation, squamoid eccrine ductal carcinoma, morpheiform basal cell carcinoma, eccrine porocarcinoma with squamous differentiation, and other benign adnexal tumors such as trichoadenoma, desmoplastic trichoepithelioma, and syringoma [2, 3]. Misdiagnosis can easily occur, especially as a result of an inadequately small biopsy specimen that does not involve the deeper portion of the tumor.

Rarely, cutaneous SCC has an unusual morphological presentation with some focal MAC-like differentiation as in our case. Histologically, it is characterized by an infiltrative pattern of atypical cells forming cords, minute nests, micronodules, and foci of duct-like structures with a prominent desmoplastic stromal reaction resembling MAC. Ductal differentiation is highlighted by epithelial membrane antigen and carcinoembryogenic antigen immunostaining. It is important to know that, despite the invasive nature of MAC, the tumor cells are cytologically bland with rare to absent mitoses and a lack of cell necrosis, whereas the tumor cells in cutaneous SCC show moderate to high-grade cytologic atypia with the presence of variable mitotic activity and with or without tumoral necrosis. Moreover, a proper sampling or serial sections will often reveal an in situ component in SCC.

Another rare tumor known as squamoid eccrine ductal carcinoma has been described exhibiting both squamous and adnexal ductal differentiation [9, 10]. The cell origin of this tumor is controversial as it may represent a SCC arising from the eccrine ducts or a subtype of eccrine carcinoma with squamous differentiation, or it could be considered a biphenotypic carcinoma. It has been classified as a variant of cutaneous SCC and as a type of eccrine carcinoma. It usually occurs in elderly adults, on sun-damaged skin, particularly in the head and neck region. Histologically, squamoid eccrine ductal carcinoma is a poorly demarcated tumor showing a biphasic appearance and an infiltrative growth in the dermis and sometimes subcutaneous tissue. Superficially, the tumor has the same aspect as a well-differentiated SCC with epidermal connection and eventually a background of SCC in situ or actinic keratosis. In the deeper portion, there are cords and strands with sweat duct differentiation in a desmoplastic stroma. Cytologic atypia is moderate to severe. Although morphologically our tumor resembled squamoid eccrine ductal carcinoma, the presence of multiple keratin cysts suggested a SCC with MAC-like differentiation.

Cutaneous SCC with MAC-like features is an unusual cutaneous neoplasm, which should be considered in the differential diagnosis of any MAC-like tumors. However, to make the correct diagnosis, it is important to demonstrate its biphasic growth component and especially the presence of highly atypical cells.

Pathologists should be aware of this underrecognized phenomenon showing histologic features of SCC with MAC-like differentiation.

Statement of Ethics

The patient gave his informed consent for this publication.

Disclosure Statement

The authors have no conflicts of interest to disclose.

This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Is squamous cell carcinoma in situ serious?

What is adnexal extension?

What does squamous cell carcinoma in situ means?

What is the best treatment for squamous cell carcinoma in situ?