Commentary: Cryotherapy and the sebaceous glands.

Sebaceous glands are exocrine epithelial glands secreting protective surface lipids via a holocrine mechanism in which the sebocytes undergo a programmed disintegration. Sebaceous glands are found in the eyelids as the tarsal meibomian glands and the glands of Zeis near eyelash hair follicles.[1] Pathologically, the ophthalmic sebaceous gland lesions range from benign cysts and chalazia to malignant sebaceous gland carcinoma (SGC), which happens to be the most common eyelid malignancy in the Indian population.[2]

Cryotherapy has been extensively used in ophthalmology, dermatology, and surgical specialties as a primary or adjunctive treatment for lesions ranging from intraocular tumors, eyelid cysts, skin tags, warts, and acne vulgaris to cervical and hepatic cancers.[3] There are two mechanisms of cryotherapy: (a) freezing-related direct cellular injury and (b) vascular disruption of the lesion. Its role in the treatment of localized basal cell carcinomas of the eyelid has been documented in the literature with a low recurrence rate.[2] The prolonged healing time with secondary intention healing and depigmentation remains a concern with cryotherapy of the skin tumors. However, it helps in preserving the functionality of essential structures like eyelids and the surrounding lacrimal system.

The in vivo biological effect of cryotherapy on normal sebaceous glands has been evaluated with the help of coherent anti-Stokes Raman scattering microscopy by Jung et al.[4] They demonstrated that the effect of lipid crystallization had a limited role in causing cellular disruption. Instead, sebocyte loss occurred at temperatures lower than those required for lipid crystallization. In addition, the cryo-treated sebaceous glands began recovering 1–2 weeks after treatment.

Ray Jalian et al.[5] also investigated the role of controlled local skin cooling in causing preferential injury to sebaceous glands to understand its mechanism in treating acne vulgaris. They observed that cooling-induced damage led to a 20% reduction in sebum output for 2 weeks, with minimal collateral injury to surrounding tissues. A higher number of freeze–thaw cycles and slower thawing resulted in more significant tissue injury. Immunohistochemistry-based expression of Ki67 (a proliferative marker) and keratin 15 (a progenitor basal cell marker) was not disrupted by cooling. This led them to conclude that cooling-induced damage was temporary and occurred due to disruption of cellular architecture, enzymatic activity, and decreased lipid content. The sebum output recovered after 4 weeks. Though both these studies used a temperature higher than what is used in ophthalmic practice, they did conclusively demonstrate the limited level of cytotoxicity as well as the temporary duration of the effect of cryotherapy on sebaceous glands.

The ophthalmic literature describes the use of cryotherapy as an adjunct in addressing the pagetoid spread seen in eyelid SGC.[6] Lisman (1989) first reported the use of cryotherapy to manage the map biopsy-proven sites of pagetoid spread in six cases of sebaceous gland carcinoma, thereby avoiding exenteration.[7] Shields et al.[6] advocated the application of triple freeze cryotherapy on conjunctival edges to eliminate residual tumor cells. On the contrary, Esmaeli et al.[8] reported satisfactory outcomes in 50 patients of SGC without the need for cryotherapy. A survey of practice patterns in Nordic countries revealed that only 27% of respondents offered cryotherapy as an adjunctive treatment for addressing the pagetoid spread in SGC.[9] Thus, the biological effect of cryotherapy on sebaceous glands is limited and reversible. The reassurance provided by triple freeze and slow thaw to the margins may not be reliable in clinical practice.

This fact has been highlighted by Alam et al.[10] in the present issue of this journal. They performed a histopathological study on a portion of excised SGC tumor that was subjected to cryotherapy. Greater than 50% of viable tumor cells along with extensive areas of necrosis were observed on microscopy, and the authors concluded that the cell damage induced by cryotherapy is insufficient for achieving adequate tumor control.

We believe that an early diagnosis and timely treatment using a wide (~3-mm margin) full-thickness excision, intraoperative frozen section control, and map biopsy for pagetoid spread remains the preferred practice pattern. The adjunctive use of cryotherapy remains doubtful in the SGC of eyelids. Close monitoring and regular follow-up to observe for recurrences are vital in the long-term management of patients.