Squamous Cell Carcinoma Arising in Chronic Inflammatory Dermatoses
Squamous cell carcinoma (SCC) is a known sequela of chronic inflammatory conditions of the skin. Labial discoid lupus erythematosus (DLE), oral lichen planus (OLP), and lichen sclerosus have a relatively short lag time from dermatosis onset to manifestation of malignancy; cutaneous DLE, hypertrophic lichen planus, chronic wounds, hidradenitis suppurativa (HS), and necrobiosis lipoidica can be present for decades before an associated malignancy is observed. Vigilant monitoring is essential for orolabial DLE, chronic HS, and chronic wounds because malignancies in these settings are particularly aggressive and often fatal. We summarize what is known about the nature and demographics of SCC arising within chronic inflammatory dermatoses, emphasizing lag time from dermatosis diagnosis to malignancy onset of common inflammatory conditions.
PRACTICE POINTS
- Squamous cell carcinoma can develop within chronic inflammatory dermatoses.
- Orolabial discoid lupus erythematosus (DLE), oral lichen planus, and lichen sclerosus can lead to relatively rapid tumorigenesis. Squamous cell carcinoma arising in cutaneous DLE, hidradenitis suppurativa (HS), necrobiosis lipoidica, chronic wounds, and hypertrophic lichen planus tends to appear after decades of inflammation.
- Be especially mindful of new orolabial DLE cases and chronic cases of HS and Marjolin ulcer because malignancies in these settings are particularly aggressive.
Necrobiosis Lipoidica Diabeticorum
Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.59 The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.
Epidermolysis Bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.60 Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.61 Although SCCs tend to be well differentiated in RDEB (73.9%),61 they also exhibit highly aggressive behavior.62 In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.63
As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.64 There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.65 Mutations in p53,66 local alterations in transforming growth factor β activity,67 and downstream matrix metalloproteinase activity68 have been implicated.
Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.69 Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.70 A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.71
There does not appear to be evidence for HPV involvement in RDEB-associated SCC.72 Squamous cell carcinoma development in RDEB appears to be multifactorial,73 but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.73
Conclusion
Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.
