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Beyond disfigurement: The potential for keratinocyte carcinoma in discoid lupus erythematosus

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By Warren R. Heymann, MD, FAAD
Jan. 10, 2024
Vol. 6, No. 2

Dr. Warren Heymann photo
Cosmetic disfigurement due to scars and dyspigmentation is the main complication of discoid lupus erythematosus (DLE). The current classification of cutaneous lupus erythematosus (CLE) includes acute cutaneous LE (ACLE), subacute LE (SCLE), chronic cutaneous LE (DLE, LE panniculitis, and chilblain LE), intermittent (tumid) LE, and neonatal LE. (1) DLE is the most common variant. I recently reviewed the risk for developing systemic disease that could affect the joints, kidneys, brain, heart, and lungs. The bottom line: “The data is variable, but the message is clear: Enough DLE patients may progress to SLE to warrant periodic monitoring by a review of systems and laboratory tests (ANA with reflex, CBC, metabolic profile, and urinalysis).” (2)

There is another complication of DLE — albeit rare — the risk of keratinocyte carcinoma, especially squamous cell carcinoma (SCC). This commentary will focus on that risk.

Most of the literature is case reports, some rather dramatic, such as the rhinophymatous mass in a 56-year-old woman with hypertrophic lupus erythematosus (3) or the 40-year-old woman with a long history of oral and perioral DLE who developed multiple SCC of the lip and succumbed to metastatic SCC of the tongue. (4) Only rare cases of basal cell carcinoma arising in DLE have been reported. (5)

Image for DWII about the potential for keratinocyte carcinoma in discoid lupus erythematosus
Image of DLE from JAAD 2016; 74: 1-16.

Mufti et al performed a systematic review of the literature to summarize the characteristics and outcomes of SCC as a complication of DLE. A total of 118 patients from 45 studies were included. Of the 118 patients (mean age: 50.4 years) who developed SCC within DLE lesions, the majority were males (55.9%, n = 66/118). Race was not reported in 32 patients; of the remaining 86, 16 (18.6%) were Black/African-American, 6 (7%) White, and 64 (74%) Asian. Localized DLE was present in 73.7% (n = 87/118) of the patients and generalized DLE (DLE lesions below the neck) in 21.2% (n = 25/118); 5.1% (n = 6/118) did not report DLE distribution. Positive smoking history and prior immunosuppressant use were reported in 14.4% (n = 17/118) and 12.5% (n = 5/40) of the patients, respectively. The most common sites of SCC development were the lip (53.3%, n = 65/122), forearm (11.5%, n = 14/122), and scalp (7.4%, n = 9/122). The lower lip (41.8%, n = 51/122) was more affected than the upper lip (11.5%, n = 14/122). The mean duration between DLE onset and SCC development was 15.0 years (range: 0.5-41). Of the 47 patients who reported treatment outcomes for SCC, all had undergone surgical excision. Eight patients had received radiotherapy, 1 had received chemotherapy, and 2 had received combined radiation and chemotherapy. Of those who reported metastasis and recurrences, 26.9% (n = 29/108) experienced SCC metastasis, and 40.2% (n = 41/102) reported SCC recurrences. In addition, 25.0% (n = 23/92) of the patients reported a mortality outcome due to metastasis (60.9%, n = 14/23), sepsis (4.3%, n = 1/23), and respiratory failure (4.3%, n = 1/23). (6)

The pathogenesis of keratinocyte carcinoma is unknown but is believed to be secondary to scarring, chronic inflammation, ultraviolet radiation, and immunosuppressive agents (in selected patients). Zaalberg et al subjected lupus-prone MRL/lpr and control (MRL/n) mice to a skin carcinogenesis protocol. Skin tumors developed preferentially within the cutaneous lupus inflammation without scarring in MRL/lpr mice (P < 0.01). The inflammation in MRL/lpr skin was characterized by the accumulation of regulatory T cells, mast cells, M2 macrophages, and markedly elevated transforming growth factor-β1 and IL-6 levels, which have been linked to tumor promotion. Tacrolimus treatment reduced skin inflammation and blocked cancer development in MRL/lpr mice. The authors concluded that discoid lupus inflammation promotes skin cancer in high-risk DLE patients and hypothesize that blocking such inflammation may be critical for preventing this life-threatening complication of DLE. (7)

I have seen many patients with DLE throughout my career and am hard-pressed recalling if I have seen any cases of keratinocyte carcinoma develop in DLE. The problem I have encountered is potential misdiagnosis of SCC in patients with DLE. This is particularly true for patients with hypertrophic lupus erythematosus (8) or the lupus erythematosus-lichen planus overlap syndrome (9). In the former, Ko et al demonstrated that a heavy band of CD123-positive cells (staining plasmacytoid dendrocytes) is present at the epidermal-dermal junction cases of hypertrophic LE, and only single or rare scattered clusters of CD123-positive cells are observed in SCC and actinic keratoses. (8)

In conclusion, aside from the obvious cosmetic disfiguration caused by DLE, vigilance must be maintained for the possibility of systemic disease and the rare complication of secondary keratinocyte carcinoma.

Point to Remember: Rarely, life-threatening squamous cell carcinomas may complicate discoid lupus erythematosus (DLE). Securing the diagnosis of keratinocyte carcinoma (squamous cell carcinoma more likely than basal cell carcinoma) within DLE may be challenging. Preliminary evidence suggests that treating DLE may decrease the risk of malignancy.

Our expert’s viewpoint

David A. Wetter, MD, FAAD
Professor of Dermatology
Mayo Clinic
Rochester, Minnesota

Like Dr. Heymann, I have seen several patients with localized discoid lupus erythematosus (DLE) who had their disease treated with surgery due to a previous misdiagnosis of squamous cell carcinoma (SCC), although to my knowledge I have not (yet) cared for a patient who developed SCC within a longstanding lesion of DLE. However, it behooves dermatologists to remain vigilant for the uncommon (but potentially serious) complication of keratinocyte carcinoma development within a variety of chronic cutaneous inflammatory conditions (including DLE and hidradenitis suppurativa, among others) (10). Cutaneous malignancy (mainly keratinocyte carcinoma) can also occur within longstanding ulcerated necrobiosis lipoidica (11) and chronic leg ulcers (12). In the study of Mufti et al, the lower lip was the most commonly affected location of SCC arising within DLE. Although the authors did not observe any patients who developed SCC within the oral cavity, it remains prudent to perform oral examinations in patients with DLE at the time of initial evaluation and during routine follow-up visits — the oral cavity (particularly the palate and buccal mucosa) may be overlooked sites of DLE and potential SCC development in chronic and untreated lesions. (6) The story of DLE and keratinocyte carcinoma illuminates a salient learning point which applies to several scenarios in dermatologic practice: if a condition does not respond as expected to the accepted treatment protocol, then take a step back to consider alternative diagnoses and perform testing such as a [repeat] skin biopsy to confirm the diagnosis.

  1. Bitar C, Menge TD, Chan MP. Cutaneous manifestations of lupus erythematosus: a practical clinicopathological review for pathologists. Histopathology. 2022 Jan;80(1):233-250. doi: 10.1111/his.14440. PMID: 34197657.

  2. Heymann WR. The Criteria-Dependent Risk of Systemic Lupus Erythematosus Developing in Patients with Discoid Lupus Erythematosus. J Am Acad Dermatol. 2022 Jul 7:S0190-9622(22)02259-9. doi: 10.1016/j.jaad.2022.07.005. Epub ahead of print. PMID: 35810838.

  3. Cohen L, Shah V, Chen PL, Messina J, Seminario-Vidal L. Cutaneous squamous cell carcinoma causing a rhinophymatous mass in a patient with clinically occult hypertrophic lupus erythematosus. Lupus. 2020 May;29(6):644-648. doi: 10.1177/0961203320912838. Epub 2020 Mar 22. PMID: 32202198.

  4. Arvanitidou IE, Nikitakis NG, Georgaki M, Papadogeorgakis N, Tzioufas A, Sklavounou A. Multiple primary squamous cell carcinomas of the lower lip and tongue arising in discoid lupus erythematosus: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 Feb;125(2):e22-e30. doi: 10.1016/j.oooo.2017.08.012. Epub 2017 Aug 30. PMID: 28967499.

  5. Pradhan P, Samal S, Sable M. Basal cell carcinoma arising over lesion of discoid lupus erythematosus: a rare occurrence. Lupus. 2020 Feb;29(2):210-212. doi: 10.1177/0961203319894371. Epub 2019 Dec 17. PMID: 31847697.

  6. Mufti A, Sachdeva M, Maliyar K, Sibbald RG. Squamous cell carcinoma arising within discoid lupus erythematous lesions: A systematic review. JAAD Int. 2020 Nov 30;2:1-4. doi: 10.1016/j.jdin.2020.10.001. PMID: 34409345; PMCID: PMC8362320.

  7. Zaalberg A, Moradi Tuchayi S, Ameri AH, Ngo KH, Cunningham TJ, Eliane JP, Livneh M, Horn TD, Rosman IS, Musiek A, Anadkat MJ, Demehri S. Chronic Inflammation Promotes Skin Carcinogenesis in Cancer-Prone Discoid Lupus Erythematosus. J Invest Dermatol. 2019 Jan;139(1):62-70. doi: 10.1016/j.jid.2018.06.185. Epub 2018 Jul 17. PMID: 30030152; PMCID: PMC6309656.

  8. Ko CJ, Srivastava B, Braverman I, Antaya RJ, McNiff JM. Hypertrophic lupus erythematosus: the diagnostic utility of CD123 staining. J Cutan Pathol. 2011 Nov;38(11):889-92. doi: 10.1111/j.1600-0560.2011.01779.x. PMID: 21955314; PMCID: PMC4103013.

  9. Smirnov B, Bowles AA, Strasswimmer JM, Nousari CH. Lupus Erythematosus Lichen Planus Overlap Syndrome Mimicking Squamous Cell Carcinoma. J Clin Aesthet Dermatol. 2019 Sep;12(9):36-38. Epub 2019 Sep 1. PMID: 31641416; PMCID: PMC6777702.

  10. 10. Ju T, Hernandez L, Mohsin N, et al. Evaluation of risk in chronic cutaneous inflammatory conditions for malignant transformation. J Eur Acad Dermatol Venereol. 2023 Feb;37(2):231-242.

  11. Harvey JA, Severson KA, Brumfiel CM, et al. Necrobiosis lipoidica-associated cutaneous malignancy. J Am Acad Dermatol. 2022 Jun;86(6):1428-1429.

  12. Chacon Osorio GR, Wyles SP, Comfere NI, et al. Skin cancer associated with chronic leg ulcers in the population of Olmsted County, Minnesota. Mayo Clin Proc. 2023 Jul;98(7):1035-1041.

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