AMSTERDAM – The majority of cutaneous infiltrating squamous cell carcinomas arise via direct transformation of grade 1 actinic keratoses – that is, differentiated dysplasia of the basal one-third of the epidermis – via extension of atypical keratinocytes and ultimately of tumor cells along the adnexal epithelium rather than through the classical pathway most dermatologists know, Dr. Maria Teresa Fernandez-Figueras said at the annual congress of the European Academy of Dermatology and Venereology.
This direct transformation by means of what pathologists call the differentiated pathway has important implications for clinical practice, she added.
Dr. Maria Teresa Fernandez-Figueras
“For me, this is something that should change our way of seeing these lesions. When you’re facing an actinic keratosis-1 (AK 1), I think you can no longer call it a low-grade lesion, an early lesion, or a low-risk lesion, because you don’t know if it’s going to follow the differentiated pathway. It can infiltrate at any moment. So from this point of view, all AKs carry a risk of immediate transformation – a low risk, it’s true – and thus maybe all of them require treatment,” explained Dr. Fernandez-Figueras, a pathologist at the University of Barcelona.
The classical pathway by which an AK 1 transforms into an infiltrating squamous cell carcinoma (SCC) is as follows: Before an AK 1 can become a malignant lesion, it first must transition to an AK 2, marked by progression of dysplasia to the lower two-thirds of the epidermis, and then to AK 3, with full-thickness epidermal dysplasia. That’s how most dermatologists understand the process. But there are precedents elsewhere in the body for the existence of a separate differentiated pathway.
The most notable example is vulvar carcinoma. Human papillomavirus–related vulvar malignancy is known to arise from two different pathways. In the classical pathway, vulvar intraepithelial neoplasia 1 (VIN 1) must transition to VIN 2 and then VIN 3 before transformation to SCC. But the cancer can also emerge directly from areas of differentiated dysplastic VIN 1 epidermis, bypassing VINs 2 and 3 altogether.
Dr. Fernandez-Figueras sought to study the relative importance of the two pathways in the formation of cutaneous SCC. To do so, she and two other pathologists examined pathologic specimens and reports for 503 consecutive cases of cutaneous infiltrating SCC. The majority were unsuitable for thorough evaluation because they were fragmented or curettaged, leaving a final study sample of 196 cases.
Two-thirds of all the SCCs had only AK 1 overlying the cutaneous malignancy. Another 15% had overlying AK 2, and 18% had overlying AK 3. A total of 79% of the SCCs had only AK 1 in the epidermis adjacent to the SCC, while 7% had AK 2, and 8% had AK 3; the remaining 6% were unevaluable on this score.
Proliferative growth extending along the sweat ducts and hair follicles of the adnexal epithelium over the SCC was identified in 32% of the cancerous lesions with overlying AK 1, compared with 23% of cancers with overlying AK 2 and 14% with overlying AK 3. Thirty-eight percent of SCCs with AK 1 in the adjacent epithelium had differentiated dysplastic growth migrating along the adnexal epithelium, as did 25% of SCCs with adjacent AK 2 and 11% with neighboring AK 2.
These observations suggest that the differentiated pathway is by far the more common of the two mechanisms of malignant transformation, according to Dr. Fernandez-Figueras.
“Another interesting observation was that very often the areas of invasion were coincident with the focus of adnexal extension,” she continued. “We believe that this tumor advance along the adnexal structures plays a pivotal role in transformation and inversion, especially in AK 1.”
One dermatologist in the audience challenged her. “What do you want us to do – aggressively excise all AKs?”
“I’m a pathologist; I don’t have a suggestion regarding treatment,” Dr. Fernandez-Figueras replied. “I’m just saying, don’t think that AK 1 is better than AK 3, and don’t think that making this distinction gives you any security that you can tell the patient, ‘Don’t worry, nothing is going to happen, we’ll wait until it’s AK 3.’ In my own case, I know that if I had an AK 1, I would treat it. I don’t want to wait to see if it’s going to follow the classical or the differentiated pathway. All lesions can be high grade.”
Session cochair Dr. Michael Reusch pronounced her findings and interpretation of them “completely consistent” with his own experience.
“I think from a histologic point of view, I completely share your view. Still, for the dermatologist part of us, it creates a problem as to what to do. It’s a major issue. The number of AKs out there is incredible,” commented Dr. Reusch of the University Clinics of Hamburg-Eppendorf, Germany.