Welcome to this July twenty twenty-six journal review from the Journal of the American Academy of Dermatology. We've got four pieces on the docket this time — a roundup of case reports from the sister publication JAAD Case Reports, a retrospective cohort study on racial disparities in Mohs surgery for acral lentiginous melanoma, a large database study looking at sex and tumor location in Merkel cell carcinoma, and an expert consensus guideline on topical five-fluorouracil plus calcipotriene for actinic keratosis and superficial keratinocyte carcinomas. Let's get into it.

First up is the editor's highlights column from JAAD Case Reports, written by Abby Van Voorhees. This isn't a single study — it's a curated tour through three case reports, all coming out of China this month, and it's worth walking through each because they're the kind of thing that changes what you reach for on a Tuesday afternoon.

The first case is a patient with acute generalized exanthematous pustulosis who underwent genetic screening and was found to carry an IL36RN mutation — the same gene implicated in generalized pustular psoriasis. When systemic steroids failed, the authors started spesolimab, the interleukin-36 receptor antagonist, and got a rapid response. The teaching point here is conceptual as much as therapeutic: the authors raise the question of whether acute generalized exanthematous pustulosis and generalized pustular psoriasis, which are histologically indistinguishable, might actually represent a shared phenotype in genetically susceptible patients rather than two separate diseases. That's a nice example of genotype reshaping how we think about diagnostic labels, and practically, it tells you that in a steroid-refractory pustular eruption, genetic testing plus consideration of an interleukin-36 pathway blocker is a reasonable next step.

The second case involves an oncology patient with multiple primary cancers being treated with the PD-1 inhibitor sintilimab and the multikinase inhibitor lenvatinib, who developed a lichenoid drug eruption. Rather than leaning on high-dose systemic steroids — which carry real risk in cancer patients — the authors stopped both oncologic drugs and treated with apremilast plus low-dose steroids, then were able to taper the steroid entirely about two weeks after starting the apremilast. Van Voorhees flags this as a strategy worth keeping in your back pocket: apremilast as a steroid-sparing bridge for lichenoid drug reactions in patients where you want to minimize corticosteroid exposure.

The third case is an infectious one — a Mycobacterium chelonae infection following unsterile "slimming injections," which turned out to be a genuine therapeutic slog, ultimately requiring combination rifampin and ethambutol plus surgical excision and debridement. The point here is a reminder of this organism's intrinsic drug resistance and the need for multidrug regimens plus surgical source control, not antibiotics alone — relevant any time you're consulted on an atypical mycobacterial infection following a cosmetic procedure.

Moving to the next article, this is a retrospective single-institution cohort study looking at perioperative racial disparities among patients with acral lentiginous melanoma undergoing Mohs micrographic surgery. The background here is well-trodden but important: acral lentiginous melanoma disproportionately affects people of color, who tend to present later and with more advanced disease, and Mohs is increasingly used at these acral sites for its tissue-sparing benefit. What hadn't been examined is whether perioperative disparities — time to surgery, defect size, reconstruction needs — persist once patients actually make it onto the Mohs table.

The design was a retrospective matched cohort of eighty-six patients treated at a single academic center between 2006 and 2023 — forty-three patients of color and forty-three non-Hispanic White patients, matched one-to-one on sex and age. The primary endpoint was days from biopsy to first Mohs surgery, with insurance type included as a covariate. A retrospective matched design makes sense here for a fairly rare tumor subtype at a single center — you're not going to randomize time-to-surgery, and matching on age and sex lets you isolate the race-associated signal without those two variables muddying the comparison. Secondary outcomes captured the downstream surgical burden: defect sizes, Breslow depth, Mohs stage number, digital amputation rate, and graft use.

The results: patients of color waited significantly longer for surgery — a median of forty-eight days from biopsy compared to thirty-four days for White patients. That difference persisted in an adjusted model that controlled for insurance status, meaning insurance alone doesn't explain the gap, though the confidence interval around that adjusted effect was wide enough that the finding sits right at the edge of statistical significance — worth taking seriously, but not an overwhelmingly robust effect size. Insurance type itself was not independently associated with delay. Where the disparity becomes clinically concrete is in tumor burden: patients of color had roughly three times larger pre-operative defect sizes, similarly larger post-operative defects, more than double the rate of graft reconstruction — about forty-four percent versus nineteen percent — and nearly double the Breslow depth, all statistically significant. Reassuringly, the things that reflect surgical technique itself — number of Mohs stages and digital amputation rate — were essentially identical between groups, suggesting the disparity is about disease burden at the time of surgery, not how the surgery itself was performed.

The authors are appropriately cautious in their limitations. This is retrospective, single-center, underpowered for finer subgroup analysis, and critically, they had no baseline tumor measurement at the biopsy itself — so they can't tell you whether the larger defects reflect tumor growth during the treatment delay or simply more advanced disease at initial presentation. Lumping all non-White patients into a single "people of color" category also obscures real heterogeneity — Black and Asian patients, for instance, likely have quite different disease burden and access barriers, and this study can't tease that apart. And because the cohort only includes patients who actually reached Mohs surgery, it may well underestimate the true disparity if patients of color are also facing greater barriers to ever being referred for Mohs in the first place.

For your practice, I'd call this practice-informing rather than practice-changing in a technical sense — it doesn't tell you to alter your surgical approach, since Mohs stage number and amputation rates were equivalent. But it is a data point supporting system-level interventions: faster-tracking biopsy-proven acral lentiginous melanoma in patients of color to surgery, and maintaining a lower threshold of suspicion for atypical acral pigmented lesions in richly pigmented skin, given the documented pattern of delayed recognition upstream of your clinic.

Next, a retrospective cohort study using the Mayo Clinic Platform looking at sex and tumor location as they relate to outcomes in Merkel cell carcinoma. The background problem is that prior literature has given genuinely mixed signals on whether sex independently predicts prognosis in Merkel cell carcinoma, and the authors' hypothesis is that apparent sex differences might really be a proxy for where the tumor happens to sit anatomically, rather than a true biological sex effect.

Methodologically, this pulls from a large multi-institution deidentified electronic health record dataset — over a thousand patients — with propensity matching used to build comparable subgroups, and standard chi-squared and log-rank tests for comorbidities and survival. Using a large aggregated platform like this makes sense for a rare tumor like Merkel cell carcinoma, where no single center would have adequate numbers; the tradeoff, which the authors don't dwell on but is worth flagging as my own read, is that a deidentified platform-level dataset limits how granular you can get on tumor staging, treatment details, and other clinical nuance beyond what's captured in the structured fields.

The results are the interesting part. In the overall sex-matched comparison, male patients had significantly worse survival at five and ten years, but no significant difference at one, one-and-a-half, or two years — so the sexes start out on equal footing and only diverge later. Males were also more likely to have scalp-located tumors and more likely to be immunosuppressed, both statistically significant. But here's the key maneuver: when the authors restricted the comparison to head-and-neck Merkel cell carcinoma specifically and matched males against females within that subgroup, the sex-based survival gap disappeared entirely — no difference in short-term or long-term survival, location distribution, or immunodeficiency rates. Meanwhile, when they looked at head-and-neck location itself, regardless of sex, that group had significantly worse survival at eighteen and twenty-four months compared to non-head-and-neck tumors — roughly seventy-one percent versus eighty percent, and sixty-five percent versus seventy-four percent — though that gap closed by the long-term time points. Head-and-neck tumors were also linked to a higher rate of prior squamous cell carcinoma diagnoses at several sites.

So the discussion's throughline is that anatomic location, not sex per se, appears to be doing most of the explanatory work — once you control for where the tumor is, the male-female survival gap essentially evaporates. The authors reasonably suggest the long-term male mortality disadvantage may partly reflect baseline population life expectancy differences rather than tumor biology. The limitations aren't heavily spelled out in the text, but a few are worth naming: the cohort was overwhelmingly White, which limits generalizability, the head-and-neck matched subgroup shrank to a fairly small number of patients per arm once matching was applied, and this remains a retrospective, EHR-derived dataset without deeper histopathologic or treatment granularity.

Practically, I'd file this as interesting and prognosis-clarifying rather than practice-changing at the surgical level — it doesn't change your Mohs or margin approach to Merkel cell carcinoma. But it is useful for patient counseling: head-and-neck location, independent of sex, appears to carry the higher short-term risk window, which reinforces the importance of close surveillance in that first two years regardless of which patient is in front of you.

Last is a modified Delphi expert consensus statement from the International Immunosuppression and Transplant Skin Cancer Collaborative, addressing topical combined five-fluorouracil and calcipotriene — the vitamin D analog — for actinic keratosis and superficial keratinocyte carcinomas. This is a guideline document, not an original data study, so there's no results-and-limitations arc in the usual sense — it's a synthesis of existing literature plus a structured consensus process, and it's worth understanding how that process worked because the recommendations only carry as much weight as the method behind them.

The background sets up why this combination exists: five-fluorouracil monotherapy is effective for actinic keratosis, with clearance rates roughly in the forty to seventy-five percent range, and is also used off-label for squamous cell carcinoma in situ and superficial basal cell carcinoma, but it requires weeks of twice-daily application and provokes an uncomfortable, socially limiting inflammatory reaction that erodes compliance. Adding calcipotriene appears to potentiate the five-fluorouracil effect by recruiting CD4 T cells to damaged keratinocytes, allowing a much shorter course. The foundational randomized trial here, Cunningham and colleagues from 2017, showed four days of twice-daily combination treatment produced an eighty-eight percent reduction in actinic keratoses at eight weeks, versus about twenty-six percent with five-fluorouracil alone — a large, clinically meaningful gap, not just a statistically significant one. Follow-up analyses showed the best responses on the face, in the low ninety percent range, with somewhat lower but still solid responses on the scalp and forearms. Other retrospective work has extended this to superficial keratinocyte carcinomas, with one series of over two hundred lesions showing roughly ninety percent clinical complete response with five to ten days of twice-daily treatment, similarly effective in immunosuppressed patients.

Given that promising but still fragmented, mostly small and retrospective evidence base, the ITSCC set out to build consensus. Their process: a workgroup identified areas needing clarification, conducted a literature review that turned up ten relevant studies, then built a survey distributed to a hundred and eighteen ITSCC clinician members, of whom thirty-four responded — importantly, this pool skewed toward surgical dermatologists in academic high-risk skin cancer practices, so the results reflect expert practice patterns more than general community dermatology. From those survey results and the literature, the workgroup drafted preliminary consensus statements, which then went to a nine-member expert panel using a modified Delphi method — essentially structured, anonymous voting rounds where each statement needs seventy percent agreement to be adopted, with disagreement triggering revision and a second round rather than open debate influencing votes. Of eighteen preliminary statements, eleven reached consensus immediately, six required revision and a second round, and one was dropped entirely for lack of sufficient evidence to support any recommendation — which itself is useful information, since it tells you where the panel felt the data genuinely couldn't support guidance.

The resulting recommendations: for actinic keratosis, twice-daily combination treatment for four to five days on the face and neck, extending to seven to ten days for the scalp, trunk, and extremities, or as a second attempt on the face and neck if the first course fails; for extensive or rapidly recurring actinic keratosis, scheduled retreatment every three to six months is reasonable. For squamous cell carcinoma in situ, the panel recommends seven to ten days twice daily on the face and neck, ten to fourteen days elsewhere. For actinic cheilitis, four to five days twice daily, with counseling that the local reaction can be severe. For superficial basal cell carcinoma, the panel felt comfortable saying the combination can be prescribed, but there wasn't enough evidence to recommend a specific duration, and they emphasize close clinical follow-up instead — worth noting that only about one in five surveyed clinicians even use it for this indication, so this remains the least established use case. And notably, the panel did not recommend modifying the regimen based on immunosuppression status, though they do advise closer follow-up in that population to judge whether a longer or repeated course is needed.

The authors are upfront about the limits here: small panel size, and the underlying literature is still dominated by small, mostly single-institution, retrospective studies rather than large randomized trials. So take this as expert-consensus guidance filling a real evidence gap, not Level 1 evidence.

Practically, this is genuinely useful and reasonably actionable for your practice — it gives you a defensible, citable dosing framework for combination five-fluorouracil and calcipotriene in the two scenarios where you're most likely to use it: field-treating extensive actinic keratosis, and increasingly, treating squamous cell carcinoma in situ in patients who are poor surgical candidates or have a high confluent burden of disease. I'd call the actinic keratosis and squamous cell carcinoma in situ recommendations practice-informing and ready to adopt; the superficial basal cell carcinoma indication is more of a "reasonable option with close follow-up" than a settled protocol, and worth treating with correspondingly more caution and more frequent rechecks.

That wraps our four articles for July. A reminder from this issue that pattern-matching across case reports, disparities data, tumor registries, and consensus panels all serve the same purpose — sharpening judgment where the highest-quality evidence hasn't caught up yet. Thanks for listening, and I'll see you next month.