Clinical associations and classification of immune checkpoint inhibitor-induced cutaneous toxicities: a multicentre study from the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients.

BACKGROUND: Cutaneous immune-related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs). OBJECTIVES: To investigate clinical associations of cutaneous toxicities induced by different ICI therapies. METHODS: This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models. RESULTS: In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous-type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti-CTLA4 was less frequent than anti-programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01-0·76] and vitiligo (OR 0·07, 95% CI 0·006-0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02-0·31), lichenoid reactions (OR 0·15, 95% CI 0·03-0·77) and eczematous reactions (OR 0·24, 95% CI 0·07-0·78), all compared with pruritic rash. CONCLUSIONS: Our study showed that skin-oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow-up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome. What is already known about this topic? Patients with cancer treated with different immune checkpoint inhibitors (ICIs) carry an increased risk of developing various types of skin toxicities. What are the clinical implications of this work? In this multicentre cohort study we showed that ICI-related skin toxicities do not share a single pattern and may depend on several factors, including the specific agent administered and the underlying malignancy. Among patients with macular rash, vitiligo or multiple skin toxicities, patients received ICIs more frequently for melanoma than for non-small cell lung cancer. The combination of ICI and chemotherapy compared with ICI monotherapy occurred to a lesser extent in patients with psoriatic rash lichenoid and eczematous reactions, compared with patients with pruritus. Clinical awareness and specialized dermatological consultation should be advocated.

Histopathology of Dermatologic Complications of Tattoos.

ABSTRACT: Tattoos are characterized by the introduction of exogenous pigments into the dermis. Tattoos usually serve cosmetic purposes, although they may have other causes, such as traumatic pigment implants in accidents or medical-related tattoos in the context of radiotherapy. Dermatologic adverse reactions are relatively uncommon, and they include infections, immune-mediated reactions, cutaneous lesions secondary to the Koebner phenomenon, exacerbation of preexisting dermatosis, benign and malignant neoplasms, and a miscellaneous group of dermatologic conditions that may appear in a preexisting tattoo. The aim of this study is to review the types of histopathologic reactions that may appear in a preexisting permanent tattoo.

Safety of 5α-reductase inhibitors and spironolactone in breast cancer patients receiving endocrine therapies.

PURPOSE: To provide dermatologists and oncologists with a foundation for practical understanding and uses of 5α-reductase inhibitors and spironolactone for breast cancer patients and survivors receiving endocrine therapies (ETs), including the effect of these treatments on sex hormone levels, any reported drug interactions, and any risk of malignancy. METHODS: All published studies from January 1978 through April 2018 were considered, using databases such as PubMed, Google Scholar, and Science Direct. Forty-seven studies were included in this review. RESULTS: There is no evidence of interactions between 5α-reductase inhibitors and spironolactone with ETs used in breast cancer. Sex hormone alteration with 5α-reductase inhibitor or spironolactone use is variable. Three randomized controlled trials, 1 case-control study, and 6 retrospective cohort studies, including 284 female patients, studied the effects of 5α-reductase inhibitors on serum estrogen levels. Levels were increased in 97 of 284 (34%) patients, decreased in 15 of 284 (5.3%) patients, and unchanged in 162 of 284 (57%) patients. Four retrospective cohort studies, 1 case study, and 1 double-blinded crossover study, including 95 female patients, assessed the effect of spironolactone on estrogen levels. Levels were increased in 25 of 95 (26%) patients, decreased in 6 of 95 (6.3%) patients, and unchanged in 64 of 95 (67%) patients. Ultimately, most patients did not have a significant alteration in the level of estrogen when using 5α-reductase inhibitors or spironolactone. No consistent evidence of increased risk of female breast cancer while on spironolactone was reported in 3 studies including 49,298 patients; the risk of breast cancer with the use of 5α-reductase inhibitors has not been studied. CONCLUSIONS: Most patients did not show increased estrogen levels with spironolactone and there were no data suggesting increased risk of breast cancer. Based on hormonal and pharmacological activity, spironolactone may be considered for further research on alopecia and hirsutism in breast cancer patients.

Nonmelanoma Skin Cancer in Childhood and Young Adult Cancer Survivors Previously Treated With Radiotherapy.

BACKGROUND: Radiotherapy (RT) is a risk factor for nonmelanoma skin cancer (NMSC), specifically basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), but whether features, histology, or recurrence of NMSC after RT resemble those observed in the general population is unknown. METHODS: A retrospective review (1994-2017) was performed within the Adult Long-Term Follow-Up Program and Dermatology Service at Memorial Sloan Kettering Cancer Center. Demographics, clinical features, histology, treatment, and recurrence were collected for this patient cohort that was under close medical surveillance. Pathology images were reviewed when available. RESULTS: A total of 946 survivors (mean age, 40 years [SD, 13]) were assessed for NMSC. The mean age at first cancer diagnosis was 16 years (range, 0-40 years [11]), and the most common diagnosis was Hodgkin lymphoma (34%; n=318). In 63 survivors, 281 primary in-field lesions occurred, of which 273 (97%) were BCC and 8 (3%) were SCC. Mean intervals from time of RT to BCC and SCC diagnosis were 24 years (range, 2-44 years) and 32 years (range, 14-46 years), respectively. The most common clinical presentation of BCC was macule (47%; n=67), and the most common histologic subtypes were superficial for BCC (48%; n=131) and in situ for SCC (55%; n=5). Mohs surgery predominated therapeutically (42%; n=117), the mean duration of follow-up after treatment was 6 years (range, 12 days-23 years), and the 5-year recurrence rate was 1% (n=1). CONCLUSIONS: Most NMSCs arising in sites of prior RT were of low-risk subtypes. Recurrence was similar to that observed in the general population. Current guidelines recommend surgical intervention for tumors arising in sites of prior RT because they are considered to be at high risk for recurrence. These findings suggest that an expanded role for less aggressive therapy may be appropriate, but further research is needed.

Hair disorders in patients with cancer.

Cytotoxic chemotherapies, molecularly targeted therapies, immunotherapies, radiotherapy, stem cell transplants, and endocrine therapies may lead to hair disorders, including alopecia, hirsutism, hypertrichosis, and pigmentary and textural hair changes. The mechanisms underlying these changes are varied and remain incompletely understood, hampering the development of preventive or therapeutic guidelines. The psychosocial impact of chemotherapy-induced alopecia has been well documented primarily in the oncology literature; however, the effect of other alterations, such as radiation-induced alopecia, hirsutism, and changes in hair color or texture on quality of life have not been described. This article reviews clinically significant therapy-related hair disorders in oncology patients, including the underlying pathophysiological mechanisms, severity grading scales, patient-reported quality of life questionnaires, management strategies, and future translational research opportunities.

Hair disorders in cancer survivors.

With increasing survival rates across all cancers, survivors represent a growing population that is frequently affected by persistent or permanent hair growth disorders as a result of systemic therapies, radiotherapy, surgical procedures, and therapeutic transplants. These hair disorders include persistent chemotherapy-induced alopecia, persistent radiotherapy-induced alopecia, endocrine therapy-induced alopecia and hirsutism, postsurgery alopecia and localized hypertrichosis, and persistent stem cell transplantation and targeted therapy-induced alopecia. The information contained in this continuing medical education series should facilitate a better understanding on hair disorders in cancer survivors so that adequate support and therapies may be provided.

Inflammatory dermatoses, infections, and drug eruptions are the most common skin conditions in hospitalized cancer patients.

BACKGROUND: Dermatologic conditions cause morbidity and mortality among hospitalized cancer patients. An improved understanding is critical for implementing clinical and research programs in inpatient oncodermatology. OBJECTIVE: To characterize inpatient dermatology consultations at a large comprehensive cancer center. METHODS: Retrospective database query of new admissions and medical record review of initial inpatient dermatology consultations comparing inpatients consulted and not consulted during January-December 2015. RESULTS: In total, 412 of 11,533 inpatients received 471 dermatology consultations (54% male, median age 59.5 years). Patients with hematologic cancers were 6 times more likely to receive dermatologic consultations compared with nonhematologic cancers (odds ratio 6.56, 95% confidence interval 5.35-8.05, P < .0001). Patients consulted by a dermatologist had a significantly longer length of stay than inpatients not consulted by dermatology (median 11 vs 5 days, P < .0001). Among the 645 dermatologic conditions diagnosed, the most common categories were inflammatory diseases, infections, and drug reactions; the most frequent conditions were contact dermatitis, herpes zoster, and chemotherapy-induced drug eruptions. LIMITATIONS: The study's retrospective nature and single-institution setting are potential limitations. CONCLUSION: Hematologic malignancies are a significant risk factor for dermatology inpatient consultations. A significantly longer length of stay was associated with dermatology consultations, suggesting high comorbidities in these patients. Increased dermatologic care of these inpatients might improve quality of life, dermatologic health, and ability to receive anticancer agents.

[Atypical leiomyoma in a patient with cutaneous leiomyomatosis and mutation of the enzyme fumarate hydratase]. / Leiomioma cutáneo atípico en un paciente con leiomiomatosis cutánea y mutación de la enzima fumarato hidratasa.

We report the case of a 56 year-old male with an atypical leiomyoma in the context of a cutaneous leiomyomatosis and a family history of uterine leiomyomatosis. The genetic study revealed a mutation in the gene for the enzyme fumarate hydratase, but he has not had any renal malignancy so far. Atypical leiomyoma is a rare tumor that usually presents as a single lesion and is exceptional in patients with cutaneous leiomyomatosis. The relation between fumarate hydratase enzyme mutations with multiple leiomyomas, uterine leiomyomatosis and an increased risk of developing kidney cancer is widely known. However, the role of these mutations in the development of atypical leiomyomas is still impossible to clarify given the few cases reported in the literature.

[Cutaneous and subcutaneous leiomyosarcoma: report of two cases]. / Leiomiosarcoma cutáneo y subcutáneo: reporte de dos casos.

Cutaneous leiomyosarcomas are uncommon malignant tumors of smooth muscle. We report herein two cases of cutaneous leiomyosarcoma, one of dermal and other of subcutaneous vascular origin, confirmed by histology and immunohistochemistry. Both cases were treated with wide surgical excision, one with local recurrence. No metastases were detected at follow-up. Leiomyosarcomas should be considered in lesions with histologic features of spindle cell malignancy. It is necessary in most of the cases a histological differentiation with specific immunohistochemical markers. The treatment of choice is radical excision with wide margins, achieving satisfactory results.

Dermoscopy of acral angioma serpiginosum.

Angioma serpiginosum (AS) is an unusual vascular disorder that typically affects female patients, begins in childhood and stabilizes in adulthood and not frequently involve acral skin. We herein present a 13 year-old girl with an asymptomatic erythematous punctuate first noticed on the right palm three years ago, with a proximal serpiginous progression up to the forearm. On examination there was a nonblanching erythematous punctuate on the palm and the inner aspect of right hand and forearm. Dermoscopy showed an erythematous parallel ridge pattern with some red globules and dots spreading on a linear arrangement, and the acrosyringia openings were not affected. Histopathological study showed dilated capillaries in the dermal papillae. This feature is consistent with angioma serpiginosum (AS). To the best of our knowledge, this is the first report that shows a dermoscopic image of a palmar AS. The dermoscopic pattern described in this case could aid in the diagnosis of AS and could add a value in the differential diagnosis with vascular lesions on acral skin.

[Exudative onycholysis and acute bacterial paronychia related to BIBF-1120 and paclitaxel: response to topical therapy]. / Onicólisis exudativa y paroniquia bacteriana aguda en relación con BIBF-1120 y paclitaxel: respuesta a la terapia tópica.

A case of a 50 years-old breast cancer patient treated with weekly paclitaxel and BIBF 1120 is reported herein. At the end of the twelfth cycle of chemotherapy, the patient developed distal onycholysis with intense hyponychium serous exudates, pain and malodor in all her fingernails. It was treated with topical fusidic acid and 1% methylprednisolone aceponate two times daily, with an excellent clinical response from the first three days of treatment. Bacterial paronychia with nail plate loss of the fifth left fingernail was observed a week after the topical therapy was started, with positive cultures for Methicillin susceptible Staphylococcus aureus. There are few reported cases of exudative onycholysis associated with chemotherapy. However, these are especially related to paclitaxel. No recurrences of nail disturbances were observed weeks after the end of chemotherapy. Topical corticosteroids and fusidic acid could be considered as a therapeutic option when exudative onycholysis related to paclitaxel is established

Drug reactions with eosinophilia and systemic symptoms induced by immune checkpoint inhibitors: an international cohort of 13 cases.

Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), drug reactions with eosinophilia and systemic symptoms (DRESS) have been very rarely reported. The objective of this study is to better define the clinical and histologic features, treatment and prognosis of ICI-related DRESS. This retrospective case series was conducted between 01 January 2015 and 31 December 2021 by the dermatology departments of five international networks involved in drug reactions. Inclusion criteria were age ≥18 years old, DRESS with Regiscar score ≥4 (probable or certain) and ICI as a suspect drug. Clinical, biologic and follow-up data were extracted from the medical charts. Thirteen patients were included. The median time to onset was 22 days (3-11). No patients had a high-risk drug introduced in the past 3 months. A majority of patients presented fever (92%), diffuse exanthema (77%) and facial edema (69%). Biologic features included hypereosinophilia in eight patients (61.5%), hyperlymphocytosis in 3 (23%), elevated liver function tests in 11 (85%, grade 1 or 2 in most cases) and renal involvement in 5 (38%). Two patients (15%) had lung involvement. PCR evidence of viral replication was detected in five patients (38.5%). Treatment involved discontinuation of the suspect ICI and systemic steroids with variable dose and duration regimens. Among the four patients in which ipilimumab + nivolumab combination therapy was initially suspected, one was rechallenged with nivolumab monotherapy with good tolerance. Five patients were switched to another anti-PD-1 plus low-dose systemic steroids, with good tolerance in four cases. No patient died because of DRESS. DRESS induced by ICI are rare and of moderate severity. A consensus for management is still pending.

Shared decision-making quality and decisional regret in patients with low-risk superficial basal cell carcinoma: A prospective, multicenter cohort study.

Background: Many therapies are available to treat low-risk superficial basal cell carcinoma (lr-sBCC), which may complicate the shared decision-making (SDM) process. Objective: To assess the SDM process of patients and physicians when deciding lr-sBCC therapy as well as the factors that may influence the SDM process. Methods: A prospective, multicenter cohort study was conducted over 18 months, from October 2018 to April 2020, in 3 tertiary university hospitals and 1 private hospital. Results: This study included 107 patients. There was a weak positive correlation between Shared Decision-Making Questionnaire-Patient version (SDM-Q-9) and Shared Decision-Making Questionnaire-Physician version (SDM-Q-Doc) (Spearman's correlation coefficient [rs] [105] = 0.21; P = .03). Most patients (71%) chose a nonsurgical treatment after the SDM process. Patients with higher satisfaction with the SDM had lower decisional conflict and decisional regret (P < .001). Patients aged >80 years had higher rates of significant decisional conflict. When evaluating treatment decisions, the highest median score for decisional conflict (22, IQR [16]; P = .01) was observed among patients who chose a surgical excision. Limitations: Patients may have self-selected to participate. Conclusion: This study suggests that some patients may prefer less invasive therapies for lr-sBCC. The SDM process may reduce decisional conflict and decisional regret.

Detection of novel therapies using a multi-national, multi-institutional registry of cutaneous immune-related adverse events and management.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) remain a prevalent and common sequelae of immune checkpoint inhibitor (ICI) therapy, often necessitating treatment interruption and prolonged immune suppression. Treatment algorithms are still poorly defined, based on single-institution case reports without adequate safety assessments, and subject to publication bias. METHODS: Data in this registry were collected through a standardized REDCap form distributed to dermatologists via email listserv. RESULTS: Ninety-seven cirAEs were reported from 13 institutions in this registry. Topical and systemic steroids were the most common treatments used; however, targeted treatment matched to disease morphology was identified at numerous sites. Novel cirAE therapy uses that to our knowledge have not been previously described were captured including tacrolimus for the treatment of follicular, bullous, and eczematous eruptions and phototherapy for eczematous eruptions. Moreover, further evidence of cirAE treatment applications sparsely described in literature were also captured in this study including dupilumab and rituximab for bullous eruptions, phototherapy for lichenoid and psoriasiform eruptions, and acitretin for psoriasiform eruptions, among others. No serious adverse events were reported. Numerous targeted therapeutics including dupilumab, rituximab, and psoriasis biologics, among others, were associated with a cirAE grade improvement of ≥2 grades in every patient treated. CONCLUSION: This study suggests that a multi-institutional registry of cirAEs and management is not only feasible but that the information collected can be used to detect, evaluate, and rigorously assess targeted treatments for cirAEs. Further expansion and modification to include treatment progression may allow for sufficient data for specific treatment recommendations to be made.

Shared decision making for patients with breast and gynecologic malignancies undergoing chemotherapy associated with persistent alopecia.

Objective: To assess patient-perceived involvement in shared decision making among those diagnosed with breast or gynecologic malignancies undergoing chemotherapy associated with persistent chemotherapy-induced alopecia (pCIA). We also sought to identify factors that influence shared decision making. Methods: We recruited patients from the Gynecologic Medical Oncology and Breast Medicine Services at a large academic center for this prospective cohort study. All patients were scheduled to start chemotherapy between June 1, 2017 and December 31, 2017. Following medical consultation, including discussion of the risk of pCIA, patients completed the 9-item Shared Decision Making Questionnaire (SDM-Q-9). Clinical and sociodemographic information was also collected. Univariate analysis was used to evaluate SDM-Q-9 total scores and their constituents for all variables. Results: Sixty-one patients completed the survey. The median total SDM-Q-9 score was 95.6 (95% CI: 90-100). Most patients (n = 57, 93%) reported a high level of involvement (SDM-Q-9 total score > 66). There was no difference in total scores between patients with breast compared with gynecologic cancer (P > .05). By individual item, the scores for item Q1 ("My doctor made clear that a decision needs to be made") were significantly lower for Black patients and those with advanced disease (P < .05). Conclusions: Most patients indicated they were adequately involved in shared decision making regarding chemotherapy treatment options and their risk for pCIA. Patients from underrepresented populations and those with advanced disease may benefit from additional support from their clinicians to better address the anticipated psychosocial impacts of pCIA and facilitate the provision of optimal and equitable care.