Incidence and mortality trends of primary cutaneous melanoma: A 50-year Rochester Epidemiologic Project study.

Background: National cancer reporting-based registry data, although robust, lacks granularity for incidence trends. Expert opinion remains conflicted regarding the possibility of melanoma overdiagnosis in the context of rising incidence without a corresponding rise in mortality. Objective: To characterize 10- and 50-year trends in melanoma incidence and mortality. Methods: Multicenter, population-based epidemiologic study utilizing the Rochester Epidemiology Project for Olmsted County, Minnesota residents diagnosed with melanoma from 01/01/1970 to 12/21/2020. Age- and sex-adjusted incidence and disease-specific mortality are calculated. Results: Two thousand three hundred ten primary cutaneous melanomas were identified. Current age- and sex-adjusted incidence rates increased 11.1-fold since 1970s (P < .001). Over the last decade, there is an overall 1.21-fold (P < .002) increase, with a 1.36-fold increase (P < .002) among females and no significant increase among males (1.09-fold increase, P < .329). Melanoma-specific mortality decreased from 26.7% in 1970s to 1.5% in 2010s, with a hazard ratio (HR) reduction of 0.73 (P < .001) per 5-year period. Increased mortality was associated with Breslow thickness (HR 1.35, P < .001), age at diagnosis (HR 1.13, P = .001) left anatomic site (HR 1.98, P = .016), and nodular histogenic subtype (HR 3.08, P < .001). Limitations: Retrospective nature and focused geographic investigation. Conclusion: Melanoma incidence has continued to increase over the past decade, most significantly in females aged 40+. Trend variations among age and sex cohorts suggests external factors beyond overdiagnosis may be responsible. Disease-specific mortality of melanoma continues to decrease over the last 50 years.

Increasing Incidence and Decreasing Mortality of Melanoma in Elderly Adults: An Epidemiologic Study in Olmsted County, Minnesota.

BACKGROUND AND OBJECTIVE: Primary cutaneous melanoma incidence is increasing in elderly individuals. This population-based cohort examines incidence and mortality rates among adults aged 61 years and older with cutaneous melanoma. MATERIALS AND METHODS: Using the Rochester Epidemiology Project, patients aged 61 years of age or older with a first lifetime diagnosis of cutaneous melanoma between January 1, 1970 and December 31, 2020 were identified. RESULTS: The age- and sex-adjusted incidence rate increased from 16.4 (95% CI, 8.2-24.6) per 100,000 person-years in 1970 to 1979 to 201.5 (95% CI, 185.1-217.8) per 100,000 person-years in 2011 to 2020 (12.3-fold increase). There was a 16.0x increase in males and an 8.5× increase in females. Melanoma incidence has stabilized in males (1.2-fold increase, p = .11) and continues to significantly increase in females (2.7-fold increase, p < .001). Older age at diagnosis was significantly associated with an increased risk of death (HR 1.23 per 5-year increase in age at diagnosis, 95% CI, 1.02-1.47). CONCLUSION: Melanoma incidence continues to increase since 1970. The incidence has risen in elderly females, but has stabilized in males. Mortality has decreased throughout this period.

Association of Lower Extremity Lymphedema and Nonmelanoma Skin Cancers.

OBJECTIVE: To determine whether patients with lymphedema of a lower extremity (LE) had a greater risk of skin cancer than those without lymphedema. PATIENTS AND METHODS: This retrospective cohort study included patients with LE lymphedema examined at Mayo Clinic in Rochester, MN, USA, from January 1, 2000, through December 31, 2020. All patients with the phrase "lower extremity lymphedema" and a diagnostic code for lymphedema present in their electronic health record, as well as their age-, race-, and sex-matched controls without lymphedema, were included in the study. A Kaplan-Meier curve was constructed to examine the time to development of the first skin cancer for the lymphedema cohort and the controls. A Cox proportional hazards regression model was used to calculate hazard ratios. RESULTS: In total, 4437 patients had lymphedema within the study period. Compared with the matched control group, the lymphedema group had a significantly increased risk of skin cancer. For the subset of patients with unilateral lymphedema, the lymphedematous extremity was 2.65 times as likely as the nonlymphedematous LE to have skin cancer, particularly basal cell carcinoma. CONCLUSION: Lower extremity lymphedema appears to be a risk factor for squamous cell carcinoma, basal call carcinoma, and as expected, angiosarcoma. Clinicians caring for patients with LE lymphedema should be aware of this increased risk and monitor at-risk patients accordingly.

Increasing Incidence and Decreasing Mortality of Cutaneous Melanoma in Middle-Aged Adults: An Epidemiologic Study in Olmsted County, Minnesota.

OBJECTIVE: To identify changes in the incidence and mortality of cutaneous melanoma in the fastest-growing segment of the US population, middle-aged adults. PATIENTS AND METHODS: Using the Rochester Epidemiology Project, patients aged 40 to 60 years with a first lifetime diagnosis of cutaneous melanoma between January 1, 1970, and December 31, 2020, while a resident of Olmsted County, Minnesota, were identified. RESULTS: A total of 858 patients with a primary cutaneous first-time melanoma were identified. The overall age- and sex-adjusted incidence rate increased from 8.6 (95% CI, 3.9 to 13.3) per 100,000 person-years in 1970-1979 to 99.1 (95% CI, 89.5 to 108.7) per 100,000 person-years in 2011-2020 (11.6-fold increase). There was a 52.1-fold increase in women and a 6.3-fold increase in men between these 2 periods. In recent years (2005-2009 vs 2015-2020), the incidence has stabilized in men (1.01-fold increase; P=.96) and continues to significantly increase in women (1.5-fold increase; P=.002). Among 659 patients with invasive melanoma, 43 deaths were due to melanoma, and male sex was significantly associated with an increased risk of death (hazard ratio, 2.95; 95% CI, 1.45 to 6.00). A more recent diagnosis of melanoma was significantly associated with a decreased risk of death due to melanoma (hazard ratio, 0.66 per 5-year increase in calendar year of diagnosis; 95% CI, 0.59 to 0.75). CONCLUSION: Melanoma incidence has significantly increased since 1970. During the past 15 years, the incidence has continued to rise in middle-aged women (approximately 50% rise in incidence) but has stabilized in men. Mortality decreased in a linear fashion throughout this time.

An update on long-term outcomes of pediatric follicular mucinosis over a 20-year period: a retrospective cohort study.

BACKGROUND: Follicular mucinosis (FM) is a rare disease characterized by mucin accumulation in the follicular unit. FM's etiology is still widely debated since its first description in 1957. Follicular mucinosis is usually reported to be benign in children, although reports of malignant transformation, most commonly mycosis fungoides, exist. The present project aims to demonstrate that children with a diagnosis of follicular mucinosis have positive long-term outcomes and do not develop mycosis fungoides. MATERIALS AND METHODS: This is a retrospective cohort study where patients with a diagnosis of follicular mucinosis ages 22 years and below were identified. Data surrounding the patient's diagnosis of FM, differential diagnosis, treatments, and long-term outcomes were collected. Patients who were lost to follow-up were contacted by phone for an update on the status of their skin and overall health. RESULTS: Out of 14 patients with follow-up information, none developed subsequent mycosis fungoides or other hematologic malignancies. CONCLUSION: Pediatric patients with follicular mucinosis will likely present with limited disease and not experience malignant transformation.

Cutaneous manifestations of ANCA-associated vasculitis: a retrospective review of 211 cases with emphasis on clinicopathologic correlation and ANCA status.

BACKGROUND: ANCA-associated vasculitis (AAV) may present a wide array of dermatological manifestations. Patients may remain ANCA negative, rendering diagnosis challenging for dermatologists if they depend heavily on ANCA testing to either confirm or rule out AAV. OBJECTIVE: To compare clinical and histopathological features of AAV patients with skin lesions who are ANCA positive versus those who are ANCA negative. METHODS: Retrospective review of medical charts to identify patients diagnosed with AAV by clinical and pathologic criteria who also had cutaneous manifestations. RESULTS: Search revealed that 211 out of 932 (23%) patients had cutaneous manifestations. Of those, 40/211 (20%) patients had persistently ANCA-negative serology. Eosinophilic granulomatosis with polyangiitis (EGPA) comprised the largest cohort. Palpable purpura was the most prominent clinical feature. The most common histopathological feature was leukocytoclastic vasculitis (LCV) in 19 (29%) specimens, extravascular granuloma in 14 (22%), followed by perivascular infiltrate in 12 (18%), with eosinophils in nine. In the ANCA-negative subgroup, perivascular infiltrate was more common followed by LCV but without statistically significant difference. CONCLUSIONS: Diagnosis of AAV should not be based on ANCA testing alone since a considerable number of patients with cutaneous lesions may be ANCA negative. The clinical or histopathologic findings of skin lesions in this study group did not vary based on ANCA status.

Levofloxacin-Associated Bullous Pemphigoid in a Hemodialysis Patient After Kidney Transplant Failure.

BACKGROUND Patients with end-stage renal disease (ESRD) who require dialysis can develop a variety of skin conditions, such as pruritus, xerosis, skin infections, and autoimmune reactions. Bullous pemphigoid (BP) is an autoimmune bullous disorder with an increasing incidence. It can be caused by over 90 medications, but levofloxacin-induced BP in hemodialysis patients has not yet been reported. This report is of a 27-year-old woman with ESRD on hemodialysis who developed BP after levofloxacin treatment. CASE REPORT A 27-year-old woman with hemodialysis after kidney transplantation failure was started with levofloxacin for suspected urinary tract infection 1.5 months prior to admission. Her urinary tract infection symptoms were improved after 3 weeks of levofloxacin treatment, but a serious rash developed, presenting with progressive bullous throughout the body and facial involvement. A thorough workup showed a remarkably elevated hemidesmosomal antigen, BP180 (116 RU/mL), and cutaneous indirect immunofluorescence on human salt-split skin substrate was positive for serum basement membrane zone IgG with an epidermal pattern. Skin biopsy direct immunofluorescence staining showed continuous linear C3 deposition along the basement membrane zone. Prednisone 60 mg daily was started with a taper schedule. She no longer had new skin rash during a follow-up of over 3 months. CONCLUSIONS To the best of our knowledge, this is the first case of levofloxacin-induced BP in a patient undergoing hemodialysis. This report highlights the importance of recognizing skin reactions associated with ESRD in dialysis patients, the correct diagnosis by biopsy and histopathology, and the correct and timely management.

Histopathology of autoimmune bullous dermatoses: what's new?

Autoimmune bullous dermatoses are characterized by the presence of tissue-bound and often circulating pathogenic autoantibodies targeting structural components of the skin and/or mucous membranes. The diagnostic workup for this heterogeneous group of disorders consists of a multi-step process, of which the light microscopic examination is a crucial component. This review is organized following a classification scheme that is based on two main histopathologic features, namely level of intraepithelial split and composition of the inflammatory infiltrate. Overall, we aim to place emphasis on the histopathologic clues that can assist pathologists in differential diagnosis and review the updates in the literature.

Cutaneous manifestations of antineutrophil cytoplasmic antibody-associated vasculitis (AAV): a concise review with emphasis on clinical and histopathologic correlation.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a group of small vessel vasculitides grouped by commonalities of clinical manifestations and ANCA testing. Skin findings are not uncommon, although there is considerable overlap and many times nonspecificity. In general, patients with skin findings tend to have more significant systemic illness, and skin lesions most often develop simultaneously or following onset of systemic symptoms. There are clinical and pathological clues of help in the differentiation of skin findings in these disorders. Purpura of various forms with leukocytoclastic vasculitis is common to all AAV. Granulomatosis with polyangiitis (GPA) comprises the largest number of patients with an AAV. Upper airway, oral, ear, and facial lesions, with or without granuloma, are more commonly seen in this AAV. Pyoderma gangrenosum-like lesions, including facial location, while not common are most closely associated with GPA. Eosinophilic granulomatosis with polyangiitis (EGPA) as its name implies is more closely associated with eosinophilic, allergic, or asthmatic conditions. Papular lesions of the extensor extremities showing extravascular granulomatous changes are characteristic but not specific for EGPA. Microscopic polyangiitis (MPA) is more closely associated with livedoid skin changes, and vascular inflammation tends to be deeper in the skin than with the other AAV. Extravascular granulomas are not expected. While the skin findings in AAV can be nonspecific and overlapping, combining careful full skin examination with histopathologic study of selected lesions is critical to making the correct diagnosis and in ruling out other similar diseases not ANCA related. The aim of this article is to encourage increased participation by dermatologists and dermatopathologists in the care of these patients.

Pyoderma gangrenosum-like skin ulceration in antineutrophil cytoplasmic antibody-associated vasculitis: a retrospective case series.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) can be associated with various cutaneous manifestations. Several case reports have described skin ulceration resembling pyoderma gangrenosum (PG), particularly in granulomatosis with polyangiitis (GPA); however, the true incidence of this PG-like ulceration in various diseases is unknown. In addition, PG is frequently misdiagnosed, and diagnosis may rely on exclusion of other causes of ulcers. We aimed to describe clinical and histopathological features of PG-like ulcerations occurring in association with AAV and identify clues to differentiate these ulcers from PG. Retrospective search was conducted to include patients with AAV presenting with PG-like ulcers treated at our institution. This large case series highlights presentation of PG-like ulcers occurring in patients with AAV. Care should be taken to avoid delayed or missed diagnosis of AAV. Distinction between AAV and PG is challenging yet mandatory for proper treatment. Diagnosis relies on a constellation of detailed cutaneous clinical examination, systemic symptoms or illness, histopathological features and laboratory tests.

Do histopathological features correlate with systemic manifestations in dermatomyositis? Analysis of 42 skin biopsy specimens from 22 patients.

BACKGROUND: Understanding whether specific histopathologic features on skin biopsy are predictive of systemic associations in dermatomyositis (DM) would be useful to guide clinical screening. METHODS: Through retrospective medical record search, clinical and laboratory findings of patients with DM were documented. Existing skin biopsy slides were re-reviewed blindly. RESULTS: Of all biopsy specimens (n = 42), the most frequent histopathological finding was vacuolar interface dermatitis (95%). Other features included perivascular lymphocytic infiltrate (71%), increased dermal mucin (40%), vessel wall thickening (12%), follicular plugging (9.5%), and dermal sclerosis (7%). Neutrophilic infiltrate was observed in three biopsies from a patient with adalimumab-associated DM. Vasculitis was not observed. There was no statistically significant difference in the presence of any histopathological feature and that of various systemic manifestations (i.e., myopathy, interstitial lung disease [ILD] and malignancy). However, we observed that dense lichenoid infiltrate rather than pauci-inflammatory changes correlated with severe itching (p < 0.001). Patients with MDA-5 antibodies were significantly more likely to have vasculopathy than those without (p = 0.029*). CONCLUSIONS: No dermatopathologic feature was reliably predictive of myopathy, ILD, or malignancy. This finding implies that, regardless of histopathologic findings, patients should be screened for associated conditions as clinically indicated.

Intravascular histiocytosis: mimicker of cellulitis, angiosarcoma, inflammatory breast cancer, and others.

BACKGROUND: Intravascular histiocytosis is an underrecognized reactive skin condition characterized by the clinical finding of poorly demarcated erythematous to violaceous patches and plaques. The diagnosis is confirmed by the histologic findings of intraluminal histiocytes on skin biopsy and exclusion of an alternative diagnosis. METHODS: A review of patients with a histologic diagnosis of intravascular or intralymphatic histiocytosis and seen at Mayo Clinic, Rochester, Minnesota, from January 1, 2010, to October 10, 2020, was performed. Histologic and clinical information was collected from the medical records. RESULTS: Nine patients were identified. Clinical impressions prior to biopsy varied widely, and no clinician included intravascular histiocytosis in the initial clinical differential diagnosis. Eight patients had preceding trauma to the affected area. CONCLUSION: Intravascular histiocytosis remains a rare skin condition. Clinical identification remains low. Our cases add support to the hypothesis that intravascular histiocytosis is a reactive condition often preceded by trauma and/or surgery.

Impact of adding an IgG4 conjugate to routine direct immunofluorescence testing for subepithelial and intraepithelial autoimmune blistering disorders.

BACKGROUND: Certain autoimmune bullous dermatoses are mediated by autoantibodies of the IgG4 subclass. We determined the diagnostic impact of adding IgG4 to our conventional direct immunofluorescence (DIF) panel. METHODS: For all cases submitted to our referral laboratory for DIF over 1 month (n = 630), we performed IgG4 testing and collected consecutive biopsy specimens showing definite or indeterminate linear or cell-surface deposition of IgG, IgG4, and/or C3. On retrospective blinded review, we classified the pattern and whether the findings were definite, indeterminate, or negative. When present, substantial background staining was recorded. RESULTS: Seventy DIF specimens met the inclusion criteria. Of 22 (31.4%) specimens equivocal for linear or cell-surface deposition, 9 (40.9%) had definitive IgG4 findings, either linear (3 of 14 equivocal linear cases; 21.4%) or cell-surface (6 of 8 equivocal cell-surface cases; 75.0%). Background deposition was substantial in 14 cases (20.0%) for IgG but in none for C3 or IgG4. CONCLUSION: IgG4 allowed the classification of over 40% of DIF cases that were otherwise equivocal by IgG and C3. IgG4 staining showed lower levels of non-specific background staining than IgG or C3. IgG4 appears to contribute most value in cases with cell-surface deposition or with equivocal linear IgG deposition and negative C3 results.

Disseminated intravascular coagulopathy: a complication of Stevens-Johnson syndrome/toxic epidermal necrolysis.

BACKGROUND: The purpose of this study was to retrospectively assess clinical characteristics and mortality rate of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients who developed disseminated intravascular coagulation (DIC). METHODS: A systematic retrospective chart review of all patients with concurrent clinical diagnosis of DIC and SJS/TEN between July 1, 2012, and January 1, 2020, at the Mayo Clinic was performed. RESULTS: The incidence of DIC in patients with SJS/TEN was 1.3% at our institution (5 of 396 DIC patients). Triggers of SJS/TEN included lamotrigine, clofarabine, antibiotics, and sepsis. Two patients diagnosed with SJS and two patients with TEN succumbed to the disease. CONCLUSION: DIC is a rare underlying risk in patients with SJS/TEN and is associated with increased mortality. Early clinician awareness and aggressive intervention is advised.

Histopathologic features of noninfectious granulomatous disorders involving the skin.

Granulomatous dermatoses may represent primary skin inflammation or can serve as the harbinger of a multitude of underlying systemic disorders or drug reactions. Taken together with clinical findings, the microscopic features from skin biopsy can allow recognition of various patterns and facilitate a precise diagnosis. Accurate classification of entities in this category of inflammatory dermatoses may prompt clinicians to investigate for underlying systemic problems, thereby allowing the pathologist to add considerable value in the care of affected patients. This review article categorizes clinical and microscopic features of common and uncommon causes of noninfectious dermal and subcutaneous granulomatous inflammation.