Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer.

BACKGROUND: Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions. MAIN BODY: Approximately 0.15-0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS. CONCLUSION: Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.

Clinical features of atypical presentations of mucocutaneous herpes simplex virus infection observed in immunosuppressed individuals. Part II: the knife-cut sign.

The knife-cut sign is a distinctive manifestation of herpes simplex virus (HSV) type 1 or HSV type 2 infection that has been described in at least 10 immunocompromised patients. It appears as an extremely painful linear erosion or fissure in an intertriginous area such as the body folds beneath the breast, or within the abdomen, or in the inguinal region. Also, concurrent HSV infection at other mucocutaneous sites, or viscera, or both have been observed. The patients had medical conditions (at least 9 patients) and/or immunosuppressive drug therapy (6 patients). The diagnosis of HSV infection was confirmed by viral culture (8 patients), biopsy (4 patients), direct fluorescence antibody testing (3 patients), immunohistochemistry staining (2 patients), polymerase chain reaction (2 patients), or Western blot serologic assay (1 patient). Knife-cut sign-associated HSV infection is potentially fatal; three patients died. However, clinical improvement or complete healing occurred in the patients who received oral valacyclovir (1 patient), or intravenous acyclovir (2 patients), or intravenous acyclovir followed by foscarnet (1 patient). In summary, HSV infection associated with a positive the knife-cut sign is a potentially fatal variant of HSV infection that occurs in the intertriginous areas of immunocompromised patients and usually requires intravenous antiviral therapy.

Clinical features of atypical presentations of mucocutaneous herpes simplex virus infection observed in immunosuppressed individuals. Part I: herpetic geometric glossitis.

Herpetic geometric glossitis is a unique morphologic variant of HSV (herpes simplex virus) type 1 infection on the dorsum of the tongue that presents as an extremely painful linear central lingual fissure with a branched pattern. in the center of the tongue; there is a branched pattern of fissures that extend bilaterally from the central linear fissure. Herpetic geometric glossitis has been reported in 11 patients; 8 of these individuals were immunocompromised. Medical conditions and immunosuppressive medication treatment (7 patients) or only medical disorders (3 patients) or neither (1 patient) were present. HSV type 1 infection was diagnosed by viral culture in (7 patients), Tzanck preparation (2 patients) or clinically (2 patients). Mucocutaneous HSV infection at non-lingual locations--including the lips, labial mucosa, face and chest--were observed in 5 patients. All patients' symptoms and lesions responded to treatment with oral antiviral therapy: acyclovir (9 patients), famciclovir (1 patient) or valacyclovir (1 patient). The lingual pain and dorsal tongue fissures completely resolved completely within two to 14 days. In summary, herpetic geometric glossitis is a unique HSV type 1 infection, usually in immunocompromised patients, that occurs on the dorsal tongue and responds completely after treatment with orally administered antiviral therapy.

Basal cell carcinoma in situ of the skin revisited: case reports of the superficial type and fibroepithelioma type of this in situ cutaneous neoplasm.

Cutaneous basal cell carcinoma in situ is a recently proposed subtype of this skin cancer. It is characterized by either restriction of the tumor cells within the epidermis or the presence of tumor cells contiguous with the overlying epidermis that extend into the underlying dermis, or both. Importantly, cancer invasion-demonstrated by non-contiguous aggregates of basaloid tumor cells in the dermis-is not a feature of in situ basal cell carcinoma of the skin. A 63-year-old woman with cutaneous basal cell carcinoma in situ-superficial type that presented as an erythematous scaly plaque on her abdomen and a 61-year-old man with a cutaneous basal cell carcinoma in situ-fibroepithelioma type that presented as a flesh-colored smooth exophytic nodule on his back are reported. The characteristics of in situ basal cell carcinoma of the skin in these individuals are summarized. In conclusion, similar to other cutaneous malignant neoplasms-such as squamous cell carcinoma, malignant melanoma, and Merkel cell carcinoma-basal cell carcinoma of the skin can also present as an in situ cancer.

Patients with a new-onset cutaneous sebaceous neoplasm following immunosuppression should be evaluated for Muir-Torre syndrome with germline mismatch repair gene mutation analysis: case reports.

Patients with Muir-Torre syndrome may have a systemic malignancy and a sebaceous neoplasm such as an adenoma, epithelioma, and/or carcinoma. The syndrome usually results from a germline mutation in one or more mismatch repair genes. Iatrogenic or acquired immunosuppression can promote the appearance of sebaceous tumors, either as an isolated event or as a feature of Muir-Torre syndrome and may unmask individuals genetically predisposed to the syndrome. Two iatrogenically immunosuppressed men with Muir-Torre syndrome features are described. Similar to these immunocompromised men, Muir-Torre syndrome-associated sebaceous neoplasms have occurred in solid organ transplant recipients, human immunodeficiency virus-infected individuals, and patients with chronic diseases who are treated with immunosuppressive agents. Muir-Torre syndrome-associated sebaceous neoplasms occur more frequently and earlier in kidney recipients, who are receiving more post-transplant immunosuppressive agents, than in liver recipients. The development of sebaceous neoplasms is decreased by replacing cyclosporine or tacrolimus with sirolimus or everolimus. Specific anti-cancer vaccines or checkpoint blockade immunotherapy may merit exploration for immune-interception of Muir-Torre syndrome-associated sebaceous neoplasms and syndrome-related visceral cancers. We suggest germline testing for genomic aberrations of mismatch repair genes should routinely be performed in all patients-both immunocompetent and immunosuppressed-who develop a Muir-Torre syndrome-associated sebaceous neoplasm.

Cutaneous perivascular epithelioid cell tumor (PEComa): case report and world literature review of clinical and molecular characteristics.

Perivascular epithelioid cell tumor (PEComa) expresses melanocytic and smooth muscle markers. A man with a primary malignant cutaneous (distal left forearm) PEComa is reported. Immunohistochemistry demonstrated MiTF, HMB-45, caldesmon, desmin, and smooth muscle actin, as well as BCL1, CD10, and CD68. Next generation sequencing showed four pathogenic genomic aberrations involving BIRC3, FANCC, TP53, and TSC1 genes. His work-up was negative for metastatic disease; a wide local excision was performed. Including the reported patient, cutaneous PEComa has been described in 65 individuals: primary benign (N=58), primary malignant (N=5), and metastatic malignant (N=2). Cutaneous PEComa typically presented as a painless, slowly growing nodule of <2 centimeters on the lower extremity of a woman in her fifth decade. The neoplasms consisted of epithelioid cells, spindle cells, or both. The most reliable markers were MiTF (100%), HMB45 (94%), and NKIC3 (94%) for melanocytes and smooth muscle actin (43%) and desmin (40%) for smooth muscle. There has been no reported recurrence of a primary cutaneous benign or malignant PEComa after complete excision. Genomic alterations in malignant PEComas frequently involve TSC1 and TSC2 genes (mTOR activators), as well as TFE3 fusions. In November 2021, the FDA approved nab-sirolimus (mTOR inhibitor) for PEComas.

Multiple skin neoplasms at one site (MUSK IN A NEST): collision tumor consisting of epidermal (macular seborrheic keratosis) and dermal (lichen amyloidosis) components.

A collision tumor is a neoplastic lesion comprised of two or more tumors consisting of distinct cell populations in the concurrent location. Multiple skin neoplasms at one site (MUSK IN A NEST) is a term recently coined to describe two or more cutaneous benign or malignant tumors occurring at the same anatomic site. In retrospective studies, seborrheic keratosis and cutaneous amyloidosis have both individually been documented as a component of a MUSK IN A NEST. This report describes a 42-year-old woman who presented with a pruritic skin condition on her arms and legs of 13 years' duration. Skin biopsy results showed epidermal hyperplasia with hyperkeratosis, hyperpigmentation of the basal layer with mild acanthosis, and evidence of amyloid deposition in the papillary dermis. Based on the clinical presentation and pathology findings, a concurrent diagnosis of macular seborrheic keratosis and lichen amyloidosis was established. A MUSK IN A NEST consisting of a macular seborrheic keratosis and lichen amyloidosis is likely a more common occurrence than implied by the paucity of published cases of this phenomenon.

Novel somatic alterations in unicentric and idiopathic multicentric Castleman disease.

OBJECTIVES: Castleman disease (CD) is a heterogeneous group of disorders involving systemic inflammation and lymphoproliferation. Recently, clonal mutations have been identified in unicentric CD (UCD) and idiopathic multicentric CD (iMCD), suggesting a potential underlying neoplastic process. METHODS: Patients with UCD or iMCD with next generation sequencing (NGS) data on tissue DNA and/or circulating tumor DNA (ctDNA) were included. RESULTS: Five patients were included, 4 with iMCD and 1 with UCD. Four patients (80%) were women; median age was 40 years. Three of five patients (60%) had ≥1 clonal mutation detected on biopsy among the genes included in the panel. One patient with iMCD had a 14q32-1p35 rearrangement and a der(1)dup(1)(q42q21)del(1)(q42) (1q21 being IL-6R locus) on karyotype. This patient also had a NF1 K2459fs alteration on ctDNA (0.3%). Another patient with iMCD had a KDM5C Q836* mutation, and one patient with UCD had a TNS3-ALK fusion but no ALK expression by immunohistochemistry. CONCLUSIONS: We report 4 novel somatic alterations found in patients with UCD or iMCD. The 1q21 locus contains IL-6R, and duplication of this locus may increase IL-6 expression. These findings suggest that a clonal process may be responsible for the inflammatory phenotype in some patients with UCD and iMCD.

Basal cell carcinoma associated with non-neoplastic cutaneous conditions: a comprehensive review.

Basal cell carcinoma (BCC) can be a component of a collision tumor in which the skin cancer is present at the same cutaneous site as either a benign tumor or a malignant neoplasm. However, BCC can also concurrently occur at the same skin location as a non-neoplastic cutaneous condition. These include autoimmune diseases (vitiligo), cutaneous disorders (Darier disease), dermal conditions (granuloma faciale), dermal depositions (amyloid, calcinosis cutis, cutaneous focal mucinosis, osteoma cutis, and tattoo), dermatitis, miscellaneous conditions (rhinophyma, sarcoidal reaction, and varicose veins), scars, surgical sites, systemic diseases (sarcoidosis), systemic infections (leischmaniasis, leprosy and lupus vulgaris), and ulcers. The relationship between the BCC and the coexisting non-neoplastic condition may be coincidental or possibly related to the development of the BCC; alternatively, the development of the BCC may be unrelated to the coexisting non-neoplastic conditions and secondary to either a Koebner isomorphic response or a Wolf isotopic response in an immunocompromised district of skin. This paper reviews several of the case reports and studies that describe the association of BCC with these non-neoplastic cutaneous conditions.

Acquired giant plantar fibrokeratoma: case report and review.

Acquired digital fibrokeratoma is a benign fibrous tumor usually located on the toes and fingers. A 63-year-old man with an acquired giant plantar fibrokeratoma is described. He presented with an asymptomatic exophytic nodule of ten years duration; there is no history of trauma to the site. It measured 15x10x5mm and was located on the plantar foot proximal to the third toe. Excisional biopsy established the diagnosis of fibrokeratoma. Giant acquired fibrokeratoma,has been described in 16 patients including ours: three women and 13 men. They are located on either the upper extremity (one man) or the lower extremity (15 individuals). Acquired plantar fibrokeratoma is rare. Including our patient, it has been reported in 11 patients: one woman and ten men. The woman was 13 years of age and the men ranged from 15 to 77-years-old. Plantar acquired fibrokeratomas are located on either the plantar aspect of the toes, the sole of the foot, or the heel. An excisional biopsy provided adequate treatment without subsequent recurrence of both giant and plantar fibrokeratomas.

Social media (SoMe) enhances exposure of dermatology articles.

Social media (SoMe) refers to a variety of virtual platforms used to enhance sharing of information. To evaluate the influence of SoMe with regards to views and downloads of published dermatology articles, we conducted a retrospective study from July 2020-March 2021 examining articles published on Instagram and Twitter under Dermatology Online Journal (DOJ) accounts and compared these with type-matched and issue-matched articles that were not posted on social media. During this time period, 163 total articles of the three types used for social media (Case Report, Case Presentation, and Photo Vignette) were published in DOJ and 15 were promoted via SoMe. Utilization of SoMe demonstrated a significant (P<0.0001) positive effect with regards to both views (175.5±16.4) and downloads (31.5±4.0) over matched articles not published on SoMe. Similar trends illustrating the positive effect of SoMe on readership have been previously observed in the field of dermatology as well as other medical specialties. Most direct accessions to articles arrived via Instagram rather than Twitter, diverging from previous studies on SoMe use in medical journals. Social media, in particular Instagram, can be a successful platform to enhance the exposure of peer-reviewed medical information.

Dyshidrosiform Bullous Pemphigoid.

Dyshidrosiform bullous pemphigoid is a variant of bullous pemphigoid. At least 84 patients with dyshidrosiform bullous pemphigoid have been described. Dyshidrosiform bullous pemphigoid usually presents with pruritic blisters in elderly individuals; the hemorrhagic or purpuric lesions on the palms and soles can be the only manifestation of the disease. However, bullae may concurrently or subsequently appear on other areas of the patient's body. Patients typically improve after the diagnosis is established and treatment is initiated. The mainstay of therapy is systemic corticosteroids, with or without topical corticosteroids, and systemic dapsone or immunosuppressants. Drug-related or nickel-induced dyshidrosiform bullous pemphigoid improves after stopping the associated agent; however, systemic therapy has also been required to achieve resolution of the blisters. Similar to classic bullous pemphigoid, neurologic conditions and psychiatric disorders have been observed in dyshidrosiform bullous pemphigoid patients. The new onset of recurrent or persistent blisters on the palms, soles, or both of an elderly individual should prompt the clinician to consider the diagnosis of dyshidrosiform bullous pemphigoid.

Quantitative associations between health insurance and stage of melanoma at diagnosis among nonelderly adults in the United States.

BACKGROUND: Health insurance plays a critical role in the accessibility to and quality of health care for patients with melanoma in the United States. Current knowledge regarding the association between insurance status and stage of melanoma is limited because few studies to date have simultaneously controlled for factors known to influence the risk of diagnosis of late-stage melanoma. The current study was conducted to examine the association between health insurance status and stage of melanoma at the time of diagnosis in nonelderly adults, accounting for known risk factors for late-stage diagnosis. METHODS: In this cross-sectional study, the authors analyzed the National Cancer Data Base for cases of invasive melanoma diagnosed between 2004 and 2015 among individuals aged 26 to 64 years. Using the American Joint Committee on Cancer melanoma staging system, early-stage melanoma was defined as stage I or stage II whereas late-stage melanoma was defined as stage III or stage IV. Late-stage diagnosis was the primary outcome compared across 4 insurance types (private, Medicaid, none, and unknown). Adjusted covariates were age, sex, race/ethnicity, educational level, income, year of diagnosis, number of comorbidities, and facility location. Logistic regression was used for univariable and multivariable analyses. RESULTS: Among 177,247 cases, individuals with Medicaid or no health insurance were found to have 3.12 (95% CI, 2.97-3.28) and 2.21 (95% CI, 2.10-2.33) times greater odds, respectively, of being diagnosed with late-stage melanoma compared with individuals with private insurance after adjusting for risk factors in late-stage diagnosis. CONCLUSIONS: Future investigation into insurance disparities in the diagnosis of late-stage melanoma may help to prioritize melanoma screening in populations with nonprivate insurance.

What's in a name? a new nomenclature has been proposed For eosinophilic dermatosis of hematologic malignancy (EDHM): hematologic-related malignancy-induced eosinophilic dermatosis (He Remained).

Hematologic-related malignancy-induced eosinophilic dermatosis (He Remained) has recently been introduced as a new nomenclature to describe the eosinophilic dermatosis that has previously been observed in patients with hematologic malignancies. The condition has been reported in 208 patients; the ratio of men to women is 1.3:1. It is most commonly observed in chronic lymphocytic leukemia patients (77%, 160/208 patients). The chronic and relapsing eosinophilic dermatosis typically presents with pruritic lesions that are pleomorphic in morphology and mimic other conditions. The definitive pathogenesis of He Remained is still being established. However, neoplastic leukemia B cells - directly or indirectly (by stimulating a reactive polyclonal T cell response) - likely have an etiologic role in the pathogenesis of this condition in chronic lymphocytic leukemia patients. In addition, recruitment of eosinophils to the skin may occur secondary to an immune shift toward a T helper 2 type response, possibly caused by the neoplastic cells, that results in these T cells producing interleukin 4. Clinical observations, currently based on the prompt (within four weeks) and sustained (at least 12 weeks to 6 months) resolution of He Remained in two elderly men with He Remained, suggests that dupilumab may be the treatment of choice in chronic lymphocytic leukemia patients with this condition.

Cutaneous undifferentiated pleomorphic sarcoma is a pleomorphic dermal sarcoma.

Pleomorphic dermal sarcoma is a cutaneous soft tissue sarcoma that presents as a rapidly enlarging tumor, typically on a sun-exposed location of elderly individuals. The neoplasm shares many similar features - clinical, pathologic, immunohistochemical and genomic - with atypical fibroxanthoma. However, adverse histologic characteristics (deep subcutaneous invasion, tumor necrosis, lymphovascular invasion, and/or perineural invasion) differentiate pleomorphic dermal sarcoma from atypical fibroxanthoma and may account for the more aggressive biologic behavior of pleomorphic dermal sarcoma: local recurrence and metastases. The features of a woman with pleomorphic dermal sarcoma are described. Her sarcoma presented as a rapidly growing ulcerated red nodule on the left side of her face. Imaging studies were performed prior to surgery. The tumor was extirpated with a wide local excision and she received postoperative radiotherapy. There has been no recurrence or metastasis at one-year follow-up. Pleomorphic dermal sarcoma has previously been referred to as a malignant fibrous histiocytoma (until the term became antiquated) and an undifferentiated pleomorphic sarcoma. However, the latter term includes not only neoplasms from the skin but also sarcomas from internal organs, retroperitoneal and osteoid origin. Therefore, when classifying this undifferentiated soft tissue sarcomas of cutaneous origin, the term pleomorphic dermal sarcoma may be preferred.

The use of drug calendars for the diagnosis of cutaneous drug eruptions in the age of electronic medical records.

A morbilliform drug eruption is the most common condition leading to a dermatology consultation for a patient in the hospital. Timing is an important diagnostic tool since the onset of a skin rash usually takes place within days-to-weeks of the start of the implicated drug. A comprehensive, thorough, and reliable drug history by the clinician is essential. Therefore, to assist in the task of determining the causative medication of a new skin rash in a hospitalized patient, the creation of a drug calendar is recommended. The development of an electronic version of the drug calendar offers several benefits over the manual version. As the use of electronic medical records continues to become the standard in medicine, the electronic drug calendar will serve as an invaluable tool for the diagnosis of drug hypersensitivity.

Terbinafine-induced lichenoid drug eruption: case report and review of terbinafine-associated cutaneous adverse events.

Terbinafine is an antifungal agent used in the treatment of hair, nail, and skin dermatophyte infections. Skin side effects to terbinafine are not common. Lichenoid drug eruption is a medication-related adverse cutaneous event; the lesion morphology and pathology mimic lichen planus. A woman with onychomycosis developed a lichenoid drug eruption one week after starting terbinafine. The features of her dermatosis and the characteristics of two additional men who also experienced terbinafine-induced lichenoid drug eruption are discussed. They were receiving a daily terbinafine dosage of either 125mg or 250mg to treat onychomycosis or tinea cruris. The lichenoid drug eruption presented as diffuse or symmetric lesions within one to two weeks after starting terbinafine treatment. The extremities, chest, abdomen, and/or trunk were common sites. Less frequent locations were the lips, nails, palms, soles, and suprapubic region; lesions did not occur on the oral or genital mucosa. The eruption resolved after discontinuation of the medication (with or without treatment using topical corticosteroids, systemic corticosteroids, or both). In addition, more frequently occurring terbinafine-associated cutaneous adverse events (such as urticaria, erythematous eruptions, pruritus, acute generalized exanthematous pustulosis, subacute cutaneous lupus erythematosus, and papulosquamous conditions) are reviewed.

Case report and review of solitary cutaneous focal mucinosis: a unique primary cutaneous mucinosis unrelated to mucinosis-associated systemic diseases.

Localized deposition of mucin in the upper dermis is referred to as cutaneous focal mucinosis. Patients with this condition either present with a single skin lesion (solitary cutaneous focal mucinosis) or numerous skin lesions (multiple cutaneous focal mucinosis). A man with solitary cutaneous focal mucinosis is described and the features of this condition are reviewed. Solitary cutaneous focal mucinosis has a slight male predominance and typically presents in adults, ranging in age from 29 years to 60 years, as a nodule or papule that is flesh-colored or white and most commonly located on an extremity or the trunk. Microscopic examination shows deposition of mucin in the upper dermis; the overlying epidermis can be normal, atrophic or hyperplastic. The skin lesion is often removed at the time of biopsy. However, recurrence has not been observed when the mucin deposition is present at the edge of the biopsy or excision specimen. Although the pathogenesis of this condition remains to be established, in contrast to individuals with multiple cutaneous focal mucinosis, solitary cutaneous focal mucinosis is a unique primary cutaneous mucinosis unrelated to mucinosis-associated systemic diseases.

Nevus sebaceus with syringocystadenoma papilliferum, prurigo nodularis, apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma: case report and review of nevus sebaceus-associated conditions.

Nevus sebaceus is a benign skin hamartoma of congenital onset that grows during puberty, and in adulthood can develop secondary benign and malignant neoplasms. The most common benign neoplasms occurring in nevus sebaceus are believed to be syringocystadenoma papilliferum, trichilemmoma, and trichoblastoma. A patient with nevus sebaceus developed not only syringocystadenoma papilliferum but also prurigo nodularis within her hamartomatous lesion; multiple biopsies were necessary to establish the diagnoses. Excision of the residual nevus sebaceus also revealed an apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma. Also, it is important to select the appropriate biopsy site and size when evaluating a patient for secondary neoplasms within their nevus sebaceous. Indeed, more than one biopsy may be required if additional diagnoses are suspected.

Concurrent Scabies Incognito and Crusted Scabies With Scalp Lesions Masquerading as Erythrodermic Dermatitis: Scabies Surrepticius in an Immunosuppressed Nonagenarian With Hyperkeratotic Plaques on her Head

I read with interest the excellent report by Tolkachjhov et al1 that describes the delay in diagnosis of a scabies infestation in a 90-year-old woman. Her condition mimicked dermatitis not only on clinical presentation but also on evaluation of skin biopsies.