Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe. Thus, awareness represents the key operating factor. Our purpose was to overview the field of CCAs following a double perspective: the constellation of the risk factors, and the presence of the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. This is a narrative review. A PubMed-based search of English-language original articles offered the basis of this comprehensive approach. Multiple risk factors underlying different levels of statistical evidence have been listed such as chronic biliary diseases and liver conditions, inflammatory bowel disease, parasitic infections (e.g., Opisthorchis viverrini, Clonorchis sinensis), lifestyle influence (e.g., alcohol, smoking), environmental exposure (e.g., thorotrast, asbestos), and certain genetic and epigenetic interplays. With regard to the endocrine panel, a heterogeneous spectrum should be taken into consideration: non-alcoholic fatty liver disease, obesity, type 2 diabetes mellitus, and potential connections with vitamin D status, glucagon-like peptide 1 receptor, or the galanin system, respectively, with exposure to sex hormone therapy. Amid the numerous dermatologic, hematologic, renal, and neurologic paraneoplastic manifestations in CCAs, the endocrine panel is less described. Humoral hypercalcaemia of malignancy stands as the most frequent humoral paraneoplastic syndrome in CCAs, despite being exceptional when compared to other paraneoplastic (non-endocrine) manifestations and to its reported frequency in other (non-CCAs) cancers (it accompanies 20-30% of all cancers). It represents a poor prognosis marker in CCA; it may be episodic once the tumour relapses. In addition to the therapy that targets the originating malignancy, hypercalcaemia requires the administration of bisphosphonates (e.g., intravenous zoledronic acid) or denosumab. Early detection firstly helps the general wellbeing of a patient due to a prompt medical control of high serum calcium and it also provides a fine biomarker of disease status in selected cases that harbour the capacity of PTHrP secretion. The exact molecular biology and genetic configuration of CCAs that display such endocrine traits is still an open matter, but humoral hypercalcaemia adds to the overall disease burden.

A 50-year-old man presented with nephrotic syndrome. Electron microscopy analysis of a kidney biopsy specimen showed fibrillary glomerulonephritis, a rare glomerular disease, while histological analysis of a liver tumor biopsy confirmed an intrahepatic cholangiocarcinoma. The paraneoplastic nature of fibrillary glomerulonephritis is debated but after curative treatment of the hepatic nodule, remission of nephrotic syndrome was confirmed at 6-, 12- and 24-months follow-up. To our knowledge, this is the first description of a paraneoplastic fibrillary glomerulonephritis associated with a cholangiocarcinoma, supported by complete remission achieved following cancer treatment.

Subacute cutaneous lupus erythematosus (SCLE) is a dermatosis that occurs in genetically predisposed individuals. The exogenous stimulus that triggers this condition is usually unknown; however, medication is often implicated. Malignancy is a rare cause. We present a case of paraneoplastic SCLE to cholangiocarcinoma and briefly review the features of this interesting entity.

The skin can be key to early diagnosis of systemic malignancies. In the second part of this review, we present various skin conditions that can, in certain contexts, reveal the presence of malignancy. The skin conditions are presented in groups based on a diverse range of morphological characteristics. Specifically, the following groups are analyzed: erosive and blistering lesions; inflammatory papules and nodules; xerosis, ichthyosis, and generalized exfoliative dermatitis; symptoms such as pruritus; abnormal hair distribution patterns; sweating disorders; benign tumors that can form part of hereditary syndromes associated with a risk of visceral cancer; and finally, oral and nail abnormalities. This review highlights the importance of the skin in the study of systemic malignancies.

Erythema multiforme (EM) is an uncommon, immune-mediated disorder that presents with cutaneous or mucosal lesions or both. In herpes simplex virus (HSV)-associated EM, the findings are thought to result from cell-mediated immune reaction against viral antigen-positive cells that contain the HSV DNA polymerase gene (pol). The target lesion, with concentric zones of color change, represents the characteristic cutaneous finding seen in this disorder. Although EM can be induced by various factors, HSV infection continues to be the most common inciting factor. Histopathologic testing and other laboratory investigations may be used to confirm the diagnosis of EM and to differentiate it from other clinical imitators. Imitators of EM include urticaria, Stevens-Johnson syndrome, fixed drug eruption, bullous pemphigoid, paraneoplastic pemphigus, Sweet's syndrome, Rowell's syndrome, polymorphus light eruption, and cutaneous small-vessel vasculitis. Because disease severity and mucosal involvement differ among patients, treatment should be tailored to each patient, with careful consideration of treatment risk vs benefit. Mild cutaneous involvement of EM can be managed primarily with a goal of achieving symptomatic improvement; however, patients with HSV-associated recurrent EM and idiopathic recurrent EM require treatment with antiviral prophylaxis. Inpatient hospitalization may be required for patients with severe mucosal involvement that causes poor oral intake and subsequent fluid and electrolyte imbalance. With this review, we strive to provide guidance to the practicing dermatologist in the evaluation and treatment of a patient with EM.