Cutaneous paraneoplastic syndromes

A variety of cutaneous abnormalities can be seen in patients with malignant diseases, some of which are infectious, with others representing direct involvement of the skin by the underlying disorder. Yet another group of lesions can be regarded as associated markers of the malignant process, and, as such, are termed “paraneoplastic.” This review considers the latter collection of conditions, grouping them by the generic type of malignancy that is usually linked to the paraneoplasia. Some of the processes show a predominant association with alimentary tract malignancies (acanthosis nigricans, acrodermatitis paraneoplastica, florid cutaneous papillomatosis, necrolytic migratory erythema, palmoplantar keratoderma, pancreatic fat necrosis, and pityriasis rotunda). Others are usually linked to a hematolymphoid malignancy (acquired ichthyosis, exfoliative erythroderma, necrobiotic xanthogranuloma, pemphigus paraneoplastica, plane xanthoma, pyoderma gangrenosum, scleromyxedema, Sweet syndrome, and leukocytoclastic vasculitis). Finally, yet another collection of paraneoplastic skin disorders can associate themselves with anatomically-diverse malignancies (Leser–Trelat syndrome, Trousseau syndrome, dermatomyositis, erythema gyratum repens, hypertrichosis lanuginosa acquisita, papuloerythroderma of Ofuji, tripe palms, and multicentric reticulohistiocytosis). Recognition of these processes by the pathologist can be a valuable step in the characterization of underlying malignant diseases.     

Paraneoplastic endocrine syndromes: A review

The paraneoplastic endocrine syndromes (“ectopic” or “inappropriate” hormone production) comprise a wide array of symptom complexes associated with malignant or less commonly benign neoplasms. Most of the syndromes are associated with the production of peptide hormones, which, in some instances, have autocrine stimulatory effects. Hypercalcemia, the most common paraneoplastic endocrine syndrome, may be due to the systemic release of parathyroid hormone-related protein (PTHrP), factors that may be produced locally (cytokines), or by a combination of these mechanisms. A spectrum of other syndromes may be related to the production of specific hormones or growth factors, including insulin-like growth factor and fibroblast growth factor 23. Molecular mechanisms responsible for the development of these syndromes are poorly understood. Mutational events not only may initiate neoplastic transformation but may also lead to the activation (re-expression) of genes responsible for hormone production. Additionally, epigenetic events such as methylation may also be responsible for the development of these syndromes. It is likely that a multiplicity of genetic and epigenetic events may contribute to the development of paraneoplastic endocrine syndromes. Presented in part at the 2003 Meeting of the Endocrine Pathology Society (United States and Canadian Academy of Pathology), Washington, D.C.     

Neurological paraneoplastic syndromes.

Paraneoplastic neurological syndromes are uncommon, however, their diagnosis is of major practical importance. The identification of antibodies in the serum or cerebrospinal fluid in central nervous system paraneoplastic syndromes confirms the clinical diagnosis of a paraneoplastic syndrome and allows early identification of an underlying tumour at a stage when it is localised and more amenable to treatment. The failure to identify antibodies in patients with characteristic presentations of underlying neurological paraneoplastic syndromes does not exclude an underlying cancer. Necrotising myelopathy, dermatomyositis, and chronic inflammatory demyelinating polyneuropathy all occur more frequently than expected in patients with cancer but autoantibodies have not yet been identified. Although significant advances have been made in diagnosis, further research is needed in the detection of autoantibodies and the elucidation of their role in the aetiology of neurological disease.     

Autonomic paraneoplastic neurological syndromes

Autonomic paraneoplastic neurological syndromes (PNS) typically present as chronic gastrointestinal pseudo-obstruction or orthostatic hypotension and usually occur in association with other PNS rather than in isolation. Although rare, they are often debilitating, sometimes fatal, and probably seriously underdiagnosed. Here, we discuss the clinical, immunological and oncological features of these syndromes and review the molecular and cellular mechanism that may underlie the triggering and maintenance of their autoimmune pathogenesis.     

The etiology of paraneoplastic autoimmunity

Although they may sometimes appear similar, paraneoplastic autoimmunity has a unique pathogenesis, different from the classical autoimmune diseases not associated with cancer. When distinguished clinically, paraneoplastic autoimmunity is more severe and often presents with a broader range of clinical signs and symptoms. Management of these patients is difficult and is usually centered in part on treatment of the underlying malignancy. Self-antigens recognized in the setting of paraneoplastic autoimmunity can be diverse, and the number of determinants recognized within a single antigen can be numerous. This review uses prototypic examples of paraneoplastic immune-mediated diseases and their associated malignancies to describe the mechanisms by which immune dysregulation can occur in the setting of cancer. Specific diseases covered include paraneoplastic pemphigus, Sweet’s syndrome, pyoderma gangrenosum, thymoma-associated multiorgan autoimmunity, myasthenia gravis, autoimmune hemolytic anemia, immune thrombocytopenia, and the paraneoplastic neurological syndromes. The malignancies discussed include thymoma, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia, among others. The mechanisms by which cancers induce autoimmunity are broken down into the following categories: disruption of central tolerance, peripheral immune dysregulation, and alteration of self-antigens. For each category, examples of paraneoplastic autoimmune diseases and their associated malignancies are discussed. Finally, mechanisms by which cancer treatment can lead to autoimmunity and examples of polymorphisms that are linked to both cancer and autoimmunity are discussed.     

Dermatopathology in endocrine disease

Through multiple complex mechanisms, the endocrine system plays a vital regulatory role in virtually every organ system including the skin. Cutaneous lesions may be seen incidentally in patients with endocrine disorders. Alternatively, certain skin conditions are seen exclusively in the setting of endocrine disorders and may rarely be the first clinical symptom of the underlying endocrinopathy. Although clinical examination is often sufficient, a tissue biopsy may still be needed to arrive at or confirm the diagnosis and to direct therapy. In many cases, the cutaneous condition might improve or resolve completely after treatment of the underlying endocrine disorder. In this review, we summarize the most common skin conditions associated with endocrine disorders, uncovering their relationship to the underlying endocrinopathy, demonstrating their clinicopathologic presentation, and highlighting their typical modalities of treatment.     

Pediatric pigmented dermatofibrosarcoma protuberans (Bednár tumor): case report and review of the literature with emphasis on the differential diagnosis

Dermatofibrosarcoma protuberans (DFSP) is a fibrous tumor of intermediate malignant potential that usually affects the trunk of young to middle-aged adults. On histological examination, it is characterized by a monomorphous population of spindle cells arranged in a storiform or cartwheel pattern. Bednár tumor (BT), formerly known as storiform pigmented neurofibroma, is currently considered the pigmented variant of DFSP due to the histological and cytogenetic similarities between these two lesions. There are very few reports on BT affecting pediatric patients. We describe a case of BT affecting the dorsal aspect of the left forearm of a 6-year-old-male patient and emphasize the diagnostic clues to distinguish this unusual cutaneous neoplasm from other pigmented lesions, including pigmented (melanotic) neurofibroma (PMN), psammomatous melanotic schwannoma (PMS), neurocristic cutaneous hamartoma (NCH), and desmoplastic malignant melanoma (DMM). We would like to stress that surgical pathologists and dermatopathologists need to be aware of the prototypical histological appearance of BT as there is the risk of misdiagnosing it either as pigmented tumors associated with neurocutaneous syndromes, such as PMN and PMS, or as a highly malignant melanocytic neoplasm (DMM).     

Paraneoplastic neurological syndromes

Paraneoplastic neurological syndromes are immune‐mediated erroneous attacks on the central or peripheral nervous systems, or both, directed originally against the tumour itself. They have been known for more than 40 years, but recently the discovery of new subgroups of paraneoplastic encephalitis syndromes with a remarkably good response to immune therapy has ignited new clinical and scientific interest. Knowledge of these subgroups and their associated autoantibodies is important in therapeutic decision‐making. However, the abundance of new autoantibodies and syndromes can be confusing. This review paper summarizes current knowledge and new developments in the field of paraneoplastic neurological syndromes, their classification, pathophysiology and treatment.     

Pediatric fibroblastic and myofibroblastic lesions

Fibrous lesions of infancy and childhood are a heterogeneous group of entities composed predominantly of fibroblasts and myofibroblasts, ranging from reactive lesions to neoplasms with a range of malignant potential. Although rare, their correct recognition by histopathology is important clinically as they exhibit a wide range of behaviors and may be associated with distinct underlying syndromes. Contributions from molecular diagnostics have enabled more accurate diagnosis, and have changed our concepts of some tumor types. In this review, we discuss the clinicopathologic spectrum of fibroblastic and myofibroblastic lesions of childhood and adolescence.     

Paraneoplastic immune-mediated neurological effects of systemic cancers

Cancer patients may develop paraneoplastic neurological conditions associated with autoantibodies directed against neural or neuromuscular tissues. These syndromes are frequently manifested in advance of the cancer presentation by several months or years necessitating a detailed and expensive investigation to search for the presence of a malignancy. In such cases additional assistance may be obtained by the early employment of whole body 18F flurodeoxyglucose positron emission tomography as a cancer screening imaging procedure for early cancer diagnosis and potential therapy. Effective therapy of the primary cancer consists the best current therapy for a given paraneoplastic syndrome. However, other forms of immune modulation, such as plasma exchange, intravenous gamma globulin, other immune therapies and symptomatic treatment for certain PNS may have additional benefit.     

Conflicting consequences of immunity to cancer versus autoimmunity to neurons: Insights from paraneoplastic disease

Immunologists are well aware that cancer regression and increased patient survival with the use of checkpoint inhibitors, such as ipilimumab, an antibody directed against cytotoxic T‐lymphocyte–associated antigen 4, CTLA‐4 (CD152), is accompanied by concomitant autoimmunity. For over 30 years, a small group of investigators have shown that the rare paraneoplastic syndromes are caused by immunity to shared antigens found on both tumors and on components of the nervous system. In this issue of the European Journal of Immunology, Blachère et al. [Eur. J. Immunol. 2014. 44: 3240–3251] elucidate some of the molecular mechanisms underlying the tolerance to neuronal antigens which share epitopes with oncologic antigens, observed in the context of paraneoplastic syndromes in mice. The presence of the shared tumor antigen on a nonhematopoietic cell underlies the basis for a certain level of tolerance in CD4⁺ and CD8⁺ T cells, preventing these cells from attacking the brain, but allowing them to lyse the tumor upon transfer into tumor‐bearing recipient mice. Comparisons between the paraneoplastic syndromes and the new autoimmune conditions seen with antibodies to immune checkpoints at CD152 or at CD279 are likely to illuminate shared mechanisms and solutions to these vexing diseases.     

Paraneoplastic syndromes and other systemic disorders associated with neuroendocrine neoplasms

Neuroendocrine paraneoplastic syndromes (PNS) consist of metabolic disorders that accompany benign and malignant neoplasms but remain unrelated to mass effects or invasion by the primary tumor or its metastases. The underlying pathogenesis responsible for PNS usual clinical presentation relies on aberrant production of protein hormones, proteins and other substances by the tumor. Prompt recognition of characteristic signs and symptoms combined with serological identification of key substances may result in early diagnosis of PNS and its underlying malignancy. For these reasons, healthcare professionals should familiarize themselves with tumor-induced hypercalcemia, syndrome of inappropriate antidiuretic hormone, carcinoid syndrome, virilisation syndrome, gynecomastia, acromegaly, Cushing syndrome, osteogenic osteomalacia, tumor-induced hypoglycemia, necrolytic migratory erythema, and watery diarrhea, hypokalemia and achlorydria syndrome. Medical awareness for PNS can improve patient outcomes through earlier administration of cancer therapy and treatment, better symptomatic relief and prolong overall survival.     

Mediastinum thymoma diagnosed by FNA and ThinPrep technique: a case report

Thymoma is a primary tumor of the thymus epithelial cells. It may be asymptomatic or accompanied with atypical clinical symptoms or paraneoplastic syndromes, such as myasthenia gravis. The biological behavior of thymomas is unpredictable. The invasion of the capsule or the adjacent tissues is the major diagnostic criterion for the malignant behavior of these tumors. This is an interesting case of thymoma diagnosed by fine-needle aspiration biopsy (FNA) and ThinPrep technique, in a 54-year-old female patient with a history of gastric adenocarcinoma. Cytology of the mediastinum mass revealed a mixed population of epithelial cells and lymphocytes. The tumor was excised and the histopathological examination supported the cytological diagnosis. Thymomas commonly constitute a problem in differential diagnosis of mediastinum masses. FNA biopsy in correlation with ThinPrep technique and immunocytochemistry may play a significant role in clarifying the nature of these lesions and may contribute to the early management and choice of the optimal therapeutic manipulation.     

Skin involvement in cutaneous and systemic vasculitis

Cutaneous vasculitides are a heterogeneous group of inflammatory disorders affecting skin blood vessels. They may be triggered by several factors, such as infection or drug, or may be related to underlying disease, notably connective tissue or malignancies. However, vasculitis occurs without any demonstrable triggering agents in a relevant number of patients. On the other hand, vasculitic skin lesions may manifest as a component of vasculitis affecting also internal organs; in someone of these patients, skin involvement occurs initially as the sole sign of disease, leading to consider cutaneous vasculitis a diagnosis of exclusion. In this review, we have focused on the most common variants of cutaneous vasculitis, including cutaneous small vessel vasculitis and urticarial vasculitis as well as Henoch–Schönlein purpura, a systemic form in which however skin involvement often predominates. We have also argued on livedoid vasculopathy, a cutaneous entity which, although nonfrankly vasculitic in origin, is frequently associated with connective tissue disease. Finally, we have analyzed the variety of cutaneous manifestations that may develop during the course of the main systemic vasculitides, such as Wegener's granulomatosis, Churg–Strauss syndrome and polyarteritis nodosa.     

Autoimmune pathogenesis of paraneoplastic neurological syndromes

"Remote effects" of cancer on the nervous system (paraneoplastic syndromes) are disorders of the nervous system of unknown cause that occur almost exclusively, or with greatly increased frequency, in patients with identifiable or occult cancer. There are several hypotheses concerning the pathogenesis of these rare disorders. One hypothesis is that the underlying tumor and portions of the nervous system share antigens and that an autoimmune response generated against the tumor causes the nervous system disorder. Evidence supporting this hypothesis includes the ability to transmit the Lambert-Eaton Syndrome (a paraneoplastic syndrome involving the neuromuscular junction) to experimental animals by infusing IgG from patients with the disorder, the presence of autoantibodies against Purkinje cell neurons in some patients with paraneoplastic cerebellar degeneration, and the presence of autoantibodies against many neurons in patients with sensory neuronopathy and encephalomyelitis. Other evidence supporting the hypothesis is presented in this review.     

Prognosis in patients with thin malignant melanoma: influence of regression

It has been suggested that patients with thin malignant melanoma displaying evidence of histological regression may have a poor prognosis. In the present study, the case histories of 353 patients with clinical stage I cutaneous malignant melanoma up to 0.7 mm thick were reviewed to determine if either active or past regression in these lesions was a poor prognostic sign. Lesions were reported as displaying evidence of partial regression if either (a) a portion of the melanoma had a heavy lymphocytic infiltrate associated with loss of tumour cells or the presence of degenerating tumour cells, or (b) a portion of the melanoma was replaced by vascular fibrous tissue with or without pigment-containing phagocytes. The incidence of regression in this study (58%) was similar to that reported in another recent large study on thin lesions (53%). Only slightly more regressed than unregressed lesions metastasized (8% versus 5% respectively). A high proportion of first recurrences from these thin lesions developed at sites remote from the primary lesion (lung, bone or in subcutaneous tissues or lymph nodes wide of the line of spread). However, the presence or absence of regression in thin lesions did not appear to influence the site of first recurrence. Cumulative 10-year survival rates for patients whose lesions displayed or did not display evidence of either active or past regression were nearly identical.(ABSTRACT TRUNCATED AT 250 WORDS)     

Breast lesions of uncertain malignant nature and limited metastatic potential: proposals to improve their recognition and clinical management

Breast lesions comprise a family of heterogeneous entities with variable patterns of presentation, morphology and clinical behaviour. The majority of breast lesions are classified traditionally into benign and malignant conditions and their behaviour can, in the vast majority of cases, be predicted with a reasonable degree of accuracy. However, there remain lesions which show borderline features and lie in a grey zone between benign and malignant, as their behaviour cannot be predicted reliably. Defined pathological categorization of such lesions is challenging, and for some entities is recognized to be subjective and include a range of diagnoses, and forms of terminology, which may trigger over‐ or undertreatment. The rarity of these lesions makes the acquisition of clinical evidence problematic and limits the development of a sufficient evidence base to support informed decision‐making by clinicians and patients. Emerging molecular evidence is providing a greater understanding of the biology of these lesions, but this may or may not be reflected in their clinical behaviour. Herein we discuss some breast lesions that are associated with uncertainty regarding classification and behaviour, and hence management. These include biologically invasive malignant lesions associated with uncertain metastatic potential, such as low‐grade adenosquamous carcinoma, low‐grade fibromatosis‐like spindle cell carcinoma and encapsulated papillary carcinoma. Other lesions of uncertain malignant nature remain, such as mammary cylindroma, atypical microglandular adenosis, mammary pleomorphic adenoma and infiltrating epitheliosis. The concept of categories of (1) breast lesions of uncertain malignant nature and (2) breast lesions of limited metastatic potential are proposed with details of which histological entities could be included in each category, and their management implications are discussed.     

Hauttumoren als Markerläsionen hereditärer Tumorsyndrome

A number of hereditary tumor syndromes are associated with characteristic dermal neoplasms and knowledge and early diagnosis of these lesions may facilitate the diagnostic of the underlying syndrome. These syndromes include Muir-Torre syndrome, associated with cystic sebaceomas, Cowden syndrome, associated with multiple tricholemmomas, Carney complex associated with multiple superficial angiomyxomas, Birt-Hogg-Dubé syndrome associated with multiple fibrofolliculomas, tuberous sclerosis associated with multiple facial angiofibromas and so-called Koenen tumors, patients with renal cell cancer associated with pilar leiomyomatosis and uterine leiomyomas, Gardner syndrome associated with Gardner fibromas and nevoid basal cell carcinoma associated with multiple basal cell carcinomas in young patients.     

Importance of plasmapheresis in the treatment of paraneoplastic cerebellar degeneration

Paraneoplastic neurologic syndromes are disorders of the nervous system function caused by cancer but not due to metastatic disease, vascular or metabolic deficits, infections, nutritive deficiency, nor side effects of antineoplastic drugs or irradiation. Immunologic factors probably play the crucial role in the pathogenesis of paraneoplastic neurologic syndromes, but nonimmunologic mechanisms that include metabolic abnormalities and competition for substrate are also involved. Paraneoplastic cerebellar degeneration most commonly occurs in the setting of gynecologic cancers, but it accompanies the small-cell lung cancer too. Other tumors are infrequently associated with cerebellar degeneration. Several paraneoplastic antibodies have been identified in patients with paraneoplastic cerebellar degeneration. Their association with particular cancers may help identify an occult lesion. Anti-Yo antibodies are directed against Purkinje cell antigens and occur in patients with cerebellar degeneration who have breast cancer or gynecologic tumors. A target antigen of anti-Yo antibody is CDR2 protein that is normally expressed only in the brain and testis. Patients with paraneoplastic cerebellar degeneration present with dizziness, nausea and vomiting followed by gait instability, diplopia, gait and appendicular ataxia, dysarthria and dysphagia. Therapeutic options include tumor excision, chemotherapy and/or irradiation, and adjuvant therapy with glucocorticoids, immunoglobulins and plasmapheresis. The role of plasmapheresis in the treatment of paraneoplastic cerebellar degeneration is still uncertain. Reports of its efficacy are anecdotal. We present patient with paraneoplastic cerebellar degeneration with positive anti-Yo antibodies and tumor of the ovaries whose neurologic status significantly improved after four daily plasmaphereses, which was accompanied by a fourfold decrease in the anti-Yo antibodies titer. Further investigations are needed to define a protocol for plasmapheresis in the treatment of patients with paraneoplastic syndromes.     

Immunocytochemical characterisation of cutaneous lymphomas other than mycosis fungoides

The immunophenotypic properties of 25 cutaneous non-Hodgkin lymphomas other than mycosis fungoides or Sezary syndrome were investigated and correlated with clinical and histopathological data. The 11 low grade lymphomas were all of B cell origin, whereas the 14 high grade lymphomas comprised B and T cell tumours, true histiocytic proliferations, and one "nul" cell lymphoid neoplasm. For the high grade lymphomas correct prediction of the immunological phenotype based on morphological criteria was only possible in three cases. In contrast, all of the low grade lymphomas showed the non-epidermotropic infiltration pattern considered to be characteristic of cutaneous B cell tumours. For these conditions, however, immunophenotypic investigations provided a convenient means of improving discrimination between benign (polyclonal) and malignant (monoclonal) lesions, and also showed similarities with nodal lymphomas in terms of expression of lymphoid subset markers and composition of the non-neoplastic white cell infiltrate. No differences were identified between primary and secondary or concurrent cutaneous and extracutaneous lymphomas. Cutaneous non-Hodgkin lymphomas other than mycosis fungoides or Sezary syndrome constitute a heterogeneous group of neoplasms and most of these disorders are likely to represent cutaneous equivalents of nodal malignancies. Immunophenotypic investigations form a useful supplement to their histogenetic characterisation and may provide a common conceptual basis for their classification.