Paraneoplastic syndromes: Definitions, classification, pathophysiology and principles of treatment.

Paraneoplastic syndromes (PNS) are rare clinical syndromes due to the systemic effects of tumours; they are unrelated to tumour size, invasiveness or metastases. Recent years have seen considerable advances leading to improved understanding of their pathophysiology and increased recognition of new PNS entities and PNS associated tumours. While of paramount importance, diagnosis is still frequently missed or delayed. Diverse organs and systems are affected by the associated tumours- which may be benign or malignant. PNS can occur concurrently with tumour diagnosis, before tumour is diagnosed and even after tumours have been resected. Also, there are autoimmune diseases later progressing to PNS when occult tumours are identified. Another confounding factor is that many PNS clinically resemble non-neoplastic diseases. PNS are largely due to two main causes: those due to tumour secretions of hormones, functionally active peptides, enzymes cytokines or to tumours operating through auto-immune/immunological mechanisms with cross-reacting antibodies between neoplastic and normal tissues. Remission of symptoms often follows resection of humoral secretory tumours but not always of tumours due to immunological mechanisms. Classifications schemes vary but most currently place PNS in one of five groups: endocrine, neurological, musculocutaneous, haematological and other. Due to advances both in diagnostic techniques in identifying tumours as well as in therapy, early diagnosis not only results in improved prognosis of both PNS and associated tumours but also enables monitoring response to treatment and early detection of recurrence. This article covers definition, general principals of classification, diagnosis, pathophysiology and treatment, with emphasis on tumour related PNS serving as an introduction to the following articles.

Paraneoplastic itch: an expert position statement from the Special Interest Group (SIG) of the International Forum on the Study of Itch (IFSI).

In clinical practice, the term "paraneoplastic itch" is used to describe itch in patients with cancer. Patients with hematological or solid tumor malignancies can be affected. In general, paraneoplastic itch is considered a rare disorder. However, paraneoplastic itch in hematological malignancies such as polycythemia vera and lymphoma are relatively frequent while other forms of paraneoplastic itch are in fact extremely rare. The true frequency of this symptom is unclear, epidemiological data in this field are limited. Itch in malignant disease may additionally impair patients' quality of life. A population-based cohort study showed that chronic itch without concomitant skin changes is a risk factor for having undiagnosed hematologic and bile duct malignancies. Paraneoplastic itch is rather resistant to treatment. In 2012, an interdisciplinary interest group of physicians and researchers was founded, aiming to generate a clear definition of paraneoplastic itch. In this paper we briefly review the current knowledge and aim to define what can be summarized under the term "paraneoplastic itch".

Cutaneous manifestations of systemic non-Hodgkin lymphomas (NHL): study and review of literature.

Systemic non-Hodgkin lymphomas are often accompanied by cutaneous manifestations, which are not always looked out for. Nevertheless, these alterations can be very important because their presence is lied to the clinical behaviour of the underlying malignancy, with an early recognition being fundamental. The aim of this study was to make order in this topic and propose a preliminary classification of the cutaneous manifestations associated with non-Hodgkin lymphomas. We performed a retrospective chart review of 62 haematological patients affected by non-Hodgkin systemic lymphomas with dermatological manifestations, who were evaluated from January 2007 to December 2011, and combined these results with a systematic review of Pub medical literature from 1937 to 2011 on this topic. A preliminary classification of these manifestations has been proposed, dividing them in specific and non-specific ones, along with a description of the clinical features and those cases observed in our department. A preliminary approach has been proposed for the study of these manifestations that could be helpful in understanding the biological behaviour and aid early recognition of a flare up in systemic non-Hodgkin lymphomas.

Which antibody and which cancer in which paraneoplastic syndromes?

Paraneoplastic neurological syndromes can be associated with the presence of onconeural antibodies. These antibodies are the result of an immune response against a tumour that is ectopically expressing a neuronal antigen. The 'classical' onconeural antibodies (anti-Hu, Yo, Ma2, CRMP-5, amphiphysin and Ri) are directed against intracellular antigens and are strongly associated with underlying malignancy. By contrast, onconeural antibodies directed against cell surface antigens (eg, anti-NMDA, VGKC, AChR) have a weaker tumour association. This article gives a practical overview of the tumour associations, and the neurological associations, of the onconeural antibodies. There is also guidance on how to investigate occult malignancy in antibody positive cases.

Paraneoplastic syndromes in cancers of unknown primary: An unknown field for oncologists.

Paraneoplastic syndromes are signs or symptoms that result from tissue damage at locations remote from tumour sites. Paraneoplastic syndromes associated with cancer of unknown primary (CUP) are not well recognized as they are rarely reported. These syndromes can impair various organ functions and include endocrine, neurologic, dermatologic, rheumatologic, hematologic and several other system alterations. To our knowledge, the association between the histological CUP type and the paraneoplastic syndrome has never been assessed. In some instances, paraneoplastic syndromes can become the major clinical problems determining survival. However, they can also herald earlier the occurrence of CUP in patients with asymptomatic tumors. In this article, we review the available literature of CUP patients presenting paraneoplastic syndromes by trying to collect all available published cases during the last three decades. One additional goal of this article is to make practicing oncologists aware of the coexistence of paraneoplastic syndromes in patients with CUP.

Regulatory T cells in paraneoplastic neurological syndromes.

Focusing on CD4(+)CD25(+) regulatory T lymphocytes (T(reg)), we studied the gene expression of T(reg) functional molecules in peripheral blood lymphocytes of patients with paraneoplastic neurological syndrome (PNS), including Lambert-Eaton myasthenic syndrome (LEMS) with small cell lung carcinoma (SCLC) and anti-Hu- or anti-Yo-antibody-positive PNS. T(reg)-rich subsets were sorted from the patients' peripheral blood mononuclear cells, and the mRNA expression levels of their functional genes were measured. The expression levels of FOXP3, TGF-beta and CTLA4 mRNA in T(reg)-rich subsets of PNS patients were down-regulated compared with that of SCLC patients without PNS. These results suggest that T(reg) dysfunction plays a role in PNS development.

[Adult-onset Still's disease and hepatic angiosarcoma, a fortuitous association or a paraneoplastic syndrome: a case-report]. / Maladie de Still de l'adulte et angiosarcome hépatique, une association fortuite ou un syndrome paranéoplasique: à propos d'un cas.

Adult-onset Still's disease is a systemic disorder without specific histological feature. Diagnosis requires to rule out any other disorder including neoplasia. Nevertheless, patients with paraneoplastic adult-onset Still's disease have been reported. We report a patient with an adult-onset Still's disease who presented with a liver involvement at onset. Two years later, a liver angiosarcoma was diagnosed. This report underlines the difficulty of the diagnosis of the adult-onset Still's disease even in the presence of Yamaguchi et al.'s [J Rheumatol 19 (1992) 424-30] and Fautrel et al.'s [Medicine 81 (2002) 194-200] classification criteria and may suggest a link between the initial clinical picture and the discovery nearly two years later, of a liver angiosarcoma.

Paraneoplastic syndromes in patients with cancer of the larynx and hypopharynx.

Paraneoplastic syndromes may be the first sign of a malignancy. They are systemic, nonmetastatic manifestations associated with a variety of malignant neoplasms and occurring in a minority of cancer patients. These associations of symptoms and signs are not directly related to the site or local manifestations of a malignant tumor or its metastases, but their recognition may facilitate the detection of malignancies or recurrences. Paraneoplastic syndromes are categorized into 6 types: dermatologic or cutaneous, endocrine, hematologic, neurologic, osteoarticular or rheumatologic, and ocular. Different oncotypes have rarely been associated with paraneoplastic syndromes in patients with cancer of the larynx and hypopharynx. The world literature has been reviewed.

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.

Paraneoplastic syndromes of gynecologic neoplasms.

PURPOSE AND DESIGN: The purpose of this review is to define and describe the paraneoplastic syndromes associated with gynecologic neoplasms. A comprehensive search of MEDLINE from 1966 to January 1996 and Cancerlit was performed. One hundred twenty-two reports were reviewed. RESULTS: Twenty-four paraneoplastic syndromes have been associated with gynecologic malignancies. Six anatomic systems are affected by these syndromes. However, except for disseminated intravascular coagulation and hypercalcemia, these syndromes are rare. CONCLUSION: Paraneoplastic syndromes are not frequently associated with gynecologic malignancies. The diagnosis of these syndromes is essential, as they can be occasionally life-threatening. Some paraneoplastic syndromes can be used as marker of progression or regression of the underlying malignancy.

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.

Paraneoplastic neurologic syndromes.

Malignancies may produce indirect effects on the central and peripheral nervous systems, as well as on muscle. Certain autoantibodies have been detected in some of these paraneoplastic syndromes, and these antibodies most likely play a role in their pathogenesis. This article describes the currently accepted paraneoplastic neurologic syndromes along with current information regarding their pathogenesis.

Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus.

BACKGROUND: Recent studies suggest that paraneoplastic pemphigus (PNP) is a heterogeneous autoimmune syndrome involving several internal organs and that the pathophysiological mechanisms mediating cutaneous, mucosal, and internal lesions are not limited to autoantibodies targeting adhesion molecules. OBJECTIVE: To classify the diverse mucocutaneous and respiratory presentations of PNP and characterize the effectors of humoral and cellular autoimmunity mediating epithelial tissue damage. METHODS: We examined 3 patients manifesting the lichen planus pemphigoideslike subtype of PNP. A combination of standard immunohistochemical techniques, enzyme-linked immunosorbent assay with desmoglein (DSG) baculoproteins, and an immunoprecipitation assay were used to characterize effectors of humoral and cellular autoimmunity in patients with PNP and in neonatal wild-type and DSG3-knockout mice with PNP phenotype induced by passive transfer of patients' IgGs. RESULTS: In addition to the known "PNP antigenic complex," epithelial targets recognized by PNP antibodies included 240-, 150-, 130-, 95-, 80-, 70-, 66-, and 40/42-kd proteins but excluded DSG1 and DSG3. In addition to skin and the epithelium lining upper digestive and respiratory tract mucosa, deposits of autoantibodies were found in kidney, urinary bladder, and smooth as well as striated muscle. Autoreactive cellular cytotoxicity was mediated by CD8(+) cytotoxic T lymphocytes, CD56(+) natural killer cells, and CD68(+) monocytes/macrophages. Inducible nitric oxide synthase was visualized both in activated effectors of cellular cytotoxicity and their targets. Keratin 14-positive basal epithelial cells sloughed from the large airways and obstructed small airways. CONCLUSIONS: The paraneoplastic disease of epithelial adhesion known as PNP in fact represents only 1 manifestation of a heterogeneous autoimmune syndrome in which patients, in addition to small airway occlusion and deposition of autoantibodies in different organs, may display a spectrum of at least 5 different clinical and immunopathological mucocutaneous variants (ie, pemphiguslike, pemphigoidlike, erythema multiforme-like, graft-vs-host disease-like, and lichen planus-like). We suggest that the more encompassing term "paraneoplastic autoimmune multiorgan syndrome," or PAMS, be applied. The pathophysiological mechanisms of PAMS involve both humoral and cellular autoimmunity responses. Epithelial cell membrane antigens other than DSG1 or DSG3 are targeted by effectors of PAMS autoimmunity. Apoptosis of damaged basal cells mediates epithelial clefting, and respiratory failure results possibly from obstruction of small airways with sloughed epithelial cells.

Paraneoplastic syndromes.

The paraneoplastic syndromes are effects of cancer that occur at sites remote from the primary tumor and its metastases. Recognition of these disorders is important from both diagnostic and therapeutic viewpoints. The important paraneoplastic syndromes involving the endocrine, nervous, hematologic, and dermatologic systems are discussed in this article.

Cancer related syndromes from a comparative viewpoint.

Neoplasms are the most prominent portion of the neoplastic disease process. The cancer patient is affected by hormonal, metabolic, immunologic and paraneoplastic discrepancies. Paraneoplastic syndromes consist a large group of body abnormalities which appear in a specific manner. Why special components of such abnormalities occur together is nearly always unknown. This article gives a tabulation of the paraneoplastic and other neoplasia-related syndromes providing certain key characteristics in each case.

Syndrome of inappropriate antidiuretic hormone secretion associated with head neck cancers: review of the literature.

In a minority of patients with malignant tumors, signs and symptoms develop that cannot be explained on the basis of the mass effect produced by the primary tumor or its metastases, or production of a hormone normally associated with the tissue type that has given rise to the malignant tumor; these peculiar symptom complexes are known as paraneoplastic syndromes, and may be divided into endocrinologic, dermatologic, hematologic, neurologic, and osteoarticular manifestations. In the head and neck region in particular, the syndrome of inappropriate antidiuretic hormone production (SIADH, or Schwartz-Bartter syndrome) is a well-recognized form of paraneoplastic syndrome that may accompany head and neck malignancies. Most of such tumors are squamous carcinomas, with lesser numbers of olfactory neuroblastomas, small cell neuroendocrine carcinomas, adenoid cystic carcinomas, and undifferentiated carcinomas; sarcoma was reported in only a single instance. The lesions associated with the development of SIADH have most often been located in the oral cavity, and less often in the larynx, nasopharynx, hypopharynx, nasal cavity, maxillary sinus, parapharyngeal space, salivary glands, and oropharynx. Key features of SIADH include serum hypo-osmolality; an unexpectedly high urinary specific gravity; an absence of edema or dehydration; normal adrenal, thyroid, and renal function; hyponatremia; and an elevation of plasma vasopressin.

Cutaneous paraneoplastic syndromes.

Paraneoplastic syndromes are caused by hormones or other substances produced by cancer cells and may be the first sign of cancer. A wide range of paraneoplastic syndromes, including endocrine, neurologic, and cutaneous disorders, occurs in patients with cancer. More than 30 cutaneous paraneoplastic syndromes have been identified; this article reviews some of the more common syndromes--acanthosis nigricans, Paget's Disease, acquired ichthyosis, telangiectasia, hypertrichosis lanuginosa acquisita, erythroderma, Bazex's Syndrome, and necrotizing migratory erythema. When these syndromes are diagnosed during the course of a malignancy, professional caregivers may misinterpret them as indicative of metastatic disease or other disorders and patients may be misdiagnosed and not receive optimal treatment. Paraneoplastic syndromes also compromise quality of life by often causing skin impairment and discomfort. Therefore, nurses must be aware of the signs and symptoms of these cutaneous disorders and know how to care for patients with paraneoplastic syndromes.

Les syndromes paranéoplasiques.

Paraneoplastic syndromes affecting the nervous system are rare but devastating complications of systemic cancer. The neurologic disorder usually precedes identification of the cancer and can affect any portion of the nervous system including cerebral cortex, cerebellum, spinal cord, peripheral nerves, neuromuscular junction or muscle. A single area or cell type of the nervous system may be affected or the entire neuraxis may be involved. The pathogenesis of paraneoplastic syndromes involving the nervous system is believed to be immune-mediated: the current hypothesis is that antigens usually expressed only in neurons are expressed in a cancer; the immune system recognizes the antigen in the cancer as foreign and mounts an immune response that slows the growth of the tumor but damages the nervous system. The diagnosis of a paraneoplastic syndrome is made either by identifying a small cancer in a patient with a neurologic disorder of unknown etiology or by identifying paraneoplastic autoantibodies in the serum of patients. The treatment involves identification and treatment of the causal cancer and immunosuppression to suppress both the humoral and cellular immune response.

[Pathology of paraneoplastic syndromes. Review]. / Patologie paraneoplastického syndromu. Souborný referát.

A review of current opinion on paraneoplastic syndrome pathology is presented. It is supplemented by a reference to the author's own cases (paraneoplastic cerebellar degeneration with Purkinje cell lesion and vacuolar spongiform degeneration of the granuloneuronal layer of the cerebellar cortex).