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.

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.

PET/TC con 18F-FDG en la valoración de pacientes con sospecha de síndrome paraneoplásico neurológico / 18F-FDG PET/CT in the evaluation of patients suspected of paraneoplastic neurological syndrome

Objetivo. Definir el impacto diagnóstico de la PET/TC con 18F-FDG en función de las características clínicas del síndrome paraneoplásico neurológico (SPN). Material y métodos. Estudio retrospectivo multicéntrico y longitudinal de pacientes con sospecha de SPN. El cuadro clínico se clasificó en síndrome clásico (SC) o no clásico (SNC). Tras el seguimiento se estableció el diagnóstico de SPN definitivo o posible. Los cuadros que no encajaron en ninguna de las categorías previas se catalogaron como no clasificables. Se analizó el estado de los anticuerpos onconeuronales. La PET/TC se clasificó en positiva o negativa para la detección de malignidad. Se determinó la relación entre los hallazgos PET/TC y el diagnóstico final. Se analizaron las diferencias entre variables (Chi cuadrado de Pearson) y la relación entre el resultado de la PET/TC y el diagnóstico definitivo. Resultados. Se analizaron 64 pacientes. El 30% de los cuadros clínicos se catalogaron como SC y el 42% como SNC. Tras el seguimiento el 20% se clasificó en SPN posible y el 16% en definitivo. El 13% de los pacientes tenía anticuerpos onconeuronales positivos. El hecho de poseer un SPN definitivo se relacionó con un resultado positivo de la PET/TC (p = 0,08). Se demostró relación significativa entre la positividad de los anticuerpos y el diagnóstico final de proceso neoplásico (p = 0,04). La PET/TC fue eficaz en la correcta localización tumoral en 5/7 casos con cáncer invasivo. Conclusiones. La PET-TC mostró un mayor porcentaje de resultados positivos en pacientes con diagnóstico de SPN definitivo. A pesar de la baja prevalencia de malignidad en nuestra serie, la PET/TC detectó malignidad en una significativa proporción de pacientes con cáncer invasivo (AU)

Objective. This study aimed to determine the diagnostic impact of 18F-FDG PET/CT based on the clinical features of paraneoplastic neurological syndrome (PNS). Material and methods. Multicenter retrospective and longitudinal study of patients with suspicion of PNS. The clinical picture was classified into classic (CS) and non-classic syndrome (NCS). After the follow-up, the definitive or possible diagnosis of PNS was established. The pictures that did not match any of the previous criteria were categorized as non-classifiable. The state of the onco-neural antibodies was studied. The PET/CT was classified as positive or negative for the detection of malignancy. The relationship between PET/CT findings and the final diagnosis was determined. The differences between variables (Pearson test X2) and the relationship between the results of the PET/CT and the final diagnosis were analyzed. Results. A total of 64 patients were analyzed, classifying 30% as CS and 42% as NCS. After the follow-up, 20% and 16% of subjects were diagnosed as possible and definitive PNS, respectively. Positive onco-neural antibodies were found in 13% of the patients. A definitive diagnosis of PNS was associated with a positive PET/CT (P = .08). A significant relation between antibodies expression and final diagnosis of neoplasia (P = .04) was demonstrated. The PET/CT correctly localized malignancy in 5/7 cases of invasive cancer. Conclusions. The PET/CT showed a higher percentage of positive results in patients with definitive diagnosis of PNS. Despite the low prevalence of malignancy in our series, the PET/CT detected malignancy in a significant proportion of patients with invasive cancer (AU)

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".

Identifying potential clinical syndromes of hepatocellular carcinoma using PSO-based hierarchical feature selection algorithm.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Clinical symptoms attributable to HCC are usually absent, thus often miss the best therapeutic opportunities. Traditional Chinese Medicine (TCM) plays an active role in diagnosis and treatment of HCC. In this paper, we proposed a particle swarm optimization-based hierarchical feature selection (PSOHFS) model to infer potential syndromes for diagnosis of HCC. Firstly, the hierarchical feature representation is developed by a three-layer tree. The clinical symptoms and positive score of patient are leaf nodes and root in the tree, respectively, while each syndrome feature on the middle layer is extracted from a group of symptoms. Secondly, an improved PSO-based algorithm is applied in a new reduced feature space to search an optimal syndrome subset. Based on the result of feature selection, the causal relationships of symptoms and syndromes are inferred via Bayesian networks. In our experiment, 147 symptoms were aggregated into 27 groups and 27 syndrome features were extracted. The proposed approach discovered 24 syndromes which obviously improved the diagnosis accuracy. Finally, the Bayesian approach was applied to represent the causal relationships both at symptom and syndrome levels. The results show that our computational model can facilitate the clinical diagnosis of HCC.

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.

Paraneoplastic autoimmune multiorgan syndrome: 20 years after.

The purpose of this review is to provide insight and clarification in the quandary of classification and delineate clinical and histological features and pathophysiology of paraneoplastic pemphigus. This is a paraneoplastic disease of epithelial autoimmunity and adhesion originally described by Dr. Anhalt in 1990. Paraneoplastic pemphigus represents only one manifestation of the heterogeneous autoimmune syndrome in which patients, in addition to small airways occlusion, may display a spectrum of at least five clinical variants of the mucocutaneous disease [i.e. pemphigus-like, pemphigoid-like, erythema multiforme-like, graft-versus-host disease-like, and lichen planus-like, termed paraneoplastic autoimmune multiorgan syndrome (PAMS)]. There is a need for the expanded, inclusive classification of diverse mucocutaneous and respiratory presentations of PAMS. Multiple specific effectors of humoral and cellular autoimmunity mediating epithelial damage have been identified. An update of advances in clinical and basic research on PAMS and in management and overall prognosis of PAMS is provided.

Síndromes paraneoplásicas: o que o cirurgião-dentista precisa saber?: [revisão] / Paraneoplastic syndromes: what does the surgeon-dentist needs to know?: [review]

Introdução: o termo paraneoplasia é um conjunto de distúrbios clínicos, bioquímicos, hormonais, neurológicos e/ou hematológicos associados com neoplasias malignas, mas não diretamente relacionados com invasão tumoral primária ou metástase. As síndromes paraneoplásicas podem ser o primeiro sinal de uma malignidade. Revisão de literatura: as síndromes que estão mais comumente relacionadas com a prática odontológica são: de Lambertt-Eaton, de Gardner, de Cowden, de Peutz-Jeghers, de Sjõgren, a neoplasia endócrina múltipla, a neurofibromatose múltipla de Von Recklinghausen, o carcinoma nevóide de células basais, a acantose nigrans e o pênfigo paraneoplásico. Conclusão: o diagnóstico precoce das neoplasias malignas favorece o seu prognóstico e as síndromes paraneoplásicas auxiliam neste diagnóstico. É de suma importância que os Cirurgiões-dentistas conheçam tais síndromes de modo a diagnosticá-las o mais rápido possível e encaminhar os pacientes ao tratamento especializado.

Introduction: the term paraneoplastic is a clinical, biochemical, hormonal, neurological and/or associated disorder with hematologic malignancies, but not directly related to primary tumor invasion and metastasis. Paraneoplatic syndromes may be the first sign of a malignancy. Review of literature: the syndromes that are most commonly related to dentistry are of lambertt-Eaton, Gardner, Cowden disease, Peutz-Jeghers, Sjõgren, multiple endocrine neoplasic, multiple neurofibromatosis of Von Recklinghausen, nevoid basal cell carcinoma, acanthosis nigrans and pemphigus paraneoplastic. Conclusion: early diagnosis of malignant neoplasms favors prognosis and paraneoplastic syndromes assist in diagnosis. It is important that surgeons-dentists know these events in order to diagnose them as soon as possible and refer these patients to specialized treatment.

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 patients with primary oral cancers: a systematic review.

The aim of this study was to review all the paraneoplastic syndromes of primary tumours of the oral cavity. Metastatic tumours of the mouth and primary tumours of the oropharynx (including tonsils), and major salivary glands were excluded. The primary search was conducted on PubMed, Scopus and EMBASE, and included every paraneoplastic syndrome from a primary oral tumour described in English, French, or German papers during the last 20 years. The secondary search was conducted by handpicking articles from reviews on paraneoplastic syndromes of the head and neck. The aim of the tertiary search was to identify conditions that had been reported only rarely. We then cross-referenced "mouth neoplasm" with every paraneoplastic condition cited in relevant review articles. We classified the paraneoplastic syndromes that arose from tumours of the head and neck into six categories: endocrine, dermatological, vascular and haematological, rheumatoid, ocular, and neurological. The following conditions are described in this review: syndrome of inappropriate antidiuretic hormone production, hypercalcaemia, hypercalcaemia-leucocytosis syndrome, ectopic production of beta-human chorionic gonadotrophin, Bazex syndrome, Sweet syndrome, tripe palm syndrome, pemphigus, pityriasis rotunda, neutrophilic leukemoid reaction, cerebral venous sinus thrombophlebitis, digital ischaemia, dermatomyositis, necrotising myopathy, autoimmune retinal degeneration, and subacute cerebellar degeneration. Paraneoplastic syndromes of the oral cavity are a heterogeneous group. Most syndromes occur from squamous cell carcinoma and their aetiology is poorly understood. They are important to recognise as they can be the presenting complaint of a malignant tumour, change the prognosis, and considerably reduce the quality of life.

[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.

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.

A review of the cutaneous paraneoplastic associations and metastatic presentations of ovarian carcinoma.

Ovarian carcinoma possesses cutaneous and paraneoplastic associations. The aim of this study was to review the paraneoplastic associations and metastatic presentations of ovarian carcinoma. PubMed was searched through December 2006 for references to cutaneous metastatic ovarian carcinoma (CMOC). CMOC occurs in 2-7% of cases, manifests in advanced disease and indicates a poor prognosis. The paraneoplastic associations of ovarian carcinoma include acanthosis nigricans, Raynaud's phenomenon, scleroderma, dermatomyositis and palmar fasciitis with polyarthritis. Dermatomyositis, in particular, can precede the diagnosis of ovarian carcinoma. Ovarian carcinoma has many cutaneous paraneoplastic effects and metastatic presentations, all of which portend a poor prognosis. Dermatomyositis is sometimes the initial manifestation of ovarian cancer, thus women > 40 years of age with dermatomyositis should be checked for ovarian carcinoma. It is possible that paraneoplastic dermtomyosititis can be distinguished from nonparaneoplastic dermatomyostitis by the former's lack of (i) associated Raynaud's phenomenon, (ii) response to treatment, (iii) autoantibodies, (iv) overlap and association with other collagen vascular diseases and (v) the presence of the prodromal symptoms of ovarian carcinoma such as gastrointestinal symptoms, urinary symptoms and/or fatigue or malaise.

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 disorders of the central nervous system: update on diagnostic criteria and treatment.

Although the discovery of antineuronal antibodies has facilitated the diagnosis of paraneoplastic neurological disorders (PNDs), the recognition and treatment of these disorders remain a challenge. Some antineuronal antibodies have a more syndrome-specific association than others, and some syndromes evoke a paraneoplastic etiology more frequently than others. Because antineuronal antibodies may occur in cancer patients without PND, their detection does not necessarily imply that a neurological disorder is paraneoplastic. This review analyzes these issues and suggests a diagnostic strategy based on criteria derived from clinical and immunological findings and the presence or absence of cancer. We provide an update on the clinical features treatment of classic PND of the central nervous system, with the proposal of a general treatment strategy. In addition, we analyze the evidence of a hypothetically effective antitumor immunity in patients with PND, which if confirmed would have implications for treatment of the cancer and PND.

Paraneoplastic syndromes: detection of malignant tumors using [(18)F]FDG-PET.

AIM: Paraneoplastic syndromes (PS) comprise a variety of clinical symptoms and diseases associated with underlying malignancy. Differentiation towards benign autoimmune diseases is necessary due to different therapeutic options. This diagnostic challenge includes cost- and time-consuming methods and is not successful in many cases. The aim of this study was the evaluation of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for detecting or ruling out malignancy in these patients. METHODS: In this retrospective work-up a total of 30 patients with suspected PS (m:f = 17:13, mean age 55, range 22-76 years) were examined with [(18)F]FDG-PET between 1996 and 2001. Diagnoses were erythrodermia, cerebellar degeneration, dermatomyositis, polyneuropathia and others. PET scans were compared to histopathological (n=14), radiological and follow up data (mean follow up 3.6 years, range 1-6 years). RESULTS: In 7 out of 30 patients (23%) an underlying malignancy was detected. Six out of 7 malignant neoplasms showed a distinctly increased glucose consumption. One benign neoplasm caused increased tracer uptake, another PET positive patient refused biopsy and showed no growth of a malignant tumour during clinical follow up of 28 months. The remaining 21 patients without suspicious glucose consumption did not demonstrate a malignancy in other diagnostic modalities or during subsequent clinical follow-up. CONCLUSION: [(18)F]FDG-PET seems to be a useful tool in the diagnostic work-up of patients with suspected paraneoplastic syndrome.

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.