Paraneoplastic Syndromes Across Organ Systems: A Literature-Based Diagnostic Guide

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ACHAIKI IATRIKI | 2026; 45(1):31–38

Review

Dimitra Taprantzi

Department of Internal Medicine, University Hospital of Patras, Rio Patras, Greece

Received: 26 Feb 2025; Accepted: 10 Jul 2025

Corresponding author: Dimitra Taprantzi, MD, Ph, Tel.: +30 2610 999587, E- mail: dimitratap@hotmail.com

Keywords: Paraneoplastic syndrome, symptoms, diagnosis, endocrine, neurologic, hematologic, dermatologic, malignancies

 

Abstract

Paraneoplastic syndromes (PSs) are rare and often under-recognized cancer-related conditions resulting in tissue or organ disorders distant from the primary tumor and its metastases. These syndromes reflect systemic effects of malignancies that are not attributable to direct tumor invasion, compression, or metastasis. Recent medical data have improved our understanding of these syndromes, but the majority of them are still difficult to diagnose due to their protean manifestations and overlapping features with other diseases. They are a diverse group of clinical symptoms that can affect the neurological, endocrine, dermatological, gastrointestinal, and hematologic systems, and therefore our knowledge of these syndromes is helpful in the diagnosis and treatment of the related tumor. In many cases PS occur concurrently with the diagnosis of the underlying malignancy but in others, they can be a harbinger of a growing undiagnosed neoplasm and thus the skills of a medical doctor are challenged. Timely recognition of PS not only facilitates early diagnosis of potentially curable malignancies but also helps to avoid mismanagement of symptoms. This review focuses on the diagnosis and potential mechanisms of the most known paraneoplastic syndromes, highlighting the importance of interdisciplinary evaluation and immunological testing.

INTRODUCTION

Paraneoplastic syndromes (PS) are a diverse group of symptoms that arise as a result of a neoplasm, but which cannot be directly assigned to the primary malignancy and its metastases. Although PS are well known, establishing a diagnosis of the PS itself and the underlying malignancy is challenging. Their clinical presentation often mimics primary autoimmune, infectious, or degenerative conditions, which may result in delayed or missed diagnosis. In some instances, PS can precede the development of a tumor up to five years, potentially enabling the early diagnosis of a curable malignancy [1]. According to our current knowledge, some of the known PS arise by different mechanisms, such as secretion of antibodies and cross-reaction between normal host cells and tumor cells, secretion of peptides and hormones of the tumor but in the majority of them, there are limited data to explain their pathophysiology. In particular, immunological dysregulation involving both humoral and cellular immune responses appears to play a pivotal role in the development of these syndromes. PSs may affect diverse organ systems such as neurological, endocrine, dermatologic and hematologic system [2].

A literature review shows that PSs occur in up to 8% of patients with a malignancy [3]. This figure may be underestimated due to the complexity and variability of clinical manifestations, as well as underreporting in clinical practice. In view of the above, the purpose of this review is a practical approach of the diagnosis of the most known paraneoplastic syndromes. By categorizing them according to the organ systems involved and exploring their immunopathogenic basis, this review aims to enhance clinicians’ ability to recognize, investigate, and manage these rare but clinically significant conditions.

METHODOLOGY

This review is based on data extracted from peer-reviewed publications indexed in PubMed. Emphasis was placed on selecting literature published within the past 15-20 years to ensure the inclusion of the most current and clinically relevant information. The analysis focused on paraneoplastic syndromes that are well-established and commonly encountered in clinical practice.

Neurological Paraneoplastic syndromes

The pathophysiology of the paraneoplastic neurological syndromes (PNS) is not totally understood, but immunological mechanisms are most possibly involved. There is strong evidence that antibodies and T-cells fight against antigens expressed on the malignancy, but some of these antigens also reside in cells of the nervous system [4]. This immunological cross-reactivity leads to an autoimmune attack against components of the central and peripheral nervous systems, resulting in various neurological deficits.

Antibodies related to PNS may be found either in plasma or cerebrospinal fluid and are categorized in two groups: antibodies against intracellular neuronal antigen (previously known as onconeuronal antibodies) and antibodies against cell surface or against synaptic proteins. Onconeuronal antibodies are divided in well-characterized and partially characterized. Well-characterized antibodies are those that are strongly associated with a tumor, and the most known are anti-Hu, Yo, CV2, Ri, Ma2a, and anti- amphiphysin. Partially characterized antibodies are those that are not specifically correlated with a special type of tumor and these are anti-Tr, ANNA3, PCA2, Zic4, and mGluR1. These antibodies can guide diagnosis and may serve as biomarkers to identify occult malignancies, particularly when clinical presentation is atypical.

PNSs can affect the central nervous system, peripheral nervous system and neuromuscular junction and muscle. The most usual PNSs are Lambert-Eaton myasthenic syndrome and Guillain-Barré syndrome [5]. Other common manifestations include subacute cerebellar degeneration, limbic encephalitis, and encephalomyelitis, which may present with cognitive changes, psychiatric symptoms, or seizures.

In 2004, a panel of experts recommended diagnostic criteria for PNSs and a few years later the diagnostic criteria were updated by the PNS-care panel of experts [6]. According to 2004 criteria, the PNSs are divided into classical and non-classical syndromes. Neurologic diseases that have been found to be strongly correlated with malignancies are included in Classical PNSs. Classical PNS of central nervous system include encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration and opsoclonus-myoclonus, classical PNS of peripheral nervous system are subacute sensory neuropathy and chronic gastrointestinal pseudo obstruction and classical PNS of neuromuscular junction and muscle include Lambert-Eaton myasthenic syndrome and dermatomyositis.

According to the panel, there are three aspects of evidence required to characterize a PNS as definite or possible: the presence of a classical neurological syndrome, a confirmed tumor diagnosis and the detection of well-characterized onconeural antibodies [6]. Specifically, in order to characterise a syndrome as definite, it should satisfy one of the following criteria: a) by the time of making diagnosis of a classical PNS, cancer should appear within the following five years, b) neurological disease that it is not included in the list of classical PNS which does not resolve spontaneously but it resolves with malignancy treatment, c) non-classical PNS with positive onconeuronal antibodies and appearance of the malignancy within the following five years and d) neurological disease with positive well-characterized onconeural antibodies and no evidence of cancer’s existence.

Possible PNSs could be a) classical PNS with negative antibodies, b) neurological syndrome with positive partially characterized antibodies and no proof of malignancy, and c) non – classical neurological disease with negative antibodies and appearance of a tumor within the following two years.

In 2021, the panel changed the definition of classical and non-classical syndromes and introduced a more refined stratification system. They divided PNS into three categories (definite, probable and possible) using the PNS-care score, which combines the clinical symptoms with the presence of certain antibodies and the presence of malignancy in imaging testing as shown in Table 1 [7]. According to the PNS scoring system PNS is definite when the score is above 8, probable when the score is between 6 and 8, possible when it is 4 or 5, and there is no possibility of the clinical symptom being a PNS when the score is lower than 4. This structured approach improves diagnostic accuracy, minimizes overdiagnosis, and supports clinical decision-making.

The use of the PNS scoring system requires appropriate categorisation of antibodies and clinical symptoms. The antibodies are divided into three categories according to their frequency of cancer involved as shown in Table 2 [8]. Some neurological clinical presentations have been categorised into high-risk, intermediate risk and low risk phenotypes. High risk phenotypes are known also as classical PNS (according to 2004 guidelines) and they are strongly connected to malignancy presence. These are encephalomyelitis, limbic encephalitis, rapidly progressive cerebellar syndrome, opsoclonus-myoclonus, sensory neuronopathy, gastrointestinal pseudo-obstruction (enteric neuropathy) and Lambert-Eaton myasthenic syndrome. Intermediate-risk phenotypes are conditions associated with the presence of a tumor and warrant investigation when no other cause is found. These are encephalitis, Morvan syndrome, myelopathy, Stiff-person syndrome and polyradiculoneuropathies [7]. A combination of clinical judgment and the scoring system plays a vital role in uncovering hidden malignancies. Recognition of these risk phenotypes is crucial in the early detection of hidden cancers, particularly in neurologically unexplained or refractory syndromes.

A combination of thorough clinical judgment, immunologic testing, imaging studies, and the PNS scoring system plays a vital role in uncovering underlying malignancies and directing timely therapeutic interventions. Multidisciplinary collaboration between neurologists, oncologists, and immunologists is essential for optimal patient outcomes.

Paraneoplastic Endocrine Syndromes

The majority of endocrine PSs are a result of secretion of bioactive substances from malignant cells. The tumor can be of endocrine or non-endocrine origin. Lung, colon, skin and breast cancer are the most common cancers connected to endocrine PSs. These syndromes are often the result of ectopic hormone production, in which tumor cells acquire the ability to synthesize and secrete peptide hormones or hormone-like substances that mimic physiological processes, leading to distinct clinical presentations.

The most common PSs in this category are syndrome of inappropriate anti-diuretic hormone secretion (SIADH), Cushing’s syndrome, hypoglycaemia, and hypercalcemia. The severity of clinical symptoms is not correlated with the malignancy’s stage.

SIADH is a result of hypersecretion of inappropriate anti-diuretic hormone ADH and it usually appears with euvolemic hyponatremia, small cell lung cancer is one of the most common malignancies causing SIADH. ADH activates ADH receptor 2 (V2) located on the basolateral membrane of renal collecting duct cells to enhance the water permeability of the apical membrane and thus water reabsorption [9]. In normal circumstances the hypersecretion of ADH is controlled by osmoreceptors that try to maintain plasma osmolality within normal limits. In cancer patients, ADH secretion is not fully suppressed and ectopic production of ADH may also occur [10], leading to euvolemic hyponatremia. If left untreated, this condition can result in neurological symptoms, including seizures and altered mental status.

Another very common endocrine PS is hypercalcemia. Hypercalcemia of paraneoplastic origin is neither a result of bone metastases nor a result of direct dysfunction of the parathyroid gland [11]. It occurs because of the secretion of PTH-related protein, which binds to the PTH receptor, and it is most commonly connected to squamous cell tumors and small cell lung cancer (SCLC) and more rarely in GI-NETs, phaeochromocytomas and carcinoid tumors. Additionally paraneoplastic hypercalcemia can be a result of ectopic production of 1,25-dihydroxy (OH)2 vitamin D and it is usually associated with hematologic malignancies [12]. This form of hypercalcemia may be severe and refractory to standard treatments, necessitating aggressive interventions.

Cushing’s syndrome is also a common endocrine PS. A total of 10% of people with Cushing syndrome are considered to have a malignancy. It is caused by abnormal tumor production of adrenocorticotropic hormone (ACTH) or more rarely of corticotrophin-releasing hormone (CRH). Different types of lung malignancies are the most common tumors being associated with Cushing’s syndrome (bronchial carcinoids, SCLC] [13]. Tumors with neuroendocrine cells of the thymus or pancreas are also connected to PS Cushing’s syndrome [14]. The resultant hypercortisolism leads to classical signs such as central obesity, hypertension, glucose intolerance, and muscle weakness, which can significantly impair patient quality of life.

Another rare clinical endocrine PS is hypoglycaemia. The most common mechanism is ectopic production of insulin by islet (e.g. insulinoma) and non-islet tumors (e.g., gastrointestinal stromal tumors) [15]. Another possible mechanism is the secretion of peptides like insulin-growth factor 1 and 2 (IGF-1 and IGF-2, respectively), which bind to insulin receptors [16]. Additionally, in some cases, hypoglycaemia is a result of autoimmune mechanisms, involving the production of autoantibodies that stimulate insulin receptors [17]. Hypoglycaemia can be life-threatening if not promptly identified and treated.

In all cases, the endocrine manifestations of PS can obscure the underlying malignancy and may lead to delays in cancer diagnosis. Therefore, awareness of these paraneoplastic phenomena and their biochemical profiles is critical for early recognition and comprehensive management.

Paraneoplastic dermatologic syndromes

Dermatologic manifestations are a significant component of PS. These cutaneous signs may precede, coincide with, or follow the diagnosis of cancer, and they often provide valuable diagnostic clues. Necrolytic migratory erythema (NME), also called glucagonoma syndrome because its appearance is connected to this tumor, is a skin rash consisting of erythematous plaques in the perineum, upper and lower extremities and face. In due course the lesions increase in size and their borders become crusting. NME and hair loss are common symptoms presenting simultaneously in glucagonoma [18]. This syndrome is frequently accompanied by other systemic symptoms such as weight loss, glucose intolerance, and anemia, and its presence should prompt evaluation for pancreatic neuroendocrine tumors.

Acanthosis nigricans maligna is another dermatosis connected with malignancies. Dark symmetrical hyperpigmented skin areas of sudden onset usually appear in the axilla, groin, and cervical regions. A small percentage of patients have hyperpigmentation of the palms, and this condition is called tripe palms. This type of dermatoses relates to breast, liver, pancreas, gastric and ovarian cancer. Its appearance is associated with poor prognosis. Histologically, these lesions are characterized by papillomatosis, hyperkeratosis, and basal layer hyperpigmentation. Cytokines produced by the malignancy seem to have a pivotal role in fibroblast and keratinocyte stimulation [19].

Another form of acanthosis nigricans is the Leser -Trelat sign [20], which is the abrupt appearance of multiple seborrheic keratoses usually appearing in the upper part of the body. It is connected with gastric and colorectal carcinoma, other abdominal malignancies and less often with lymphomas [21, 22]. This phenomenon is believed to be mediated by epidermal growth factors released by the tumor, and recognition of this sign should prompt a thorough search for underlying malignancy.

Paraneoplastic pemphigus is a usual malignant dermatosis connected to haematological diseases such as non-Hodgkin lymphoma, chronic lymphocytic leukaemia and thymoma. Painful erosive areas and ulcers appear throughout the body as a result of IgG-mediated mechanism. More specifically autoantibodies bind to desmosomes and disrupt the connection between keratinocytes [23]. It has a poor prognosis, and the mortality rate reaches 90%.

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is characterized by painful plaques accompanied by fever, arthralgias and increased inflammatory markers. There are diagnostic criteria. To establish a diagnosis of Sweet, two major and at least two minor criteria are typically required. Major criteria are abrupt onset of painful nodules and characteristic neutrophil infiltration without vasculitis on biopsy. Minor criteria are temperature above 38, association with an underlying malignancy or an inflammatory response, elevated inflammatory markers (leukocyte count above 10.000, ESR above 20, increased CRP), and a great response to glucocorticoids [24]. Sweet syndrome may be associated with haematologic malignancies such as acute myeloid leukaemia, or with solid tumors such as breast or gastrointestinal cancer.

Dermatomyositis (DM) patients present with a variety of skin manifestations. They exhibit flat papules on extensor surfaces (elbows and hand joints) called Gottron papules accompanied by proximal muscle weakness (50% of the patients). A heliotropic eruption of the periorbital area is another pathognomonic feature of DM. It appears as an erythematous rash affecting the upper eyelids with or without periorbital oedema. In 1975, the Bohan and Peter criteria were established to facilitate the diagnosis of dermatomyositis as shown in Table 3 [25]. The association of DM with malignancies such as ovarian, pancreatic, and gastric carcinomas, as well as non-Hodgkin lymphomas, makes malignancy screening a vital component of DM workup [26, 27].

Paraneoplastic hematologic syndromes

Paraneoplastic eosinophilia, granulocytosis and thrombocytosis are common hematologic disorders in malignancies. The above are the result of the production of cytokines and other substances such as interleukin-5 (IL-5), Granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) respectively [28]. These hematologic abnormalities may serve as indirect indicators of tumor activity and can sometimes resolve with successful treatment of the underlying malignancy.

Pure red cell aplasia is also a common paraneoplastic manifestation in various malignancies. It is characterized by a marked reduction or absence of erythroid precursors in the bone marrow, leading to normocytic normochromic anaemia. This condition has been observed particularly in association with thymoma, and in some lymphoproliferative disorders [29].

Migratory thrombophlebitis, also known as Trousseau’s syndrome because it was first described by the French internist Armand Trousseau, is characterized by thrombosis in unusual sites and is connected to the hypercoagulable state of malignancies [2]. Trousseau’s syndrome frequently affects deep veins of the limbs, but also involves visceral and cerebral vessels, and is most commonly associated with pancreatic, lung, and gastric adenocarcinomas. Its pathogenesis is attributed to tumor-related production of procoagulant factors, mucins, and cytokines, leading to platelet activation and fibrin deposition [2]. Early identification of such abnormalities may guide physicians to investigate for occult malignancies, particularly when standard risk factors for thrombosis or cytopenia are absent.

Disseminated intravascular coagulation (DIC) is a rare paraneoplastic syndrome characterized by the triad of prolongation of coagulation times, thrombocytopenia and hypofibrinogenemia [30]. It results from widespread activation of the coagulation cascade, leading to both thrombotic and bleeding complications. DIC is most commonly associated with haematological and non-haematological malignancies, especially mucin-secreting adenocarcinomas. The presence of DIC in a cancer patient is associated with poor prognosis and requires urgent management.

Autoimmune hemolytic anemia (AIHA) is another paraneoplastic phenomenon usually found in hematologic malignancies such as lymphomas but there have also been incidents of AIHA in patients with solid tumors. The majority of AIHA is caused by warm antibodies (IgG-mediated) and less often provoked by cold antibodies (C3-mediated) [31]. AIHA may present with pallor, jaundice, fatigue, and splenomegaly, and requires both immunosuppressive and tumor-directed therapies.

In addition, cancer-associated microangiopathic hemolytic anemia (CA-MAHA) is another PS in which peripheral blood smear shows red cell schistocytes with negative direct and indirect Coombs tests. It leads to obstruction in small vessels and platelet consumption [32]. This life-threatening condition is characterized by haemolysis, thrombocytopenia, and end-organ damage, mimicking thrombotic thrombocytopenic purpura (TTP). It is most often associated with disseminated gastric, breast, or lung carcinoma and usually carries a dismal prognosis.

Overall, hematologic paraneoplastic syndromes may be the initial or sole manifestation of malignancy. They often require prompt recognition and interdisciplinary coordination between haematologists and oncologists to manage both the syndrome and the underlying tumor. Continued vigilance and comprehensive laboratory evaluation are critical when confronted with unexplained hematologic abnormalities.

CONCLUSION

From all the above, it is obvious that PSs cover a great range of clinical and laboratory findings. The manifestation of characteristic clinical symptoms in certain paraneoplastic syndromes should prompt clinicians to consider an underlying malignancy, thereby facilitating earlier diagnosis, timely intervention, and improved patient prognosis. These syndromes often act as a biological “early warning system,” particularly in the absence of obvious tumor-related signs. Their identification can significantly alter the clinical trajectory and improve patient outcomes.

Paraneoplastic antibodies hold significant potential as biomarkers for the early detection of underlying malignancies. Their presence may serve as a crucial diagnostic clue, prompting clinicians to initiate timely investigations for occult cancers. By incorporating antibody screening into the diagnostic workup of patients with unexplained neurological or systemic symptoms, healthcare providers may improve early cancer identification, enabling earlier intervention and potentially enhancing patient outcomes. Moreover, advances in serologic profiling and imaging have led to the development of scoring systems, such as the updated PNS criteria, that offer structured, evidence-based approaches to diagnosis.

The optimal approach to treating PSs involves not only addressing the associated symptoms but also eradicating the underlying malignancy. In oncology, new treatments are continuously emerging, offering hope that malignancies, and the paraneoplastic syndromes associated with them, particularly those with poor prognoses, may become more effectively treatable. Immunotherapies and molecularly targeted agents have already shown success in altering tumor behaviour and may indirectly lead to the resolution of paraneoplastic manifestations.

Further research is imperative to unravel the complex immunological and molecular mechanisms underlying these syndromes. Potential areas of study include the discovery of novel antibodies, the refinement of predictive scoring tools, and the development of immunomodulatory therapies specifically tailored for PS. A multidisciplinary approach that bridges oncology, immunology, neurology, and dermatology is essential for future progress.

In conclusion, heightened clinical suspicion, a systematic diagnostic framework, and ongoing research collaboration are the cornerstones of improving outcomes for patients with paraneoplastic syndromes.

Conflict of interest

None to declare

Declaration of funding sources

None to declare

Author contributions

Dimitra Taprantzi was responsible for the conceptualization, literature review, drafting, revision, and final approval of the manuscript.

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