Introduction

Paraneoplastic syndromes (PNS) refer to nonmetastatic tumour-associated manifestations that arise from malignancies located in distant anatomical sites. In certain instances, PNS may present as the initial or predominant clinical indication of an underlying cancer. Consequently, the prompt recognition of PNS can aid in the investigation of an as-yet undiagnosed malignancy. While the skin is commonly affected by peripheral nervous system (PNS) disorders, occurrences of PNS in skin neoplasms, including aggressive ones like malignant melanoma, have been infrequently documented. Herein, we compile the reported evidence of PNS associated with the growth of malignant melanoma. The objective of our study was to develop a typology of the range of peripheral nervous system (PNS) disorders. This typology serves as a valuable tool for clinicians in their daily practice and also provides a foundation for future research in comparative and mechanistic investigations. To accomplish this objective, we conducted a comprehensive literature review and present the outcomes as a research synthesis.

Aim

A literature study was conducted in order to identify and summarize the characteristics and meta-analysis of existing studies in this particular field.

Material and methods

A study conducted on 28 September 2023 was aimed to identify relevant literature. The PubMed and Medline databases were searched using different variations of two primary keywords: “melanoma” and “paraneoplastic syndromes”. Additionally, other variations of the aforementioned key terms, namely “PNS” and “MM”, have been used in our study. The selected publication dates encompassed the time period from 1986 to 2023. A total of 392 papers, including abstracts, original texts, and case reports, were identified. A total of 270 publications were removed from the analysis. The literature review only comprised original publications written solely in the English language, focusing on a research population consisting of individuals with melanoma and paraneoplastic syndromes (PNS). The review included case series, case reports, and experimental randomized controlled trials. The analysis focused on the general characteristics of the patient with melanoma with associated paraneoplastic syndrome (PNS) (age at the time of diagnosis, sex, location of melanoma, stage of malignancy, metastasis, cancer treatment, recurrence, predilection, timing of PNS).

A total of 59 patients diagnosed with paraneoplastic syndrome (PNS) associated with malignant melanoma were included in the study. Table 1 visually depicts the study selection process. The earliest recorded instance of melanoma with associated paraneoplastic syndrome (PNS) dates back to 1986. The literature incorporated in this review consists of a total of 57 original papers [1–57] (Tables 2, 3).

Results

We did not find any review paper that compiles the topic of melanoma-associated PNS. Our literature search yielded only papers reporting solitary cases (57 papers reporting 59 PNS cases associated with melanoma) (Table 2). Table 3 compiles the core clinical features of the patients. Of the 59 patients with melanoma-associated PNS, 34 were male (57.63%) and 25 were female (42.37%). The most common localization of melanoma was extremities (16/59, or 27.12% of all reported PNS cases). There were reports of twenty-six distinct PNS entities (Table 2). Melanoma-associated retinopathy (MAR) syndrome was the most reported PNS (25/59 cases, 42.37% of all reported PNS cases). The median age of the patients at the time of PNS diagnosis was 63.07 years (range: 34–83 years). In most cases (44/59 patients), PNS was diagnosed either concurrently or after the melanoma, considering the timing of PNS manifestation. Resolution of paraneoplastic syndrome after melanoma treatment was observed in 42.59% of the cases.

Discussion

Paraneoplastic syndromes (PNS) are tumour-associated manifestations that occur outside the primary tumour site and are not caused by the spread of cancer cells to other parts of the body [58, 59]. Paraneoplastic syndromes (PNS) are present in a significant proportion of individuals with tumours and can predominantly impact various organ systems such as the neuromuscular/musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, endocrine, or renal systems [59]. The literature has identified several systemic symptoms of these diseases, such as thrombocytopenia, nephrotic syndrome, dermatomyositis, and opsoclonus-myoclonus syndrome. Furthermore, in certain instances, PNS might serve as the initial or most notable indication of an underlying cancer; therefore, promptly identifying them can assist in the investigation of an undetected malignancy. From a pathophysiologic perspective, the majority of paraneoplastic syndrome (PNS) disorders can be attributed to either endocrine phenomena caused by biomolecules produced by tumours, or immunological mechanisms mediated by autoimmunity [60, 61]. Visceral tumours can affect the skin directly or indirectly. Direct involvement refers to the presence of tumour cells within the skin. This can happen either through direct expansion or by the metastasis of the tumour. Almost all types of internal cancer have the ability to spread to the skin through metastasis. The skin can be affected indirectly by visceral tumours, leading to various distinct inflammatory, proliferative, metabolic, and neoplastic changes even in the presence of actual tumour cells. This diverse group of disorders includes inherited syndromes associated with skin manifestations and an increased incidence of systemic neoplasia, cutaneous changes resulting from hormone secretion by tumours, and a wide spectrum of proliferative and inflammatory disorders reported in patients with internal malignancies. Curth’s postulates are a well-known set of clinical criteria that were created to help evaluate the temporal relationship between an underlying malignancy and a specific dermatological condition. The criteria are as follows: 1) The malignancy and the skin disease are of concurrent onset. 2) The malignancy and the skin disease run a parallel course. Successful treatment of the tumour leads to regression of the skin disease, and recurrence of the tumour leads to a return of cutaneous signs and symptoms. 3) The relationship between the skin disease and the malignancy is uniform. A specific tumour cell type or site is associated with a characteristic cutaneous eruption. 4) Based on sound case-control studies, a statistically significant association exists between the malignancy and a specific cutaneous disease. and/or 5) A genetic association exists between the malignancy and a specific cutaneous disease. Not all criteria must be met to postulate a relationship between a skin disease and an underlying malignancy [62]. While the skin is commonly affected by paraneoplastic syndrome (PNS) disorders [62, 63], PNS have been rather rarely reported in the course of skin neoplasms, even in relation to the biologically more aggressive ones, like malignant melanoma and Merkel cell carcinoma [64, 65].

Melanoma-associated retinopathy (MAR) was the PNS most frequently reported in patients with melanoma. In MAR syndrome, ocular symptoms usually manifest years after the diagnosis of skin melanoma, and the onset of MAR may herald the presence of metastatic disease. Melanoma-associated retinopathy syndrome is more frequent in males and typically presents as night blindness of acute onset. Additional symptoms may encompass photopsia, flashing, and peripheral field impairment [66].

There is a lack of consensus about the management of melanoma paraneoplastic retinopathies. Generally, the utilization of steroids and immunosuppressive medications, plasmapheresis, or intravenous immunoglobulins is not beneficial. Some reports say that steroids can make eye symptoms worse, but another report says that the paraneoplastic autoimmune response is an immune system defence against the spread of melanoma, and that using an immunosuppressive treatment may take away this protection for the patient [32]. Conducting larger therapy studies is highly challenging due to the limited number of people affected by these illnesses [67, 68].

The management of MAR-induced vision impairment has proven generally inefficacious. Nevertheless, on certain occasions, the utilization of a combination of cytoreductive surgery, x-irradiation, intravenous corticosteroids, plasma exchange, and IVIg has demonstrated some advantageous effects.

According to Guy et al. study, IVIg has demonstrated efficacy in treating paraneoplastic vision loss associated with MAR syndrome in two out of three individuals [69]. It has proven beneficial in treating various autoimmune neurologic diseases, such as Guillain-Barré syndrome, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, multiple sclerosis, dermatomyositis, and immunologic ophthalmologic conditions like ocular cicatricial pemphigoid, refractory uveitis, and linear IgA bullous disease limited to the eye [70–76].

Opsoclonus is characterized by the occurrence of spontaneous, irregular, and high-amplitude coordinated eye movements in all directions of vision, without any pauses between the movements. Three distinct clinical contexts detect paraneoplastic opsoclonus-myoclonus syndrome (POMS): (i) paediatric patients diagnosed with neuroblastoma; (ii) adult female patients with Ri-Ab, typically associated with breast cancer; and (iii) adult patients with small-cell lung carcinoma as the predominant tumour type. Other tumours, like melanoma have been linked to individual case reports [77].

Researchers have not yet fully understood the underlying mechanisms of the POMS. The observed clinical distinctions between POMS and idiopathic opsoclonus-myoclonus indicate varying pathways based on the triggering stimulus [78]. POMS is thought to occur due to an immunological response triggered by molecular mimicry between the tumour and a specific set of neurons in the central nervous system [78, 79]. Nevertheless, it is not uncommon for antineuronal antibodies to be absent as evidenced by a significant number of patients, especially in previously documented cases of melanoma-associated POMS [7, 78, 80]. Paraneoplastic neurological syndromes encompass a range of conditions, such as paraneoplastic cerebellar degeneration (PCD), paraneoplastic limbic encephalitis, subacute sensory neuropathy, paraneoplastic opsoclonus-myoclonus, and Lambert-Eaton myasthenic syndrome [81]. Paraneoplastic degenerative cerebellar ataxia refers to the sudden or gradual loss of coordination in a patient who has been diagnosed with cancer within the past 5 years, or who has particular onconeural antibodies present [82]. The correlation between PCD and malignant melanoma has previously been linked to carbonic anhydrase-related protein VIII.

There have been a few reports of patients who have malignant melanoma (MM) in coexistence with or heralding the clinical manifestations of dermatomyositis. Dermatomyositis can either precede, coincide with, or be diagnosed after the development of MM.

Regardless of the time of diagnosis, researchers have shown that MM staging is the most significant prognostic factor identified [43]. Although rare, there is an increasingly poor prognosis associated with the presence of dermatomyositis in patients with advanced MM. Dermatomyositis activity may serve as an indicator of disease progression and activity associated with MM [24].

There is a considerable controversy as to whether the presence of multiple trichilemmal cysts with melanoma can be a paraneoplastic syndrome. The casuistic report on the presence of multiple trichilemmal cysts with melanoma, as presented in the article by Savarese et al., necessitates verification and more observations. The literature does not document any previous correlation between trichilemmal cysts and neoplasia. However, in Cowden syndrome, several trichilemmomas have been linked to the development of neoplasms such as melanoma [48]. Perrotta et al. [37] reported a case of polymyalgia rheumatica in a male patient with three distinct neoplasms who was treated with pembrolizumab. They suggested that polymyalgia rheumatica could be caused by the neoplasms (not specifically melanoma) or could be a side effect of pembrolizumab treatment. The treatment with pembrolizumab triggered the patient’s symptoms a few months after it was started. Researchers have described immune-related adverse events induced by cancer immunotherapy in various clinical settings. The uniqueness of this case lies in the patient’s occurrence of three distinct neoplasms, including a particularly uncommon instance of male breast cancer. It is up for debate, nevertheless, whether the pembrolizumab or the neoplasms themselves caused the start of polymyalgia rheumatica syndrome.

Gambichler et al. [57] documented a case of abruptly progressing digital ischemia in an older patient with malignant melanoma. Paraneoplastic acral vascular syndrome (PAVS) is an uncommon occurrence that is seen in individuals with adenocarcinomas and other types of malignancies. Nevertheless, there remains a subject of debate regarding the potential involvement of immune checkpoint inhibition in the pathogenesis of PAVS in individuals with malignancies. In this specific instance, PAVS could be classified as either a paraneoplastic syndrome or a consequence of immune checkpoint inhibitor medication.

Descriptions of cases of melanoma-associated PNS are sparsely reported in the medical literature. This is in distinct contrast with the high incidence of melanoma, at least among Caucasians. Future studies should inquire whether melanoma-associated PNS are truly rare events or whether they are simply underrecognized and consequently underreported conditions.