Relapsing polychondritis is a very rare disease that affects multiple organs. It is characterised by recurrent episodes of inflammation of cartilaginous structures and other connective tissues, rich in glycosaminoglycan. Clinical symptoms concentrate in auricles, nose, larynx, upper airways, joints, heart, blood vessels, inner ear, cornea and sclera. Several cases were reported in the literature of relapsing polychondritis with features of a mixed paraneoplastic syndrome in combination with leukaemia, lymphomas, myelodysplastic syndrome and rarely with carcinoma [11, 12]. Chondritis may precede or follow the diagnosis. Malignancy-induced relapsing polychondritis as paraneoplastic syndrome is most often reported in association with myelodysplastic syndrome [13, 14].

Cohen [8] states that in addition to myelodysplastic syndrome, paraneoplastic polychondritis is often associated with the incidence of other hematologic malignancies. Less often relapsing polychondritis is related to solid tumours.

Recently, increased attention has been paid to the mixed paraneoplastic syndromes in polymyalgia rheumatica (PMR) and giant cell arteritis. Polymyalgia rheumatica may occasionally occur also in association with colon cancer [15, 16]. It is important to follow up the patient not only in terms of PMR clinical symptoms but also of potential malignancy (weakness, exacerbating anaemia and elevation of erythrocyte sedimentation rate), after previous treatment of the syndrome with glucocorticoids and its recurrence [15, 16]. After diagnosis of colon cancer and successful radical treatment, reliable remission was achieved both of polymyalgia rheumatica and the malignancy. It should be pointed out in this respect that PMR may occur also in association with ductal breast cancer, where the above-mentioned paraneoplastic syndrome may be signalled by younger age of female patients, relatively lower erythrocyte sedimentation rate and finally by a weaker response to glucocorticoids [17].

Paraneoplastic syndrome in PMR may occur also with prostate cancer [18]. Three patients presented with clinical symptoms of PMR, and laboratory tests revealed raised prostate-specific antigen (PSA) and were subsequently diagnosed with carcinoma of the prostate. The authors highlight the importance of clinical and laboratory screening, as well as examination of the skeleton in order to detect potential metastases of the prostate carcinoma (in one of the three diagnosed patients). Megalakaki et al. [19] presented a case report of chronic idiopathic neutropenia preceding polymyalgia rheumatica (5 years), with acute myeloid leukaemia that developed after another 3 years, and the patient died of sepsis. The causal relationship between the described diseases cannot be established in this case, but a possible coincidence of the three diseases cannot be excluded, either.

As for paraneoplastic mixed syndromes, the relation should be mentioned between development of polymyalgia rheumatica and myelodysplastic syndrome. Liozon et al. [20] described cases of concurrent giant cell arteritis (GCA) and malignancy. They report malignancy frequency at 7.4 % and point out myelodysplastic syndrome (MDS) as the precipitating factor for development of GCA.

The relation between MDS and frequency of autoimmune or systemic disease of connective tissues has been reported in the literature at 7–60 % [21–23]. Polymyalgia rheumatica is considered to be the consequence of MDS [24, 25]; on the other hand, GCA does not occur too often in association with MDS [26]. Several reports were, however, published of a concurrent incidence of aortitis and MDS [27, 28]. The available findings show that vasculitis, although not very frequent, may be often a complication in patients with MDS/MPS (myelodysplastic and myeloproliferative) disease. Therefore, clinical examination in the presence of PMR/GCA should exclude a potential share of MDS in the development of paraneoplastic syndrome associated with PMR/GCA (Table 12.2).

Another disease which is part of the group of mixed paraneoplastic syndromes is multicentric reticulohistiocytosis (MR). It is a rare multisystemic disorder of unknown aetiology, which is manifested by papulonodular skin, mucosal and synovial lesions and potentially destructive symmetrical polyarthritis with a tendency to involve multiple organs. Histopathology reveals characteristic histiocytic and multinucleated giant cell infiltrate with eosinophilic ground-glass cytoplasm, with secondary lipid inclusions [29]. It typically develops in fifth age decade, and its incidence is higher in women [30]. Data in the literature show that almost 28 % of patients with MR have a malignancy [31–33]. MR is often associated with cancer of breast, stomach, cervix, ovary and pancreas.

Hematologic malignancies were also reported in association with this disease, as well as axilla sarcoma, melanoma and mesothelioma. Chun-Hsiung et al. [34] reported a case of a 60-year-old female patient who developed papulonodular skin eruptions with progressive osteolytic bone damage bilaterally over the hands, humeral head and acromioclavicular joints within 2 years. CT examination revealed increased thickness in the retropharyngeal wall and submucosal nodular lesions in the region of arytenoid structures of the larynx.

Histological examination confirmed reticulohistiocytoma, infiltration of numerous CD68(+) histiocytes and multinucleated giant cells with abundant eosinophilic ground-glass cytoplasm. Aggressive treatment with methylprednisolone and MTX was effective and remission of the disease was achieved.

Osteogenic osteomalacia is a very rare syndrome. Musculoskeletal symptoms may appear several months up to several years prior to diagnosis of a tumour. It occurs most often in association with benign tumours of the bones (haemangioma) or soft tissues of mesenchymal origin, less frequently with malignant tumours (haemangiopericytoma, angiosarcoma, myoma, angiofibroma, osteoblastoma, chondroblastoma, neurinoma) [1, 35, 36]. These tumours produce humoral factor phosphatonin that affects proximal renal tubules and inhibits phosphate reabsorption. Another mechanism is increased calcitriol and metabolism abnormality, resulting in decrease of the serum levels [2]. Typical clinical features include muscle pain and weakness, pain in the back, joints and diffuse bone pain. Removal of the tumour improves the patient’s condition in the course of several days or months postoperatively. Where it is impossible to remove the whole tumour, substitution therapy with calcitriol and phosphate should be applied [35].

Remitting seronegative symmetrical synovitis with pitting oedema (RS₃PE) syndrome has been recently included in the group of paraneoplastic syndromes. It was first reported by McCarty [37]. It has been found out that the disease may occur in association with rheumatic diseases in elderly patients, including rheumatoid arthritis, spondyloarthropathy, polymyalgia rheumatica, rarely sarcoidosis, polyarteritis nodosa and giant cell arteritis. In 1988, Sibilia et al. pointed out that RS3PE was detected also in tumorous diseases. The first to describe it were Roldan Molina et al. [38], who observed the disease 4 months before the patient was diagnosed with non-Hodgkin lymphoma. Later, Olivé et al. [39] found in 27 patients RS3PE and also its paraneoplastic form, namely, T-lymphomas and myelodysplastic syndrome, during onset of polyarthritis.

It has been found out that RS3PE may occur also in solid tumours, e.g. in endometrial adenocarcinoma [40]. One case was also reported of a patient with gastric carcinoma [41], and, finally, one patient had a pancreatic carcinoma. Sibilia et al. [42] focused on description of RS3PE in six male patients, with the mean age of 74 years, with solid tumours. All six patients met the following criteria: bilateral pitting oedema of both hands, sudden onset of polyarthritis, age >50 years and absence of rheumatoid factor. Four patients suffered from prostatic carcinoma, one had gastric carcinoma and one patient had colonic adenocarcinoma. The clinical presentation was characterised by the classical form of RS3PE syndrome and by exacerbation of the general condition, sometimes with fever. All the patients were seronegative, with the absence of the rheumatoid factor and antinuclear antibodies in the serum. In these six patients, the articular manifestations regressed totally or partially in response to corticosteroids, sometimes at low doses, associated in most cases with specific antitumour therapy. The mean survival following detection of RS₃PE was 11 months. Five patients died of metastatic dissemination of their cancer and one of myocardial infarction. Based on these clinical findings, the authors have concluded that RS₃PE is a heterogeneous syndrome that can reveal a solid tumour, notably an adenocarcinoma. The authors assume that although the pathogenic mechanism is unknown, this could involve a type of paraneoplastic polyarthritis linked to the synthesis of a factor such as IL-6.

Some authors share the opinion that RS3PE syndrome is often associated with a number of inflammatory rheumatic diseases, mainly in the older age and in connection with malignancy [43–45].

A significant issue is the incidence of antinuclear antibodies in malignant diseases. Solans-Laque et al. [5] conducted a study to determine the prevalence of antinuclear antibodies (ANAs) in patients with malignancies and to investigate if their presence might be related to the development of musculoskeletal symptoms or paraneoplastic rheumatic syndromes. Antinuclear antibodies were detected in 76 of 274 (27.7 %) patients with malignancies and in nine of 140 (6.4 %) healthy subjects.