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The term “palmar fasciitis and polyarthritis syndrome” (PFPAS) was first described by Medsger et al.1 in 1982 for a disorder characterized by a symmetric arthritis with flexion contractures and thickening of the palmar fascia coexisting with ovarian carcinoma. Since that seminal report published 30 years ago, only 48 additional cases of PFPAS have been described in the literature, and these have been associated with a number of different neoplasms, including gynecologic malignancies (ovarian and fallopian tube cancers),2–16 pancreatic adenocarcinoma,17–20 non—small cell and small cell lung carcinoma,3,20–22 breast carcinoma,23–26 prostate carcinoma,27 gastric cancer,28 colon cancer,20 transitional cell carcinomas of the urinary tract,6,20,29 carcinoma of unknown origin,17 and hematologic malignancies17,30 (Appendix Table 1).
In this case report, we describe a patient with advanced prostate cancer who developed PFPAS during the course of his disease progression, and we summarize and review the clinical characteristics, associated malignancies, and potential therapies for PFPAS.
A 60-year-old man presented to the urology clinic with hematospermia and microscopic hematuria. A test for prostate-specific antigen (PSA) showed a level of 34 ng/mL in January of 2011. Ultrasound-guided needle biopsies of the prostate gland were performed, revealing prostate adenocarcinoma in 7 of 12 cores, with a maximum Gleason score of 5 + 5 = 10. Staging tests showed enlarged pelvic and retroperitoneal lymph nodes on computed tomography (CT) scan consistent with metastatic prostate cancer, and bone scan results were unremarkable. Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide) was initiated, resulting in a PSA nadir of 0.8 ng/mL achieved after approximately 3 months. Seven months later, the patient noticed rectal bleeding and the PSA level increased to 13.6 ng/mL. He underwent a proctoscopy that revealed locally recurrent prostate cancer invading into his rectal wall, which was treated with a course of external-beam radiation therapy in January 2012. Bicalutamide 50 mg/d was added to his treatment regimen with continuation of his LHRH agonist at that time. However, neither a PSA decline nor a radiographic response was achieved with the addition of bicalutamide.
Two months later, the patient began to experience symptoms of polyarthritis with bilateral pain and swelling and stiffness in his hands, wrists, knees, ankles, and feet. He also noticed thickening and erythema of his palmar skin followed by rapid progression to flexion contractures in both hands. Physical examination revealed synovitis of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints with marked restriction of movement, and the skin of the palms was leathery and rock-hard to palpation consistent with palmar fasciitis (Fig. 1). The patient had pain and decreased range of motion in his cervical spine, elbows, knees, ankles, and feet. The patient showed no signs of Raynaud’s phenomenon. At an initial rheumatologic consultation, the results of laboratory tests, including full blood count, antinuclear antibody (ANA), uric acid, erythrocyte sedimentation rate (ESR), and an antibody screen (anti—double-stranded DNA, anti-centromeric protein, anti—extractable nuclear antigen, anti-topoisomerase I, anti-cyclin citrullinated protein) were all unremarkable. Plain-film x-rays of the hands showed no findings of acute bony, soft tissue, or joint space abnormalities. A bone scan was consistent with an inflammatory polyarthropathy, without evidence of osseous metastasis. A diagnosis of PFPAS was made. Although this syndrome is often resistant to anti-inflammatory and anti-rheumatic therapies, prednisone 10 mg/d was initiated in combination with methotrexate (MTX) 15 mg weekly (plus folic acid 1 mg/d), on the basis of the belief that rheumatologic paraneoplastic syndromes are immune-mediated. The patient did not experience significant improvement in his symptomatology with this regimen.
Five months later, in July 2012, after a further elevation in PSA (to 76 ng/mL) and new evidence of bone metastases in the pelvis and spine, a diagnosis of metastatic castration-resistant prostate cancer was made and abiraterone 1000 mg/d was added to his treatment regimen (and bicalutamide was discontinued). The introduction of abiraterone resulted in a brief stabilization of PSA and radiographic disease lasting approximately 6 months. However, because the patient had not noticed significant symptomatic or functional improvement in his rheumatologic symptoms, adalimumab (anti-TNF therapy) was added to MTX and prednisone after the patient was counseled about the theoretic risk of accelerated cancer progression using this agent. During the next several weeks, joint mobility, pain, and swelling modestly improved; however, the palmar fasciitis and flexion contractures persisted.
In January of 2013, despite the use of abiraterone together with LHRH agonist therapy, the patient experienced further radiographic disease progression with new metastatic lesions in the liver, lungs, adrenal gland, multiple lymph node areas, and bones. Because of the uncertain safety profile of tumor necrosis factor (TNF) inhibitors in the setting of active metastatic cancers and the limited benefit achieved in his rheumatologic symptoms, adalimumab and MTX were both discontinued at that time. The patient quickly initiated cytotoxic chemotherapy with docetaxel, and the abiraterone was discontinued. At the time of writing, the patient has received 4 cycles of docetaxel with a significant clinical response: The PSA level has decreased to 2.4 ng/mL, and this was accompanied by a partial radiographic response in soft tissue target lesions on CT scan. Rheumatologic symptoms are largely unchanged, but have not continued to worsen.
PFPAS is a paraneoplastic condition that traditionally occurs in women (85% of all reported cases) and is usually seen in association with ovarian cancer or other gynecologic malignancies. This is only the second description of this syndrome occurring in the context of prostate adenocarcinoma. Genitourinary malignancies, including transitional cell carcinoma of the urinary tract and prostate adenocarcinoma, represent approximately 10% of all reported cases of PFPAS (5/49). By taking into account the relative infrequency of this syndrome in men, the underlying malignancy has been found to be prostate cancer in 2 of the 7 male patients with PFPAS reported thus far (Table 1). Although the number of cases of PFPAS associated with genitourinary malignancies is small, the clinical constellation of signs and symptoms of this syndrome in these patients seems similar to that observed in the context of other malignancies, such as the gynecologic cancers. In other words, there do not seem to be any genitourinary cancer-specific distinguishing features of this syndrome.
The underlying mechanism for paraneoplastic PFPAS is currently unknown. However, it is likely that fibrogenic and connective tissue growth factors and autoimmune mechanisms produced by the neoplasm are responsible for the development of PFPAS, because complement and immunoglobulin deposits have been found in some of the fascial tissues.3,5,23 There has been no direct or consistent link with any particular autoantibodies. However, the ESR is usually elevated, ANA is often weakly positive, and rheumatoid factor (RF) is almost always negative.
Traditionally, the severity of paraneoplastic syndromes is unrelated to the size of the primary tumor or the extent of metastatic disease. In most cases of PFPAS, the rheumatologic symptoms preceded the detection of the underlying malignancy,1,3,5–11,15–18,20,21,23,26,28 whereas in some cases the PFPAS occurred simultaneously with14,17,24 or after the initial cancer diagnosis.2,4,6,19,22,29 It may also develop as the first symptom of cancer recurrence or progression (as was the case in our patient).2,8,12,25,27,30,31 Indeed, in both cases of prostate cancer-related PFPAS, the rheumatologic symptoms appeared at the time of progression to the castration-resistant state. Exacerbation of inflammatory joint symptoms during subsequent relapse/progression of the underlying malignancy may also occur.14
Clinical features of PFPAS include pain and diffuse synovitis of the hands (usually at the MCP and PIP joints) and a symmetric polyarthritis with rapid progression of palmar fasciitis with flexion contractures of the hands. Unlike the scleroderma-related syndromes (which this condition may mimic), patients with PFPAS universally lack evidence of sclerodactyly. Although arthritic symptoms may involve multiple additional joints (as was the case in our patient, thus the term “polyarthritis”), plantar fasciitis is less common and has been reported in only 5 patients.1,2,17,22,27 The development of symptoms (especially in the palms and hands) is usually rapid, leaving the patient severely disabled in the span of several days or weeks.
Laboratory tests, such as acute-phase reactants and the presence of antibodies, generally provide unremarkable results.1–9,12,14–20,22,24,25,29 ANA and rarely RF are the most common antibodies detected in PFPAS cases, suggesting a potential role for autoimmunity; however, these antibodies are not specific, are often present at low titers,3,17,28 and may be found commonly in patients with cancer who do not show any signs or symptoms of rheumatologic disease. Therefore, the prototype of PFPAS seems to be a seronegative disorder. However, to further differentiate true paraneoplastic rheumatic syndromes from the coincidental co-occurrence of rheumatologic symptoms with cancer, autoantibodies may contribute to differentiate the 2 entities. The main differential diagnosis for PFPAS includes systemic sclerosis (scleroderma syndromes), which can be ruled out through specific autoantibody screens, the absence of Raynaud’s phenomenon, and the presence of normal nail-fold capillaries. In addition, the presence of synovitis and the rapid progression of contractures of the hands make Dupuytren’s disease an unlikely diagnosis.
PFPAS is generally a nonerosive form of arthropathy producing radiologic findings of periarticular demineralization and narrowing of joint compartments without erosions.1,7,23,25,28 However, in most cases, x-rays of the joints show no abnormalities (as was the case in our patient).2,6,9,11,16,17,19,21,29 As the disease progresses, contractures develop and x-ray films of the hands may show flexion deformities of the MCP and PIP joints.3,8,15 In some instances, PIP joints may be affected preferentially with relative sparing of MCP joints, although this is uncommon.14
The histopathologic abnormalities in PFPAS are nonspecific and have unclear diagnostic value. Biopsies may demonstrate features of nodular fasciitis,8 mononuclear or lymphocytic infiltrates,3,5,8,12,17,21,24 fibroblastic proliferation,6,8 and perivascular27 or diffuse fibrosis.3,5,8,12,17 Biopsy is not generally recommended to confirm the diagnosis, which is usually performed on clinical grounds.
Corticosteroids are often used as a first-line therapy. The efficacy of systemic steroids in patients with PFPAS is somewhat disappointing, with infrequent improvement of the polyarthritis and no effect on the joint contractures.1–4,6–9,12,14,16–23,25,30,31 Results have been largely disappointing with the use of conventional disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate,12,19,21,29 hydroxychloroquine,6,14 D-penicillamine,17,27 and sulfasalazine.14 More recently, TNF inhibitors12 have been attempted as a second-line treatment or in combination with corticosteroids.14,29 Although there is no clear demonstration of symptom improvement with TNF inhibitors such as adalimumab (as used in our patient) for this indication, the lack of effective therapy for this disabling syndrome and the belief that it is an immune-mediated disorder have led to its use as a second-line therapy in some patients. However, of particular concern for patients with cancer are the immunosuppressive effects of anti-TNF antibody therapies and their potential effect on accelerating cancer progression. Although it is hard to prove, the rapid acceleration of the disease in our patient and the development of widespread soft tissue metastases occurring during the course of treatment with adalimumab make us wonder whether this therapy may have accelerated his cancer progression. Surgery, chemotherapy, and radiotherapy for specific underlying oncologic disorders seem to be the only treatment with a positive effect on the inflammatory component of PFPAS.1,5,8,10–12,16,22–24,26,28,30 However, contractures are often irreversible and usually persist despite anti-inflammatory, DMARD, and anti-cancer therapies.1,2,4–9,12,14,16–19,23,25,27,30,31 In a few cases, flexion contractures modestly improved with effective anti-neoplastic therapy.11,15,28
PFPAS is a rare paraneoplastic syndrome that usually occurs in women and that is characterized by a nonerosive polyarthritis and fibrosis of the palmar fascia, resulting in contractures of the hands. We presented the second case of PFPAS associated with advanced prostate cancer and described an apparent acceleration of cancer progression during anti-TNF antibody therapy. The fact that PFPAS is generally resistant to anti-inflammatory and anti-rheumatic therapies emphasizes the importance of early diagnosis and treatment of the underlying malignancy to prevent development of permanent flexion contractures. In addition, clinicians should consider prostate cancer and other malignancies as the underlying diagnosis in a male patient presenting with PFAPS and no known history of cancer.
The authors have stated that they have no conflicts of interest.