Fasciitis and Panniculitis

The frequent recognition of skin and subcutaneous tissues as a target of neoplastic disease is likely because, in part, of the visibility of the skin and the dense innervation of these structures, resulting in pain and other sensations when the pathologic condition develops. A large number and variety of individual dermatologic manifestations of cutaneous or internal malignancy are described. Comprehensive descriptions of malignant dermatoses have been published elsewhere. However, several paraneoplastic rheumatic syndromes predominantly or prominently involve the skin and subcutaneous tissues and are explained here.

Palmar fasciitis with or without polyarthritis is a rare condition characterized by progressive fibrosis of the hands, resulting in flexion contractures that may suggest the Dupuytren contracture. However, the process is bilateral and usually rapidly progressive. The skin may develop a woody texture suggestive of scleroderma or a more inflammatory appearance that may suggest reflex sympathetic dystrophy. Coincident development of carpal tunnel syndrome has been described. Patients with this condition also frequently have polyarticular arthralgias and joint tenderness, which may suggest inflammatory arthritis. The syndrome was first described in association with ovarian cancer, and this tumor association remains the most commonly described. However, palmar fasciitis has also been reported in association with several other malignancies, including breast, cervical, bladder, endometrial, gastric, hepatocellular, and lung cancer. Although response to steroids has been reported, the condition is usually refractory to therapy; however, successful treatment of the underlying malignancy may improve or halt its progression.

Fasciitis, characterized by inflammation and fibrous thickening of the subcutaneous septa and fascia, occurs in the proximal extremities and occasionally the trunk as a distinct clinical manifestation of autoimmune or infectious disease, which includes eosinophilic fasciitis and the fasciitis-panniculitis syndrome, as well as erythema nodosum. Subcutaneous adipose tissue inflammation, or panniculitis, was first described in association with pancreatic disease by Chiari in 1883. The fasciitis-panniculitis syndrome has been reported occasionally in patients with various forms of malignancy; Hodgkin and non-Hodgkin lymphoma are the most commonly represented, but myeloma and gastric adenocarcinoma have also been reported. In this syndrome, subcutaneous inflammation tends to develop in parallel with the progression of the neoplasm. A clinical syndrome of subcutaneous nodules, fat necrosis, and polyarthritis has been well documented in association with acute and chronic pancreatitis and, in particular, with pancreatic cancer. When all 3 aspects are present (panniculitis, polyarthritis, and pancreatic disease), it is referred to as PPP.

Pancreatic panniculitis most commonly presents as erythema nodosum, often on the lower extremities but also in the atypical areas involving the trunk and upper extremities. Histopathology of these nodules demonstrates fat necrosis, resulting in the distinct pathologic findings of ghost cells and calcified adipocytes. The arthritis that may develop in these cases seems to most commonly affect the ankles; however, it can lead to long-bone pain as well. The arthropathy seems secondary to periarticular fat necrosis. It is speculated that the panniculitis, as well as the arthropathy, is caused by local autodigestion of subcutaneous or medullary fat from excess systemic levels of digestive pancreatic enzymes such as amylase, lipase, and trypsin. Pancreatic panniculitis may also occur in association with other pancreatic diseases, including pancreas divisum and drug-induced pancreatitis. However, panniculitis may also develop in association with precancerous, intraductal papillary mucinous adenoma, as well as adenocarcinoma of the pancreas. Limited case reports also exist describing erythema nodosum in the setting of parathyroid cancer, lung cancer, and hepatocellular carcinoma without evidence to suggest an underlying connective tissue disease. Unlike autoimmune panniculitis, paraneoplastic panniculitis or erythema nodosum characteristically does not respond to nonsteroidal antiinflammatory drugs or glucocorticoid therapy. However, similar to other paraneoplastic rheumatologic manifestations of cancer, there may be benefit from treating the underlying cancer. For example, in a patient with hepatocellular carcinoma, who developed erythema nodosum 2 years before the development of tumor, nonsteroidal antiinflammatory drugs and corticosteroids were ineffective in treating the lesions. However, after the tumor was removed, all the skin lesions disappeared without any further treatment. Complete tumor resection is often impossible in pancreatic cancer.

Scleroderma

Sclerodermatous skin changes may also be seen in association with malignancy. However, interpretation of the association between scleroderma and cancer is complicated because some epidemiologic studies have suggested that patients with scleroderma have an increased risk of malignancy and because the chemotherapeutic agents used to treat cancer can cause skin changes similar to those seen in patients with scleroderma. Nevertheless, a close temporal association between the onset of systemic sclerosis (scleroderma) and cancer has been described in case reports, particularly for breast cancer. Other malignancies have also been associated with the onset of scleroderma, including pulmonary, ovarian, and gastrointestinal malignancies. These cases indicate that at least in some instances, skin fibrosis may be a paraneoplastic process. A group of patients with a close temporal relationship between the onset of scleroderma and the diagnosis of malignancy have been described, who also produce anti-RNA polymerase autoantibodies. RNA polymerase III expression was enhanced in the tumors of these patients, suggesting that RNA polymerase III is a tumor-associated antigen target and, furthermore, that an immune response to this or other autoantigens may be the underlying mechanism of the paraneoplastic development of scleroderma. It remains to be determined whether RNA polymerase antibodies are a predictive biomarker for patients who develop both scleroderma and cancer. This finding has recently been corroborated in a European population.

The Raynaud phenomenon, a common manifestation of scleroderma, can also be an isolated manifestation of occult malignancy and, in some cases, the presenting manifestation. The Raynaud phenomenon together with panniculitis has also been described as a cutaneous manifestation of myeloma.

POEMS Syndrome

A group of cutaneous manifestations of plasma cell dyscrasias have been described as part of a distinct paraneoplastic syndrome with rheumatic features called POEMS syndrome, the acronym for polyneuropathy (peripheral neuropathy), organomegaly, endocrinopathy, M-(monoclonal) protein, and skin abnormalities. This syndrome is also called the Crow-Fukase syndrome in recognition of its original descriptors. Multiple myeloma is the most common plasma cell disorder described with this syndrome, but monoclonal gammopathy of undetermined significance, Castleman disease, and plasmacytoma are also seen. Notably, the myelomas described with the POEMS syndrome are usually osteosclerotic, rather than the osteolytic bone lesions typically seen in multiple myeloma. Patients with POEMS syndrome may also develop peripheral edema, anasarca, ascites, or pleural effusion. The most commonly described skin manifestation of POEMS syndrome is hyperpigmentation. However, thickening of the skin, sclerodermatous changes, hypertrichosis, Raynaud phenomenon, whitening of the nails, clubbing, or cutaneous angiomas may present as part of this syndrome. The pathogenesis of POEMS syndrome is unknown. However, the unifying feature of the various manifestations of this rare condition is the presence of a plasma cell dyscrasia, which has led to the hypothesis that cytokines produced by plasma cells are responsible for many of the clinical manifestations of the disease. Tumor necrosis factor α, IL-6, and IL-1β have been implicated, but the most commonly elevated serum cytokine that has been detected in these patients is vascular endothelial growth factor (VEGF). This is also consistent with increased vascularity seen in the involved tissues in POEMS syndrome, which has led some to propose that VEGF has a central role in the disease. The anti-VEGF monoclonal antibody bevacizumab has been used to treat patients with POEMS syndrome, with variable success.

Inflammatory Myopathies

A well-recognized overlap between rheumatic and paraneoplastic disease occurs in the inflammatory myopathies. Polymyositis and dermatomyositis are characterized by autoimmune inflammatory infiltration of the muscle tissue. This pathologic condition in polymyositis is distinguished by the presence of endomysial inflammation in which multifocal, predominantly CD4 ⁺ lymphocytes infiltrate and invade the muscle fibers, whereas the muscle inflammation in dermatomyositis comprises mixed B- and T-cell perivascular, interfascicular, and perifascicular infiltration, resulting in characteristic perifascicular muscle fiber atrophy. In both cases, the muscle inflammation results in myonecrosis and proximal muscle weakness. Dermatomyositis is further distinguished by the presence of 1 or more of a group of characteristic cutaneous manifestations, including Gottron’s sign, periorbital heliotrope rash, frequent dilation of periungual capillaries, a thickening and coarsening of the fine dermal structures of the hands (mechanics hands), and erythroderma that may occur on the chest, back and shoulders, face, or generally. Pathologic changes in the skin include dermal perivascular infiltration by CD4 ⁺ T cells and capillary dilatation.

An increased incidence of malignancy has been reported with these inflammatory myopathies, but there has been controversy in the literature as to whether the epidemiologic data supporting a cancer association are accurate. However, it is now well established that the incidence of malignancy is increased in patients with dermatomyositis, particularly among older patients, in whom the incidence of the associated malignancy may be as high as 25%. The pathologic changes seen in cancer-associated dermatomyositis are the same as those observed in the idiopathic autoimmune disease. Most malignancies present within 1 year before or after the diagnosis of inflammatory myopathy. The risk is greatest for middle-aged to elderly patients, aged 45 years or older, although younger patients with the new onset of dermatomyositis also have an increased risk for malignant disease. Therefore, older age, as well as poor response to immunosuppressive therapy, should prompt concern for possible malignancy. Age-appropriate cancer screening is indicated for these patients, as well as diagnostic evaluation of any other unexplained signs or symptoms that may signal the presence of occult malignancy, particularly over the first 3 years of the disease. The most commonly described malignancies associated with dermatomyositis are those of the ovaries, gastrointestinal tract, breast, lung, and lymphomas. The evidence of an association of polymyositis and malignancy is less striking than that of dermatomyositis but may also be increased. In patients with polymyositis, an associated increased incidence of lung and bladder cancers, as well as non-Hodgkin lymphoma, has been reported. The greatest risk of the associated malignancy may be at a younger age in patients with polymyositis.

Much less is known about the association of other types of inflammatory myopathies (ie, inclusion body myositis, dermatomyositis sine myositis, and necrotizing myopathy) with an underlying malignancy. Inclusion body myositis shares some pathologic features with polymyositis and has been reported in association with malignancy, but current evidence does not clearly demonstrate an increased risk of cancer. Dermatomyositis sine myositis, also called amyopathic dermatomyositis, occurs when the skin changes of dermatomyositis are present in the absence of myopathy and, in some cases, may be associated with a paraneoplastic process. However, the number of patients with each type of cancer is too small for a specific association to be made. Nevertheless, the presence of unexplained or atypical myositis should prompt a consideration of coincident malignancy.

Cartilage and Periosteum

Cartilage is infrequently involved in neoplastic processes. The prototypical example is relapsing polychondritis, a condition that involves multiple cartilage sites and results in recurrent inflammation of the nose, ears, trachea, costochondral joints, and other tissues in which type II collagen is present. The inflammatory response is mediated proximally by antibodies to type II collagen. Up to one-third of the relapses in patients with polychondritis occur in association with another recognized disease, such as systemic vasculitis; systemic connective tissue diseases, including systemic lupus erythematosus and Sjögren syndrome; or a malignant or premalignant condition. An association between relapsing polychondritis and malignancy is well established. Most of the reports of paraneoplastic polychondritis have been in association with myelodysplastic syndrome or hematologic malignancies, but case reports of polychondritis in association with lymphoma, chondrosarcoma, and cancer of lung, bladder, colon, pancreas, and breast have been published.

Hypertrophic Pulmonary Osteoarthropathy

Hypertrophic pulmonary osteoarthropathy (HPOA) is a well-known example of a cancer-induced paraneoplastic rheumatic disorder. However, it also occurs as a primary condition that usually becomes evident in adolescence and displays autosomal dominant inheritance; sporadic cases of primary disease also occur. HPOA is characterized by proliferative ossifying periostitis of long bones associated with arthritis and clubbing. Primary HPOA also frequently includes the presence of thickened skin with prominent skin folds. In contrast to the secondary disease, symptoms are frequently mild with the primary disease. This heritable condition is also referred to as pachydermoperiostosis. Primary HPOA has recently been shown to result from a mutation in the prostaglandin degradation pathway in which a mutation in the HPGD gene results in loss of function of 15-hydroxy-prostaglandin dehydrogenase. Individuals with primary HPOA correspondingly have high urinary levels of prostaglandin E2 (PGE-2). Secondary HPOA occurs in association with a diverse group of inflammatory diseases, most notably intrathoracic infections or inflammatory processes, but also including gastrointestinal or hepatic disease. In addition, HPOA frequently develops in association with malignancy. The most common association is bronchogenic carcinoma but also includes other forms of lung cancer, particularly mesothelioma, and a variety of other malignancies occurring in the thorax or abdomen. HPOA may occur in up to 10% of patients with intrathoracic malignancies. This condition is characterized clinically by a triad of nail clubbing, ossifying periostitis, and periarticular pain, with pain being the cardinal symptom. The periostitis shows a predilection for the ends of long bones. The arthropathy of HPOA generally affects large appendicular joints but also metacarpophalangeal and metatarsophalangeal joints. There may also be surrounding swelling or edema of the soft tissues and occasionally frank synovitis with significant joint tenderness. Arthropathy may also be mild or absent. The predominant symptom is pain in the areas of periostitis, where the skin may be warm, swollen, and tender. Plain radiographs generally reveal the presence of periostitis, frequently with a line of lucency between normal bone and the proliferative periosteum. However, bone pain may occur before the development of significant periostitis. In such cases, a bone scan may be useful in revealing the uptake of radionuclide along the bone margins. Given the diversity of conditions in which HPOA occurs, it is particularly challenging to identify the possible pathogenic mechanisms. Because HPOA is frequently associated with intrathoracic processes in which right to left shunting of pulmonary blood flow is present, a leading hypothesis has been that an inactive pulmonary factor is released and activated in the peripheral circulation because of this shunting, leading to the development of HPOA. Another shunt-based hypothesis is that megakaryocytes that normally fragment into platelets in the pulmonary circulation end up in the distal peripheral circulation because of shunting, where they release high levels of platelet-derived growth factor, leading to endothelial activation and perhaps the changes seen in HPOA. However, many of the conditions associated with this syndrome, including most forms of cancer, do not result in right to left shunting, which suggests that other mechanisms must be involved. The major alternative hypothesis is that tumor factors with vascular activity, such as VEGF, are released into the circulation, resulting in the development of at least some of the vascular changes seen in HPOA. Another potential clue to the pathogenesis of secondary HPOA has been the dramatic pain reduction observed in a patient with HPOA secondary to lung cancer refractory to narcotic analgesia after treatment with a cyclooxygenase-2 inhibitor, which suggests a role of PGE-2 in the pathogenesis of HPOA. Such a link has previously been suggested and is particularly interesting in light of the role of prostaglandins in bone resorption and the observation that the genetic cause of the primary form of this condition also results in increased PGE-2.

Fasciitis and Panniculitis

The frequent recognition of skin and subcutaneous tissues as a target of neoplastic disease is likely because, in part, of the visibility of the skin and the dense innervation of these structures, resulting in pain and other sensations when the pathologic condition develops. A large number and variety of individual dermatologic manifestations of cutaneous or internal malignancy are described. Comprehensive descriptions of malignant dermatoses have been published elsewhere. However, several paraneoplastic rheumatic syndromes predominantly or prominently involve the skin and subcutaneous tissues and are explained here.

Palmar fasciitis with or without polyarthritis is a rare condition characterized by progressive fibrosis of the hands, resulting in flexion contractures that may suggest the Dupuytren contracture. However, the process is bilateral and usually rapidly progressive. The skin may develop a woody texture suggestive of scleroderma or a more inflammatory appearance that may suggest reflex sympathetic dystrophy. Coincident development of carpal tunnel syndrome has been described. Patients with this condition also frequently have polyarticular arthralgias and joint tenderness, which may suggest inflammatory arthritis. The syndrome was first described in association with ovarian cancer, and this tumor association remains the most commonly described. However, palmar fasciitis has also been reported in association with several other malignancies, including breast, cervical, bladder, endometrial, gastric, hepatocellular, and lung cancer. Although response to steroids has been reported, the condition is usually refractory to therapy; however, successful treatment of the underlying malignancy may improve or halt its progression.

Fasciitis, characterized by inflammation and fibrous thickening of the subcutaneous septa and fascia, occurs in the proximal extremities and occasionally the trunk as a distinct clinical manifestation of autoimmune or infectious disease, which includes eosinophilic fasciitis and the fasciitis-panniculitis syndrome, as well as erythema nodosum. Subcutaneous adipose tissue inflammation, or panniculitis, was first described in association with pancreatic disease by Chiari in 1883. The fasciitis-panniculitis syndrome has been reported occasionally in patients with various forms of malignancy; Hodgkin and non-Hodgkin lymphoma are the most commonly represented, but myeloma and gastric adenocarcinoma have also been reported. In this syndrome, subcutaneous inflammation tends to develop in parallel with the progression of the neoplasm. A clinical syndrome of subcutaneous nodules, fat necrosis, and polyarthritis has been well documented in association with acute and chronic pancreatitis and, in particular, with pancreatic cancer. When all 3 aspects are present (panniculitis, polyarthritis, and pancreatic disease), it is referred to as PPP.

Pancreatic panniculitis most commonly presents as erythema nodosum, often on the lower extremities but also in the atypical areas involving the trunk and upper extremities. Histopathology of these nodules demonstrates fat necrosis, resulting in the distinct pathologic findings of ghost cells and calcified adipocytes. The arthritis that may develop in these cases seems to most commonly affect the ankles; however, it can lead to long-bone pain as well. The arthropathy seems secondary to periarticular fat necrosis. It is speculated that the panniculitis, as well as the arthropathy, is caused by local autodigestion of subcutaneous or medullary fat from excess systemic levels of digestive pancreatic enzymes such as amylase, lipase, and trypsin. Pancreatic panniculitis may also occur in association with other pancreatic diseases, including pancreas divisum and drug-induced pancreatitis. However, panniculitis may also develop in association with precancerous, intraductal papillary mucinous adenoma, as well as adenocarcinoma of the pancreas. Limited case reports also exist describing erythema nodosum in the setting of parathyroid cancer, lung cancer, and hepatocellular carcinoma without evidence to suggest an underlying connective tissue disease. Unlike autoimmune panniculitis, paraneoplastic panniculitis or erythema nodosum characteristically does not respond to nonsteroidal antiinflammatory drugs or glucocorticoid therapy. However, similar to other paraneoplastic rheumatologic manifestations of cancer, there may be benefit from treating the underlying cancer. For example, in a patient with hepatocellular carcinoma, who developed erythema nodosum 2 years before the development of tumor, nonsteroidal antiinflammatory drugs and corticosteroids were ineffective in treating the lesions. However, after the tumor was removed, all the skin lesions disappeared without any further treatment. Complete tumor resection is often impossible in pancreatic cancer.

Scleroderma

Sclerodermatous skin changes may also be seen in association with malignancy. However, interpretation of the association between scleroderma and cancer is complicated because some epidemiologic studies have suggested that patients with scleroderma have an increased risk of malignancy and because the chemotherapeutic agents used to treat cancer can cause skin changes similar to those seen in patients with scleroderma. Nevertheless, a close temporal association between the onset of systemic sclerosis (scleroderma) and cancer has been described in case reports, particularly for breast cancer. Other malignancies have also been associated with the onset of scleroderma, including pulmonary, ovarian, and gastrointestinal malignancies. These cases indicate that at least in some instances, skin fibrosis may be a paraneoplastic process. A group of patients with a close temporal relationship between the onset of scleroderma and the diagnosis of malignancy have been described, who also produce anti-RNA polymerase autoantibodies. RNA polymerase III expression was enhanced in the tumors of these patients, suggesting that RNA polymerase III is a tumor-associated antigen target and, furthermore, that an immune response to this or other autoantigens may be the underlying mechanism of the paraneoplastic development of scleroderma. It remains to be determined whether RNA polymerase antibodies are a predictive biomarker for patients who develop both scleroderma and cancer. This finding has recently been corroborated in a European population.

The Raynaud phenomenon, a common manifestation of scleroderma, can also be an isolated manifestation of occult malignancy and, in some cases, the presenting manifestation. The Raynaud phenomenon together with panniculitis has also been described as a cutaneous manifestation of myeloma.

POEMS Syndrome

A group of cutaneous manifestations of plasma cell dyscrasias have been described as part of a distinct paraneoplastic syndrome with rheumatic features called POEMS syndrome, the acronym for polyneuropathy (peripheral neuropathy), organomegaly, endocrinopathy, M-(monoclonal) protein, and skin abnormalities. This syndrome is also called the Crow-Fukase syndrome in recognition of its original descriptors. Multiple myeloma is the most common plasma cell disorder described with this syndrome, but monoclonal gammopathy of undetermined significance, Castleman disease, and plasmacytoma are also seen. Notably, the myelomas described with the POEMS syndrome are usually osteosclerotic, rather than the osteolytic bone lesions typically seen in multiple myeloma. Patients with POEMS syndrome may also develop peripheral edema, anasarca, ascites, or pleural effusion. The most commonly described skin manifestation of POEMS syndrome is hyperpigmentation. However, thickening of the skin, sclerodermatous changes, hypertrichosis, Raynaud phenomenon, whitening of the nails, clubbing, or cutaneous angiomas may present as part of this syndrome. The pathogenesis of POEMS syndrome is unknown. However, the unifying feature of the various manifestations of this rare condition is the presence of a plasma cell dyscrasia, which has led to the hypothesis that cytokines produced by plasma cells are responsible for many of the clinical manifestations of the disease. Tumor necrosis factor α, IL-6, and IL-1β have been implicated, but the most commonly elevated serum cytokine that has been detected in these patients is vascular endothelial growth factor (VEGF). This is also consistent with increased vascularity seen in the involved tissues in POEMS syndrome, which has led some to propose that VEGF has a central role in the disease. The anti-VEGF monoclonal antibody bevacizumab has been used to treat patients with POEMS syndrome, with variable success.

Inflammatory Myopathies

A well-recognized overlap between rheumatic and paraneoplastic disease occurs in the inflammatory myopathies. Polymyositis and dermatomyositis are characterized by autoimmune inflammatory infiltration of the muscle tissue. This pathologic condition in polymyositis is distinguished by the presence of endomysial inflammation in which multifocal, predominantly CD4 ⁺ lymphocytes infiltrate and invade the muscle fibers, whereas the muscle inflammation in dermatomyositis comprises mixed B- and T-cell perivascular, interfascicular, and perifascicular infiltration, resulting in characteristic perifascicular muscle fiber atrophy. In both cases, the muscle inflammation results in myonecrosis and proximal muscle weakness. Dermatomyositis is further distinguished by the presence of 1 or more of a group of characteristic cutaneous manifestations, including Gottron’s sign, periorbital heliotrope rash, frequent dilation of periungual capillaries, a thickening and coarsening of the fine dermal structures of the hands (mechanics hands), and erythroderma that may occur on the chest, back and shoulders, face, or generally. Pathologic changes in the skin include dermal perivascular infiltration by CD4 ⁺ T cells and capillary dilatation.

An increased incidence of malignancy has been reported with these inflammatory myopathies, but there has been controversy in the literature as to whether the epidemiologic data supporting a cancer association are accurate. However, it is now well established that the incidence of malignancy is increased in patients with dermatomyositis, particularly among older patients, in whom the incidence of the associated malignancy may be as high as 25%. The pathologic changes seen in cancer-associated dermatomyositis are the same as those observed in the idiopathic autoimmune disease. Most malignancies present within 1 year before or after the diagnosis of inflammatory myopathy. The risk is greatest for middle-aged to elderly patients, aged 45 years or older, although younger patients with the new onset of dermatomyositis also have an increased risk for malignant disease. Therefore, older age, as well as poor response to immunosuppressive therapy, should prompt concern for possible malignancy. Age-appropriate cancer screening is indicated for these patients, as well as diagnostic evaluation of any other unexplained signs or symptoms that may signal the presence of occult malignancy, particularly over the first 3 years of the disease. The most commonly described malignancies associated with dermatomyositis are those of the ovaries, gastrointestinal tract, breast, lung, and lymphomas. The evidence of an association of polymyositis and malignancy is less striking than that of dermatomyositis but may also be increased. In patients with polymyositis, an associated increased incidence of lung and bladder cancers, as well as non-Hodgkin lymphoma, has been reported. The greatest risk of the associated malignancy may be at a younger age in patients with polymyositis.

Much less is known about the association of other types of inflammatory myopathies (ie, inclusion body myositis, dermatomyositis sine myositis, and necrotizing myopathy) with an underlying malignancy. Inclusion body myositis shares some pathologic features with polymyositis and has been reported in association with malignancy, but current evidence does not clearly demonstrate an increased risk of cancer. Dermatomyositis sine myositis, also called amyopathic dermatomyositis, occurs when the skin changes of dermatomyositis are present in the absence of myopathy and, in some cases, may be associated with a paraneoplastic process. However, the number of patients with each type of cancer is too small for a specific association to be made. Nevertheless, the presence of unexplained or atypical myositis should prompt a consideration of coincident malignancy.

Cartilage and Periosteum

Cartilage is infrequently involved in neoplastic processes. The prototypical example is relapsing polychondritis, a condition that involves multiple cartilage sites and results in recurrent inflammation of the nose, ears, trachea, costochondral joints, and other tissues in which type II collagen is present. The inflammatory response is mediated proximally by antibodies to type II collagen. Up to one-third of the relapses in patients with polychondritis occur in association with another recognized disease, such as systemic vasculitis; systemic connective tissue diseases, including systemic lupus erythematosus and Sjögren syndrome; or a malignant or premalignant condition. An association between relapsing polychondritis and malignancy is well established. Most of the reports of paraneoplastic polychondritis have been in association with myelodysplastic syndrome or hematologic malignancies, but case reports of polychondritis in association with lymphoma, chondrosarcoma, and cancer of lung, bladder, colon, pancreas, and breast have been published.

Hypertrophic Pulmonary Osteoarthropathy

Hypertrophic pulmonary osteoarthropathy (HPOA) is a well-known example of a cancer-induced paraneoplastic rheumatic disorder. However, it also occurs as a primary condition that usually becomes evident in adolescence and displays autosomal dominant inheritance; sporadic cases of primary disease also occur. HPOA is characterized by proliferative ossifying periostitis of long bones associated with arthritis and clubbing. Primary HPOA also frequently includes the presence of thickened skin with prominent skin folds. In contrast to the secondary disease, symptoms are frequently mild with the primary disease. This heritable condition is also referred to as pachydermoperiostosis. Primary HPOA has recently been shown to result from a mutation in the prostaglandin degradation pathway in which a mutation in the HPGD gene results in loss of function of 15-hydroxy-prostaglandin dehydrogenase. Individuals with primary HPOA correspondingly have high urinary levels of prostaglandin E2 (PGE-2). Secondary HPOA occurs in association with a diverse group of inflammatory diseases, most notably intrathoracic infections or inflammatory processes, but also including gastrointestinal or hepatic disease. In addition, HPOA frequently develops in association with malignancy. The most common association is bronchogenic carcinoma but also includes other forms of lung cancer, particularly mesothelioma, and a variety of other malignancies occurring in the thorax or abdomen. HPOA may occur in up to 10% of patients with intrathoracic malignancies. This condition is characterized clinically by a triad of nail clubbing, ossifying periostitis, and periarticular pain, with pain being the cardinal symptom. The periostitis shows a predilection for the ends of long bones. The arthropathy of HPOA generally affects large appendicular joints but also metacarpophalangeal and metatarsophalangeal joints. There may also be surrounding swelling or edema of the soft tissues and occasionally frank synovitis with significant joint tenderness. Arthropathy may also be mild or absent. The predominant symptom is pain in the areas of periostitis, where the skin may be warm, swollen, and tender. Plain radiographs generally reveal the presence of periostitis, frequently with a line of lucency between normal bone and the proliferative periosteum. However, bone pain may occur before the development of significant periostitis. In such cases, a bone scan may be useful in revealing the uptake of radionuclide along the bone margins. Given the diversity of conditions in which HPOA occurs, it is particularly challenging to identify the possible pathogenic mechanisms. Because HPOA is frequently associated with intrathoracic processes in which right to left shunting of pulmonary blood flow is present, a leading hypothesis has been that an inactive pulmonary factor is released and activated in the peripheral circulation because of this shunting, leading to the development of HPOA. Another shunt-based hypothesis is that megakaryocytes that normally fragment into platelets in the pulmonary circulation end up in the distal peripheral circulation because of shunting, where they release high levels of platelet-derived growth factor, leading to endothelial activation and perhaps the changes seen in HPOA. However, many of the conditions associated with this syndrome, including most forms of cancer, do not result in right to left shunting, which suggests that other mechanisms must be involved. The major alternative hypothesis is that tumor factors with vascular activity, such as VEGF, are released into the circulation, resulting in the development of at least some of the vascular changes seen in HPOA. Another potential clue to the pathogenesis of secondary HPOA has been the dramatic pain reduction observed in a patient with HPOA secondary to lung cancer refractory to narcotic analgesia after treatment with a cyclooxygenase-2 inhibitor, which suggests a role of PGE-2 in the pathogenesis of HPOA. Such a link has previously been suggested and is particularly interesting in light of the role of prostaglandins in bone resorption and the observation that the genetic cause of the primary form of this condition also results in increased PGE-2.