Shari A. Brazinsky
The extrathoracic manifestations of bronchogenic carcinoma can be categorized into those related to local spread, those related to metastases, and those that are independent of cancer spread, namely, the paraneoplastic syndromes.
MANIFESTATIONS OF LOCAL SPREAD
Local spread, which causes extrathoracic manifestations, is most often caused by superior sulcus tumors involving the eighth cervical and first thoracic nerves. Patients complain of pain in the shoulder and along the ulnar distribution of the arm. Paravertebral involvement of the sympathetic chain can cause a Horner syndrome. Tumor also can involve the recurrent laryngeal nerve and produce hoarseness. Superior vena cava syndrome is caused by tumor compression anywhere along the course of this vessel. Other extrathoracic symptoms may result from spread into the mediastinum, with involvement of the heart and esophagus.
METASTATIC DISEASE
Although metastatic disease is common in patients dying of lung cancer (96%), symptomatic disease is less frequent. Metastases are most common in lymph nodes (70%), liver (49%), brain (30%), adrenals (25%), bone (30%), and kidneys (18%), although they can involve any organ or tissue. Lymph node, adrenal, and renal metastases are rarely symptomatic. Bony metastases can produce local pain and even spinal cord compression if the vertebral bodies are involved. The diagnosis and treatment of spinal cord compression is a medical emergency and should always be considered in this setting, particularly if neurologic symptoms are present. Liver involvement is generally asymptomatic but can cause abdominal discomfort. Brain metastases can mimic cerebrovascular disease or primary intracranial neoplasm.
PARANEOPLASTIC SYNDROMES
The paraneoplastic syndromes can be characterized as (1) constitutional, (2) hematologic, (3) skeletal, (4) neuromuscular, (5) cutaneous, (6) vasculitic, and (7) endocrine. The most common constitutional syndromes are weight loss, anorexia, and fatigue. Tumor size alone does not explain the presence or magnitude of symptoms, and their cause(s) is unknown. Cachexia is a significant prognostic factor in the course of lung cancer. Recent studies suggest that cytokines such as tumor necrosis factor-α, interleukin (IL)-6 and IL-1β influence cachexia, as well as loss of muscle mass and adipose tissue. Megestrol acetate, a synthetic progestin, has been found to improve well-being, as well as allow weight gain, in many types of lung cancer.
Normochromic, normocytic anemia occurs in less than 10% of patients with bronchogenic carcinoma and is unrelated to marrow infiltration or therapy. A number of coagulopathies are associated with lung cancer. They include migratory thrombophlebitis (Trousseau syndrome), disseminated intravascular coagulation, chronic hemorrhagic diathesis, nonbacterial thrombotic endocarditis, and arterial embolization. Trousseau syndrome often involves unusual sites such as the upper extremities or the vena cava and is frequently unresponsive to anticoagulant therapy. Non–small-cell carcinomas have also been associated with tumor-related leukocytosis, which is cytokine mediated and carries an ominous prognosis.
Hypertrophic pulmonary osteoarthropathy occurs in 4% to 12% of patients with lung cancer, most commonly with epidermoid carcinoma and only rarely with small-cell carcinoma (5%). It consists of periosteal new bone formation in the long bones, with digital clubbing and symmetric arthritis. Vasomotor instability is often present with episodic blanching, swelling, and diaphoresis of the hands and feet. The ankles, wrists, and long bones can be very painful and tender. Although new bone growth is present, the syndrome does not seem to be caused by ectopic human growth hormone production, but it may be mediated by autonomic reflexes. It usually regresses after tumor removal, vagotomy, or thoracotomy without tumor resection. Prognosis does not appear to be altered if this syndrome is present, and tumor recurrence is frequently accompanied by recurrent osteopulmonary arthropathy. Unilateral facial pain and cluster headaches can be referred pain, or caused by hypertrophic osteopathy or paraneoplastic circulating humoral factors. Pain can be relieved by radiotherapy, tumor resection with vagotomy or medical treatment with nonsteroidal anti-inflammatory agents or a bisphosphonate.
An increasing number of neuromuscular syndromes have been associated with bronchogenic carcinoma, most commonly small-cell carcinoma. These syndromes may precede the clinical appearance of the tumor by months to years. The most potentially devastating are cerebral encephalopathy and cortical cerebellar degeneration, both of which can occur precipitously. Peripheral neuropathies, usually sensorimotor and often presenting as pain and paraesthesias of the lower extremities, occur in up to 15% of patients with lung cancer. This can be followed by the gradual onset of a neuropathic arthropathy. Lambert–Eaton myasthenic syndrome (LEMS) occurs in 6% of patients with small-cell carcinoma and differs from myasthenia gravis primarily by an increase in the muscle action potential on repetitive stimulation and the lack of improvement in muscle strength with anticholinesterases. Studies suggest the antibodies associated with LEMS may confer a survival advantage, as the median survival with small-cell lung carcinoma was prolonged by more than 10 months in patients who tested positive for it. SOX1 antibodies presence in LEMS predicts the presence of small-cell carcinoma of the lung. Symmetric proximal muscle neuromyopathy associated with muscle wasting is also common. Non–small-cell tumors have been reported with a paraneoplastic necrotizing myopathy. Paraneoplastic encephalomyelitis, frequently associated with small-cell carcinoma, is characterized by inflammatory infiltrates and neuronal loss. A rapidly progressive binocular vision loss, termed cancer-associated retinopathy, has been described in patients with small-cell carcinoma. Also associated with small-cell carcinoma is an adult-onset opsoclonus–myoclonus syndrome. There is no specific immunoreactivity, and the paraneoplastic variety has a worse prognosis than if idiopathic. If the tumor is treated effectively, significant neurologic recovery is noted.
The cause of these neuromuscular paraneoplastic syndromes is generally not known. Evidence has been found, however, for an autoimmune basis for several of these syndromes. In these cases, antibodies have been found that cross-react with tumor and normal tissue antigens. In LEMS, the antibodies cross-react with presynaptic voltage-gated calcium channels at the neuromuscular junction. In cancer-associated retinopathy, antibodies to a tumor antigen cross-react with a subset of retinal ganglion cells (to the photoreceptor protein recoverin). Prednisone therapy has been reported to reduce antibody titers and stabilize visual fields. A heterogeneous group of cases including of paraneoplastic encephalomyelitis, cerebellar degeneration, LEMS, and sensory neuronopathy with small-cell carcinoma associated with a specific antibody in the serum or cerebral spinal fluid is considered part of the anti-Hu syndrome (bearing the name of the first patient in whom the antibody was discovered). These include the presence of high titers of Hu antibody associated with more severe cerebellar degeneration than in the subset without the antibody. An anti-Purkinje cell antibody has also been found in some patients with para-neoplastic cerebellar degeneration. In patients with lung cancer, however, the antibody is rarely found, and the clinical picture is less severe and slower to develop than when the syndrome is associated with other types of cancer. Lower motor neuron disease as a paraneoplastic syndrome has also been seen with anti-Hu antibody. In terms of early diagnosis of malignancy, presence of paraneoplastic neuronal autoantibodies is associated with successful positron emission tomography (PET)–CT directed cancer search in 18% of patients.
Some studies have found more than one antibody present in patients with paraneoplastic syndrome, raising the possibility of multimodal autoantibody production. Such autoantibodies are found to be associated with other paraneoplastic syndromes. Gastrointestinal motor dysfunction is now known to be associated with small-cell carcinoma (with multiple paraneoplastic autoantibodies) and can precede the recognition of tumor by months to years. Dysfunction includes delayed gastric emptying, esophageal dysmotility, and abnormal autonomic reflexes.
Cutaneous manifestations include features of dermatomyositis, hyperpigmentation caused by ectopic production of melanocyte-stimulating hormone, and acanthosis nigricans. The last is a hyperkeratotic, hyperpigmented dermatosis with small papillomatous lesions giving the skin a velvety texture. It is symmetric and prominent in skin folds. When it occurs after age 40, it is almost always associated with cancer (90% intra-abdominal, 5% lung). Dermatomyositis has been associated with an autoantibody to a nuclear complex of unknown function. Other rare manifestations include erythema gyratum (thickened, bandlike urticarial plaques imparting a “knotty pine” appearance) with small-cell carcinoma, universal hypertrichosis lanuginosa with epidermoid carcinoma, and rapidly progressive digital necrosis with small-cell carcinoma. Recently, benign dermatosis granuloma annulare, interstitial granulomatous dermatitis, tripe palms, and subacute cutaneous lupus erythematosus were reported as being temporally associated with carcinoma of the lung, and regressed with successful treatment of the malignancy.
Non–small-cell carcinomas have been associated with cutaneous vasculitis and purpura rheumatica. Disseminated vasculitis has now been reported with small-cell carcinoma of the lung. A nonsystemic subacute vasculitic neuropathy called paraneoplastic vasculitic neuropathy
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