Case 29-2006 — A 43-Year-Old Woman with Painful Nodules on the Fingertips, Shortness of Breath, and Fatigue
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《新英格兰医药杂志》
Presentation of Case
Dr. Tessa Cigler (Cancer Center): A 43-year-old woman was admitted to this hospital because of painful nodules on the fingertips, shortness of breath, and fatigue.
Systemic lupus erythematosus (SLE) had been diagnosed 12 years earlier at another hospital. Her symptoms at that time included arthralgias involving the knees and wrists, an ischemic right third toe, and livedo reticularis of her legs. The results of an antinuclear-antibody test was positive, and antiphospholipid antibodies were not detected. A biopsy specimen of the sole of her right foot showed intravascular fibrin thrombi without evidence of vasculitis. She was treated with prednisone, nifedipine, and prazosin and received anticoagulation therapy with heparin followed by warfarin for 6 months thereafter.
Since that time, relatively mild symptoms of polyarthralgias and Raynaud's phenomenon had been managed with nonsteroidal antiinflammatory medications and hydroxychloroquine. Seven months before admission she began to have urticarial skin lesions on the left arm and buttocks. She saw a rheumatologist at another hospital; levels of anti–double-stranded DNA antibodies and C-reactive protein and the erythrocyte sedimentation rate were elevated. She was treated with 30 mg of prednisone daily, and these signs and symptoms resolved; use of the corticosteroid was tapered during the next 2 months and then discontinued. During the same period, her voice became hoarse. Examination by an otolaryngologist disclosed edema and erythema of the vocal cords, and proton-pump inhibitors were prescribed for presumed gastric reflux.
Four months before admission she transferred her care to a rheumatologist at this hospital. Three months before admission, diffuse urticarial skin lesions again developed. Laboratory-test results are shown in Table 1. Examination of a skin-biopsy specimen disclosed changes consistent with the presence of tumid lupus. Prednisone (10 mg daily) was begun, and the lesions resolved.
Table 1. Results of Immunologic Laboratory Tests.
Two weeks before admission the patient had symptoms involving the fingers that were suggestive of Raynaud's phenomenon, and dark lesions developed on her fingertips, as did bruises over her back and thighs. One week before admission she saw her rheumatologist, who noted that the fingers of both hands, in particular the right index finger, were cold and blue; multiple small, painful, purple nodules were present on the fingertips; and there were ecchymoses on the back and thighs. Laboratory-test results are shown in Table 1. The dose of prednisone was increased to 15 mg daily, and hydroxychloroquine to 400 mg daily. Her symptoms did not improve. Fatigue, decreased appetite, dyspnea on exertion, chest pain on inspiration, and nocturnal wheezing developed, and 1 week later she was admitted to the hospital.
The patient did not have fever, chills, weight loss, chest pain, hair loss, or worsening arthralgias. She had had a positive tuberculin skin test as a teenager, for which she recalled receiving antibiotics. She had smoked one pack of cigarettes a day for the past 20 years. She had a stable chronic cough. She drank alcohol socially and did not use intravenous drugs. Her teeth had been cleaned by her dentist approximately 1 month earlier. She had recently married and lived with her husband. She worked as a secretary and a housecleaner. Her mother, a sister, and a brother also had SLE. Another sister and brother were well. Her medications were prednisone (15 mg), naproxen (1000 mg), and hydroxychloroquine (400 mg) daily.
On admission, she appeared comfortable. The temperature was 36.8°C, the blood pressure 140/80 mm Hg, the pulse 80 beats per minute, and the respiratory rate 20 breaths per minute, with an oxygen saturation of 99% while she was breathing room air. There was a mobile left axillary lymph node, 1 cm in diameter, with no cervical or supraclavicular lymphadenopathy. Examination of the heart and lungs was normal. There was mild bilateral tenderness of the metatarsophalangeal joint, but no obvious synovitis or deformities. Her fingers were cool and cyanotic, and the fingertips and the left big toe were mottled, with small, violaceous, tender, subcutaneous nodules. Splinter hemorrhages were present under the fingernails. Scattered ecchymoses but no petechiae were present on her back, legs, arms, and abdomen.
An electrocardiogram showed first-degree atrioventricular block, a prolonged QT interval, and nonspecific T-wave abnormalities. Levels of serum electrolytes, albumin, globulin, angiotensin-converting enzyme, lupus anticoagulant, anticardiolipin antibodies, protein C, activated protein C, and protein S were normal, as were the results of liver-function tests, prothrombin and partial-thromboplastin times, a test for prothrombin gene mutation, and a complete blood count. The lactate dehydrogenase level was 284 U per liter. The erythrocyte sedimentation rate was 36 mm per hour. One of five cultures of blood drawn during the first 3 days grew pan-sensitive coagulase-negative staphylococci.
A chest radiograph revealed mediastinal fullness suggestive of lymphadenopathy; the peripheral lung fields were clear. A ventilation–perfusion scan showed a low probability of a pulmonary embolus. Computed tomography (CT) of the chest the next day revealed extensive lymphadenopathy in the prevascular, subcarinal, paratracheal, and axillary regions; two nodules, one 1.5 by 2.0 cm, in the left lower lobe of the lung, and the other 7 mm in diameter, in the left upper lobe; and a small, left-sided pleural effusion. A transthoracic echocardiogram obtained on the third hospital day revealed a patent foramen ovale and mild mitral regurgitation.
A diagnostic procedure was performed on the fourth hospital day.
Differential Diagnosis
Dr. Matthew D. Gilman: The chest radiograph obtained on admission (Figure 1A) reveals thickening of the right paratracheal stripe and widening of the left superior mediastinum, indicating the presence of mediastinal lymphadenopathy. A small focus of subsegmental atelectasis is present in the left lower lobe. A CT scan of the chest without contrast medium, obtained on the next day, shows an enlarged right supraclavicular lymph node and extensive mediastinal lymphadenopathy (Figure 1B) involving the right paratracheal, prevascular, aorticopulmonary, and subcarinal positions, as well as the left hilum. A small, left-sided pleural effusion and a small pericardial effusion are visible.
Figure 1. Imaging Studies of the Chest.
A chest radiograph (Panel A) shows thickening of the right paratracheal stripe and widening of the left superior mediastinum (arrows), indicating the presence of mediastinal lymphadenopathy. Axial CT of the chest (Panel B) obtained without contrast medium in a mediastinal window shows enlarged mediastinal lymph nodes in the right paratracheal and prevascular positions (arrows). Axial CT of the chest in a lung window (Panel C) shows a nodule (arrow), 1.5 by 2.0 cm, in the superior segment of the left lower lobe with distal subsegmental atelectasis. A small, left-sided pleural effusion is also visible.
Lung windows from the same CT scan of the chest show a nodule, 1.5 by 2.0 cm, in the superior segment of the left lower lobe with distal subsegmental atelectasis (Figure 1C). A second nodule, 7 mm in diameter, is visible in the left upper lobe.
Dr. Anwer Qureshi: The transthoracic echocardiogram shows mild mitral regurgitation and mildly thickened mitral-valve leaflets with no valvular vegetations. A small, patent foramen ovale is present, and right-to-left shunting is apparent after the administration of agitated saline into a peripheral vein.
Dr. Karen H. Costenbader: This 43-year-old woman with a 12-year history of SLE, characterized by Raynaud's phenomenon, an ischemic digit, arthralgias, lymphopenia, and high titers of antinuclear antibodies and antibodies against double-stranded DNA, was admitted with cold and mottled fingers, small and tender violaceous nodules on the fingertips, and splinter hemorrhages of the nail beds. Recently, she had had worsening polyarthralgias, Raynaud's symptoms, urticarial rash, fatigue, and bruising. Chest radiographs revealed extensive mediastinal lymphadenopathy, and CT showed two nodules in the left lung and a small pleural effusion. I am aware of the diagnosis, although I was not involved in this patient's care. Nevertheless, the case provides an opportunity to discuss the differential diagnosis of this constellation of findings in a patient with SLE.
Primary Raynaud's phenomenon is common in young women. Clues that Raynaud's phenomenon is secondary to an underlying connective-tissue disease or other process include the rapid onset of severe disease later in life, with irreversible ischemia, digital pitting, ulceration, and even gangrene, dilatation and dropout of the periungual capillaries. Skin changes such as skin thickening, sclerodactyly, calcinosis, or telangiectasias signal systemic involvement by a connective-tissue disease. Although some of the symptoms of this patient can be attributed to worsening SLE-associated Raynaud's phenomenon, we also need to consider immune-mediated small-vessel vasculitis, a hypercoagulable state, endocarditis, and rarer entities (Table 2).
Table 2. Differential Diagnosis of Acutely Worsening or Severe Raynaud's Phenomenon.
Vasculitis
Vascular disease in patients with SLE can be classified into two broad categories — inflammatory and thrombotic. Vasculitis in patients with SLE is the result of immune-complex formation and can affect vessels in any organ, including kidneys, lungs, skin, intestines, heart, and nerves. In this patient, the cutaneous lesions could be due to vasculitis, but the splinter hemorrhages would not be explained by vasculitis.
Mixed cryoglobulinemia, usually type 3, can develop in patients with SLE and cause small-vessel vasculitis.1 Clinical manifestations of cryoglobulinemic vasculitis include palpable purpura and digital ischemia and could account for the lesions seen in this patient. This patient did not have evidence of a cryoprotein; however, false negative cryoglobulin results are common owing to cooling of the sample during transportation.
Thrombotic Vascular Occlusion
Most of the thrombotic vascular injury seen in patients with SLE is mediated by antiphospholipid antibodies. Approximately 30% of patients with SLE have detectable antiphospholipid antibodies, including anticardiolipin, lupus anticoagulant, and anti–2-glycoprotein I antibodies, at some time during their lives.2 These antibodies to negatively charged phospholipids cause spontaneous arterial and venous thromboses in vessels of any size. Antiphospholipid-antibody syndrome is defined by the presence of an elevated titer of anticardiolipin IgG or IgM or lupus anticoagulant antibody on two or more occasions at least 6 weeks apart and by either spontaneous vascular thrombosis or recurrent pregnancy loss (often in the third trimester due to placental insufficiency).3 This patient's tests for antiphospholipid antibodies were negative, but titers fluctuate depending on the activity of disease and treatment, so that the value of an individual negative test is low.
Other hypercoagulable states, such as deficiencies of protein C and protein S, factor V Leiden, and antithrombin III deficiency tend to be associated with venous thromboembolism much more commonly than with arterial thromboembolism; they are less likely to account for the presenting features in this case and are ruled out by laboratory testing. Protein S deficiency has been associated with SLE because of antiprotein S antibodies.4 Although these syndromes can be ruled out, a hypercoagulable state associated with malignant conditions and causing arterial thromboembolism could explain the clinical presentation.
Another possibility in this case is so-called chilblains lupus, a rare manifestation of SLE in which violaceous digital plaques and nodules develop after exposure to cold, damp climates, as in classic idiopathic chilblains lesions. Histologically, the lesions of chilblains lupus contain papillary and deep dermal T-cell infiltrates, with dermal edema and necrotic keratinocytes.5 Chilblains lupus has been associated with anti-Ro (SS-A) antibodies, Raynaud's phenomenon, and changes in the nail-fold capillary.6 This patient did not have anti-Ro antibodies, and splinter hemorrhages usually are not seen with chilblains. These usually occur in the fall and winter, and this patient presented in late summer.
Endocarditis
Infection with common and uncommon pathogens is a leading cause of complications and death in patients with SLE. The high rates of infection are attributable to inherited and acquired complement deficiencies, functional asplenia due to saturation of Fc receptors by circulating immune complexes,7 immunoglobulin deficiencies, and defects in phagocyte function, as well as immunosuppressant medications. Patients with SLE are at high risk for infection with encapsulated organisms, such as pneumococcus,8 neisseria,9 and salmonella.10
Bacterial endocarditis is a concern in this patient given the presence of splinter hemorrhages in the nail beds and finger lesions suggestive of classic Osler nodes, caused by deposition of immune complexes. Libman–Sacks endocarditis, characterized by sterile verrucous vegetations most often on the mitral valve, is associated with antiphospholipid antibodies and can cause embolic complications, valvular incompetence, heart failure, and bacterial infection.11 Splinter hemorrhages, embolic lesions, and a new murmur are clues to its presence. Endocarditis, either bacterial or nonbacterial, could explain the cutaneous manifestations in this case. A transthoracic echocardiogram did not reveal valvular vegetations, but a transesophageal echocardiogram would be more sensitive for the detection of these lesions.
Lymphadenopathy and Pulmonary Nodules
This patient had mediastinal and axillary lymphadenopathy. Lymphadenopathy due to lupus lymphadenitis is common in patients with SLE and particularly affects cervical and axillary lymph nodes.12 It is characterized by a diffuse reactive hyperplasia, often with extensive necrosis, and a lymph-node biopsy is useful in establishing the diagnosis and ruling out infectious and malignant processes. Massive mediastinal lymphadenopathy like that in this patient, however, is rarely due to SLE alone. This patient had a history of a positive test for tuberculosis and was at risk for reactivation, since she had been taking prednisone for several months. In addition to the lymphadenopathy, this patient had two nodules in the left lower lung and a small pleural effusion. The pulmonary manifestations of SLE are summarized in Table 3. Pneumonia, due to both typical and atypical pathogens, is common. Pleuritic chest pain can occur with or without an associated pleural effusion or detectable friction rub. Pleural effusions are usually small or moderate in size and can be recurrent and bilateral. The pulmonary infiltrates and pleural effusion could be manifestations of SLE in this patient, but together with the lymphadenopathy and evidence of vascular disease, they lead to concern about the possibility of cancer.
Table 3. Pleuropulmonary Manifestations of SLE.
Patients with lupus are at increased risk for both non-Hodgkin's lymphoma and lung cancer.13,14 The reasons for the elevated risks are unclear but may include a common genetic predisposition, exposure to causative agents, the use of immunosuppressant medications, immunologic dysfunction, or a combination of these. In addition, this patient is a smoker and thus is at increased risk for lung cancer.
In summary, in this woman with established SLE, new systemic symptoms, massive mediastinal lymphadenopathy with lung nodules, and digital embolic lesions, a neoplasm or infection involving the lung and lymph nodes and complicated by endocarditis would have been at the top of my list of diagnoses. Since patients with SLE are at increased risk for both lymphoma and lung cancer and because of this patient's history of smoking, I would favor a diagnosis of lung cancer, although infection or lymphoma cannot be ruled out. I would recommend a tissue biopsy of either the lung or the lymph nodes and cytologic evaluation of the pleural effusion.
Dr. Karen H. Costenbader's Diagnosis
Cancer of the lung and mediastinal lymph nodes complicating SLE, with associated endocarditis and thrombotic vasculopathy.
Pathological Discussion
Dr. Rosemary H. Tambouret: In this patient with lung nodules and mediastinal lymphadenopathy, several approaches could be used to make a tissue diagnosis. Bronchoscopy, percutaneous fine-needle aspiration with CT guidance, or open-lung biopsy (by means of thoracoscopy or thoracotomy) can be used to obtain samples of the lung nodules. Samples of the mediastinal lymph nodes can be obtained by mediastinoscopy, by bronchoscopy with transbronchial needle aspiration, or by fine-needle aspiration during transesophageal endoscopic ultrasonography. One advantage of bronchoscopy with transbronchial needle aspiration is that samples of both the lung nodules and the mediastinal lymph nodes can be obtained in one procedure.15 Sensitivity is improved when on-site rapid interpretation of cellular material by a cytopathologist is used to ensure adequacy of the sample.16 The samples must be sent to the following departments: cytology and surgical pathology for tissue diagnosis, flow cytometry for evaluation for a lymphoma or leukemia, and microbiology for ruling out an infection.
The patient underwent a bronchoscopy, which disclosed widening of the carina and narrowing of the left-lower-lobe bronchus. A bronchial mucosal lesion was not identified. Multiple cytologic samples were obtained, including bronchial brushings, bronchoalveolar-lavage fluid from the left lower lobe, and multiple blind transbronchial needle-aspiration samples from the area of the widened carina. Samples were sent for cultures and flow cytometry. The transbronchial needle-aspiration samples revealed the presence of large malignant cells consistent with adenocarcinoma (Figure 2A). With the use of immunocytochemistry, the tumor cells stained for cytokeratin, which is consistent with an epithelial tumor, but they did not stain for thyroid transcription factor 1, a nuclear protein expressed exclusively in epithelial cells of the thyroid and lung and in 54 to 76% of cases of lung cancer.17 Cytologic evaluation of the pleural effusion in this patient was also performed (Figure 2B) and was positive for adenocarcinoma.
Figure 2. Cytologic Analysis (Papanicolaou's Stain).
Cytologic analysis of the transbronchial needle aspirate (Panel A) showed large malignant cells present singly and in small groups. Cytologic analysis of the pleural effusion obtained 4 days after the bronchoscopy (Panel B) showed only a few malignant cells admixed with many lymphocytes. Cytologic evaluation of the pleural effusion obtained 4 months later (Panel C) showed abundant malignant cells.
Dr. Nancy Lee Harris (Pathology): After the diagnosis of carcinoma was made, an oncology consultant elucidated the rest of the story.
Dr. Panos Fidias: The combination of splinter hemorrhages, peripheral embolic events, and a heart murmur in this patient raises the possibility of nonbacterial thrombotic endocarditis, which is characterized by the deposition of fibrin on normal or superficially degenerated valves.18 In more than 90% of cases the vegetations are located on the mitral or aortic valves, and they are typically small (<3 mm to 10 mm), making detection with transthoracic echocardiography challenging.19 Nonbacterial thrombotic endocarditis is associated with the presence of an advanced cancer in up to 85% of patients.20 In an echocardiographic study of patients with solid tumors, 19% (28% of those with lung cancer) had vegetations.21 Thromboembolic events occurred in 24% of patients who had vegetations, as compared with 8% of those with normal findings on echocardiography. Thus, this patient with advanced lung cancer is at high risk for nonbacterial thrombotic endocarditis and embolic events.
Nonbacterial thrombotic endocarditis is a manifestation of hypercoagulability of malignancy, first described by Trousseau,22 and up to 20% of patients with the disease have laboratory evidence of disseminated intravascular coagulation.19 In this patient, levels of d-dimers measured on the fourth hospital day were markedly elevated (3712 ng per milliliter, vs. a normal level of <500 ng per milliliter). The diagnostic procedure was a transesophageal echocardiogram.
Dr. Panos Fidias's Diagnosis
Nonbacterial thrombotic endocarditis due to non–small-cell lung cancer.
Diagnostic Discussion
Dr. Qureshi: Views of the heart were obtained from the midesophageal position of the probe. Vegetations were seen on both the anterior (Figure 3A, and Video 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org) and posterior (Figure 3B, and Video 2 of the Supplementary Appendix) mitral-valve leaflets. The mitral-valve structure and function are not markedly compromised. In the proper clinical setting, these findings are consistent with the diagnosis of nonbacterial thrombotic endocarditis. The aortic, tricuspid, and pulmonary valves were normal. There was no atrial clot or aortic disease, and a small, patent foramen ovale with left-to-right shunting was again noted on color Doppler imaging.
Figure 3. Transesophageal Echocardiogram.
Mild thickening of the mitral-valve leaflets is present, with a broad-based vegetation on the anterior mitral leaflet (Panel A, arrow). The commissural view of the mitral valve shows another vegetation, with a nodular appearance, attached to the posterior mitral leaflet near its base (Panel B, arrow). LA denotes left atrium, LV left ventricle, and RV right ventricle.
Discussion of Management
Dr. Fidias: Patients who have cancer with thromboembolic events appear to have a worse prognosis than those without such events. A large Danish study23 found that patients who presented with thrombosis at the time of their cancer diagnosis had a 1-year survival rate of only 12%, as compared with 36% in the control group. The poor prognosis was largely due to the presence of a more advanced cancer, since 44% of patients with venous thromboembolism had distant metastases, in contrast to 35% of other patients. Progressive disease is the most frequent cause of death for these patients.24 Staging studies were performed on this patient after the diagnostic biopsy and transesophageal echocardiogram.
Dr. Gilman: Positron-emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) performed 6 days after admission (Figure 4) shows increased uptake of FDG in the right supraclavicular lymph node and markedly increased uptake of FDG in all mediastinal lymph nodes, the left hilar lymph node, and the nodule in the superior segment of the left lower lobe. The findings are consistent with hypermetabolic neoplasm in the superior segment of the left lower lobe and the mediastinum.
Figure 4. PET with FDG.
An axial image of the thorax shows markedly increased uptake of FDG in enlarged mediastinal lymph nodes.
Dr. Fidias: The American College of Chest Physicians Consensus Conference on Antithrombotic Therapy25 recommended heparin for patients with nonbacterial thrombotic endocarditis and systemic or pulmonary emboli, as well as for patients with aseptic vegetations and disseminated cancer or debilitating disease. The use of heparin is further supported by a recent study comparing low-molecular-weight heparin (dalteparin) therapy with warfarin therapy for the prevention of recurrent venous thromboembolism in patients with cancer; in the study, significantly fewer events occurred in patients treated with dalteparin than in those in the oral-anticoagulation group.26 Anticoagulation with low-molecular-weight heparin was used in this patient.
Control of the underlying cancer is important in the prevention of recurrent thrombosis.27 This patient has an unresectable stage IIIB non–small-cell lung cancer. A platinum-based chemotherapy is the standard of care for patients with advanced non–small-cell lung cancer and improves survival and quality of life for patients with lung cancer as compared with supportive care alone.28 A large randomized study comparing four combinations of chemotherapy found no significant differences in any of the survival outcomes.29 With current regimens, patients with a good performance status are expected to have a response rate of 30%, a median survival of 9 to 10 months, and a 1-year survival rate of 30%.
Dr. Cigler: The patient was discharged on the 10th hospital day. When she was seen in the oncology clinic 2 weeks later, the lesions on her fingertips and the splinter hemorrhages had improved markedly after therapy with low-molecular-weight heparin.
She was enrolled in a clinical trial investigating the use of standard agents, carboplatin and paclitaxel, in combination with a study drug called TLK286. She received two cycles of chemotherapy, during which her energy level increased and her shortness of breath decreased. Restaging CT at that point revealed a partial response to therapy, with a slight decrease in the size of the nodule in the left lower lobe and several of the mediastinal lymph nodes. After two additional cycles of chemotherapy, CT and repeated PET revealed progression of disease.
Four months after her initial presentation, before the patient was able to begin second-line chemotherapy, progressive shortness of breath and dyspnea on exertion developed, and CT revealed a large, left-sided pleural effusion with collapse of the left lung. Cytologic evaluation of the fluid disclosed adenocarcinoma (Figure 2C). A chest tube was placed, but her respiratory status progressively declined and hypotension developed, with decreased oxygen saturation and decreased consciousness. After discussion with her family and in accordance with her previously stated wishes, she was made comfortable on a morphine drip and died the next day.
Anatomical Diagnosis
Non–small-cell lung cancer with associated nonbacterial thrombotic (marantic) endocarditis.
Dr. Costenbader reports having received consulting fees from the Foundation for Informed Medical Decision Making and grant support from the American College of Rheumatology and the Arthritis Foundation, from the Harvard Medical School 50th Anniversary Scholars in Medicine Award, and from the Kirkland Scholarship for Study in SLE. Dr. Fidias reports having received lecture fees from AstraZeneca. Dr. Tambouret reports having received lecture fees and grant support from TriPath Imaging. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital (K.H.C.); the Departments of Medicine (K.H.C., P.F., A.Q.), Radiology (M.D.G.), and Pathology (R.H.T.), Harvard Medical School; the Hematology/ Oncology Unit (P.F.), the Cardiology Division, Cardiac Ultrasound Laboratory (A.Q.), and the Departments of Radiology (M.D.G.) and Pathology (R.H.T.), Massachusetts General Hospital — all in Boston.
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Dr. Tessa Cigler (Cancer Center): A 43-year-old woman was admitted to this hospital because of painful nodules on the fingertips, shortness of breath, and fatigue.
Systemic lupus erythematosus (SLE) had been diagnosed 12 years earlier at another hospital. Her symptoms at that time included arthralgias involving the knees and wrists, an ischemic right third toe, and livedo reticularis of her legs. The results of an antinuclear-antibody test was positive, and antiphospholipid antibodies were not detected. A biopsy specimen of the sole of her right foot showed intravascular fibrin thrombi without evidence of vasculitis. She was treated with prednisone, nifedipine, and prazosin and received anticoagulation therapy with heparin followed by warfarin for 6 months thereafter.
Since that time, relatively mild symptoms of polyarthralgias and Raynaud's phenomenon had been managed with nonsteroidal antiinflammatory medications and hydroxychloroquine. Seven months before admission she began to have urticarial skin lesions on the left arm and buttocks. She saw a rheumatologist at another hospital; levels of anti–double-stranded DNA antibodies and C-reactive protein and the erythrocyte sedimentation rate were elevated. She was treated with 30 mg of prednisone daily, and these signs and symptoms resolved; use of the corticosteroid was tapered during the next 2 months and then discontinued. During the same period, her voice became hoarse. Examination by an otolaryngologist disclosed edema and erythema of the vocal cords, and proton-pump inhibitors were prescribed for presumed gastric reflux.
Four months before admission she transferred her care to a rheumatologist at this hospital. Three months before admission, diffuse urticarial skin lesions again developed. Laboratory-test results are shown in Table 1. Examination of a skin-biopsy specimen disclosed changes consistent with the presence of tumid lupus. Prednisone (10 mg daily) was begun, and the lesions resolved.
Table 1. Results of Immunologic Laboratory Tests.
Two weeks before admission the patient had symptoms involving the fingers that were suggestive of Raynaud's phenomenon, and dark lesions developed on her fingertips, as did bruises over her back and thighs. One week before admission she saw her rheumatologist, who noted that the fingers of both hands, in particular the right index finger, were cold and blue; multiple small, painful, purple nodules were present on the fingertips; and there were ecchymoses on the back and thighs. Laboratory-test results are shown in Table 1. The dose of prednisone was increased to 15 mg daily, and hydroxychloroquine to 400 mg daily. Her symptoms did not improve. Fatigue, decreased appetite, dyspnea on exertion, chest pain on inspiration, and nocturnal wheezing developed, and 1 week later she was admitted to the hospital.
The patient did not have fever, chills, weight loss, chest pain, hair loss, or worsening arthralgias. She had had a positive tuberculin skin test as a teenager, for which she recalled receiving antibiotics. She had smoked one pack of cigarettes a day for the past 20 years. She had a stable chronic cough. She drank alcohol socially and did not use intravenous drugs. Her teeth had been cleaned by her dentist approximately 1 month earlier. She had recently married and lived with her husband. She worked as a secretary and a housecleaner. Her mother, a sister, and a brother also had SLE. Another sister and brother were well. Her medications were prednisone (15 mg), naproxen (1000 mg), and hydroxychloroquine (400 mg) daily.
On admission, she appeared comfortable. The temperature was 36.8°C, the blood pressure 140/80 mm Hg, the pulse 80 beats per minute, and the respiratory rate 20 breaths per minute, with an oxygen saturation of 99% while she was breathing room air. There was a mobile left axillary lymph node, 1 cm in diameter, with no cervical or supraclavicular lymphadenopathy. Examination of the heart and lungs was normal. There was mild bilateral tenderness of the metatarsophalangeal joint, but no obvious synovitis or deformities. Her fingers were cool and cyanotic, and the fingertips and the left big toe were mottled, with small, violaceous, tender, subcutaneous nodules. Splinter hemorrhages were present under the fingernails. Scattered ecchymoses but no petechiae were present on her back, legs, arms, and abdomen.
An electrocardiogram showed first-degree atrioventricular block, a prolonged QT interval, and nonspecific T-wave abnormalities. Levels of serum electrolytes, albumin, globulin, angiotensin-converting enzyme, lupus anticoagulant, anticardiolipin antibodies, protein C, activated protein C, and protein S were normal, as were the results of liver-function tests, prothrombin and partial-thromboplastin times, a test for prothrombin gene mutation, and a complete blood count. The lactate dehydrogenase level was 284 U per liter. The erythrocyte sedimentation rate was 36 mm per hour. One of five cultures of blood drawn during the first 3 days grew pan-sensitive coagulase-negative staphylococci.
A chest radiograph revealed mediastinal fullness suggestive of lymphadenopathy; the peripheral lung fields were clear. A ventilation–perfusion scan showed a low probability of a pulmonary embolus. Computed tomography (CT) of the chest the next day revealed extensive lymphadenopathy in the prevascular, subcarinal, paratracheal, and axillary regions; two nodules, one 1.5 by 2.0 cm, in the left lower lobe of the lung, and the other 7 mm in diameter, in the left upper lobe; and a small, left-sided pleural effusion. A transthoracic echocardiogram obtained on the third hospital day revealed a patent foramen ovale and mild mitral regurgitation.
A diagnostic procedure was performed on the fourth hospital day.
Differential Diagnosis
Dr. Matthew D. Gilman: The chest radiograph obtained on admission (Figure 1A) reveals thickening of the right paratracheal stripe and widening of the left superior mediastinum, indicating the presence of mediastinal lymphadenopathy. A small focus of subsegmental atelectasis is present in the left lower lobe. A CT scan of the chest without contrast medium, obtained on the next day, shows an enlarged right supraclavicular lymph node and extensive mediastinal lymphadenopathy (Figure 1B) involving the right paratracheal, prevascular, aorticopulmonary, and subcarinal positions, as well as the left hilum. A small, left-sided pleural effusion and a small pericardial effusion are visible.
Figure 1. Imaging Studies of the Chest.
A chest radiograph (Panel A) shows thickening of the right paratracheal stripe and widening of the left superior mediastinum (arrows), indicating the presence of mediastinal lymphadenopathy. Axial CT of the chest (Panel B) obtained without contrast medium in a mediastinal window shows enlarged mediastinal lymph nodes in the right paratracheal and prevascular positions (arrows). Axial CT of the chest in a lung window (Panel C) shows a nodule (arrow), 1.5 by 2.0 cm, in the superior segment of the left lower lobe with distal subsegmental atelectasis. A small, left-sided pleural effusion is also visible.
Lung windows from the same CT scan of the chest show a nodule, 1.5 by 2.0 cm, in the superior segment of the left lower lobe with distal subsegmental atelectasis (Figure 1C). A second nodule, 7 mm in diameter, is visible in the left upper lobe.
Dr. Anwer Qureshi: The transthoracic echocardiogram shows mild mitral regurgitation and mildly thickened mitral-valve leaflets with no valvular vegetations. A small, patent foramen ovale is present, and right-to-left shunting is apparent after the administration of agitated saline into a peripheral vein.
Dr. Karen H. Costenbader: This 43-year-old woman with a 12-year history of SLE, characterized by Raynaud's phenomenon, an ischemic digit, arthralgias, lymphopenia, and high titers of antinuclear antibodies and antibodies against double-stranded DNA, was admitted with cold and mottled fingers, small and tender violaceous nodules on the fingertips, and splinter hemorrhages of the nail beds. Recently, she had had worsening polyarthralgias, Raynaud's symptoms, urticarial rash, fatigue, and bruising. Chest radiographs revealed extensive mediastinal lymphadenopathy, and CT showed two nodules in the left lung and a small pleural effusion. I am aware of the diagnosis, although I was not involved in this patient's care. Nevertheless, the case provides an opportunity to discuss the differential diagnosis of this constellation of findings in a patient with SLE.
Primary Raynaud's phenomenon is common in young women. Clues that Raynaud's phenomenon is secondary to an underlying connective-tissue disease or other process include the rapid onset of severe disease later in life, with irreversible ischemia, digital pitting, ulceration, and even gangrene, dilatation and dropout of the periungual capillaries. Skin changes such as skin thickening, sclerodactyly, calcinosis, or telangiectasias signal systemic involvement by a connective-tissue disease. Although some of the symptoms of this patient can be attributed to worsening SLE-associated Raynaud's phenomenon, we also need to consider immune-mediated small-vessel vasculitis, a hypercoagulable state, endocarditis, and rarer entities (Table 2).
Table 2. Differential Diagnosis of Acutely Worsening or Severe Raynaud's Phenomenon.
Vasculitis
Vascular disease in patients with SLE can be classified into two broad categories — inflammatory and thrombotic. Vasculitis in patients with SLE is the result of immune-complex formation and can affect vessels in any organ, including kidneys, lungs, skin, intestines, heart, and nerves. In this patient, the cutaneous lesions could be due to vasculitis, but the splinter hemorrhages would not be explained by vasculitis.
Mixed cryoglobulinemia, usually type 3, can develop in patients with SLE and cause small-vessel vasculitis.1 Clinical manifestations of cryoglobulinemic vasculitis include palpable purpura and digital ischemia and could account for the lesions seen in this patient. This patient did not have evidence of a cryoprotein; however, false negative cryoglobulin results are common owing to cooling of the sample during transportation.
Thrombotic Vascular Occlusion
Most of the thrombotic vascular injury seen in patients with SLE is mediated by antiphospholipid antibodies. Approximately 30% of patients with SLE have detectable antiphospholipid antibodies, including anticardiolipin, lupus anticoagulant, and anti–2-glycoprotein I antibodies, at some time during their lives.2 These antibodies to negatively charged phospholipids cause spontaneous arterial and venous thromboses in vessels of any size. Antiphospholipid-antibody syndrome is defined by the presence of an elevated titer of anticardiolipin IgG or IgM or lupus anticoagulant antibody on two or more occasions at least 6 weeks apart and by either spontaneous vascular thrombosis or recurrent pregnancy loss (often in the third trimester due to placental insufficiency).3 This patient's tests for antiphospholipid antibodies were negative, but titers fluctuate depending on the activity of disease and treatment, so that the value of an individual negative test is low.
Other hypercoagulable states, such as deficiencies of protein C and protein S, factor V Leiden, and antithrombin III deficiency tend to be associated with venous thromboembolism much more commonly than with arterial thromboembolism; they are less likely to account for the presenting features in this case and are ruled out by laboratory testing. Protein S deficiency has been associated with SLE because of antiprotein S antibodies.4 Although these syndromes can be ruled out, a hypercoagulable state associated with malignant conditions and causing arterial thromboembolism could explain the clinical presentation.
Another possibility in this case is so-called chilblains lupus, a rare manifestation of SLE in which violaceous digital plaques and nodules develop after exposure to cold, damp climates, as in classic idiopathic chilblains lesions. Histologically, the lesions of chilblains lupus contain papillary and deep dermal T-cell infiltrates, with dermal edema and necrotic keratinocytes.5 Chilblains lupus has been associated with anti-Ro (SS-A) antibodies, Raynaud's phenomenon, and changes in the nail-fold capillary.6 This patient did not have anti-Ro antibodies, and splinter hemorrhages usually are not seen with chilblains. These usually occur in the fall and winter, and this patient presented in late summer.
Endocarditis
Infection with common and uncommon pathogens is a leading cause of complications and death in patients with SLE. The high rates of infection are attributable to inherited and acquired complement deficiencies, functional asplenia due to saturation of Fc receptors by circulating immune complexes,7 immunoglobulin deficiencies, and defects in phagocyte function, as well as immunosuppressant medications. Patients with SLE are at high risk for infection with encapsulated organisms, such as pneumococcus,8 neisseria,9 and salmonella.10
Bacterial endocarditis is a concern in this patient given the presence of splinter hemorrhages in the nail beds and finger lesions suggestive of classic Osler nodes, caused by deposition of immune complexes. Libman–Sacks endocarditis, characterized by sterile verrucous vegetations most often on the mitral valve, is associated with antiphospholipid antibodies and can cause embolic complications, valvular incompetence, heart failure, and bacterial infection.11 Splinter hemorrhages, embolic lesions, and a new murmur are clues to its presence. Endocarditis, either bacterial or nonbacterial, could explain the cutaneous manifestations in this case. A transthoracic echocardiogram did not reveal valvular vegetations, but a transesophageal echocardiogram would be more sensitive for the detection of these lesions.
Lymphadenopathy and Pulmonary Nodules
This patient had mediastinal and axillary lymphadenopathy. Lymphadenopathy due to lupus lymphadenitis is common in patients with SLE and particularly affects cervical and axillary lymph nodes.12 It is characterized by a diffuse reactive hyperplasia, often with extensive necrosis, and a lymph-node biopsy is useful in establishing the diagnosis and ruling out infectious and malignant processes. Massive mediastinal lymphadenopathy like that in this patient, however, is rarely due to SLE alone. This patient had a history of a positive test for tuberculosis and was at risk for reactivation, since she had been taking prednisone for several months. In addition to the lymphadenopathy, this patient had two nodules in the left lower lung and a small pleural effusion. The pulmonary manifestations of SLE are summarized in Table 3. Pneumonia, due to both typical and atypical pathogens, is common. Pleuritic chest pain can occur with or without an associated pleural effusion or detectable friction rub. Pleural effusions are usually small or moderate in size and can be recurrent and bilateral. The pulmonary infiltrates and pleural effusion could be manifestations of SLE in this patient, but together with the lymphadenopathy and evidence of vascular disease, they lead to concern about the possibility of cancer.
Table 3. Pleuropulmonary Manifestations of SLE.
Patients with lupus are at increased risk for both non-Hodgkin's lymphoma and lung cancer.13,14 The reasons for the elevated risks are unclear but may include a common genetic predisposition, exposure to causative agents, the use of immunosuppressant medications, immunologic dysfunction, or a combination of these. In addition, this patient is a smoker and thus is at increased risk for lung cancer.
In summary, in this woman with established SLE, new systemic symptoms, massive mediastinal lymphadenopathy with lung nodules, and digital embolic lesions, a neoplasm or infection involving the lung and lymph nodes and complicated by endocarditis would have been at the top of my list of diagnoses. Since patients with SLE are at increased risk for both lymphoma and lung cancer and because of this patient's history of smoking, I would favor a diagnosis of lung cancer, although infection or lymphoma cannot be ruled out. I would recommend a tissue biopsy of either the lung or the lymph nodes and cytologic evaluation of the pleural effusion.
Dr. Karen H. Costenbader's Diagnosis
Cancer of the lung and mediastinal lymph nodes complicating SLE, with associated endocarditis and thrombotic vasculopathy.
Pathological Discussion
Dr. Rosemary H. Tambouret: In this patient with lung nodules and mediastinal lymphadenopathy, several approaches could be used to make a tissue diagnosis. Bronchoscopy, percutaneous fine-needle aspiration with CT guidance, or open-lung biopsy (by means of thoracoscopy or thoracotomy) can be used to obtain samples of the lung nodules. Samples of the mediastinal lymph nodes can be obtained by mediastinoscopy, by bronchoscopy with transbronchial needle aspiration, or by fine-needle aspiration during transesophageal endoscopic ultrasonography. One advantage of bronchoscopy with transbronchial needle aspiration is that samples of both the lung nodules and the mediastinal lymph nodes can be obtained in one procedure.15 Sensitivity is improved when on-site rapid interpretation of cellular material by a cytopathologist is used to ensure adequacy of the sample.16 The samples must be sent to the following departments: cytology and surgical pathology for tissue diagnosis, flow cytometry for evaluation for a lymphoma or leukemia, and microbiology for ruling out an infection.
The patient underwent a bronchoscopy, which disclosed widening of the carina and narrowing of the left-lower-lobe bronchus. A bronchial mucosal lesion was not identified. Multiple cytologic samples were obtained, including bronchial brushings, bronchoalveolar-lavage fluid from the left lower lobe, and multiple blind transbronchial needle-aspiration samples from the area of the widened carina. Samples were sent for cultures and flow cytometry. The transbronchial needle-aspiration samples revealed the presence of large malignant cells consistent with adenocarcinoma (Figure 2A). With the use of immunocytochemistry, the tumor cells stained for cytokeratin, which is consistent with an epithelial tumor, but they did not stain for thyroid transcription factor 1, a nuclear protein expressed exclusively in epithelial cells of the thyroid and lung and in 54 to 76% of cases of lung cancer.17 Cytologic evaluation of the pleural effusion in this patient was also performed (Figure 2B) and was positive for adenocarcinoma.
Figure 2. Cytologic Analysis (Papanicolaou's Stain).
Cytologic analysis of the transbronchial needle aspirate (Panel A) showed large malignant cells present singly and in small groups. Cytologic analysis of the pleural effusion obtained 4 days after the bronchoscopy (Panel B) showed only a few malignant cells admixed with many lymphocytes. Cytologic evaluation of the pleural effusion obtained 4 months later (Panel C) showed abundant malignant cells.
Dr. Nancy Lee Harris (Pathology): After the diagnosis of carcinoma was made, an oncology consultant elucidated the rest of the story.
Dr. Panos Fidias: The combination of splinter hemorrhages, peripheral embolic events, and a heart murmur in this patient raises the possibility of nonbacterial thrombotic endocarditis, which is characterized by the deposition of fibrin on normal or superficially degenerated valves.18 In more than 90% of cases the vegetations are located on the mitral or aortic valves, and they are typically small (<3 mm to 10 mm), making detection with transthoracic echocardiography challenging.19 Nonbacterial thrombotic endocarditis is associated with the presence of an advanced cancer in up to 85% of patients.20 In an echocardiographic study of patients with solid tumors, 19% (28% of those with lung cancer) had vegetations.21 Thromboembolic events occurred in 24% of patients who had vegetations, as compared with 8% of those with normal findings on echocardiography. Thus, this patient with advanced lung cancer is at high risk for nonbacterial thrombotic endocarditis and embolic events.
Nonbacterial thrombotic endocarditis is a manifestation of hypercoagulability of malignancy, first described by Trousseau,22 and up to 20% of patients with the disease have laboratory evidence of disseminated intravascular coagulation.19 In this patient, levels of d-dimers measured on the fourth hospital day were markedly elevated (3712 ng per milliliter, vs. a normal level of <500 ng per milliliter). The diagnostic procedure was a transesophageal echocardiogram.
Dr. Panos Fidias's Diagnosis
Nonbacterial thrombotic endocarditis due to non–small-cell lung cancer.
Diagnostic Discussion
Dr. Qureshi: Views of the heart were obtained from the midesophageal position of the probe. Vegetations were seen on both the anterior (Figure 3A, and Video 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org) and posterior (Figure 3B, and Video 2 of the Supplementary Appendix) mitral-valve leaflets. The mitral-valve structure and function are not markedly compromised. In the proper clinical setting, these findings are consistent with the diagnosis of nonbacterial thrombotic endocarditis. The aortic, tricuspid, and pulmonary valves were normal. There was no atrial clot or aortic disease, and a small, patent foramen ovale with left-to-right shunting was again noted on color Doppler imaging.
Figure 3. Transesophageal Echocardiogram.
Mild thickening of the mitral-valve leaflets is present, with a broad-based vegetation on the anterior mitral leaflet (Panel A, arrow). The commissural view of the mitral valve shows another vegetation, with a nodular appearance, attached to the posterior mitral leaflet near its base (Panel B, arrow). LA denotes left atrium, LV left ventricle, and RV right ventricle.
Discussion of Management
Dr. Fidias: Patients who have cancer with thromboembolic events appear to have a worse prognosis than those without such events. A large Danish study23 found that patients who presented with thrombosis at the time of their cancer diagnosis had a 1-year survival rate of only 12%, as compared with 36% in the control group. The poor prognosis was largely due to the presence of a more advanced cancer, since 44% of patients with venous thromboembolism had distant metastases, in contrast to 35% of other patients. Progressive disease is the most frequent cause of death for these patients.24 Staging studies were performed on this patient after the diagnostic biopsy and transesophageal echocardiogram.
Dr. Gilman: Positron-emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) performed 6 days after admission (Figure 4) shows increased uptake of FDG in the right supraclavicular lymph node and markedly increased uptake of FDG in all mediastinal lymph nodes, the left hilar lymph node, and the nodule in the superior segment of the left lower lobe. The findings are consistent with hypermetabolic neoplasm in the superior segment of the left lower lobe and the mediastinum.
Figure 4. PET with FDG.
An axial image of the thorax shows markedly increased uptake of FDG in enlarged mediastinal lymph nodes.
Dr. Fidias: The American College of Chest Physicians Consensus Conference on Antithrombotic Therapy25 recommended heparin for patients with nonbacterial thrombotic endocarditis and systemic or pulmonary emboli, as well as for patients with aseptic vegetations and disseminated cancer or debilitating disease. The use of heparin is further supported by a recent study comparing low-molecular-weight heparin (dalteparin) therapy with warfarin therapy for the prevention of recurrent venous thromboembolism in patients with cancer; in the study, significantly fewer events occurred in patients treated with dalteparin than in those in the oral-anticoagulation group.26 Anticoagulation with low-molecular-weight heparin was used in this patient.
Control of the underlying cancer is important in the prevention of recurrent thrombosis.27 This patient has an unresectable stage IIIB non–small-cell lung cancer. A platinum-based chemotherapy is the standard of care for patients with advanced non–small-cell lung cancer and improves survival and quality of life for patients with lung cancer as compared with supportive care alone.28 A large randomized study comparing four combinations of chemotherapy found no significant differences in any of the survival outcomes.29 With current regimens, patients with a good performance status are expected to have a response rate of 30%, a median survival of 9 to 10 months, and a 1-year survival rate of 30%.
Dr. Cigler: The patient was discharged on the 10th hospital day. When she was seen in the oncology clinic 2 weeks later, the lesions on her fingertips and the splinter hemorrhages had improved markedly after therapy with low-molecular-weight heparin.
She was enrolled in a clinical trial investigating the use of standard agents, carboplatin and paclitaxel, in combination with a study drug called TLK286. She received two cycles of chemotherapy, during which her energy level increased and her shortness of breath decreased. Restaging CT at that point revealed a partial response to therapy, with a slight decrease in the size of the nodule in the left lower lobe and several of the mediastinal lymph nodes. After two additional cycles of chemotherapy, CT and repeated PET revealed progression of disease.
Four months after her initial presentation, before the patient was able to begin second-line chemotherapy, progressive shortness of breath and dyspnea on exertion developed, and CT revealed a large, left-sided pleural effusion with collapse of the left lung. Cytologic evaluation of the fluid disclosed adenocarcinoma (Figure 2C). A chest tube was placed, but her respiratory status progressively declined and hypotension developed, with decreased oxygen saturation and decreased consciousness. After discussion with her family and in accordance with her previously stated wishes, she was made comfortable on a morphine drip and died the next day.
Anatomical Diagnosis
Non–small-cell lung cancer with associated nonbacterial thrombotic (marantic) endocarditis.
Dr. Costenbader reports having received consulting fees from the Foundation for Informed Medical Decision Making and grant support from the American College of Rheumatology and the Arthritis Foundation, from the Harvard Medical School 50th Anniversary Scholars in Medicine Award, and from the Kirkland Scholarship for Study in SLE. Dr. Fidias reports having received lecture fees from AstraZeneca. Dr. Tambouret reports having received lecture fees and grant support from TriPath Imaging. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital (K.H.C.); the Departments of Medicine (K.H.C., P.F., A.Q.), Radiology (M.D.G.), and Pathology (R.H.T.), Harvard Medical School; the Hematology/ Oncology Unit (P.F.), the Cardiology Division, Cardiac Ultrasound Laboratory (A.Q.), and the Departments of Radiology (M.D.G.) and Pathology (R.H.T.), Massachusetts General Hospital — all in Boston.
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