Red Snapper or Crab?
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《新英格兰医药杂志》
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows.
A 68-year-old man originally from the Philippines presented with a three-month history of increasing dyspnea on exertion and orthopnea. He also reported an unintentional weight loss of 7 kg (15 lb), night sweats, and abdominal bloating. He stated that he had not had fever, chills, cough, vomiting, chest pain, or swelling of the legs.
The patient's dyspnea could be due to congestive heart failure, pulmonary disease, anemia, or deconditioning associated with a cachexia-inducing illness. The absence of upper and lower gastrointestinal symptoms, even in the presence of abdominal bloating, points me away from further consideration of luminal gastrointestinal disorders. Ascites could account for the increasing abdominal girth, and in a patient who has lost weight, it may indicate a chronic infection, cancer, or cirrhosis.
Because tuberculosis is endemic in the Philippines, tuberculous peritonitis is a consideration. Patients with extrapulmonary tuberculosis often present without associated pulmonary infection, so the absence of a cough is not inconsistent with this diagnosis. Any intraabdominal cancer can lead to abdominal distention as a result of a mass effect or malignant ascites, which may occur by way of widespread hepatic metastasis or peritoneal carcinomatosis.
The patient's medical history included prostate cancer with bony metastasis (stage D2), which had been diagnosed 15 years previously and treated by radical prostatectomy, followed by radiation therapy and bilateral orchiectomy. The patient had had a positive tuberculin skin test with purified protein derivative, without prior active tuberculosis or antituberculosis therapy, and had a history of gastroesophageal reflux and hypercholesterolemia. His medications were rabeprazole and simvastatin. He had last traveled to the Philippines two years previously and had never used tobacco or illicit substances. He had served in the Navy for 20 years and had then worked as a custodian.
The positive tuberculin skin test is not surprising, but his history of service in the Navy is intriguing. He may have worked in shipyards where asbestos is abundant, raising the possibility of malignant peritoneal mesothelioma. Pleural mesothelioma, which is more common, could also explain his dyspnea. If gastroesophageal reflux was diagnosed without endoscopic confirmation, gastric carcinoma is possible. I am still considering ascites to be the cause of his abdominal bloating and weight loss. The only identifiable risk factor for liver disease is his country of origin, where hepatitis B infection is common. Tuberculosis, gastrointestinal cancer, and malignant mesothelioma can all cause ascites. Metastatic prostate cancer could account for the weight loss, but cardiopulmonary and gastrointestinal manifestations are uncommon in that form of cancer.
The patient was afebrile, and his pulse, respiratory rate, and blood pressure were normal. Examination of the chest revealed dullness to percussion and an absence of breath sounds posteriorly over three quarters of the right hemithorax. The heart sounds and jugular venous pulses were normal, and there was no peripheral edema. The abdomen was distended, but there was no tenderness, organomegaly, or fluid wave.
The hematocrit was 34 percent, with a normal mean corpuscular volume. The platelet count was 439,000 per cubic millimeter, and the white-cell count 9800 per cubic millimeter; the differential count was normal. Serum electrolyte levels, renal function, and the results of liver function tests were normal. The serum albumin level was 3.6 g per deciliter, and the international normalized ratio was 1.0. Prostate-specific antigen was undetectable. Chest radiography revealed no abnormalities except for a right-sided pleural effusion (Figure 1), which appeared to be freely mobile in the lateral decubitus view. The electrocardiogram was unremarkable. The patient was admitted to the hospital.
Figure 1. Posteroanterior Chest Radiograph Showing a Right-Sided Pleural Effusion.
The normal results on the cardiovascular examination and the absence of edema make congestive heart failure, the most common cause of pleural effusion, unlikely. I remain suspicious of tuberculosis as a possible diagnosis. The fact that prostate-specific antigen was undetectable essentially rules out metastatic prostate cancer, with rare exceptions; pleural effusion would be unusual in metastatic prostate cancer. A malignant pleural effusion is plausible, but a primary cancer is not evident. Cirrhosis is unlikely without the characteristic findings on physical examination or laboratory evidence of chronic liver disease. An ultrasound study would be useful to confirm the presence of ascites in the absence of known liver disease or marked abdominal distention. If ascites due to cirrhosis were unexpectedly found, hepatic hydrothorax would be a consideration. Pleural effusion and abdominal bloating could be explained by an abdominal tumor with metastases to the lung or by a bronchogenic carcinoma with an associated paraneoplastic autonomic neuropathy.
Infection (particularly tuberculosis) and cancer remain my primary considerations. The tests that will guide my decision making are analysis of the pleural fluid and computed tomography (CT) of the abdomen.
CT scanning of the chest showed the right-sided pleural effusion, but no pulmonary parenchymal nodules, enlarged lymph nodes, or pleural plaques were visible. On CT scanning of the abdomen, all the organs were normal, but there were multiple enhancing omental nodules (Figure 2), along with minimal ascites confined to the pelvis. Thoracentesis was performed, and 1 liter of bloody fluid was removed. Findings on analysis of the fluid were as follows: total protein level, 7.2 mg per deciliter; lactate dehydrogenase level, 745 U per liter; red-cell count, 220,000 per cubic millimeter; and white-cell count, 11,000 per cubic millimeter (35 percent neutrophils, 32 percent lymphocytes, 25 percent monocytes, and 8 percent mesothelial cells). The total protein level in the serum was 8.2 mg per deciliter, and the serum lactate dehydrogenase level was 192 U per liter. Cultures of the pleural fluid grew no bacteria, and stains of the pleural fluid for acid-fast bacilli were negative. Cytologic examination revealed mesothelial cells without malignant features. The patient's dyspnea resolved after thoracentesis, and he asked to be discharged.
Figure 2. CT Scan of the Abdomen, Showing Omental Nodules (Arrow) in the Anterior Aspect of the Left Upper Abdomen.
The patient has a bloody, exudative effusion according to Light's criteria (which indicate that the effusion is exudative when at least one of the following is true: when the ratio of pleural-fluid protein to serum protein is greater than 0.5, the ratio of pleural-fluid lactate dehydrogenase to serum lactate dehydrogenase is greater than 0.6, or the pleural-fluid lactate dehydrogenase level is greater than two thirds the upper limit of the normal range for serum lactate dehydrogenase). He also has a diseased omentum with a small amount of ascites. Bloody pleural fluid usually signifies one of three processes: trauma, cancer, or pulmonary embolism.
The pleura and the peritoneum may be affected simultaneously in a number of diseases, including primary tumors (e.g., mesothelioma), infections (e.g., tuberculosis), metastatic carcinoma (usually adenocarcinoma), and systemic lupus erythematosus. Each would cause an exudative effusion, and the results in this case are not sufficiently characteristic to narrow the differential diagnosis further.
The patient's positive tuberculin skin test, night sweats, and pleural-fluid pleocytosis with an elevated protein level suggest tuberculosis. The negative stain for acid-fast bacilli is not surprising, since a tuberculous pleural effusion is a hypersensitivity reaction to a small number of bacilli in the pleural space. However, fever often accompanies tuberculous pleuritis, the effusion is typically lymphocytic, and rarely are there numerous mesothelial cells. Mesothelioma remains a serious concern because of the possible asbestos exposure (a long latency period would be typical) and because of the aggressive disease that affects two serosal surfaces. The absence of pleural thickening or irregularity on the CT scan of the chest would be uncharacteristic, but malignant mesothelial cells are often absent in the pleural fluid. Finally, I must consider the possibility that another tumor has metastasized to the pleura and peritoneum. Cytologic studies may be negative for malignant cells in a patient with a malignant pleural effusion, but this patient's history, laboratory data, and images do not suggest another primary cancer.
Two weeks after hospital discharge, the patient presented with fever and with pain and swelling of the left side of the neck. He otherwise felt well and stated that he had not had dyspnea since his discharge. He had not sustained trauma to the neck or undergone surgical procedures involving the neck. On examination, the left side of the neck was indurated, with overlying erythema, and was exquisitely tender; the oropharynx was unremarkable. The white-cell count was 16,000 per cubic millimeter.
Is this acute inflammatory mass a lymph node? The differential diagnosis of cervical lymphadenopathy is primarily one of infection versus cancer. The fever, tenderness, erythema, and leukocytosis favor the former, particularly a bacterial lymphadenitis. Tuberculous lymphadenitis deserves consideration, although intense pain and inflammation are not typical of that disease. If this new finding is not lymphadenopathy, bacterial infections such as cellulitis, infection of the branchial-cleft cyst, submandibular abscess, or suppurative thrombosis of the internal jugular vein are possible.
This finding is perplexing. The neck abnormality sounds like an acute bacterial infection, but the pleural–peritoneal disease seems chronic in nature, and I cannot easily link the two. If inflammatory soft tissue cannot be distinguished from lymphadenopathy on physical examination, I would obtain a neck CT scan.
CT scanning revealed thrombosis of the left internal jugular vein with extensive surrounding inflammation, but no mass or lymphadenopathy. Chest radiography revealed reaccumulation of the right-sided pleural effusion. The patient was readmitted for anticoagulant therapy.
Spontaneous thrombosis of a neck vein is very uncommon and leads me to suspect a hypercoagulable state, perhaps from an underlying cancer. Could a pulmonary embolus be responsible for the pleural effusion in this case? Pulmonary embolism is usually an acute condition and is out of step with the tempo of this patient's illness. Am I missing some other cause of his exudative pleural effusion?
Because the patient had previously undergone abdominal surgery and pelvic irradiation, pleuroscopy (rather than laparoscopy) was performed. The findings included an area of abnormal-appearing tissue deep in the posterior inferior pleural space on the right side. Intraoperative frozen sections of this tissue were examined, and the findings were interpreted as indicative of metastatic carcinoma, consistent with a primary focus in the prostate. Talc pleurodesis was performed to prevent reaccumulation of pleural fluid, and the patient was discharged.
I am fairly convinced that the patient does not have tuberculosis, since it would be difficult to confuse carcinoma with a tuberculous granuloma. I also doubt that he has metastatic prostate cancer, because recurrence would be extremely unusual in a patient who has been free of disease for 15 years since treatment and in whom prostate-specific antigen is undetectable. Because mesothelioma could be misinterpreted as adenocarcinoma, I would await further review of the tissue by a pathologist. If the diagnosis remains in question, I would obtain another biopsy specimen. Since the pleural surface would be inaccessible after pleurodesis, I would further investigate the omental nodules. I am increasingly interested in knowing what the patient did while in the Navy.
At a clinic visit one week later, the patient reported anorexia and persistent abdominal distention. Repeated abdominal CT scanning showed an increase in the number and size of the omental nodules and in the amount of ascitic fluid. Ultrasound-guided paracentesis yielded 20 ml of clear yellow fluid with a serum–ascitic fluid albumin gradient of 0.7 g per deciliter. The ascitic fluid contained 15,400 white cells per cubic millimeter (30 percent neutrophils, 5 percent lymphocytes, 35 percent monocytes, and 30 percent mesothelial cells) and 1900 red cells per cubic milliliter. Bacterial and mycobacterial cultures were sterile. Cytologic examination showed inflammatory cells and normal-appearing mesothelial cells. The final interpretation of the biopsy specimens obtained during pleuroscopy was hemorrhagic fibrin clot with a small, benign-appearing overgrowth of mesothelial cells, a finding not consistent with the presence of metastatic prostate carcinoma.
Since the ascites originates from the peritoneum, the low serum–ascitic fluid albumin gradient (less than 1.1 g per deciliter) was expected. (In contrast, processes that result in portal hypertension are associated with an elevated serum–ascitic fluid albumin gradient .) The cell counts and the white-cell differential count are not diagnostic and again raise the question of tuberculosis as opposed to cancer. The white-cell count is substantially elevated, and the neutrophil count is greater than 250 per cubic millimeter, but I doubt that he has spontaneous bacterial peritonitis. That condition almost always occurs in the setting of liver disease and is usually accompanied by a predominance of neutrophils.
This patient has two diseased serosal surfaces with exudative effusions, complicated by hypercoagulability, and there is no strong evidence of tuberculosis, which is the competing diagnosis. I think that he has malignant pleural and peritoneal mesothelioma and would thus proceed with laparoscopic peritoneal biopsy.
Exploratory laparoscopy revealed a peritoneal surface with diffuse plaques and an omentum caked with soft, nodular plaques. Pathological evaluation of the biopsy specimens by immunocytochemistry and electron microscopy revealed malignant mesothelioma. On further questioning, the patient reported that while serving in the Navy he had been continually exposed to asbestos-covered pipes, both while scraping and repainting them and while working below deck as a cook.
Commentary
The venerable adage that careful history taking and physical examination usually lead to the correct diagnosis is especially true in perplexing cases. Unfortunately, because of advances in medical technology and specialized diagnostic tests, physicians have begun to place less emphasis on these skills. Despite the methodical evaluation of this patient by his physicians, the diagnosis remained elusive. The discussant, however, zeroed in on two key aspects of the history: the patient's country of origin (an area where tuberculosis is endemic) and his service in the Navy (a clue to potential asbestos exposure). The discussant was then able to place infection with Mycobacterium tuberculosis (sometimes called the "red snapper" because of its characteristic appearance on acid-fast staining) and cancer (Latin for crab) at the top of his differential diagnosis for this patient with diseased pleural and peritoneal surfaces. As additional information was presented, he interpreted it in the context of these two historical linchpins.
Disseminated tuberculosis (with pleuritis and peritonitis) was appropriately considered because of the patient's positive tuberculin skin test. The likelihood of tuberculous pleuritis was lessened by the absence of typical clinical findings (e.g., fever, cough, and pleuritic chest pain)1 and the atypical findings in the pleural fluid (more than 5 percent mesothelial cells and an absence of a lymphocytic predominance).1,2 The patient's history of metastatic prostate cancer was also considered and briefly led to an incorrect diagnosis. Despite the initial misreading of the pleural biopsy specimen, the discussant recognized that metastatic prostate cancer was unlikely because prostate-specific antigen was undetectable.3 Mesothelioma can be mistaken for adenocarcinoma histologically.4 The distinction can be, and was in this case, made by immunocytochemical staining and electron microscopy. Although the findings described made disseminated tuberculosis or prostate cancer unlikely, several features suggested mesothelioma as a potential diagnosis. The combination of several factors — the possibility of heavy asbestos exposure (not recognized until late in the workup), the involvement of both the pleural and the peritoneal surfaces, the long latency period between the exposure and the onset of symptoms, and hypercoagulability — led the discussant to the correct diagnosis: malignant mesothelioma.
Asbestos was used extensively in World War II–era ships. Its use did not decline until the mid-1970s, when the adverse health consequences of prolonged exposure became widely known. Exposure to asbestos can cause the fibrotic interstitial lung disease called asbestosis; it has also been linked to lung cancer (and the risk appears to increase synergistically with tobacco use), malignant mesothelioma, and benign pleural disorders (pleural plaques and effusions). Although asbestosis has been recognized since the early 1900s, asbestos exposure was not linked to malignant mesothelioma until the 1960s.5
The incidence of mesothelioma in the United States rose during the 1970s and early 1980s, primarily as a result of occupational exposure during the preceding decades, and was projected to peak in 2000.6 Malignant mesothelioma may arise from the pleural or peritoneal surfaces or, less commonly, the pericardium or tunica vaginalis. Pleural involvement is more common than peritoneal involvement, which usually occurs in persons with the heaviest asbestos exposure. After inhalation, the lung's mucociliary system attempts to clear the asbestos fibers. Fibers that are coughed up and swallowed may lead to peritoneal mesothelioma. A latency period of 20 to 40 years between asbestos exposure and the onset of symptoms of mesothelioma is typical.
Peritoneal mesothelioma tends to progress locally, resulting in vague abdominal symptoms, including pain, increased girth (due to malignant ascites), and weight loss.7,8 Examination of the abdomen usually reveals evidence of ascites but little else.8 As the tumor advances locally, it may cause bowel obstruction. Surgical debulking followed by intraperitoneal chemotherapy may be attempted in selected patients with localized disease. Palliative systemic chemotherapy is an option for those with advanced disease.
Because of the rarity of peritoneal mesothelioma and its frequently nonspecific features at the time of presentation, the diagnosis is often delayed. Five months elapsed between this patient's initial presentation and the correct diagnosis. Because the prognosis is poor and treatment options are limited, this delay probably did not alter the outcome, but it may have been avoidable. Two main factors contributed to the delay. First, the patient was discharged from the hospital twice (once at his request) before his evaluation had been completed. Although rapid discharge may help constrain costs, it may not be optimal for patients who require certain diagnostic tests or evaluations by multiple subspecialists. Second, there was an initial reluctance to perform exploratory abdominal surgery (to obtain biopsy specimens of the omental nodules) because of the patient's prior abdominal surgery and pelvic irradiation. This initial decision not to obtain specimens of the omental nodules was not revisited for several months. Had the patient's extensive asbestos exposure been recognized earlier, the primary and consulting physicians would probably have pursued exploratory abdominal surgery soon after the nondiagnostic pleuroscopy.
More than half a century ago, Platt asserted that most diagnoses could be made on the basis of the history alone.9 Subsequent studies have confirmed that the history is the key to the final diagnosis in 56 to 82 percent of cases.10,11,12 The commonly passed-on clinical aphorism, "What you do not ask, you will not find out," remains true.
Supported by a Career Development Award from the Health Services Research and Development Program of the Department of Veterans Affairs and a Patient Safety Developmental Center Grant (P20-HS11540) from the Agency for Healthcare Research and Quality (both to Dr. Saint).
Source Information
From the Primary and Specialty Medical Care Service, Veterans Affairs Puget Sound Health Care System, and the Department of Medicine, University of Washington School of Medicine — both in Seattle (P.B.C., B.A.L.); the San Francisco Veterans Affairs Medical Center and the Department of Medicine, University of California at San Francisco School of Medicine — both in San Francisco (G.D.); and the Ann Arbor Veterans Affairs Medical Center and the Department of Internal Medicine and the Patient Safety Enhancement Program, University of Michigan Health System — both in Ann Arbor (S.S.).
Address reprint requests to Dr. Cornia at the Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way (S-111-GIMC), Seattle, WA 98108-1597, or at paul.cornia@med.va.gov.
References
Light RW. Pleural diseases. 3rd ed. Baltimore: Williams & Wilkins, 1995.
Valdés L, Alvarez D, San José E, et al. Tuberculous pleurisy: a study of 254 patients. Arch Intern Med 1998;158:2017-2021.
Ruckle HC, Klee GG, Oesterling JE. Prostate-specific antigen: concepts for staging prostate cancer and monitoring response to therapy. Mayo Clin Proc 1994;69:69-79.
Antman KH. Natural history and epidemiology of malignant mesothelioma. Chest 1993;103:Suppl:373S-376S.
Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos in the North Western Cape Province. Br J Ind Med 1960;17:260-271.
Price B. Analysis of current trends in United States mesothelioma incidence. Am J Epidemiol 1997;145:211-218.
Mohamed F, Sugarbaker PH. Peritoneal mesothelioma. Curr Treat Options Oncol 2002;3:375-386.
Asenio JA, Goldblatt P, Thomford NR. Primary malignant peritoneal mesothelioma: a report of seven cases and a review of the literature. Arch Surg 1990;125:1477-1481.
Platt R. Two essays on the practice of medicine. Manch Univ Med Sch Gaz 1947;26:139-45.
Hampton JR, Harrison MJG, Mitchell JRA, Prichard JS, Seymour C. Relative contributions of history-taking, physical examination, and laboratory investigation to diagnosis and management of medical outpatients. Br Med J 1975;2:486-489.
Sandler G. Importance of the history in the medical clinic and the cost of unnecessary tests. Am Heart J 1980;100:928-931.
Peterson MC, Holbrook JH, Von Hales D, Smith NL, Staker LV. Contributions of the history, physical examination, and laboratory investigation in making medical diagnoses. West J Med 1992;156:163-165.(Paul B. Cornia, M.D., Ben)
A 68-year-old man originally from the Philippines presented with a three-month history of increasing dyspnea on exertion and orthopnea. He also reported an unintentional weight loss of 7 kg (15 lb), night sweats, and abdominal bloating. He stated that he had not had fever, chills, cough, vomiting, chest pain, or swelling of the legs.
The patient's dyspnea could be due to congestive heart failure, pulmonary disease, anemia, or deconditioning associated with a cachexia-inducing illness. The absence of upper and lower gastrointestinal symptoms, even in the presence of abdominal bloating, points me away from further consideration of luminal gastrointestinal disorders. Ascites could account for the increasing abdominal girth, and in a patient who has lost weight, it may indicate a chronic infection, cancer, or cirrhosis.
Because tuberculosis is endemic in the Philippines, tuberculous peritonitis is a consideration. Patients with extrapulmonary tuberculosis often present without associated pulmonary infection, so the absence of a cough is not inconsistent with this diagnosis. Any intraabdominal cancer can lead to abdominal distention as a result of a mass effect or malignant ascites, which may occur by way of widespread hepatic metastasis or peritoneal carcinomatosis.
The patient's medical history included prostate cancer with bony metastasis (stage D2), which had been diagnosed 15 years previously and treated by radical prostatectomy, followed by radiation therapy and bilateral orchiectomy. The patient had had a positive tuberculin skin test with purified protein derivative, without prior active tuberculosis or antituberculosis therapy, and had a history of gastroesophageal reflux and hypercholesterolemia. His medications were rabeprazole and simvastatin. He had last traveled to the Philippines two years previously and had never used tobacco or illicit substances. He had served in the Navy for 20 years and had then worked as a custodian.
The positive tuberculin skin test is not surprising, but his history of service in the Navy is intriguing. He may have worked in shipyards where asbestos is abundant, raising the possibility of malignant peritoneal mesothelioma. Pleural mesothelioma, which is more common, could also explain his dyspnea. If gastroesophageal reflux was diagnosed without endoscopic confirmation, gastric carcinoma is possible. I am still considering ascites to be the cause of his abdominal bloating and weight loss. The only identifiable risk factor for liver disease is his country of origin, where hepatitis B infection is common. Tuberculosis, gastrointestinal cancer, and malignant mesothelioma can all cause ascites. Metastatic prostate cancer could account for the weight loss, but cardiopulmonary and gastrointestinal manifestations are uncommon in that form of cancer.
The patient was afebrile, and his pulse, respiratory rate, and blood pressure were normal. Examination of the chest revealed dullness to percussion and an absence of breath sounds posteriorly over three quarters of the right hemithorax. The heart sounds and jugular venous pulses were normal, and there was no peripheral edema. The abdomen was distended, but there was no tenderness, organomegaly, or fluid wave.
The hematocrit was 34 percent, with a normal mean corpuscular volume. The platelet count was 439,000 per cubic millimeter, and the white-cell count 9800 per cubic millimeter; the differential count was normal. Serum electrolyte levels, renal function, and the results of liver function tests were normal. The serum albumin level was 3.6 g per deciliter, and the international normalized ratio was 1.0. Prostate-specific antigen was undetectable. Chest radiography revealed no abnormalities except for a right-sided pleural effusion (Figure 1), which appeared to be freely mobile in the lateral decubitus view. The electrocardiogram was unremarkable. The patient was admitted to the hospital.
Figure 1. Posteroanterior Chest Radiograph Showing a Right-Sided Pleural Effusion.
The normal results on the cardiovascular examination and the absence of edema make congestive heart failure, the most common cause of pleural effusion, unlikely. I remain suspicious of tuberculosis as a possible diagnosis. The fact that prostate-specific antigen was undetectable essentially rules out metastatic prostate cancer, with rare exceptions; pleural effusion would be unusual in metastatic prostate cancer. A malignant pleural effusion is plausible, but a primary cancer is not evident. Cirrhosis is unlikely without the characteristic findings on physical examination or laboratory evidence of chronic liver disease. An ultrasound study would be useful to confirm the presence of ascites in the absence of known liver disease or marked abdominal distention. If ascites due to cirrhosis were unexpectedly found, hepatic hydrothorax would be a consideration. Pleural effusion and abdominal bloating could be explained by an abdominal tumor with metastases to the lung or by a bronchogenic carcinoma with an associated paraneoplastic autonomic neuropathy.
Infection (particularly tuberculosis) and cancer remain my primary considerations. The tests that will guide my decision making are analysis of the pleural fluid and computed tomography (CT) of the abdomen.
CT scanning of the chest showed the right-sided pleural effusion, but no pulmonary parenchymal nodules, enlarged lymph nodes, or pleural plaques were visible. On CT scanning of the abdomen, all the organs were normal, but there were multiple enhancing omental nodules (Figure 2), along with minimal ascites confined to the pelvis. Thoracentesis was performed, and 1 liter of bloody fluid was removed. Findings on analysis of the fluid were as follows: total protein level, 7.2 mg per deciliter; lactate dehydrogenase level, 745 U per liter; red-cell count, 220,000 per cubic millimeter; and white-cell count, 11,000 per cubic millimeter (35 percent neutrophils, 32 percent lymphocytes, 25 percent monocytes, and 8 percent mesothelial cells). The total protein level in the serum was 8.2 mg per deciliter, and the serum lactate dehydrogenase level was 192 U per liter. Cultures of the pleural fluid grew no bacteria, and stains of the pleural fluid for acid-fast bacilli were negative. Cytologic examination revealed mesothelial cells without malignant features. The patient's dyspnea resolved after thoracentesis, and he asked to be discharged.
Figure 2. CT Scan of the Abdomen, Showing Omental Nodules (Arrow) in the Anterior Aspect of the Left Upper Abdomen.
The patient has a bloody, exudative effusion according to Light's criteria (which indicate that the effusion is exudative when at least one of the following is true: when the ratio of pleural-fluid protein to serum protein is greater than 0.5, the ratio of pleural-fluid lactate dehydrogenase to serum lactate dehydrogenase is greater than 0.6, or the pleural-fluid lactate dehydrogenase level is greater than two thirds the upper limit of the normal range for serum lactate dehydrogenase). He also has a diseased omentum with a small amount of ascites. Bloody pleural fluid usually signifies one of three processes: trauma, cancer, or pulmonary embolism.
The pleura and the peritoneum may be affected simultaneously in a number of diseases, including primary tumors (e.g., mesothelioma), infections (e.g., tuberculosis), metastatic carcinoma (usually adenocarcinoma), and systemic lupus erythematosus. Each would cause an exudative effusion, and the results in this case are not sufficiently characteristic to narrow the differential diagnosis further.
The patient's positive tuberculin skin test, night sweats, and pleural-fluid pleocytosis with an elevated protein level suggest tuberculosis. The negative stain for acid-fast bacilli is not surprising, since a tuberculous pleural effusion is a hypersensitivity reaction to a small number of bacilli in the pleural space. However, fever often accompanies tuberculous pleuritis, the effusion is typically lymphocytic, and rarely are there numerous mesothelial cells. Mesothelioma remains a serious concern because of the possible asbestos exposure (a long latency period would be typical) and because of the aggressive disease that affects two serosal surfaces. The absence of pleural thickening or irregularity on the CT scan of the chest would be uncharacteristic, but malignant mesothelial cells are often absent in the pleural fluid. Finally, I must consider the possibility that another tumor has metastasized to the pleura and peritoneum. Cytologic studies may be negative for malignant cells in a patient with a malignant pleural effusion, but this patient's history, laboratory data, and images do not suggest another primary cancer.
Two weeks after hospital discharge, the patient presented with fever and with pain and swelling of the left side of the neck. He otherwise felt well and stated that he had not had dyspnea since his discharge. He had not sustained trauma to the neck or undergone surgical procedures involving the neck. On examination, the left side of the neck was indurated, with overlying erythema, and was exquisitely tender; the oropharynx was unremarkable. The white-cell count was 16,000 per cubic millimeter.
Is this acute inflammatory mass a lymph node? The differential diagnosis of cervical lymphadenopathy is primarily one of infection versus cancer. The fever, tenderness, erythema, and leukocytosis favor the former, particularly a bacterial lymphadenitis. Tuberculous lymphadenitis deserves consideration, although intense pain and inflammation are not typical of that disease. If this new finding is not lymphadenopathy, bacterial infections such as cellulitis, infection of the branchial-cleft cyst, submandibular abscess, or suppurative thrombosis of the internal jugular vein are possible.
This finding is perplexing. The neck abnormality sounds like an acute bacterial infection, but the pleural–peritoneal disease seems chronic in nature, and I cannot easily link the two. If inflammatory soft tissue cannot be distinguished from lymphadenopathy on physical examination, I would obtain a neck CT scan.
CT scanning revealed thrombosis of the left internal jugular vein with extensive surrounding inflammation, but no mass or lymphadenopathy. Chest radiography revealed reaccumulation of the right-sided pleural effusion. The patient was readmitted for anticoagulant therapy.
Spontaneous thrombosis of a neck vein is very uncommon and leads me to suspect a hypercoagulable state, perhaps from an underlying cancer. Could a pulmonary embolus be responsible for the pleural effusion in this case? Pulmonary embolism is usually an acute condition and is out of step with the tempo of this patient's illness. Am I missing some other cause of his exudative pleural effusion?
Because the patient had previously undergone abdominal surgery and pelvic irradiation, pleuroscopy (rather than laparoscopy) was performed. The findings included an area of abnormal-appearing tissue deep in the posterior inferior pleural space on the right side. Intraoperative frozen sections of this tissue were examined, and the findings were interpreted as indicative of metastatic carcinoma, consistent with a primary focus in the prostate. Talc pleurodesis was performed to prevent reaccumulation of pleural fluid, and the patient was discharged.
I am fairly convinced that the patient does not have tuberculosis, since it would be difficult to confuse carcinoma with a tuberculous granuloma. I also doubt that he has metastatic prostate cancer, because recurrence would be extremely unusual in a patient who has been free of disease for 15 years since treatment and in whom prostate-specific antigen is undetectable. Because mesothelioma could be misinterpreted as adenocarcinoma, I would await further review of the tissue by a pathologist. If the diagnosis remains in question, I would obtain another biopsy specimen. Since the pleural surface would be inaccessible after pleurodesis, I would further investigate the omental nodules. I am increasingly interested in knowing what the patient did while in the Navy.
At a clinic visit one week later, the patient reported anorexia and persistent abdominal distention. Repeated abdominal CT scanning showed an increase in the number and size of the omental nodules and in the amount of ascitic fluid. Ultrasound-guided paracentesis yielded 20 ml of clear yellow fluid with a serum–ascitic fluid albumin gradient of 0.7 g per deciliter. The ascitic fluid contained 15,400 white cells per cubic millimeter (30 percent neutrophils, 5 percent lymphocytes, 35 percent monocytes, and 30 percent mesothelial cells) and 1900 red cells per cubic milliliter. Bacterial and mycobacterial cultures were sterile. Cytologic examination showed inflammatory cells and normal-appearing mesothelial cells. The final interpretation of the biopsy specimens obtained during pleuroscopy was hemorrhagic fibrin clot with a small, benign-appearing overgrowth of mesothelial cells, a finding not consistent with the presence of metastatic prostate carcinoma.
Since the ascites originates from the peritoneum, the low serum–ascitic fluid albumin gradient (less than 1.1 g per deciliter) was expected. (In contrast, processes that result in portal hypertension are associated with an elevated serum–ascitic fluid albumin gradient .) The cell counts and the white-cell differential count are not diagnostic and again raise the question of tuberculosis as opposed to cancer. The white-cell count is substantially elevated, and the neutrophil count is greater than 250 per cubic millimeter, but I doubt that he has spontaneous bacterial peritonitis. That condition almost always occurs in the setting of liver disease and is usually accompanied by a predominance of neutrophils.
This patient has two diseased serosal surfaces with exudative effusions, complicated by hypercoagulability, and there is no strong evidence of tuberculosis, which is the competing diagnosis. I think that he has malignant pleural and peritoneal mesothelioma and would thus proceed with laparoscopic peritoneal biopsy.
Exploratory laparoscopy revealed a peritoneal surface with diffuse plaques and an omentum caked with soft, nodular plaques. Pathological evaluation of the biopsy specimens by immunocytochemistry and electron microscopy revealed malignant mesothelioma. On further questioning, the patient reported that while serving in the Navy he had been continually exposed to asbestos-covered pipes, both while scraping and repainting them and while working below deck as a cook.
Commentary
The venerable adage that careful history taking and physical examination usually lead to the correct diagnosis is especially true in perplexing cases. Unfortunately, because of advances in medical technology and specialized diagnostic tests, physicians have begun to place less emphasis on these skills. Despite the methodical evaluation of this patient by his physicians, the diagnosis remained elusive. The discussant, however, zeroed in on two key aspects of the history: the patient's country of origin (an area where tuberculosis is endemic) and his service in the Navy (a clue to potential asbestos exposure). The discussant was then able to place infection with Mycobacterium tuberculosis (sometimes called the "red snapper" because of its characteristic appearance on acid-fast staining) and cancer (Latin for crab) at the top of his differential diagnosis for this patient with diseased pleural and peritoneal surfaces. As additional information was presented, he interpreted it in the context of these two historical linchpins.
Disseminated tuberculosis (with pleuritis and peritonitis) was appropriately considered because of the patient's positive tuberculin skin test. The likelihood of tuberculous pleuritis was lessened by the absence of typical clinical findings (e.g., fever, cough, and pleuritic chest pain)1 and the atypical findings in the pleural fluid (more than 5 percent mesothelial cells and an absence of a lymphocytic predominance).1,2 The patient's history of metastatic prostate cancer was also considered and briefly led to an incorrect diagnosis. Despite the initial misreading of the pleural biopsy specimen, the discussant recognized that metastatic prostate cancer was unlikely because prostate-specific antigen was undetectable.3 Mesothelioma can be mistaken for adenocarcinoma histologically.4 The distinction can be, and was in this case, made by immunocytochemical staining and electron microscopy. Although the findings described made disseminated tuberculosis or prostate cancer unlikely, several features suggested mesothelioma as a potential diagnosis. The combination of several factors — the possibility of heavy asbestos exposure (not recognized until late in the workup), the involvement of both the pleural and the peritoneal surfaces, the long latency period between the exposure and the onset of symptoms, and hypercoagulability — led the discussant to the correct diagnosis: malignant mesothelioma.
Asbestos was used extensively in World War II–era ships. Its use did not decline until the mid-1970s, when the adverse health consequences of prolonged exposure became widely known. Exposure to asbestos can cause the fibrotic interstitial lung disease called asbestosis; it has also been linked to lung cancer (and the risk appears to increase synergistically with tobacco use), malignant mesothelioma, and benign pleural disorders (pleural plaques and effusions). Although asbestosis has been recognized since the early 1900s, asbestos exposure was not linked to malignant mesothelioma until the 1960s.5
The incidence of mesothelioma in the United States rose during the 1970s and early 1980s, primarily as a result of occupational exposure during the preceding decades, and was projected to peak in 2000.6 Malignant mesothelioma may arise from the pleural or peritoneal surfaces or, less commonly, the pericardium or tunica vaginalis. Pleural involvement is more common than peritoneal involvement, which usually occurs in persons with the heaviest asbestos exposure. After inhalation, the lung's mucociliary system attempts to clear the asbestos fibers. Fibers that are coughed up and swallowed may lead to peritoneal mesothelioma. A latency period of 20 to 40 years between asbestos exposure and the onset of symptoms of mesothelioma is typical.
Peritoneal mesothelioma tends to progress locally, resulting in vague abdominal symptoms, including pain, increased girth (due to malignant ascites), and weight loss.7,8 Examination of the abdomen usually reveals evidence of ascites but little else.8 As the tumor advances locally, it may cause bowel obstruction. Surgical debulking followed by intraperitoneal chemotherapy may be attempted in selected patients with localized disease. Palliative systemic chemotherapy is an option for those with advanced disease.
Because of the rarity of peritoneal mesothelioma and its frequently nonspecific features at the time of presentation, the diagnosis is often delayed. Five months elapsed between this patient's initial presentation and the correct diagnosis. Because the prognosis is poor and treatment options are limited, this delay probably did not alter the outcome, but it may have been avoidable. Two main factors contributed to the delay. First, the patient was discharged from the hospital twice (once at his request) before his evaluation had been completed. Although rapid discharge may help constrain costs, it may not be optimal for patients who require certain diagnostic tests or evaluations by multiple subspecialists. Second, there was an initial reluctance to perform exploratory abdominal surgery (to obtain biopsy specimens of the omental nodules) because of the patient's prior abdominal surgery and pelvic irradiation. This initial decision not to obtain specimens of the omental nodules was not revisited for several months. Had the patient's extensive asbestos exposure been recognized earlier, the primary and consulting physicians would probably have pursued exploratory abdominal surgery soon after the nondiagnostic pleuroscopy.
More than half a century ago, Platt asserted that most diagnoses could be made on the basis of the history alone.9 Subsequent studies have confirmed that the history is the key to the final diagnosis in 56 to 82 percent of cases.10,11,12 The commonly passed-on clinical aphorism, "What you do not ask, you will not find out," remains true.
Supported by a Career Development Award from the Health Services Research and Development Program of the Department of Veterans Affairs and a Patient Safety Developmental Center Grant (P20-HS11540) from the Agency for Healthcare Research and Quality (both to Dr. Saint).
Source Information
From the Primary and Specialty Medical Care Service, Veterans Affairs Puget Sound Health Care System, and the Department of Medicine, University of Washington School of Medicine — both in Seattle (P.B.C., B.A.L.); the San Francisco Veterans Affairs Medical Center and the Department of Medicine, University of California at San Francisco School of Medicine — both in San Francisco (G.D.); and the Ann Arbor Veterans Affairs Medical Center and the Department of Internal Medicine and the Patient Safety Enhancement Program, University of Michigan Health System — both in Ann Arbor (S.S.).
Address reprint requests to Dr. Cornia at the Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way (S-111-GIMC), Seattle, WA 98108-1597, or at paul.cornia@med.va.gov.
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