Case 15-2003 — A 47-Year-Old Man with Waxing and Waning Pulmonary Nodules Five Years after Treatment for Testicular Seminoma

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Presentation of Case

A 47-year-old man was evaluated in the pulmonary clinic because of waxing and waning pulmonary lesions several years after treatment for seminoma.

The patient had been well until five years earlier, when a left testicular seminoma was diagnosed. A left radical orchiectomy was performed; there was no evidence of lymphatic or blood-vessel invasion, and the resection margins, epididymis, and spermatic cord were free of tumor. A computed tomographic (CT) study of the chest, performed after the oral administration of contrast material, disclosed slight anterior pericardial thickening, with no axillary, hilar, or mediastinal lymphadenopathy or evidence of pulmonary parenchymal or pleural abnormality. Abdominopelvic CT scanning, performed after the oral administration of contrast material, and a staging lymphangiographic examination showed no evidence of metastatic disease.

The patient was an executive who drank moderate amounts of alcohol and did not smoke. He had a history of scoliosis, which hadbeen treated by placement of a Harrington rod 16 years previously. His only symptom was severe, recurrent heartburn. His brotherand his mother both had renal cancer, which had been treated with surgery alone, and his mother also had breast cancer; agrandfather had gastric cancer, and a grandmother had an unspecified cancer. His wife and children were well. The results of an extended physical examination, including examination of the remaining testis, were unremarkable. The patient's body weight was 102.7 kg. The human chorionic gonadotropin and alpha-fetoprotein levels were normal. Over a period of one month, radiation treatment was administered to the iliac, para-aortic, and paracaval lymphnodes (total dose, 2970 cGy). Intermittent nausea was controlled with prochlorperazine, and the heartburn was partially relieved with antacids.

At a follow-up visit one year after the beginning of radiation therapy, the patient reported having a nonproductive cough. A chest radiograph was clear. At a visit two years after treatment for the seminoma, the findings on abdominopelvic CT scanning performed after the administration of contrast material wereunchanged. Thirty-three months after his initial treatment, he reported having pain and edema in both legs and bouts of exertional dyspnea. Physical examination disclosed no abnormalities except for ++ ankle edema. Chest radiographs were clear. Ultrasonographic examination of the legs showed no evidence of deep venous thrombosis, and the findings on a ventilation–perfusion pulmonary scan indicated a low probability of pulmonary embolism. Theresults of urinalysis, the blood count, and the levels of urea nitrogen, creatinine, glucose, conjugated and total bilirubin, albumin, electrolytes, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were normal. The human chorionic gonadotropin and alpha-fetoprotein levels were also normal.

Nine months later (18 months before the diagnostic procedure), the patient returned with a slightly painful, tender, pustular rash above the left eyebrow. Herpes zoster was suspected, and acyclovir was prescribed. Sixteen days later, a chest radiograph revealed new development of a very vague, mass-like lesion, 3.2 cm in diameter, in the periphery of the left lower lobe; it was suspected to be a primary or metastatic cancerous lesion. Three days later, a CT scan of the chest (Figure 1), obtained without the intravenous administration of contrast material, disclosed multiple peripheral opacities, which were patchy andhad a ground-glass appearance; there was also a ring-like opacity, 2.8 by 2.2 cm, in the left lower lobe, corresponding to the abnormality on the conventional chest radiographs. Nonspecific pericardial thickening was again seen. There was no mediastinal or hilar lymphadenopathy, and no other change was evident.

View larger version (68K): [in this window] [in a new window] Figure 1. CT Scan of the Chest Obtained 18 Months before the Diagnostic Procedure. There are multiple peripheral nodular opacities at the level of the aortic arch, some of which have a ground-glass appearance (Panel A). At the level of the lung bases, there are additional lesions. The largest nodule, located in the left lower lobe, has a ground-glass appearance with an irregular rim of increased density, but without cavitation (Panel B).

After another three days, the patient's physician elicited anapproximately two-year history of intermittent nonproductivecough, without recent dyspnea. The lungs were clear, and therewas questionable ankle edema. The cutaneous lesions had cleared.Another thoracic CT scan, obtained nine days later without theintravenous administration of contrast material, revealed multiplesubpleural ground-glass and nodular opacities, which appearedto be essentially stable; the large mass in the left lower lobepersisted but appeared less opaque than it had previously. Twonew nodules, 2 and 4 mm in diameter, in the right lower lobeand major fissure raised concern about possible metastasis.A CT-guided biopsy was not performed because of the partialimprovement of the large lesion and also because of the patient'sneed to take a business trip two days later.

Three weeks later, a repeated thoracic CT scan, obtained without the intravenous administration of contrast material, showed that many of the nodules throughout the lungs had decreased in size. The ground-glass nodule in the left lower lobe had enlarged to 4.2 by 2.6 cm, and a nodule in the right lower lobehad increased in diameter from 4 to 6 mm. Two weeks later, positron-emission tomographic (PET) scanning, performed with the use of 18F-fluorodeoxyglucose, disclosed no abnormal uptake that corresponded to the abnormalities shown on the most recent CT scan. The variability of the nodulesand the absence of abnormalities on the PET scan led to the conclusion that a needle biopsy was not urgently required.

Two months later, another thoracic CT scan again showed, in both lungs, multiple subpleural nodular opacities, a few of which had resolved but the majority of which had increased in size; in addition, there were many new lesions. The same day, a double-contrast upper-gastrointestinal series with a small-bowelstudy revealed a normal bowel-gas pattern. The mucosa of the esophagus, stomach, and proximal small bowel was normal. There was slight slowing of the primary stripping waves in the esophagus, with residual contrast material in the esophagus and secondary contractions. Severe gastroesophageal reflux was evident to the level of the thoracic inlet, without a hiatal hernia. No evidence of aspiration was observed. A fine-needle aspiration biopsy of a nodule at the periphery of the left upper lobe showed no evidence of cancer; organizing fibrin, reactive bronchial epithelial cells, histiocytes, and lymphocytes were present.No malignant cells were found on cytologic examination.

The patient continued to have heartburn but noted improvement while taking omeprazole. His weight was stable, and no abnormalities were discovered on physical examination. Lansoprazole was substituted for the omeprazole.

Four months later, another thoracic CT scan showed that the pulmonary nodules and peripheral opacities had become less opaque and had assumed a ground-glass appearance. A few appeared to have increased slightly in size. Multiple new, peripheral densities, which had patchy, ground-glass, and nodular appearances, had developed. No intrathoracic lymphadenopathy or pleural effusion was detected, and the level of human chorionic gonadotropin was normal. Four months later, another thoracic CT scan (Figure 2A) revealed numerous new, irregular opacities throughout both lungs; in the left lower lobe there was an opacity that was larger than it had been on the most recent examination. No lymphadenopathy or osseous lesions were seen. A thoracic CT scan obtained five months later (Figure 2B) again showed waxing and waning peripheral nodular opacities. Representative CT images from this period are shown in Figure 2.

View larger version (68K): [in this window] [in a new window] Figure 2. Sequential CT Scans of the Chest Obtained Five Months (Panel A) and Two Months (Panel B) before the Diagnostic Procedure. Panel A shows multiple new peripheral lesions. In Panel B, some of these lesions have resolved or appear smaller, and new lesions are present.

Two months later, the patient reported that his reflux symptomshad greatly improved since he had begun taking lansoprazole,although they had not disappeared. His weight was stable. Anotherthoracic CT scan, obtained without the intravenous administrationof contrast material, again revealed regression of some nodulesand enlargement of others. No new nodules were identified. Therewas slight pericardial thickening; no lymphadenopathy or bonylesion was detected.

A diagnostic procedure was performed.

Differential Diagnosis

Dr. Carolyn M. Fleming: May we review the radiologic studies?

Dr. Jo-Anne O. Shepard: Posteroanterior and lateral chest radiographs obtained 18 months before the diagnostic procedure showed a Harrington rod in the spine. A peripheral nodular opacity was visible in the left lower lobe; it projected over the thoracic spine on the lateral radiograph. A CT scan of the chest, obtained without the use of intravenous contrast material (Figure 1), shows mild anterior pericardial thickening, which was noted at the time of the initial staging of the seminoma, with no evidence of mediastinal lymphadenopathy. There are multiple peripheral opacities in the lungs. At the level of the aorticarch (Figure 1A), there are multiple subpleural, nodular opacities, some of which have a ground-glass appearance. At the level of the lung bases (Figure 1B), there is a larger, subpleural lesion in the left lower lobe with a ground-glass appearance and a somewhat thickened, irregular rim of increased density. No cavitation is present, and there are no pleural effusions. A CT scan obtained nine days later showed no changes in the upper-lobe lesions and no new lesions, but it did show an increase in size of the lower-lobe lesion, which had a slightly thinner rim than on the previous study.

Three weeks later, a CT scan of the chest showed no change in the upper-lobe lesions and a slight increase in the diameter of the left-lower-lobe lesion, which was slowly fading. A PET scan obtained shortly thereafter showed no uptake in these parenchymal lesions. CT scans obtained five and two months before the diagnostic procedure (Figure 2) show multiple nodular lesions in the peripheral parenchyma; some of them are rounded, with rim-like opacification but without cavitation, and they wax and wane over time. Some of these lesions became smaller and eventually disappeared, and new lesions periodically appeared and then became smaller.

Dr. Fleming: The differential diagnosis of pulmonary nodules is extensive (Table 1). However, the history, clinical presentation, and radiographic findings in this case help to narrow the possibilities. This patient's clinical course and the evolution of the radiographic findings are not consistent with the presence of infection, so I shall focus on other causes.

Cancer

The patient's history of seminoma five years before his presentation with pulmonary nodules raises the possibility of a late recurrence of his original seminoma, with metastases. Among patients with stage I seminoma treated with radiation therapy, the seminoma recurs in about 3 percent of patients, in most cases within two to three years after diagnosis and treatment.¹ However, late recurrences or metastases, up to 30 years after diagnosis and treatment, have been reported.^2,3,4 Seminomas most commonly metastasize to the para-aortic lymph nodes. However, metastases to the lung, brain, and liver also occur.¹ The patient under discussion is also at increased risk for the development of cancer in his contralateral testicle, and metastases from such a tumor are possible. However, neither the physical examination nor the laboratory tests suggest a second primary seminoma in the contralateral testis.

Patients who have undergone radiation therapy for seminoma are at increased risk for second cancers, both within and outside the radiation field. In a study of 29,000 survivors of testicular cancer,⁵ patients treated with orchiectomy and radiation therapy were found to be at significantly increased risk for the development, within 5 to 10 years after treatment, of bladder cancer, small-bowel cancer, and leukemia, but not lung cancer. An excess risk of secondary non-Hodgkin's lymphoma was also found, but it did not appear to be related to treatment.⁵ Lymphomatoid granulomatosis, believed to be a form of low-grade non-Hodgkin's lymphoma associated with Epstein–Barr virus, may be characterized by waxing and waning pulmonary nodules.⁶ The development of tumor emboli from an extrapulmonary site, with associated infarction and bleeding, is also possible.⁷ However, given the number of nodules, their waxing and waning without persistent progression, the absence of clinical symptoms, the absence of evidence of a second cancer, and the absence of findings on PET scanning, we can conclude that this patient's clinical course and radiographic findings are not consistent with a malignant process.

Noninfectious, Nonmalignant Causes of Pulmonary Nodules

Sarcoidosis has been reported in patients with seminoma at the time of diagnosis or during follow-up.^8,9,10 A retrospective review from the Mayo Clinic¹¹ showed that the risk of sarcoidosis in men with a history of treated testicular cancer was approximately 100 times that in men without such a history. However, as the authors point out, their findings may be biased, since these patients are screened more frequently than the general population.¹¹ This multisystem chronic granulomatous disease, characterized by the presence of noncaseating granulomas, can involve almost any tissue but most frequently involves mediastinal and hilar lymph nodes and the lungs. Patients typically present between the ages of 20 and 40 years, and most have no symptoms. Thelesions of sarcoidosis can wax and wane without treatment; spontaneous resolution is common.¹² Most cases of sarcoidosis associated with seminoma also involve lymphadenopathy, which can be seen on CT scanning of the chest. In addition, infiltrates show a predilection for the bronchovascular bundle, and nodules rarely exceed 1 cm in diameter. Thus, the features of this patient's radiographs would be atypical for sarcoidosis.

Patients with eosinophilic granuloma (pulmonary Langerhans'-cell histiocytosis), Wegener's granulomatosis, or Churg–Strauss disease can all present with bilateral, waxing and waning pulmonary nodules and ground-glass opacities. Those with eosinophilic granuloma usually present between the ages of 20 and 40 years, and the majority (>90 percent) are smokers; the lung disease predominantly affects the middle and upper zones, and nodular lesions are usually less than 5 mm in diameter and are associated with thin-walled cysts.^13,14 This patient is not a smoker, there are no cystic changes on his chest CT scans, and his nodular opacities do not have a lobar predominance — all of which make a diagnosis of eosinophilic granuloma unlikely.

Wegener's granulomatosis is a multisystem disorder characterized by vasculitis and necrotizing granulomas. The mean age at diagnosis is 40 to 55 years. Up to 34 percent of patients whose chest radiographs show pulmonary involvement are asymptomatic.^15,16 On CT scanning of the chest, multiple bilateral nodules or masses, up to 3 cm in diameter, may be seen.¹⁶ Although Wegener's granulomatosis can be confined to the lung, it is usually associated with upper respiratory tract disease and kidney disease. In addition, patients with untreated Wegener's granulomatosis historically have a poor outcome, with a median survival of five months.¹⁷ In this case, the absence of kidney and sinus involvement and the clinical stability make Wegener's granulomatosis an unlikely diagnosis.

Churg–Strauss disease (allergic granulomatosis and angiitis) is a multisystem disease characterized by asthma, allergic rhinitis, and peripheral-blood eosinophilia.¹⁸ This patient's clinical picture is not consistent with a diagnosis of Churg–Strauss disease.

Rheumatoid arthritis can be associated with pulmonary nodules that spontaneously resolve when the disease goes into remission. Subpleural ground-glass opacities and nodules have also been noted in progressive systemic sclerosis. However, the nodules in rheumatoid arthritis often cavitate, which is not a feature of this patient's pulmonary nodules. In addition, he had no history of rheumatoid arthritis or systemic sclerosis and no evidence of these disorders on examination.¹⁹

Chronic hypersensitivity pneumonitis and pneumoconiosis can appear as multiple pulmonary nodules on chest radiography and CT scanning.²⁰ However, this patient had no constitutional symptoms, was taking no medications, and had no reported occupational or environmental exposures that would be consistent with these diagnoses.

Chronic recurrent pulmonary embolism, septic pulmonary emboli, or hematogenous tumor metastases (tumor emboli) with associated hemorrhage could cause transient nodular infiltrates with associated ground-glass opacities.^7,19 However, given that the patient had negative findings on a workup for pulmonary embolism, had no signs or symptoms of pulmonary hypertension, and had no signs or clear source of active infection or primary tumor, thesediagnoses are unlikely.

Bronchiolitis Obliterans with Organizing Pneumonia

The histologic pattern of obliteration of the small airways by plugs of granulation tissue (bronchiolitis obliterans) associated with extension of organizing exudates distally into the alveoli (organizing pneumonia) is a common, nonspecific pattern of response to lung injury. It is seen in association with many diseases affecting the lung parenchyma (Table 2). In most cases, it is idiopathic. The disorder affects men and women equally, most commonly between the ages of 40 and 60 years. Its clinical development is usually subacute, evolving over a period of weeks to months. Some patients report an antecedent respiratory tract infection. Patients typically present with mild symptoms of a chronic, nonproductive, dry cough and dyspnea on exertion. On physicalexamination, bibasilar inspiratory crackles are common, and a midinspiratory squeak may be heard. Wheezing is rare. The findings on physical examination may be normal.²¹

The radiographic appearance of bronchiolitis obliterans with organizing pneumonia is variable.Bilateral, asymmetric consolidationis common. Patchy pneumonic foci, diffuse interstitial lungdisease, solitary foci of consolidation, and multiple or singlelung nodules may also be seen.²¹²² On chest CT scanning, patchy consolidation, usually subpleural, peribronchial, or both, is seen in 90 percent of patients. Nodules and irregular linearopacities may be seen in up to 40 percent of patients. Ground-glassattenuation, usually random in distribution, is seen in 60 percentof patients.²³ Infiltrates may be migratory, have a waxing andwaning character, increase in size, or show spontaneous regression.New infiltrates may also appear. Pulmonary effusions and lymphadenopathyare rare.²² In one case series, peripheral nodular or mass-likeopacities were the most common finding on chest CT scanning,occurring in 5 of 12 patients. Like the patient under discussion,two of these patients had resolution of nodules and subsequentreplacement by ground-glass opacities on follow-up CT scanningof the chest.²⁴

Gastrointestinal Reflux and Aspiration

In the case under discussion, the peripheral, subpleural location of the nodular infiltrates and their frequent association with surrounding ground-glass opacities in a clinically well patient are consistent with a diagnosis of bronchiolitis obliterans with organizing pneumonia. This patient had a history of heartburn and had undergone a swallowing study that revealed severe gastric reflux to the thoracic inlet. Although there was no evidence of aspiration, it is possible that aspiration was occurring, especially while the patient was sleeping and supine. The occurrence of bronchiolitis obliterans with organizing pneumonia secondary to aspiration is not well documented in the literature. A lesion called "diffuse aspiration bronchiolitis," defined as chronic inflammation of the bronchioles caused by recurrent aspiration of foreign particles, was described at autopsy in 31 of 4880 patients, many of whom had no clinical evidence of aspiration.²⁵ In one report,²⁶ bronchiolitis obliterans with organizing pneumonia resolved in four of five patients with gastroesophageal refluxdisease after they received treatment for the reflux. In addition, gastric reflux has been thought to be a cause of bronchiolitis obliterans in some patients who have received a heart–lung transplant.^27,28

In summary, I believe that bronchiolitis obliterans with organizing pneumonia, possibly due to chronic recurrent aspiration, best explains this patient's disease. However, the cause of the pulmonary lesions in this case cannot be determined from the clinical and radiographic findings alone. I would recommend a video-assisted thoracoscopic lung biopsy to confirm the diagnosis and to rule out other causes.

Dr. Robert E. Scully (Pathology): With this patient's strong family history of cancer, particularly of renal-cell carcinoma, could the lesions be metastatic from a renal-cell carcinoma?

Dr. Fleming: Given the patient's long course with no progression of any of these infiltrates, and with complete resolution of some of the most worrisome nodular infiltrates, I really doubt that this is a malignant process.

Clinical Diagnosis

Aspiration pneumonitis secondary to gastroesophageal reflux disease.

Dr. Carolyn M. Fleming's Diagnosis

Bronchiolitis obliterans with organizing pneumonia, secondary to gastroesophageal reflux disease with associated recurrent aspiration.

Pathological Discussion

Dr. Eugene J. Mark: Dr. Cameron Wright was a thoracic surgical consultant in this case. Dr. Wright, would you give us your preoperative impressions and describe the diagnostic procedure?

Dr. Cameron D. Wright (Thoracic Surgery): Dr. David J. Kanarek of the Pulmonary Medicine Unit referred this patient for a video-assisted thoracoscopic biopsy. I was perplexed by this case because of the waxing and waning nature of the infiltrates, which sometimes resolved. I was impressed by the patient's history of gastroesophageal reflux disease and also by the clinical suspicion that these lesions might be due to aspiration. In view of the patient's history of cancer and the uncertainty of the diagnosis, a thoracoscopic examination was requested. We first performed a bronchoscopic examination that showed no mucosal abnormalities of the airway and no abnormal secretions. On video-assisted thoracoscopic examination, the pleural surfaces were found to be entirely normal. There was no pleural effusion. By palpation and correlation with the findings on the CT scan, we identified two subtle nodular areas, one in the right upper lobe and one in the right lower lobe, and each was removed by a wedge excision.

Dr. Mark: On microscopical examination, the lung was found to contain nodules of lymphohistiocytic inflammation with ill-defined edges (Figure 3A). Bronchioles and alveolar ducts within the nodules were filled with branching tufts of myxoid fibrous tissue. The branching pattern indicates that this fibrosis lies within the conducting airways (Figure 3B), a finding that constitutes bronchiolitis obliterans. The histiocytes formed loose aggregates, and there were many multinucleated histiocytes of a foreign-body type (Figure 3C). Lymphohistiocytic inflammation in the alveoli constitutes organizing pneumonia. The combination of these findings indicates the presence of bronchiolitis obliterans with organizing pneumonia. A few compact granulomas with multinucleated histiocytes lay in areas away from the main inflammatory nodules (Figure 3D).

The causes of bronchiolitis obliterans with organizing pneumoniaare listed in Table 2. At this hospital, most cases that arecharacterized by a diffuse process on chest radiography areidiopathic. Granulomatous inflammation, as seen in this case,is found in bronchiolitis obliterans with organizing pneumoniaonly when the disease is due to a hypersensitivity reaction.Compact granulomas are uncommon in all forms of the disease.The multinucleated histiocytes seen in this case suggest a foreign-bodyreaction to aspirated material, which I believe is the mostlikely diagnosis. Aspiration has long been known to cause bronchiolitisin animal models²⁹ and has been documented in rare case reports,³⁰but it is among the less appreciated causes of bronchiolitisobliterans with organizing pneumonia.²¹³¹³²

Four types of aspirated material — oropharyngeal bacteria, gastric acid, food particles, and foreign bodies — can cause lung disease. The lung disease can be categorized as acute, subacute, or chronic (Table 3), depending in large part on the type and amount of aspirated material. The acute forms are diffusealveolar damage due to aspiration of gastric acid and bronchopneumonia due to aspiration of a microorganism. The subacute forms are miliary granulomatosis, diffuse aspiration bronchiolitis, and bronchiolitis obliterans with organizing pneumonia. Miliary granulomatosis^32,33 is a pattern of focal granulomatous inflammation and granulomas mimicking tuberculosis radiographically and macroscopically and is due to aspiration of vegetable particles. Diffuse aspiration bronchiolitis is defined pathologically as chronic mural inflammation with a foreign-body reaction in the bronchioles.²⁶ The onset is more insidious than that of aspiration pneumonia, and aspiration may not be recognized clinically. The most common chronic forms of lung disease due to aspiration are abscess, bronchiectasis, and interstitial fibrosis. Aspiration of foreign bodies, seen more often in children than in adults, can result in an abscessor bronchiectasis. Interstitial fibrosis and, in some cases, bronchiolitis were found on lung biopsy in 10 of 79 patients who had radiographic evidence of lung disease and a history of aspiration.³⁴

The literature on idiopathic bronchiolitis obliterans with organizingpneumonia rarely indicates whether aspiration was ruled outby history or investigation. Because gastrointestinal refluxis a common and chronic condition that could lead to recurrentepisodes of occult aspiration, gastrointestinal reflux mightbe added to the list of conditions to be ruled out, particularlyin patients with relapsing bronchiolitis obliterans with organizingpneumonia.³⁵

Dr. Shepard: The peripheral subpleural location of the lesions on this patient's radiographs is common in cases of aspiration, and the waxing and waning of these lesions would certainly be consistent with the occurrence of aspiration. The distribution of the lesions, however, is somewhat atypical. Aspiration occursmore commonly into the lower lung zones than into the upper zones. When it is seen in the upper lung zones, it more often involves the posterior dependent parts of the lung, because aspiration typically occurs in the recumbent position. Many of this patient's lesions were in the anterior upper lobe. The other unusual feature is the absence of "tree-in-bud" opacification, which is a radiographic characteristic of small-airway disease and bronchiolitis that is commonly seen after aspiration.

Dr. Mark: Dr. Kanarek has followed this patient but was unable to attend this conference. After the lung biopsy, the patient was treated with dietary modification and continued taking omeprazole, and initially he had nearly complete resolution of his heartburn. However, he later had high-grade dysphagia, with difficulty swallowing pills and an acid-reflux sensation in the back of his throat. The results of esophageal motility and 24-hour esophageal pH-probing studies were consistent with the presence of severe gastroesophageal reflux disease. Eleven months after the lung biopsy, a laparoscopic Nissen fundoplication was performed. The lung lesions have not recurred.

Anatomical Diagnosis

Bronchiolitis obliterans with organizing pneumonia due to gastroesophageal reflux and occult aspiration.

Source Information

From the Divisions of Pulmonary Medicine (C.M.F.) and Thoracic Radiology (J.O.S.) and the Department of Pathology (E.J.M.), Massachusetts General Hospital, and the Departments of Medicine (C.M.F.), Radiology (J.O.S.), and Pathology (E.J.M.), Harvard Medical School — both in Boston.

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