Infectious Pulmonary Nodules Mimicking Lung Carcinoma

Robert D. Allison, MPH, Albert L. Vincent, PhD, John N. Greene, MD, Ramon L. Sandin, MD, MS, Teresa Field, MD, PhD

Disclosures

Infect Med. 2004;21(4) 

• References

Solitary nodules are seen in about 1 in 500 chest radiographs, representing more than 150,000 patients annually. Pulmonary nodules caused by the dog heartworm Dirofilaria immitis and the fungi Histoplasma capsulatum, Cryptococcus neoformans, and Coccidioides immitis can masquerade radiologically as lung carcinoma and may prompt invasive procedures. We describe 5 cases in which nodules of infectious origin were seen on chest radiographs. Multiple imaging studies, laboratory tests, and patient risk factors (including age, sex, area of residence, history of travel, history of previous malignancy) are useful in differentiating these relatively benign infectious processes from bronchogenic carcinoma or other malignancies.

A common dilemma encountered in the outpatient primary care setting or in the hospital is the finding of an abnormal lung mass on a routine chest film. Because the leading cause of pulmonary nodules is lung cancer,^[1] look-alike infections are often diagnosed incidentally during the evaluation of a presumptive malignant process. Lung nodules visualized in patients with risk factors for pulmonary neoplasms heighten the suspicion of malignancy, often leading to aggressive surgical procedures. Suspect nodules may be subsequently identified as pulmonary dirofilariasis, cryptococcosis, histoplasmosis, or coccidioidomycosis.

Lewin and coauthors^[1] presented the case of a patient with a 20 pack-year history of cigarette smoking in whom an open thoracotomy and wedge resection of a suspicious nodule were performed; the nodule proved to be a granuloma enveloping a dead dog heartworm (Dirofilaria immitis). In an analysis of 7 cases of pulmonary coin lesions caused by D immitis, Ro and associates^[2] reported that all radiographic findings were considered highly suggestive of cancer and that thoracotomy with wedge resection was justified. In none of these cases had D immitis been considered in the differential diagnosis.

D immitis nodules may also mimic metastatic malignancies in patients with known primary prostate or bladder tumors.^[2,3] They may also coexist with lung carcinomas. Thomas and coworkers^[4] reported a case of a 61-year-old male smoker who presented with a right upper lobe cavitary lesion and a left lower lobe nodule; right upper lobectomy revealed a stage I carcinoma, while a thoracoscopic resection of the lower lobe nodule revealed Dirofilaria.

Cytologically, D immitis infection has mimicked lung cancer, as reported by Akaogi and coauthors.^[5]Transbronchial brushing was performed on a lung mass found in a 64-year-old heavy smoker, and cytologic examination revealed atypical cells in a papillary arrangement, showing nuclear enlargement, a high nuclear-to-cytoplasmic ratio, and irregularity of nuclear shape, all suggestive of carcinoma.

Fungi can also masquerade as primary or metastatic lung carcinoma. Ziomek and associates^[6]described a case of cryptococcosis that presented as a primary sulcus tumor. After an extensive workup that included bronchoscopy, a serologic test for Cryptococcus, mediastinoscopy, and a CT-guided needle biopsy, malignancy still could not be excluded and the patient underwent resection of the mass.

Both Kauffman ^[7] and Allende and coauthors^[8] found cryptococcal lung masses in patients in whom the initial diagnosis by radiography and CT was metastatic malignancy. One case of pulmonary histoplasmosis involving a mediastinal lymph node was likewise mistaken as lung cancer on radiography and CT.^[9] Thoracoscopic resection and histologic examination of a biopsy specimen of the mass led to the correct diagnosis. Without resection, pulmonary nodules caused by Coccidioides immitis can be indistinguishable from malignancy, and biopsy may be required for diagnosis.^[10,11]

In order to clarify features that are useful in the differential diagnosis of infectious processes initially suggestive of lung malignancy, we here review their clinical manifestations and risk factors, as illustrated by 5 cases seen in the department of infectious diseases at the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla, since 1997.

The initial encounter with the dog heartworm typically will be an incidental finding of a solitary peripheral coin lesion on the chest radiograph; 90% of lesions caused by Dirofilaria are solitary radiographically.^[12,13] A slight majority of patients will be asymptomatic and the remaining patients may experience cough, chest pain, wheezing, or hemoptysis and may have eosinophilia.^[14] Man is a sporadic, unsuitable host, and microfilariae rarely appear in the peripheral blood. Degenerating worms may be recognized within granulomas^[15] by their characteristic lateral cords, collagen-positive cuticle, and tendency to calcify.

White men between 40 and 60 years of age who live in areas where heartworm infection is endemic are more likely to acquire dirofilariasis.^[16] Historically, the infection ratio of males to females has been 2:1. Because D immitis is transmitted from dogs to humans by peridomestic mosquitoes, the size of the canine population, prevalence of the organism, and density of the mosquito population are determinants of transmission.^[2,4] The highest prevalence of infection occurs in the East, especially in the Mississippi Valley of the United States. However, the geographic range of D immitis has increased, and cases of dirofilariasis may be encountered in most US states and elsewhere in the world.

Surgical resection of the lung nodule is necessary for diagnosis of dirofilariasis and is usually conducted with a presumptive diagnosis of cancer in mind.^[4] Indirect hemaggluti nation and enzyme-linked immunosorbent assays are available but have low specificities, and specific IgE has not been detected.^[16,17] Skin tests, angiography, examination of bronchial washings, and sputum cytology have not been helpful.^[16] Diagnosis using fine-needle aspiration biopsy has been reported, but this method yields false-positive results^[2,16] and it may reveal irregular cells that mimic neoplasms.^[4]

A left lower lobe mass suggestive of carcinoma was found on a routine chest radiograph of a 67-year-old woman with no evidence of lymph adenopathy. The patient had received radiation and adjuvant chemotherapy for ductal carcinoma of the right breast 15 years earlier.

Bronchoscopy revealed a narrowed and erythematous lumen of the left lower lobe entrance suggesting tumor or inflammatory tissue. The patient underwent thoracotomy, and tissue was obtained for evaluation. On microscopic examination of the tissue, laminated, partly calcified bodies suggestive of degenerating D immitis were observed (Figure 1).

(Enlarge Image)

High-power view of a pulmonary nodule caused by the dog heartworm, Dirofilaria immitis, typically seen as a granuloma in a terminal arteriole. There is a shrinkage artifact between the collagen-like cuticle and the amorphous infiltrate surrounding the degenerating worm. Dark, radial striations within the nematode are the somatic muscles, and the prominent invaginations at 1 and 7 o´clock are the lateral cords.

Cryptococcus neoformans infection is acquired by inhalation of the organisms.^[18,19] Patients may present with dyspnea and cough, but asymptomatic infections and meningitis also occur. Fever is often absent in patients with cryptococcal pulmonary disease. Patients with disseminated disease may present with variable cutaneous lesions that sometimes resemble molluscum contagiosum. A solitary mass or pleural-based nodular lesions are common findings on the chest radio graph, initially suggesting a diagnosis of carcinoma.

Cryptococcus is an opportunistic organism that may cause acute infection in immunocompromised patients, in contrast to the mild or asymptomatic infections found in the general population. Among immunocompetent patients, males are affected more frequently than females and predisposing factors are absent in more than 50% of infections.^[20] C neoformans is present worldwide. The yeast is frequently found in pigeon droppings on window ledges or in barns. It may also be found in contaminated soil or decaying wood chips.

Diagnosis requires culture and histopathologic or cytologic examination of specimens obtained by bronchoscopic biopsy.^[7] The budding yeast is surrounded by a double refractive wall, a distinct capsule, and refractile granules in the cytoplasm. Sputum cultures are often negative. The latex agglutination test for the capsular polysaccharide antigen of C neoformans is useful for diagnosis in disseminated disease, but results of the test are often negative when localized pulmonary involvement is present.^[7,20]

The chest radiograph of a 48-year-old man with a history of smoking, obesity, and hypercholesterolemia demonstrated a noncalcified right lower lobe nodule suggestive of a neoplasm. He had a mild cough and low-grade fever but denied any shortness of breath, night sweats, weight loss, fatigue, or chest pain.

The patient underwent bronchoscopy and right thoracotomy with wedge resection of a 1.7-cm nodule and a smaller lesion (Figure 2). Serologic and antigen tests were negative for Cryptococcus, but the histopathologic appearance was consistent with a cryptococcoma. He was given fluconazole, 800 mg/d for 6 weeks, and his symptoms resolved.

(Enlarge Image)

The capsule of the yeast Cryptococcus neoformans stains a vivid pink-red with mucicarmine stain. In fibrocaseous cryptococcomas, organisms may be abundant or scant.

A 65-year-old man with a long-standing history of asthma and factory work complained of a decrease in functional capacity and frequent headaches during the previous year. In addition, he had experienced recent memory changes. A chest CT scan revealed a right upper lobe mass and mediastinal lymphadenopathy.

The patient underwent right thoracotomy with resection of the nodule. Culture and histopathologic examination of the nodule confirmed the presence of Cryptococcus. Antigen tests and culture of cerebrospinal fluid were negative for Cryptococcus. The patient was successfully treated with fluconazole, 800 mg/d for 6 weeks, followed by 400 mg/d for 6 months.

Following inhalation of mycelial fragments and microconidia of the fungus Histoplasma capsulatum, about 10% of persons will become ill after an incubation period of 7 to 21 days. The most frequent symptoms are chest pain, chills, fever, head ache, nonproductive cough, fatigue, and myalgia. In a few patients, erythema nodosum, erythema multiforme, or arthralgias may appear. Acute histoplasmosis may mimic pneumonitis on chest radiographs, and it must be differentiated from other types of community-acquired pneumonia. Some patients present with mediastinal lymphadenopathy that may be mistakenly attributed to a hematologic malignancy^[21] or with consolidated, calcified lesions that might be confused with pulmonary carcinoma.

H capsulatum is ubiquitous in soil but is most prevalent in the Ohio and Mississippi river valleys. Because bats shed the organism in their droppings, spelunkers are at special risk. Infection is also associated with starlings and with disruption of soil, such as by digging or filling operations. Disease occurs more frequently in men than in women by a 4:1 ratio, but there are no known racial or ethnic differences in susceptibility.

Sputum cultures are positive for H capsulatum in two thirds of patients with chronic disease, but multiple specimens must be collected.^[22] Wright or Giemsa stain reveals small (2 × 4 µm) ellipsoidal cells inside macrophages. Results of immunodiffusion and complement fixation tests have been reported to be positive in more than 80% of self-limited cases and in up to 93% of cases of cavitary histoplasmosis.^[22]A polysaccharide antigen of H capsulatum can be detected in 40% of patients with cavitary disease and in 20% of those with acute pulmonary histoplasmosis.^[21]

H capsulatum infection can be diagnosed definitively only by isolation of the organism from broncho-alveolar lavage fluid or bone marrow biopsy material.^[21,23] Small pulmonary calcifications and a positive histoplasmin skin test result are not unusual findings, indicating that past exposure is also relatively common. The treatment of choice in most cases is itraconazole, 200 mg twice daily for 6 months.

The dimorphic fungus C immitis is acquired by inhaling the arthroconidia. After a 7- to 21-day incubation period, the patient may present with cough, chest pain, shortness of breath, fever, fatigue, weight loss, or headache. Up to two thirds of infections are mild or asymptomatic.^[24] Most cases are self-limited and resolve spontaneously over a few weeks or months.^[25] A nonpruritic papular rash frequently occurs early in the illness but is often missed. Hematologic findings may include an elevated erythrocyte sedimentation rate and eosinophilia. A suspicious nodule measuring up to 5 cm in diameter appears in about 4% of patients with pulmonary infection.^[24]

C immitis is endemic in soil of the western United States, from central California through southern Texas and into Mexico. In the United States, infections tend to peak during the summer months. Immunosuppression or underlying disease is linked to infection, and common-source epidemics have been linked to soil disruption.

Because routine clinical and laboratory findings usually are not helpful in making the diagnosis of C immitis infection, an accurate travel history is of great importance.^[25] Pulmonary coccidioidomycosis (San Joaquin fever) may be diagnosed by direct examination of sputum samples and recognition of the characteristic spherules (15 to 80 µm), filled with several hundred endo spores. Bronchoalveolar lavage fluid reveals C immitis in about 50% of cases, but culture and histologic examination of tissue are more sensitive.^[26] Serum complement fixation, immunodiffusion, and enzyme immuno-assay tests are useful for patients who cannot produce sputum. Sensitivity of these tests in chronic pulmonary or self-limited coccidioidomycosis has not been established.^[24] Skin testing with Coccidioides antigens is highly specific, but results remain positive indefinitely following active infection.^[24]

A chest radiograph was ordered for a 71-year-old woman for evaluation of an abnormality seen on a routine mammogram; the radiograph revealed a right upper lobe nodule. A subsequent CT scan of the chest demonstrated a multinodular infiltrate in the upper right lobe without mediastinal adenopathy or other abnormalities. A positron emission tomography (PET) scan showed mild uptake of glucose, furthering the suspicion of malignancy.

The patient underwent a right upper lobectomy and mediastinal lymphadenectomy, leading to a histologic diagnosis of coccidioidomycosis (Figure 3). The infection resolved without further treatment, and she was scheduled for follow-up in 6 months.

(Enlarge Image)

Low-power view of a fibrocaseous pulmonary nodule stained with methenamine silver (A). Empty spherules that stain with methenamine silver and are without endospores should arouse suspicion of Coccidioides immitis infection. High-power view of an adjacent section shows a cluster of methenamine silver–positive endospores without the spherule wall (B). In the absence of developmental stages, identification of these older lesions is more difficult.

(Enlarge Image)

Low-power view of a fibrocaseous pulmonary nodule stained with methenamine silver (A). Empty spherules that stain with methenamine silver and are without endospores should arouse suspicion of Coccidioides immitis infection. High-power view of an adjacent section shows a cluster of methenamine silver–positive endospores without the spherule wall (B). In the absence of developmental stages, identification of these older lesions is more difficult.

A 76-year-old woman with a history of biannual travel to Las Vegas became ill with malaise and respiratory symptoms while there. Based on a chest radiograph, pneumonia was diagnosed; she was sent home with a prescription for a fluoroquinolone. After several weeks, her symptoms had not resolved and a CT scan revealed an abnormal mass in the right upper lobe suggestive of carcinoma. She presented to our center with a stable cough and occasional shortness of breath. A diagnosis of coccidioidomycosis was established by CT-guided biopsy of the right lung, and she was treated with 400 mg of fluconazole daily for 6 months. A repeated CT scan demonstrated resolution of the nodule, and therapy was continued for an additional 6 months.

Current concepts in the management of solitary pulmonary nodules have been reviewed by Lillington.^[27] A solitary nodule appears in about 1 in every 500 chest radiographs, representing more than 150,000 patients annually in the United States. Differentiating a solitary pulmonary nodule from lung carcinoma is thus of interest to practitioners of various specialties.^[28] Based on radiographs, about 40% of masses are tentatively diagnosed as a malignancy.^[29]

Invasive procedures are not usually justified for nodules caused by dirofilariasis, coccidioidomycosis, cryptococcosis, or histoplasmosis. However, in practice, these increasingly common possibilities are often overlooked during the initial diagnostic workup. The approach to the differential diagnosis of the pulmonary nodule is guided by multiple imaging examinations and laboratory findings.^[29,30] Essential aspects to consider include age, sex, history of smoking, and history of prior neoplasms. The patient's area of residence and a thorough travel history are helpful when considering mycotic or filarial causes of nodules.

Solitary nodules larger than 3 cm carry a significantly higher risk of malignancy and require resection.^[28]Physical characteristics that are helpful in making the diagnosis include patterns of calcification, rate of growth, and appearance of nodule margins. Although calcification is generally a favorable sign, punctate or single eccentric deposits may be present in malignant lesions.^[27] A doubling time of more than 500 days is a strong indicator that the lesion is not neoplastic, but this determination requires availability of previous chest radiographs for comparison.^[29] Lillington^[29] presents likelihood ratios for malignancy based on the appearance of nodule margins. A multiply spiculated nodule carries the greatest risk of being a neoplasm. Irregular margins and distortion of adjacent vessels are other causes for concern.^[31]

Nearly all patients presenting with lung nodules on chest films will receive CT scans. Use of high-resolution CT is recommended because it details physical characteristics of the nodule.^[29] PET is a useful noninvasive indicator of malignancy, yielding predictive values of between 77% and 100%.^[32,33]However, PET results were misleading for 1 of our patients who had coccidioidomycosis.

Swanson and colleagues^[30] and Lillington^[29] caution that every pulmonary nodule should be considered malignant until proved otherwise. A case in point is that of a 64-year-old man who had a history of smoking and had received a 6-month treatment regimen for tuberculosis following a positive result on a purified protein derivative test. He was seen at our center for the investigation of a left lower lobe lung mass and granulomatous medias tinal lymphadenitis. Bronchoscopy and left thoracotomy with medias tinal lymphadenectomy produced no evidence of malignancy. Itraconazole was given for suspected histoplasmosis. The patient returned 7 months later with increased fatigue and malaise, and his chest film and CT scan showed an enlarged left lower lung mass. A new biopsy incriminated the mass as squamous cell carcinoma.

Because their prevalence is apparently increasing, pulmonary dirofil ariasis, cryptococcosis, histoplasmosis, and coccidioidomycosis should be considered in the differential diagnosis of pulmonary nodules suggestive of malignancy.