Suspicion of Lung Cancer with Nodal Metastases in an Immunocompromised Patient

Case Editor - Jeremy Falk

Reviewed By Clinical Problems Assembly

Submitted by

William A. Bulman, MD

Senior Pulmonary and Critical Care Fellow

Columbia University Medical Center

New York, NY

Charles Powell, MD

Division of Pulmonary, Allergy and Critical Care

Columbia University Medical Center

New York, NY

Roger Maxfield, MD

Director of Interventional Bronchoscopy

Columbia University Medical Center

New York, NY

Submit your comments to the author(s).

History

The patient is a 67-year-old man with a 30 pack-year smoking history and a recently identified lung nodule. Systemic lupus erythematosis had been diagnosed in 1972. One year ago he presented with proteinuria and was found to have membranous glomerulonephritis by renal biopsy. He was started on mycophenolate and prednisone, with subsequent improvement in his renal function. Three months into therapy he developed night sweats, low-grade fevers and malaise. He was admitted to an outside hospital, where a CT scan of the chest revealed a left upper lobe pulmonary nodule with solid and ground glass components and mediastinal lymphadenopathy highly suspicious for primary lung cancer. Flexible bronchoscopy was performed for bronchoalveolar lavage and brushings; cytology was negative for malignancy; and cultures were negative for bacterial, viral and fungal pathogens. He left against medical advice without a diagnosis. Mycophenolate and prednisone were continued. The patient presented to our institution 2 months later with continued complaints of malaise, unproductive cough, bilateral hand tremor and intermittent low-grade fevers. He also reported significant, progressive memory loss; a vocalist in an amateur singing group, he found he was no longer able to remember words to songs.

Physical Exam

On physical examination, the patient was afebrile at 36.9° C, with a normal heart rate and normal blood pressure. His respiratory rate was 14 breaths per minute and SaO₂ was 100% while breathing room air. His physical exam was normal except for mild wasting, dysdiadochokinesia of the left upper extremity, and difficulty with attention and short-term recall. He was unable to remember three objects after 1 minute.

Lab

A lumbar puncture showed a mild lymphocyte predominant leukocytosis with no red cells; gram stain and fungal stains were negative. A CT scan of the chest revealed a left upper lobe nodule (Figure 1). Left paratracheal and left hilar adenopathy was noted (Figure 2). A PET scan showed FDG avidity in the left paratracheal and left hilar nodes and fainter avidity in the left upper lobe lesion (Figure 3). Comparison films were not available. An MRI of the brain showed mild atrophy and compensatory ventricular enlargement and multiple small lacunar infarcts in the basal ganglia, thalamus and periventricular white matter; no evidence of lupus cerebritis was noted. The patient underwent a bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration of the left paratracheal node. Results of Diff-Quik staining and mucicarmine staining of the specimen are shown in Figures 4 and 5.

Laboratory:

Leukocytes    3.0 x10³/mm³
Hemoglobin    9.7 g/dL
Platelets    251 x10³/mm³

Differential Neutrophils 58%, Lymphocytes 36%, Monocytes 5%, Basophils 1%

Sodium 135 mM/L

Potassium 4.5 mM/L

Chloride 105 mM/L

Bicarb 22 mM/L

BUN 20 mg/dL

Creatinine 1.3 mg/dL

Glucose 85 mg/dL

ESR 80 mm/hr

Lumbar Puncture: 56 White Cells (Neutrophils 23%, Lymphocytes 70%, Monocytes 6%, Basophils 1%); LDH 24 U/L, Protein 48 mg/dL, Glucose 35 mg/dL; Gram Stain: negative; KOH Stain: negative. Cryptococcal Antigen: negative; VDRL: nonreactive.

Chest CT: A nodule with mixed solid and ground glass elements was identified in the left upper lobe, measuring approximately 2.3 cm x 1.8 cm. Left lower paratracheal lymphadenopathy was noted measuring approximately 2.0 cm in the largest diameter. No other pulmonary nodules were identified. There was no pleural effusion, pneumothorax, or congestion (Figures 1 and 2).

PET Scan: Faintly FDG avid (SUV mean 0.9/ max 1.1 ) focus in the LUL; small FDG avid (SUV mean 3.1/max 4.3) focus in left hilar region and an FDG avid focus (SUV mean 4.4/max 5.5) in the left lower paratracheal region (Figure 3).

Figures

Figure 1. Axial view of CT scan of the chest (lung windows) showing a left upper lobe lesion with surrounding ground glass opacification.

Figure 2. Axial view of CT scan of the chest (mediastinal windows) showing an enlarged left paratracheal lymph node in the aortopulmonary window (arrow).

Figure 3. Coronal section of PET scan showing FDG-avidity in the left paratracheal area (white arrow) and left hilum (black arrow). The left upper lobe lesion was weakly positive (not shown).

Figure 4. EBUS view of the left paratracheal lymph node (outlined by dark arrows) during needle aspiration (white arrow at needle tip). Centimeter markings are in white at right of frame.

Figure 5. Diff-Quik stained EBUS-TBNA specimen.

Figure 6. Mucicarmine stained EBUS-TBNA specimen.

The presence of a PET-positive left upper lobe lung lesion with associated left hilar and left paratracheal adenopathy in a heavy smoker raises significant concerns for possible primary lung cancer with nodal metastases. Fungal infection can mimic these findings, however, and infection must be considered in the differential diagnosis, particularly in the context of immunosuppression. This patient had been on mycofenolate and prednisone for 5 months at the time of his presentation to our institution.

No malignant features are noted in the biopsy specimen. The biopsy specimen shows yeast forms which have a surrounding halo on Diff-Quik staining (Figure 5) and which are strongly positive (without a halo) on mucicarmine staining (Figure 6). Taken together, these findings are diagnostic of cryptococcosis. The pleomorphic, round or oval yeasts possess a polysaccharide capsule which does not stain with Diff-Quik (a modification of the Wright Giemsa stain), Gomori Methenamine silver or Periodic Acid Schiff stains. Mucin stains such as alcian blue and mucicarmine will stain the polysaccharide capsule. Mucicarmine will also stain the cell wall of blastomyces but only weakly, and mucicarmine does not stain histoplasma, coccidioides, or candida species. Histoplasmosis can show a halo on Giemsa or hematoxylin and eosin staining (not due to the presence of a capsule but rather to a retraction of the cytoplasm away from a poorly stained, thin cell wall), whereas no halo is seen with bastomyces, coccidioides or candida.

Cryptococcus neoformans has a worldwide distribution and is often found in association with birds, particularly pigeons and chickens, and rotting vegetation. Human infection begins in the lungs following inhalation of the basidiospore form of the fungus (1). Epidemiologic studies have shown that exposure is commonplace, with most persons over the age of 2 having positive serologies (2). The majority of exposures in immunocompetent persons are thought to result in subclinical infection, manifesting as a limited pneumonitis contained by the response of pulmonary alveolar macrophages, natural killer cells and T helper cells in the lungs and hilar lymph nodes. Although the size of the inoculum and the virulence of the particular strain affect the clinical outcome, the immune status of the exposed person plays the most important role in pathogenesis. Persons with an intact immune system frequently have asymptomatic infection. In the largest review in the literature, published in 1966, 32% of immunocompetent patients were asymptomatic, with the remainder presenting with a variety of symptoms, including cough (54%), chest pain (46%), fever (26%) and weight loss (26%) (3). Radiographic presentations are also variable, with well-defined solitary or multiple nodules being the most common; mediastinal adenopathy and pleural effusion are also occasionally seen in immunocompetent patients (4). Dissemination to other organs in immunocompetent persons is uncommon but does occur, with meningitis being the most common extrapulmonary infection. Retrospective studies have differed with respect to the percentage of normal hosts who develop central nervous system involvement in association with pulmonary cryptococcal infection, ranging from 17% to 69%. The manifestations of CNS involvement in cryptococcal infection are varied and include headache, fever, memory loss, lethargy, and personality changes. Routine sampling of CSF is not recommended, but patients with CNS symptoms or a high serum cryptococcal antigen titer (>1:250) should be considered for lumber puncture (4).

Patients with compromised immune function, particularly those with HIV, are at greater risk of infection and at greater risk of reactivation of latent infection. They are also both more likely to be symptomatic with pulmonary disease and more likely to have extrapulmonary spread. Although HIV-infected patients have emerged as the most significant risk group, patients with malignancy, organ transplantation, end-stage liver or renal disease, diabetes, sarcoidosis and patients being treated with corticosteroids or TNF-alpha blockers are at increased risk. Immunocompromised patients still present most often with single or multiple pulmonary nodules (81%), although cavitation is more common (62%), and both consolidation and ground glass changes are occasionally seen (6).

Dissemination to the CNS is significantly more common in the immunocompromised than in immune competent hosts, occurring with a very high frequency in HIV-patients (1). Immunocompetent patients and immunocompromised patients may have similar signs and symptoms with CNS involvement but differ in several important ways. Whereas normal hosts often have symptoms for weeks or months prior to diagnosis, immunocompromised patients (including both patients with HIV and patients on steroids) often have a more acute course with much shorter duration of symptoms, perhaps due to a higher organism burden or a decreased inflammatory response to infection (1).

Cryptococcal antigen testing of serum or other body fluids can be useful in diagnosis of pulmonary and CNS disease. In the standard latex agglutination test, the test is considered positive if agglutination occurs at a dilution of 1:4. In one study of non-HIV patients with isolated pulmonary cryptococcosis, serum cryptococcal antigen was positive in 73% (7). Many experts feel that a positive serum antigen test in a patient with isolated pulmonary cryptococcosis and an intact immune system may be indicative of a higher risk of dissemination and CNS disease. Serum antigen testing in patients with isolated pulmonary cryptococcosis and HIV has a high sensitivity (>95%), but false negatives do occur (1). Direct testing of bronchoalveolar lavage specimens for cryptococcal antigen can also be used in diagnosis of pulmonary cryptococcosis. One study of 35 patients (10 with HIV and 25 without) showed a sensitivity of 71% and a specificity of 99% (8).

For CNS infection, cryptococcal antigen testing of both serum and cerebrospinal fluid are highly sensitive. In a survey of the literature by Antinori et al, CSF cryptococcal antigen testing was 94.1% sensitive and serum testing was 93.6% sensitive irrespective of immune status, compared with a sensitivity of 92% for CSF culture and a sensitivity of 59.6% for India ink testing. In immunocompromised patients without HIV, such as in this case, CSF cryptococcal antigen testing was highly sensitive for CNS infection, with a sensitivity of 97.7% (9).

There are case reports in the literature of patients undergoing biopsy or resection for a clinical suspicion of malignancy who are subsequently found to have cryptococcosis. Cryptococcal nodules mimicking both primary lung cancer and metastatic cancer have been reported (10,11). A recent, small series reported positive PET findings in four of four patients with pulmonary cryptococcosis, with SUVs ranging from 0.93 to 4.85 (12).

Clinical trial data from HIV-negative patients with Cryptococcosis is unavailable. Expert panel treatment guidelines for cryptococcosis have been published by the Infectious Disease Society of America (5). In symptomatic patients with an intact immune system and no CNS involvement, the IDSA recommends:

Fluconazole, 200–400 mg/d for 6–12 months, or
Itraconazole, 200–400 mg/d for 6–12 months, or
Amphotericin B, 0.5–1 mg/kg/d (total, 1000–2000 mg)

The management of asymptomatic patients with isolated pulmonary involvement is less clear. Some recommend treatment of all patients given the potential for CNS dissemination, however small. IDSA guidelines recommend treatment of those patients with detectable levels of serum cryptococcal antigen, with the belief that these patients are at increased risk of dissemination to the CNS.

In immunocompetent patients with CNS involvement, IV induction therapy is suggested and the following regimens have been recommended:

Amphotericin B, 0.7–1 mg/kg/d plus flucytosine, 100 mg/kg/d for 2 w, then fluconazole, 400 mg/d for minimum 10 weeks, or
Amphotericin B, 0.7–1 mg/kg/d plus flucytosine, 100 mg/kg/d for 6–10 weeks, or
Amphotericin B, 0.7–1 mg/kg/d for 6–10 weeks, or
Lipid formulation of amphotericin B, 3–6 mg/kg/d for 6–10 weeks

For patients with severe pulmonary symptoms and patients with non-HIV-related immune compromise, with or without CNS disease, it is recommended that the treatment regimens for CNS cryptococcosis (above) be followed. For patients on long-term prednisone therapy, reduction of the prednisone dosage (or its equivalent) to 10 mg/d, is recommended, if possible.

Initial therapy with fluconazole for CNS involvement is discouraged. A repeat lumbar puncture is recommended after 2 weeks of treatment to assess the status of CSF sterilization. Patients with a positive culture at 2 weeks may require a longer course of induction therapy. An optional recommendation to continue fluconazole (200 mg/d) for 6–12 months is included in the guidelines.

In HIV-positive patients, particularly those with CD4+ T lymphocyte counts <200 cells/mL, the risk of CNS involvement is extremely high, and cryptococcal pneumonia should be considered a harbinger of disseminated disease and CNS infection. The treatment of cryptococcosis in patients with HIV is beyond the scope of this discussion; clinicians are referred to the IDSA recommendations for guidance (5).

Despite his negative CSF cryptococcal antigen, this patient’s symptoms of malaise and memory loss raised concerns for possible CNS involvement. Given his immunocompromised status, intravenous antifungal therapy was recommended for this patient; although the risks of nephrotoxicity with intravenous therapy were increased given the patient’s renal dysfunction and prior renal injury, it was recommended that he undergo IV induction treatment with the lipid formulation of amphotericin B, to be followed by oral fluconazole. After being fully informed of his diagnosis, the patient and his health care proxy refused treatment. He subsequently consented to oral therapy with fluconazole as an outpatient.

Pulmonary cryptococcal infection has been reported to occur within primary pulmonary malignancy (13). The possibility of a false negative biopsy in this case was considered. Close monitoring for radiographic resolution was recommended. Follow-up CT images have shown a significant decrease in the size of the pulmonary nodule and lymph nodes.

This case has been presented with the consent of the patient.

References

Mitchell TG, Perfect JR. Cryptococcosis in the era of AIDS--100 years after the discovery of Cryptococcus neoformans. Clin Microbiol Rev 1995;8(4):515-48.
Goldman DL, Khine H, Abadi J, et al. Serologic evidence for Cryptococcus neoformans infection in early childhood. Pediatrics 2001;107(5):E66.
Campbell GD. Primary pulmonary cryptococcosis. Am Rev Respir Dis 1966;94(2):236-43.
Lindell RM, Hartman TE, Nadrous HF, et al. Pulmonary cryptococcosis: CT findings in immunocompetent patients. Radiology 2005;236(1):326-31.
Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000;30(4):710-8.
Chang WC, Tzao C, Hsu HH, et al. Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients. Chest 2006;129(2):333-40.
Yamaguchi H, Ikemoto H, Watanabe K, et al. Fluconazole monotherapy for cryptococcosis in non-AIDS patients. Eur J Clin Microbiol Infect Dis 1996;15(10):787-92.
Kralovic SM, Rhodes JC. Utility of routine testing of bronchoalveolar lavage fluid for cryptococcal antigen. J Clin Microbiol 1998;36(10):3088-9.
Antinori S, Radice A, Galimberti L, et al. The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis. J Clin Microbiol 2005;43(11):5828-9.
Huang CJ, Yang MC, Ueng SH. Large cryptococcoma mimicking lung cancer in an HIV-negative, type 2 diabetic patient. J Thorac Imaging 2005;20(2):115-7.
Endo S, Saito N, Hasegawa T, et al. Pulmonary cryptococcosis mimicking pulmonary metastases in a patient treated with Tegafur-uracil after lung cancer surgery. Jpn J Thorac Cardiovasc Surg 2005;53(7):369-71.
Igai H, Gotoh M, Yokomise H. Computed tomography (CT) and positron emission tomography with [18F]fluoro-2-deoxy-D-glucose (FDG-PET) images of pulmonary cryptococcosis mimicking lung cancer. Eur J Cardiothorac Surg 2006;30(6):837-9.
Harada T, Hakuma N, Kamimura A, et al. Pulmonary cryptococcosis within a pulmonary carcinoma-review of reported cases. Intern Med 2006;45(6):369-72.

	A.	Adenocarcinoma of the lung Incorrect!
	B.	Small cell carcinoma Incorrect!
	C.	Cryptococcosis Correct!
	D.	Histoplasmososis Incorrect!
	E.	Blastomycosis Incorrect!

	A.	Platinum-based chemotherapy Incorrect!
	B.	Radiation therapy Incorrect!
	C.	Surgical resection of left upper lobe lung lesion Incorrect!
	D.	Antifungal therapy Correct!
	E.	Observation Incorrect!

Suspicion of Lung Cancer with Nodal Metastases in an Immunocompromised Patient

Submitted by

History

Physical Exam

Lab

Figures

Question 1

Question 2

References