Case of the Season

Jordan Page, Denzil Hawes-Davis, Randall Mitchem, and Michael S. Severance

A 75-YEAR-OLD white man presented to his primary care physician with complaint of recent-

onset nonproductive cough with fever. A chest radio- graph was obtained and is shown below (Fig 1). Empiric antibiotic therapy was initiated with irlstmc- tion8 for foUow-up. At 2 weeks, some improvement in symptoms was reported; however, repeat chest radio-

From the Department of Radiology, Capital Region Medical Centeg Jefferson City, MO.

Address reprint requests to Denzil Hawes-Davis, DO, Depart- ment of Radiology, Capital Region Medical Centeg 1125 Madison, Jefferson City, MO 65101.

Copyright © 1999 by W.B. Saunders Company 0037-198X/99/3403-0003510.00/0

l

Fig 1, Initial PA and lateral chest roentgenogram reveals a 3,5-cm ill-defined ovoid density in the right lower lobe. A few small scattered calcified granulomas can be seen bilaterally. No distinct hilar adenopathy is noted,

Fig 2. Ten-millimeter post-contrast axial images of the chest were obtained with representative slices shown. (A) Soft-tissue window demonstrates a 3,5 x 2.8 cm irregular and enhancing mass in the right posterior basilar segment that extends to the pleura. (B) Soft-tissue window through the level of the aortopulmonic window reveals multiple precarinal lymph nodes measuring 5 to 8 mm in size.

Seminars in Roentgenology, Vol XXXIV, No 3 (Jury), 1999: pp 165-168 165

166 PAGE ET AL

Fig 3. Although difficult to see and poorly reproducible, lung windowing demonstrates numerous micronodules in a diffuse and uniform arrangement that extend out to the pleural surface. These measure approximately 1 to 3 mm in size,

graph showed no signfiicant interval change. In view of a marked smoking history and a previous diagnosis of prostate and bladder carcinoma, further delineation of the right lower lobe process was thought necessary. Computed tomography of the thorax (Fig 2) with image-guided biopsy was scheduled.

DISCUSSION

CT-guided biopsy was complicated by pneumotho- rax and failure to obtain adequate sample. The patient was admitted for overnight observation and seen in consultation by cardiothoracic surgery for consider- ation of open lung biopsy. Video-assisted thoracoscopy followed by minithoracotomy with fight lower lobe wedge resection and mediastinoscopy with node dissec- tion were performed. Intraoperative findings included diffuse palpable 2- to 3-mm micronodules throughout the deflated lung and a rubbery 3.5-cm right lower lobe mass as well as large pleural nodes in the paratracheal regions. Frozen sections demonstrated hyperplastic, inflammatory, and granulomatous changes in both the resected mass and multiple mediastinal nodes. There was no evidence of malignancy. Supplementary hilar and subcarinal nodal dissection was carried out, and additional wedge resection was obtained for culture. Pulmonology was consulted for further elucidation and management of these unexpected benign findings.

Patient history revealed no remarkable work or travel history and no known exposure to infectious disease. Of note was that the patient underwent one course of intravesicle bacillus Calmette-Guerin (BCG) treatment for transitional cell carcinoma of the bladder 2 years earlier with resultant clinical remission of disease. However, follow up 3 to 4

months before this admission had revealed recur- rent dysplasia that prompted an additional course of intravesicle BCG immunotherapy. The patient expe- rienced transient episodes of cystitis and fever following both courses that had resolved with appropriate treatment.

Extensive laboratory and microbiology workup, including mycobacterial and fungal cultures, failed to reveal an obvious infectious, inflammatory, o1" autoim- mune origin. Final pathology report revealed lymph nodes with "hylanized granulomas" and lung tissue with "focal necrotizing granulomatous inflammation with organization." Acid-fast bacillus (AFB) and Go- mori-methenamine-silver (GMS) stain results were negative for acid fast and fungal organisms, respec- tively. Purified protein derivative (PPD) skin test was rapidly reactive at 17 ram. Deliberate reevaluation of the original radiographic studies revealed a subtle miliary pattern on chest CT, which was not eluded to on initial interpretation and difficult to see even in retro- spect (Fig 3 poorly reproducible). However, this find- ing in the context of the available medical history and clinical data as well as the surgical and histopathologi- cal findings, prompted a rather interesting diagnosis of exclusion.

The subtle finding of micronodular disease was established subsequent to the diagnosis of benign disease. High-resolution computed tomography (HRCT) would surely have allowed clearer recognition and characterization of this process, although it was not obtained. The parenchymal mass and associated ad- enopathy were thought to be representative of a malig- nant process, and the potential for benign disease was not fully considered.

Micronodules are sharply marginated 1- to 3-ram rounded opacities that represent conglomerates of granulomas or minor cells and are most readily demon- strated on HRCT.1 The broad differential for micronodu- lar interstitial disease encompasses inhalational, granu- lomatous, infectious, and metastatic processes. A working diferenfial should include sarcoidosis, histio- cystosis X, silicosis, miliary tuberculosis, fungal dis- ease, hematogenous metastasis, and lymphangitic car- cinomatosis. A perilymphatic, centrilobular, or random micronodular distributive pattern on HRCT may be used to further characterize these diseases.2 The micro- nodular pattern in this case was uniformly diffuse extending out to the pleural surface. This arrangement is indicative of a random-type distribution. Miliary tuberculosis and hematogenous metastasis are most typical of this pattern. 2

CASE OF THE SEASON 167

DIAGNOSIS

Miliary Pulmonary GranuIomatous Disease Secondary to BCG Immunotherapy

BCG is a live attenuated strain of Mycobacte- rium boris rendered less virulent through serial

passage in culture. It has traditionally been used for vaccination against M. tuberculosis in areas where

disease prevalence is high. More recently, the local

antitumor effects of BCG in the treatment of certain malignancies has been recognized. 3,4

BCG was first used intravesically in 1976. 5

Subsequent studies have documented high rates of remission and long disease-free intervals as well as superiority over other intravesicle chemotherapeu- tic agents. 6-8 Antitumor effects are dependent on

attachment of the bacillus to the damaged bladder

wall with subsequent elicitation of a cell-mediated immune response. 9,1° The resulting cytokine-

dependent cytotoxic and phagocytic cellular envi-

ronment probably confers incidental toxicity on adjacent malignant cells.

Although highly effective, this treatment is not free of potential complications. Lamm et al, 11 in a

study of 1,278 patients, reported cystitis in 91%, fever in 3.9%, and granulomatous prostatitis in 1.35%. More significant systemic complications including pneumonitis, hepatitis, arthritis, and cyto-

penia occurred in less than 1%. ~ Current practice dictates early treatment of complications according to severity. 6,12 A small number of patients have

died, presumably as a result of overwhelming systemic BCG infection, sepsis, or anaphylaxis. 11

The pathogenesis of systemic complications has not been definitively determined. Active infection due to dissemination of live organisms and hyper- sensitivity to antigenic components may be poten- tial causes. Infection implies the ability to demon- strate viable organisms through culture, and thus hypersensitivity would seem logical in their appar- ent absence. Pulmonary tuberculosis via hematog- enous spread of BCG 13 and M. boris grown in tissue culture from BCG induced granulomatous hepatitis 14 have been reported. However, previous work by the same investigators documented inabil- ity to recover organisms from BCG induced hepatic granulomas. 15 Israel-Biet et aP 6 demonstrated marked lymphcytosis with predominately T helper cells highly sensitized to PPD from bronchoalveo- lar lavage in two culture-negative patients with interstitial pneumonitis as a complication of BCG. Perhaps the impetus to label these reactions as infection versus hypersensitivity reactions is inap- propriate. Indeed, the type and severity of these reactions appears to correlate most with the pres- ence and magnitude of mycobacteria or mycobacte- rial antigens in the blood, 17 and ultimately remote organs, independent of culture. Furthermore, pro- vided the pathogenic burden is not sufficiently severe to result in overwhelming infection, the expected immune response would be type IV hypersensitivity consistent with the well-docu- mented pathogenic model for M. tuberculosis infec- tion.

REFERENCES

1. Klein JS, Fischbein NJ: Fundamentals of diagnostic radiol- ogy, in Bratand WE, Helms, CA (eds): The Lung. Baltimore, Williams and Wilkins, pp 412-494, 1994

2. Webb WR: Fundamentals of body CT, in Webb WR, Brant WE, Helms CA (eds): Lung Disease, Philadelphia, WB Saun- ders, pp 107-146, 1998

3. Gutterman JU, Mavligit G, McBride C, et aI: Active immunotherapy with BCG for recurrent malignant melanoma. Lancet 1:1208, 1973

4. Bast RC, Zbar B, Boros T, et al: BCG and cancer. N Engl J Med 290:1413, 1974

5. Morales A, Eidinger D, Bruce AW: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. JUrol 116-180, 1976

6. Brosman SA: The use of bacillus Calmette-Guerin in the therapy of bladder carcinoma in situ. J Urol 134:36, 1984

7. Lamm DL: Bacillus Calmette-Guerin immunotherapy for bladder cancer. J Urol 134:40, 1985

8. Netto Jr NR, Lemos GC: A comparison of treatment methods for the prophylaxis of superficial bladder tumors. J Urol 129:33, 1983

9. Ratliff TL, Palmer JO, McGarr JA, et al: Intravesicle bacillus Calmette-Guerin therapy for murine bladder tumors: Initiation of the response by fibronectin-mediated attachment of bacillus Calmette-Guerin. Cancer Res 47:1762, 1987

10. Zbar B, Bernstein ID, Rapp HJ: Suppression of tumor growth at the site of infection with living bacillus Calmett- Guerin. J Natl Cancer Inst 46:831, 1971

11. Lamm DL, Stogdill VD, Stogdill B J, et al: Complications of bacillus Calmette-Guefin immunotherapy in 1,278 patients with bladder cancer. J Urol 135:272, 1986

12. Knokol SC, Dehaven JI, Riggs DR, et al: Drag therapy of bacillus Calmette-Guerin sepsis. Urol Res 22:373, 1995

13. Narks J, Jenkins PA, Kilpatrick GS, et al: Pulmonary tuberculosis due to BCG. BMJ 3:229, 1971

14. Hunt JS, Silverstein MJ, Sparks FC, et al: Granulomatous

168 PAGE ET AL

hepatitis: A complication of BCG immunotherapy. Cancer 46:1759, 1980

15. Hunt JS, Silverstein MJ, Sparks FC, etal: Granulomatous hepatitis: A complication of BCG immunotherapy. Lancet 2:820, 1973

16. Israel-Biet D, Sandron VD, Ziza JM, et al: Pulmonary

complications of intravesicle Baccile Calmette-Guerin immuno- therapy. Am Rev Respir Dis 135:763, 1987

17. Tuncer S, Tekin MI, Ozen H, et al: Detection of bacillus Calmette-Guerin in the blood by the polymerase chain reaction method of treated bladder cancer patients. J Urol 158:2109, 1997