Bronchioloalveolar Carcinoma in a Child With Congenital Cystic Adenomatoid Malformation*

patients to supply differentiating power. In the meantime, however, enhanced diagnostic suspicion and prolonged ther¬ apy with

therapy,

relatively nontoxic and potentially more effective such as itraconazole, may improve outcome. D,

References Huguenin T, Dharan S, et al. Unusual

cause of lethal pulmonary aspergillosis in patients with COPD. Am J Respir Crit Care Med 1996; 154:541-44 2 Seabury JH, Samuels M. The pathogenic spectrum of as¬ pergillosis. Am J Clin Pathol 1963; 40:21-33 3 Rosenberger M, Patterson R, Mintzer R, et al. Clinical and the diagnosis of allergic bronchopul¬ immunologic criteria for Ann Intern Med 1977; 86:405-14 monary aspergillosis. 4 Pervez NK, Kleinerman J, Kattan M, et al. Pseudomembra¬ nous necrotizing bronchial aspergillosis. Am Rev Respir Dis

1 Pittet

1985; 131:961-63 5 Gerson SL, Talbot GH, Hurwitz S, et al.

Prolonged granulo-

cytopenia: the major risk for invasive pulmonary aspergillosis

in acute leukemia. Ann Intern Med

1984; 100:345-51

Glimp RA, Bayer AS. Pulmonary aspergilloma: diagnostic and considerations. Arch Intern Med 1983; 143:303-08 therapeutic 7 Gefter WB, Weingrad TR, Epstein DM, et al. "Semi-inva¬ sive" pulmonary7 aspergillosis: a new look at the spectrum of Aspergillus infections of the lung. Radiology 1981; 140:313-21 8 Binder RE, Faling LJ, Pugatch RD, et al. Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. Medicine 1982; 61:109-24 9 Dupont B. Itraconazole therapy in aspergillosis: study in 49 patients. J Am Acad Dermatol 1990; 23:607-14 10 DeBuele K, De Doncker P, Cauwenbergh G, et al The treatment of aspergillosis and aspergilloma with itraconazole: clinical results of an open international study (1982-1987). 6

Mycoses 1988; 31:476-85

MA, Tortorano AM, Pagano A, et al. European experience with itraconazole in systemic mycoses. } Am Acad

11 Viviani

Dermatol 1990; 23:587-93 CA, Wilson KH, Schwartz DB. Necrotizing pul¬ monary aspergillosis with oxalosis. Mykosen 1984; 27:535-38 Caras WE, Pluss JL. Chronic necrotizing pulmonary aspergil¬ losis: pathologic outcome after itraconazole therapy. Mayo Clin Proc 1996; 71:25-30 Hargis JL, Bone RC, Stewart J, et al. Intracavitary amphoter¬ icin B in the treatment of symptomatic pulmonary aspergillomas. Am J Med 1980; 68:389-94 Kimmerling EA, Fedrick JA, Tenholder MF. Invasive as¬ pergillosis niger with fatal pulmonary oxalosis in chronic obstructive pulmonary disease. Chest 1992; 101:870-72 Bennet MR, Weinbaum DL, Fiehler PC. Chronic necrotizing pulmonary aspergillosis treated by endobronchial amphoter¬ icin B. South Med J 1990; 83:829-32 Elliot JA, Milne LJR, Cumming D. Chronic necrotizing pulmonary aspergillosis treated with itraconazole. Thorax

12 Kauffman

13 14

15 16 17

1989; 44:820-21 18 Thommi G, Bell G, Liu J, et al.

Spectrum of invasive pulmonary aspergillosis in immunocompetent patients with chronic ob¬ structive lung disease. South Med J 1991; 84:828-31 19 Hudson LD, Monti CM. Rationale and use of corticosteroids in chronic obstructive pulmonary disease. Med Clin N Am 1990; 74:661-90 20 Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev Infect Dis 1990; 12:308-29 21 Bodey GP. Antifungal agents. In: Bodey CP, ed. Candidiasis. 2nd ed. New York: Raven Press, 1993: 371-406 22 Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994; 330:263-72 '

'

548

23 24

Denning DW, Tucker RM, Hanson LH, et al. Treatment of aspergillosis with itraconazole. Am J Med 1989; 86:791-800 Klein NC, Cunha BA. New antifungal drugs for pulmonary invasive

mycoses. Chest 1996; 110:525-32

Bronchioloalveolar Carcinoma in a Child With Congenital Cystic Adenomatoid Malformation* Robert A. Kaslovsky, MD; Sheila Purdy, MD; Barbara C. Dangman, MD; Barbara ]. McKenna, MD; Thomas Brien, MD, and Riivo lives, MD

11-year-old girl was evaluated for chest pain, and radiographic findings of multiple nodules both lungs. She underwent resection of throughout several of the lesions from her left lung, which were found at pathologic examination to be bronchioloal¬ veolar carcinoma. Her previous medical history in¬ cluded incomplete resection of a type I congenital cystic adenomatoid malformation in the neonatal period. To our knowledge, this girl is the youngest reported case of bronchioloalveolar carcinoma in a nonimmunocompromised patient, and one of several in which the association of congenital cystic adeno¬ matoid malformation and An

chest

noma

has been observed.

bronchioloalveolar carci¬

(CHEST 1997; 112:548-51)

carcinoma; cystic adenomatoid Key words: bronchioloalveolar malformation; lung cancer Abbreviations: BAC=bronchioloalveolar carcinoma; CCAM congenital cystic adenomatoid malformation

=

~D ronchioloalveolar carcinoma (BAC) is a specific subtype of adenocarcinoma of the lung, which is seen primarily in adults. We recently made this diagnosis in an 11-year-old girl who was referred to the pediatric pul¬ monology practice because of chest pain and an abnormal -*-*

chest

radiograph.

Past Medical

The child

History

was

born

Case Report at 32

weeks'

gestation by spontaneous

vaginal delivery. By 2 min of age, she became limp, cyanotic, and bradycardic, and required intubation. After stabilization, a chest radiograph showed a cystic lesion in the right lung, with medi¬ astinal shift to the left (Fig 1). At surgery, the right upper lobe lesion had the appearance of a congenital cystic adenomatoid malformation (CCAM). There was also a small area of involve-

*From the Departments of Pediatrics, Pathology, Surgery, Albany Medical College, Albany, NY.

Radiology, and Manuscript received August 28, 1996; revision accepted January 8, 1997. Reprint requests: Robert A. Kaslovsky, MD, Associate Professor of Pediatrics, Albany Medical College A 112, 47 New Scotland Ave, Albany, NY 12208 Selected

Reports

ment of the superior segment of the right lower lobe by the malformation. A right upper lobectomy was performed, but the right lower lobe was left intact. The pathologic review of the right upper lobe (Fig 2) revealed multiple cysts lined by pseudostratified columnar epithelium with associated smooth muscle in the walls of the cysts, and foci of tall mucigenic columnar epithelial cells. The findings are typical of CCAM, type I.

History 2 weeks prior to her referral, the patient had Approximately been playing softball, slid into a base, and hit her left side on the ground. Left-sided chest pain persisted over several days. She was seen by her pediatrician who obtained a chest radiograph that showed multiple pulmonary nodules (Fig 3). A CT scan of the chest was done, which showed multiple noncavitary nodules in both lungs, varying in size from 1 to 18 mm in diameter, without associated calcification (Fig 4). By the time of her evaluation, her chest pain had disappeared, and she was asymptomatic. On examination she was alert and healthy appearing, and in no acute distress. Temperature was 36.7°C orally; pulse was 64/min; respiratory rate was 12/min; BP was 89/77 mm Hg; weight was 32.5 kg (50th percentile); and height was 85.75 cm (about 30th percentile). Findings from the chest examination were remarkable only for a right thoracotomy scar. Her lungs were clear. Results of cardiac examination were normal. Abdomen findings were unremarkable. Extremities showed 1 to 2+ digital clubbing, which was familial.

Present

Figure 2. CCAM type I with cysts lined by pseudostratified columnar epithelium, associated smooth muscle walls, and foci of mucigenic columnar cells (hematoxylin-eosin, original magnifica¬

tion

X200).

Because of concern about the possibility of metastatic disease secondary to a primary tumor in the abdomen, an abdominal ultrasound examination was performed. This did not reveal any evidence of a mass. A repeated chest radiograph suggested fewer nodules in the lungs. A CT scan of the chest was repeated 2 months after the initial one. There were still multiple noncavitary both lungs, not pulmonary' parenchymal nodules throughout significantly changed from the first study. The abdomen findings were unremarkable. The patient was unavailable for follow-up for several months. However, 7 months after initial presentation, resection of several of the lesions in her left lung was performed. She had an

uneventful postoperative

Figure 1. Chest radiograph taken in the neonatal period reveals

cystic mass in the right side of the chest, with mediastinal shift to the left, and atelectasis of the left lung. a

course,

and remains

asymptomatic.

Figure 3. Chest radiograph taken after the onset of chest pain reveals multiple nodules throughout both lungs. There is no evidence of traumatic injury.

CHEST/112/2/AUGUST, 1997

549

characterized by aerogenous dissemination. Mucinous BACs, in contrast to nonmucinous variants, are often larger

is

Figure 4. CT scan of the chest reveals multiple noncavitary nodules in both lungs, varying in size from 1 to 18 mm, without calcification.

Microscopic examination of the resected lung tissue showed multiple carcinomatous foci composed of tall, well-differentiated, mucus-secreting columnar cells, growing along intact alveolar

muciphages filling adjacent alveoli. These findings typical of BAC, mucinous type (Fig 5).

septae, with

are

Discussion BAC has several distinguishing features. With an inci¬ dence that varies from 1 to 5% of all lung carcinomas,1 BAC is more slow growing than other lung cancers, sometimes with a long period of dormancy before the histologic diagno¬ sis is made. Over 50% of BACs present as asymptomatic solitary peripheral nodules, often as incidental findings on chest radiographs taken for some other reason.2 In contrast to other types of pulmonary adenocarcinomas, growth of BAC

and more widely disseminated.1 In a recent review, Barsky et al3 reported the incidence of BAC to have risen from <5% of all lung cancers in the 1950s to 24% in the 1990s. Twenty-five percent of patients with BAC had multifocal lesions, in contrast with 5% of patients with other types of lung cancer. The mean age of their BAC patients was younger than those with non-BAC lung cancers (59.2±11.5 years vs 64.1 ±13.5 years; p<0.05). The youngest reported patient in the literature is a 7-year-old girl from Poland, following extensive chemo¬ and radiation therapy for Hodgkin's disease.4 therapy In one large series of BAC,5 survival for patients with T1N0M0 neoplasms was 90.5% at 5 years, 55.4% for patients with T2N0M0 disease, only 35.9% for patients with multiple unilateral disease, and 0.0% for patients with bilateral disease. Early aggressive resection offers the potential for cure in patients with solitary peripheral nodules. The presence of bilateral disease is ominous. There are several case reports of an association between CCAM and BAC dating back to 1953.68 To our knowledge, our patient is now the youngest reported case of BAC in association with CCAM. Although she had resection of a right upper lobe CCAM in infancy, a small portion of the malformation in the right lower lobe was not removed. The epithelial cells of the malformation may have slowly prolifer¬ ated and become malignant, leading to development of BAC. Type I CCAM consists of multiple large epithelial-lined cysts, smooth muscle, elastic tissue, and in about one third of cases, mucus-producing cells are evident.9*10 The man¬ ner in which CCAM may predispose to the development of BAC is not known, but raises interesting pathogenetic possibilities. Unstable epithelium in an unresected malfor¬ mation may be more susceptible to proliferation and oncogenesis. Sheffield et al11 described premalignant changes in type I CCAM containing mucus cells. Based on our experience and a review of the literature, it may be prudent to recommend complete resection of any cystic adenomatoid malformation. The exact age at which this should be done is unclear, but because of our experience in this 11-year-old patient, it appears that it should be per¬ formed in early childhood. Pediatricians and surgeons should be aware of the potential for BAC to arise in association with unresected cystic adenomatoid malformation of the lung.

References

1

Figure 5.

BAC,

mucinous

type. Well-differentiated

mucinous

epithelium growing along alveolar walls (hematoxylin-eosin, orig¬ inal magnification X400). 550

Colby TV, Koss MN, Travis WD. Atlas of tumor pathology: tumors of the lower respiratory tract. Bethesda, Md: Armed

Forces Institute of Pathology, 1995; 203-34 2 Greco RJ, Steiner RM, Goldman S, et al. Bronchoalveolar cell carcinoma of the lung. Ann Thorac Surg 1986; 41:652-56 3 Barsky SH, Cameron R, Ossann KE, et al. Rising incidence of bronchioloalveolar lung carcinoma and its unique clinicopath¬ ologic features. Cancer 1994; 73:1163-70 4 Kowalski P, Rodziewicz R, Pejcz J. Bilateral bronchioloalveo¬ lar carcinoma of the lungs in a 7 year old girl treated for Hodgkin's disease. Tumori 1989; 75:449-51 5 Daly RC, Trastek VF, Pairolero PC, et al. Bronchoalveolar carcinoma: factors affecting survival. Ann Thorac Surg 1991; 51:368-77 6 Korol E. The correlation of carcinoma and congenital cystic Selected

Reports

emphysema of the lungs: report of 10 cases. Dis Chest 1953;

23:403-11

Copin MC, Soots JG, et al. Bronchioloalveolar carcinoma and congenital cystic adenomatoid malformation. Ann Thorac Surg 1995; 60:1126-28 8 Benjamin DR, Cahill JL. Bronchioloalveolar carcinoma of the lung and congenital cystic adenomatoid malformation. Am J Clin Pathol 1991; 95:889-92 9 Stocker JT, Drake RM, Madewell JE. Cystic and congenital lung disease in the newborn. In: Rosenberg H, Bolande R, eds. Perspectives in pediatric pathology, Chicago: Year Book Medical Publishers, 1978; 93-154 10 Parodi-Hueck L, Densler JF, Reed RC, et al. Congenital 7 Ribet ME,

cystic

11

adenomatoid malformation of the

lung.

Clin Pediatr

1979; 8:327-30 Sheffield EA, Addis BJ, Corrin B, et al. Epithelial hyperplasia and malignant change in congenital lung cysts. Clin Pathol 1987; 40:612-14

Primary Pulmonary Hypertension in a Patient With CD8/T-cell Large Granulocyte Leukemia*

Amelioration Leonard J. Morton

by Cladribine Therapy

Rossoff, MD; Joseph Genovese, DO, FCCP;

Coleman, MD; and David R. Dantzker, MD, FCCP

We report a case of primary pulmonary hypertension in an adult man with CD8/T-cell large granulocyte

leukemia. Successful treatment of his leukemia with cladribine resulted in dramatic and sustained im¬ provement of his pulmonary hypertension.

(CHEST 1997; 112:551-53) Key words: CD8/T-cell granulocyte leukemia; chronic granulo¬ cyte leukemia; cladribine; primary pulmonary' hypertension Abbreviations: Hct=hematocrit; PPH=primary pulmonary hy¬ pertension; RV=right ventricle

pulmonary hypertension (PPH) is a progressive "P rimary and lethal disease of unknown It is -¦-

usually

etiology.

characterized by pulmonary hypertension (mean pulmo¬ nary artery pressure at rest >25 mm Hg and >30 mm Hg with exercise) secondary to the narrowing or obliteration of resistance pulmonary arteries.13 We report a unique case of an adult man with a rare CD8/T-cell large granulocyte leukemia who developed PPH. He had no evidence of any other disease recognized *From the Division of Pulmonary and Critical Care Medicine, Department of Medicine (Drs. Rossoff, Genovese, and Dantz¬ ker), Long Island Jewish Medical Center, New Hyde Park, NY; and the Division of Hematology, (Dr. Coleman), New York Medical Center, New York. Hospital/Cornell received October 21, 1996; revision accepted January Manuscript 22, 1997.

Reprint requests: Leonard}. Rossoff, MD, Division of Pulmonary

and Critical Care Medicine, Room C-20, Long Island Jewish Medical Center, 270-05 76th Ave, New Hyde Park, NY 11042

as a

secondary cause of pulmonary hypertension.39 Suc¬ of his leukemia coincided with improvement of his PPH. Case Report

cessful matic

treatment

a

dra¬

A 39-year-old white man presented with complaints of palpi¬ tations and near syncope. He was well until age 22 years when he

was found to have a right lower lobe pneumonia with a purified protein derivative of 20 mm induration. The biopsy specimen of a single enlarged cervical lymph node demonstrated caseating granulomas. Acid-fast smear and culture were negative. He

received 14 months of isoniazid and ethambutol therapy that was discontinued when his hematocrit (Hct) fell to 26% (baseline, 41%). Results of a bone marrow examination and liver biopsy at that time were reportedly normal. He remained asymptomatic for 4 years when his anemia worsened (Hct, 17%) and he developed splenomegaly. The pathology report following sple-

nectomy was interpreted as showing lymphoid hyperplasia. A biopsy specimen of the liver was normal and results of the bone marrow examination were consistent with dyserythropoiesis. Fifteen years later, his Hct was 24%, leukocyte count was 12,500/mm3 with 82% lymphocytes, and platelet count was 242,000/mm3. The peripheral blood had a predominance of large granular lymphocytes with the phenotype CD2, CD3, CD5, CD8, and CD57. Rearrangement of the T-cell P-chain receptor gene, however, was not demonstrated. A bone marrow biopsy specimen revealed an infiltration of small lymphocytes which were marked as T cells. A diagnosis of CD8/T-cell large granu¬ locyte leukemia was made. He denied all risk factors for and tested negative for HIV on multiple occasions. Tests for HTLV-1 and HTLV-2 were also negative. Two years later, the patient developed near-syncope and was found on an ECG to have right axis deviation and the pattern of right ventricular (RV) strain. An initial two-dimensional, Doppler echocardiogram revealed severe right atrial and RV dilation with significant paradoxical septal motion and tricuspid regurgitation (Table 1). The pulmonary artery pressure was estimated at 110 mm Hg. On catheterization, the pulmonary7 systolic pressure was approximately 90 mm Hg with a pulmonary vascular resistance of 369 dyne s cm~° (Table 2). A ventilation-perfusion scan was interpreted as low probability for a pulmonary embolism with multiple bilateral subpleural shallow perfusion defects.10 A wedge biopsy specimen of the right middle lobe revealed severe pulmonary arteriopathy characteristic of PPH. Extensive vascular medial smooth muscle hypertrophy, duplication of the elastic lamina, and plexogenic changes with intimal lesions predomi¬ of the .

.

nantly

acellular eccentric and nonlaminar concentric type demonstrated. A few vessels also contained the concentric laminar intimal fibrosis.4 Right heart catheterization repeated to evaluate the response to sublingual nifedipine demonstrated a 35% reduction in pulmonary vascular resistance with a 40-mg cumulative dose (Table 2). He was discharged from the hospital on a dose of 120 mg long-acting nifedipine per day and subse¬ quently started on a regimen of warfarin sodium (Coumadin). Chemotherapy was initiated with 2-chlorodeoxyadine (cladrib¬ ine), 0.12 mg/kg infused over 2 h daily for 5 days every 5 weeks for a total of six cycles. Following completion of therapy, the bone marrow was somewhat hypocellular, but the patient had no evidence of lymphoproliferative disease confirmed by flow cytometry and DNA analysis. The CBC count and differential count became normal. His exercise tolerance improved dramat¬ ically and nifedipine therapy was tapered and discontinued. Warfarin therapy had been discontinued just prior to cladribine were

therapy. Three years following therapy echocardiography (Table 1), cardiopulmonary incremental exercise testing, and hemodyCHEST / 112 / 2 / AUGUST, 1997

551