T-cell Large Granulocyte Leukemia*

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

Table

1.Echocardiographic Reports*

Date

RA Dimension

RV Dimension

10/13/93 1/20/94 12/20/94

Moderate dilation Marked dilation Moderate dilation Mild dilation Normal

Marked dilation Marked dilation Marked dilation Mild dilation Mild dilation

6/26/95 10/30/95

Paradoxical

Septal Motion

namic variables

Absent Absent

.

.

Discussion PPH is, bv definition, a disorder without identifiable pulmonary arteriopathy involves the etiology. The associated muscular arteries and arterioles with three subtypes identi¬ fied on the basis of the predominating vascular lesion.11-12 in all forms of Pulmonary artery medial hypertrophy is foundassociated with pulmonary hypertension, rarely alone, usually other vascular lesions.3-411 Plexogenic pulmonary arteriopa¬ thy is recognized to occur in both the primary and secondary forms of PPH and is the most frequent type of arteriopa¬ thy.4'713 It is characterized by medial hypertrophy and de¬ structive lesions of the intima and entire wall of the artery.5'14 Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis in the presence of medial hypertrophy of the small arteries and arterioles. This patient's biopsy specimen revealed an arteriopathy with destructive elements of all these patterns. Recent case reports suggest an increased incidence of PPH in HIV-positive patients.715 Many of these, but not all, had risk factors for secondary pulmonary hypertension such as IV drugs or long-term factor VIII use. Most patients had low CD4 counts and inverted CD4/CD8 ratios. In those with normal CD4 counts, the CD4/CD8 ratio was reduced in the only case in which it was reported.16 This reflects a relative or absolute excess of CD8 cells. The pathophysiologic state of PPH is unclear, but the invariable involvement of the intima has suggested a role for the pulmonary vascular endothelium.17 Recently, spec¬ ulation has encompassed the role of prostacyclin, endoTable

mm

Hg

110 110 41

N/Af N/Af

thelium-derived nitric oxide and hyperpolarizing factor, endothelin, and platelets, but the mechanism remains unknown.18 In HIV-infected patients, there has been speculation of primary infection of the vascular endothe¬ lium; however, a recent study failed to demonstrate HIV particles in the pulmonary endothelium of these patients.7 A growth factor has been identified, elaborated by retrovirus-infected T cells, that stimulates and supports the growth of human vascular endothelial cells in cell cul¬ ture.19 Endothelial cells have been shown to elicit proliferative and cytotoxic responses by lymphocytes and secrete soluble antigens and other factors with immunoregulatory activity.20 CD8 cells also express functional interleukin-2 receptors on recognition of endothelial cellspecific antigens.21 It is thus conceivable that a modifica¬ tion of the endothelial cell-CD8/T-cell interaction in this rare leukemia and in HIV infection might directly or indirectly result in the endothelial dysfunction and the of PPH. The mechanisms of this interaction development remain unclear. Our patient demonstrated severe pulmonary hyperten¬ sion with all diagnostic studies highly characteristic of PPH. The finding of both an absolute and relative excess of CD8 to CD4 cells, similar to that seen in patients infected with HIV, was intriguing in this individual who remains without any evidence of retroviral infection or any secondary cause of pulmonary hypertension. This may be coincidental or suggest a pathophysiologic role of the CD 8/T-cell in the development of PPH. The dramatic improvement with treatment suggests that the process can be reversed to a great extent. The patient is now 3 years into remission of and has shown marked regression of his PPH without the need for vasodilator therapy. This is all

(Table 2) showed dramatic improvement. The s cm-5 without

pulmonary vascular resistance fell to 240 dyne nifedipine (65% of baseline).

Estimated PAP,

Moderate Moderate Mild Not detected Not detected

Present Present Present

atrial; PAP.pulmonary arteiy pressure. *RA=right f N/A=not able to estimate as no tricuspid regurgitation was detected.

Tricuspid Regurgitation

With Initial Effects of Nifedipine and After Induction of Clinical 2.Hemodynamic Variables* at Baseline, Remission of Leukemia

Time

Baseline lh 2h

Remissionf

Cumulative Oral Dose of Nifedipine, mg 0 20 40 0

mm

Hg

MPAP, RA, CO, mL/min Hg

mm

59 48 41 35

10.6 12.6 11.2

dyne

PVR, MAP, s cm-5 .

mm

.

Hg

79 71 69 86

369 243 214 240

pulmonary artery pressure; CO=cardiac output; PVR=pulmonary vascular resistance; MAP=mean f Denotes measurements made 36 months after initiation of chemotherapy without any vasodilators.

^RA^right atrial pressure; arterial pressure.

552

MPAP=mean

Selected

Reports

dramatic as spontaneous regression of PPH has been clearly documented and the median overall survival in PPH is only 2.8 years from time of diagnosis (National Institutes of Health Registry). The expected median survival is only 6 months in a functional class IV patient such as ours.22 Also unusual is the sustained complete (marrow) remission with six cycles of cladribine. A variety of regimens in this leukemia have had variable success but this patient remains disease free in excess of 2 years without any treatment.23 Cladribine has rarely been used for more than three or four cycles. This patient tolerated six widely spaced (5 weeks) cycles without significant complications or need for hospitalization. Fi¬ and hemodynamic nally, the coincidence of hematologic between the CD8/ a improvement suggests relationship T-cell and pulmonary vascular endothelium and smooth muscle. The failure to reverse the pulmonary vascular resistance to normal is likely a result of permanent loss of pulmonary vascular cross-sectional area. the

more

17

never

References

S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension.a national prospective study. Ann Intern Med

1 Rich

1987; 107:216-23

2 Reid LM. Structure and function in pulmonary hypertension:

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3 Reeves 4

a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163-84 5 Kay MJ, Heath D. Pathologic study of unexplained pulmo¬ nary hypertension. Hum Pathol 1985; 7:180-92 6 Pietra GG, Riittner JR. Specificity of pulmonary vascular lesions in primary pulmonary hypertension. Respiration 1987; 52:81-85 7 Mette SA, Palevsky HI, Pietra GG, et al. Primary pulmonary hypertension in association with human immunodeficiency virus infection: a possible viral etiology for some forms of hypertensive arteriopathy. Am Rev Respir Dis 1992; 145:1196-1200

tension:

8 Turner Stokes L, Turner Warwick M. Intrathoracic manifes¬ tation of SLD. Clin Rheum Dis 1982; 8:119-242 9 Tabuenco JM. Toxic oil syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet 1981; 2:567-68 10 D'Alonzo GE, Bower JS, Dantzker DR. Differentiation of

patients with primary7 and thromboembolic pulmonary hyper¬

1984';

85:457-61 tension. Chest 11 Pietra GG, Edwards WD, Kay

JM, et al. Histopathology of pulmonary hypertension: qualitative and quantitative study of pulmonary blood vessels from 58 patients in National Heart, Lung, and Blood Institute, Primary Pulmonary Hyper¬ tension Registry. Circulation 1989; 80:1198-1206 Pietra GG. Histopathology of primary pulmonary hyperten¬ sion. Chest 1994; 105:2S-6S Palevsky HI, Schloo BL, Petra GO, et al. Primary' pulmonary7 a

12 13

hypertension:

vascular structure,

morphology,

and respon¬

siveness to vasodilator agents. Circulation 1989; 80:1207-21 14 Burke AP, Far A, Venin R. The pathology of primary pulmonary hypertension. Mod Pathol 1991; 4:269-82 15 Speich R, Jenni R, Opravil M, et al. Primary pulmonary hypertension in HIV infection. Chest 1991; 100:1268-71 16 Jacques C, Richmond G, Tierney L, et al. Primary pulmonary hypertension and human immunodeficiency virus infection in a non-hemophiliac man. Hum Pathol 1992; 23:191-94

18 19

Meyrick B, Reid L. Development of pulmonary arterial changes in rats fed Crotaloria spectabilis. Am J Pathol 1979; 94:37-51 Higenbottam T. Pathophysiology of pulmonary hypertension: a role for endothelial dysfunction. Chest 1994; 105:7S-12S Nakamura S, Salahuddin SZ, Biberfeld P, et al. Kaposi's sarcoma cells: long-term culture with growth factor from 242: retrovirus-infected CD4+ T cells. Science 1988;

426-30

20 Pardi R, Bender JR. Signal requirements for the generation of CD4+ and CD8+ T cell responses to human allogeneic microvascular endothelium. Circ Res 1991; 69:1269-79 21 Mizuochi T, McKean DJ, Singer A. IL-1 as a cofactor for lymphokine-secreting CD8+ murine T cells. J Immunol

1988; 141:1571-77 22 D'Alonzo GE, Barst

RJ, Ayres SM, et al. Survival in patients with primary pulmonary7 hypertension. Ann Intern Med 1991;

23

115:343-49

Laughan JP, Kidd PG, Starkenbaum G. Treatment of large granular lymphocte leukemia with oral low-dose methotrex¬ ate.

Blood 1994; 84:2164-70

Hyperplasia of Pulmonary Neuroendocrine Cells in a Case of Childhood Pulmonary Emphysema* Mohammed Alshehri, MBBS; Ernest Cutz, MD;

Angelika Banzhoff, MD; and Gerard Canny, MBBS is very uncommon in chil¬ Pulmonary emphysema in first of life.

dren the decade documented in the literature

The few cases all due to o^antitrypsin deficiency. We present the case of a 6-year-old white boy with chronic cough and dys¬ pnea on exertion. Lung biopsy showed panacinar type emphysema with patent airways and diffuse hyperplasia of pulmonary neuroendocrine cells re¬ vealed after immunostaining for bombesin, a peptide produced by these cells. We speculate that idiopathic diffuse hyperplasia of bombesin-producing pulmo¬ nary neuroendocrine cells may contribute to the pathogenesis of unusual COPD in childhood. were

(CHEST 1997; 112:553-56)

Key words: cq-antitrypsin deficiency; panacinar emphysema "C1 mphysema is an anatomical diagnosis, defined as an abnormal permanent enlargement of the air spaces -"

distal to the terminal bronchioles accompanied by destruc¬ tion of the alveolar walls without obvious fibrosis.1 It can be divided into proximal acinar emphysema, as occurs in *From the Division of Respiratory- Medicine, Department of Paediatrics, and Department of Pathology, the Hospital for Sick

Children, Toronto, Canada.

Manuscript received September 23, 1996; revision accepted February7 5, 1997. Mohammed Alshehri, MBBS, 28 Elm StreetReprint requests: Apt. 2403, Toronto, Ontario, Canada M5G 2K5 CHEST/112/2/AUGUST, 1997

553