Vol. 68, No. 1

Pulmonary Leiomyomatosis, A Rare Cause of Miliary Infiltrates Report of Two Cases DOROTHY A. JAMERSON, M.D.,* Resident in Anesthesiology, ROBERT L. SIMMONS, M.D., Associate Professor of Surgery and Chief, Division of Thoracic Surgery,

ROSCOE C. YOUNG, JR., M.D., Associate Professor of Medicine and Director, Harden Pulmonary Laboratory, CALVIN C. SAMPSON, M.D., Professor of Pathology,

Howard University Hospital and College of Medicine, Washington, D.C.

OVER 100 different causes of miliary lesions of the lungs exist, and leiomyomatosis, although rare, must be added to the differential diagnosis of miliary lesions. Because of its rarity, the diagnosis often comes as a surprise to the physician following lung biopsy for disseminated pulmonary lesions by chest radiography. These tumorlets, benign in microscopic appearance,.are presumed malignant in behavior, indeed an ambiguous appellation. The first case of. leiomyomatosis of the lungs was reported in 1889 by Krische1. The second and third were reported by Langerhans and Minkowski in 1893 and 1901, respectively.2'3 According to Valensi,4 only 50 cases had been reported up to 1973. The amount of disability in these case reports has varied from none on one hand5-7 to severe on the other, causing disability and death from pulmonary insufficiency.8 The paucity of physiologic studies in this disease is noteworthy, having been reported in only a few cases.7'9' 10

Case No. 1. K.A.B. (#359-803) is a 37-year-old woman on the President's Council on Physical Fitness who was referred because of an abnormal chest radiograph (Fig. 1) discovered during hospitalization for oophorectomy for a benign ovarian cyst. She denied respiratory symptoms. Bronchoscopy and scalene node biopsy were negative. An open lung biopsy was performed. Approximately six years prior to evaluation, she had the "flu" followed by anosmia for which she was treated elsewhere. At that time, her chest radiograph was normal. As a teenager, she had a thyroidectomy for a "goiter". Approximately five years ago, she had a myomectomy elsewhere for benign uterine fibroids which were histologically benign. She is a para II, gravida II and an ex-cigarette smoker. Currently, she has a recurrence of her uterine

*Work done during senior student medical elective.

fibroids. Physical examination was essentially negative and routine laboratory work was normal.

The purpose of the present communication is to report two additional cases of pulmonary leiomyomatosis with pulmonary function studies and provide objective measurements of variability of disability that may occur in these patients. Both patients were women who had previous benign fibroids of the uterus documented by previous myomectomy or hysterectomy. Both patients also had thyroid disease. CASE REPORTS

JANUARY, 1976

JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

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Table 1. PULMONARY FUNCTION TESTS* Initial

STATIC LUNG VOLUME (L) IC (L) ERV (L) VC (L) FRC VTG at FRC (L) LUNG MECHANICS FVC (L) FEVi/FVC x 100 FEV3/FVC x 100

1.45 0.97 2.42 2.05 2.91

Case I 16 Mos. Later

(68)+ (91) (76) (81)

Case 2

1.43 (75) 0.82 (65)

2.38 (140) 0.61 (72)

2.25 (70) 1.74 (62)

2.99 (117) 2.70 (106)

static lung volumes compatible with restrictive lung disease (Fig. 2). Disease of small peripheral airways was absent as shown by a normal closing volume test. Alveolar ventilation, however, became more uniform but diffusing capacity was not significantly changed. Oxygen tensions at rest increased slightly however.

Table 2. PULMONARY FUNCTION TESTS Initial

2.05 80 90

2.25 80 94

2.99 67 85 177 177

MIFR200-12ooL/min

MEFR200-12ooL/min MMF L/Sec MVV L/niin CLdyn L/cmH20 CLSP cmlH.,O-'

-

1.8 90.8 (96) 0.07 0.04 0.18

SGAWcmH2O0'Sec_'

2.03 89 (95)

*Pappenheimer, J. R. Fed. Proc., 9:602-605, 1950. Gandevia, B. and P. HughJones. Thorax, 12: 290, 1957. + Percent of predicted.

Pulmonary function tests are shown in Tables 1 and 2. Initially, VC and FVC were slightly decreased. The %FEVt, %FEV3 and MVV were normal. Transfer factor for carbon monoxide was slightly decreased. There was inhomogeneity of inspired gases as noted by an abnormal single breath 02 test of alveolar gas uniformity. Specific lung compliance was normal. Specific airways conductance measured in the body box

both..lung;fields , :.:..i'.. ....^.

ALVEOLAR GAS UNIFORMITY N2 DELTA % 7' N2 WASHOUT% % CV/VC GAS TRANSFER DLCO ml/min/ mmHg K min ARTERIAL BLOOD GAS Sao2 % Pao2 mmHg Torr Paco2 mmHg Torr pH

16 (105) 14 (78)+ -

8 (35)

15 (76) 3.92

Rest

Rest

Rest

95

96

91

81 43 7.39

85 35 7.41

64 28 7.47

Ex 48

100% 02 -

555

-

35

-

-

+ Percent of predicted.

PATHOLOGICAL FINDINGS The lung biopsy consisted of a nondescript piece of firm and somewhat spongy tissue measuring 2 x 1.3 x 0.3 cm. It contained several firm homogeneous nodules ranging up to 0.2 cm. in diameter. The full extent and origin of the nodules could not be determined grossly. Histologically, the nodules were well circumscribed and composed of moderately cellular intertwining spindle cells which proved to be smooth muscle by special stains (Fig. 3 left). The nuclei were uniform in size, shape and staining intensity (Fig. 3 center). There were no abnormal mitoses or pleomorphism. The leiomyomatous cells were basically located between the alveoli and in some areas, they were found in the region of bronchioles (Fig. 3 right). Other areas of the 14

14 .:. :.

..i...

E

4.0 1.2

2.0

3.5 3.0

....

...... ..E

_

Case 2

Case I 16 Mos Later

g:

~~

~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..

_.E.i

12

12

(110

010

16

16

... 15

.....

_11X:::i::!

...........:.:.i.:. ...

::.:..... .. ..

4

4

1

2

1

2

8.j.o.' .. .............,.j

a.ir were nomlTe pain remined asmtmtc1 Fig. 1. Chest radiograph of the patient in Case No. 1. Note that there are striking miliary or micronodular infiltrates in both lung fields. was also normal. Arterial blood gases at rest, brea(hing room air were normal. The patient remained asymptomatic 16 months later. Serial chest radiographs remained unchanged, but repeat pulmonary function tests indicated a decrease in

0 TLC

1

2 Volume (L) Normal

3 RV

OTLC

1

RV

Case 1

Fig. 2. Maximal expiratory flow-volume curve of the patient in Case No. 1 showing restrictive lung disease on the right compared with that of a healthy subject on the left. Flow is plotted on the ordinate while volume is on the abscissa. One, two and three second time marks are shown. Curves are automatically plotted from computer memory at 1/4 original speed in order to avoid skewing artefact.

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Pulmonary Leiomyomatosis

Vol. 68, No. 1

lung showed focal alveolar compression around the nodules and minimal peripheral emphysema. Case No. 2 (315-184). This 61-year-old housewife, was admitted to the hospital because of progressive dyspnea on exertion. Five years previously, while vacationing abroad, she developed an upper respiratory infection with cough productive of whitish sputum. Dyspnea had progressed to the point where she was unable to do her housework. She had also been hoarse occasionally. Sixteen years ago, she had menorrhagia followed by a hysterectomy for benign fibroids. She was hypothyroid at that time and placed on thyroid extract. In the past 18 months, she had noted progressive vitiligo. She is a non-smoker.

Fig. 3. Photomicrograph of the lung (left) showing well circumscribed nodules of intertwining smooth muscle cells. Note some alveolar compression and areas of emphysema. (Masson Trichrome x 125). High power view of a leiomyomatous nodule (center). Note moderate cellularity and an absence of pleomorphism and mitosis, (H & E x 425). High power view of leiomyomatous cells encroaching on a bronchiole (right) (H & E x 425).

Physical examination revealed vitiligo, decreased chest expansion, coarse breath sounds and accentuation of the pulmonic second heart sound. Chest radiographs, not available, showed nodular densities disseminated throughout both lung fields. An electrocardiogram showed an incomplete right bundle branch block. Stool guiacs were positive for occult blood and a barium enema revealed diverticulosis. Chest radiographs revealed disseminated miliary pulmonary infiltrates similar to those in Case 1. Pulmonary function studies are shown in Tables 1 and 2. Lung volumes,%FEV, and%FEV3 were normal. Inhomogeneity of inspired gases was present as noted by the abnormal single breath test of alveolar gas uniformity. The increased physiologic dead space indicates uneven ventilation/bloodflow ratios (air shunts). Her transfer factor for carbon monoxide was only 1/3 normal. Lung compliance was normal, and significant venous admixture to the pulmonary circulation was absent. These abnormalities caused hypoxemia at rest breathing room air. Pulmonary hypertension was present as shown by an elevated pulmonary artery pressure of 40/15 with a mean of 25 mmHg during right heart catheterization. A lung biopsy revealed leiomyomatous nodules similar to those described in Case 1. DISCUSSION

When a chest radiograph, showing miliary lung disease, is presented, the common

thought of tuberculosis and perhaps a few additional possibilities are entertained, with little or no consideration for rarer causes." In addition to causing miliary lung disease, the two present cases of lieomyomatosis represent a disparity in disability, the first being asymptomatic, while the second was disabled to the point where she was unable to perform daily household chores. Physiologic evaluation in the present cases has not been able to explain the variability in disability, lung volumes being decreased in Case No. 1, but normal in Case No. 2. Oxygenation of the blood was impaired in Case No. 2. Three authors4'9" 0 separately described patients who had obstructive airways disease caused by the leiomyomata. In this respect, the present cases differed. It is not known whether the patient described in Case No. 2, with normal lung volumes, had disease of small peripheral airways since she was lost to followup prior to the discovery of the significance of tests of small airways disease. The majority of cases of pulmonary leiomyomatosis, described, occur in women usually in the 4th and 5th decade of life following hysterectomy for fibroids that are histolically benign. Although many workers believe benign fibroids of the uterus have the ability to metastasize to the lung, 7,8 12 13, it may be that hormonal stimulation may cause growth of smooth muscle already present in Table 3. CLASSIFICATION OF PULMONARY LEIOMYOMAS 1. Primary leiomyomatous hamartomas a. Solitary5 b. Multiple 2. Leiomyosarcoma 3. Benign metastasizing uterine leiomyomata 4. Leiomyomata associated with tuberous sclerosis4 5. Muscular cirrhosis of the lungs14

the lungs, airways and blood vessels. The case of Castleman and Kibbee,9 like the present cases, had pre-existing thyroid disease whose relationship to the pulmonary lesions is unclear. Other cases of pulmonary leiomyomatosis have been associated with tuberous sclerosis (epilepsy, mental deficiency and adenoma sebaceum). Chylous effusions and ascites may occur in some of

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JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

these cases,4 and present an obvious cause of respiratory embarrassment. Lieberman10 recently reported successful treatment of these complications with nitrogen mustard and diuretics. Although no satisfactory therapy exists for disseminated leiomyomas, local excision has been suggested for solitary nodules. 612 Occasionally, smooth muscle proliferation may occur in end stage pulmonary fibrosis to the extent that it has been called "muscular cirrhosis" of the lung. This type is also diffuse and may cause severe functional alterations and eventually death.14 A classification of pulmonary leiomyomas is suggested in Table 3. SUMMARY

Two unusual cases of pulmonary leiomyomatosis in women with miliary infiltrates by chest radiograph in whom "benign" uterine fibroids were found were presented. One patient was asymptomatic while the other was disabled, demonstrating the variability of disability that can occur in this disease. The asymptomatic patient had restrictive lung disease while uneven ventilation and defect in transfer of gases contributed to hypoxemia in the disabled patient. LITERATURE CITED

1. KRISCHE, G. Ein Fall von Fibromyomen des uterus mit Multiplen Metastasen bei einer Geisteskranken. Diss. Gottingen, W. F. Kastner, 1889. 2. LANGERHANS, R. Demonstration eines Prap arates von Myoma laevicellulare malignum. Berl. Klin. Wchnschr., 30:338-340, 1893.

JANUARY, 1976

3. MINKOWSKI, 0. Myommetasten in Lungen, Leber and Miskeln. Munchen. Med. Wchnschr., 48:1335, 1901. 4. VALENSI, Q. J. Pulmonary Lymphangiomyoma, A Probable Forme Frust of Tuberous Sclerosis: A Case Report and Survey of the Literature. Am. Rev. Resp. Dis., 108:1411-1415, 1973. 5. PIERCE, W. F. and R. L. ALZNAUR and C. ROLLE, Jr. Leiomyoma of the Lung: Report of a Case. AMA Arch. Path., 58:443-448, 1954. 6. ARIEL, I. M. and S. TRINIDAD. Pulmonary Metastasis from a Uterine Leiomyoma. Report of a Case: Evaluation of Differential Diagnosis and Treatment Policies. Am. J. Ob. Gyn., 94:110116, 1966. 7. DEL POZO, E. and I. R., MATTEI. Multiple Pulmonary Lieomyomatous Hamartomas. A Case Report. Am. Rev. Resp. Dis., 100:388-390, 1969. 8. STEINER, P. E. Metastasizing Fibroleiomyoma of the Uterus. Report of a Case and Review of the Literature. Am. J. Path., 15:89-109, 1939. 9. CASTLEMAN, B. and B. U. KIBBEE. Case Records of the Massachusetts General Hospital. N. Eng. J. Med., 268:550-557, 1963. 10. LIEBERMAN, J. and C. M. AGLIOZZO. Intrapleural Nitrogen Mustard for Treating Chylous Effusion of Pulmonary Lymphangioleiomatomatosis. Cancer, 33:1505-1511, 1974. 11. BEUCHNER, H. A. The Differential Diagnosis of Miliary Disease of the Lungs. Med. Clin. Nor. Amer. 43:89-112, 1959. 12. SPIRO, R. H. and C. J. MCPEAK. On the

So-Called Metastasing Leiomyoma. Cancer, 19:544-548, 1966. 13. KAPLAN. C. and A. KATOH, S. MIKIHIRO, E. ROGOW, J. H. SCOTT, W. CUSHING and J. COOPER. Multiple Leiomyomas of the Lung: Benign or Malignant. Am. Rev. Resp. Dis., 108:656-659, 1973. 14. RUBENSTEIN, L. and W. H. GUTSTEIN and H. LEPOW. Pulmonary Muscular Hyperplasia (Muscular Cirrhosis of the Lungs). Ann. Int. Med., 42:36-43, 1955.

(Sinkford, from page 62) 3. Annual Report of Dental Education. 1973-74, SupEducation and Welfare, Public Health Service Replement 15; Trend Analysis 1964-1973. port. Health Resources Adm. 4. Carnegie Commission on Higher Education: Higher 7. Institute of Medicine Report of A Study: Cost of Education and the Nation's Health. New York, Education in the Health Professions, Washington, McGraw-Hill Book 1970. D. C.: National Academy of Sciences; Parts I and 5. Annual Report of Dental Education, 1973. EnrollII, Jan. 1974. Part III, April, 1974. ment in Advanced Education Programs. 8. Annual Report of Dental Education 1973-74, Sup6. Vital Health Statistics. Series 10-Number 95. Curplement 15; Trend Analysis 1964-1973. rent Estimates from the Health Interview Survey, 9. ADA Leadership Bulletin. Vol. 5/Number 4. Feb. United States, 1973. U.S. Department of Health, 17. 1975.

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