Multiple Pulmonary Fibroleiomyomatous Hamartomata in Childhood By Meredith T. Hull, Frank Gonzalez-Crussi, and Jay L. Grosfeld Indianapolis, Indiana
9 A 9-yr-old girl with a history of rhabdomyosarcoma developed multiple pulmonary fibroleiomyomatous hamartomata. This clinical setting illustrates the tendency of these hamartomata to clinically mimic metastatic tumors. Further, this case represents the first description of multiple pulmonary fibroleiomyomatous hamartomata in a pediatric age group, and finally, in this clinical setting, supports the concept that these hamartomata represent a distinct entity apart from benign metastasizing uterine leiomyomata.
myosarcoma. In one case? MPFLH manifested during pregnancy, and the disease was clinically interpreted as metastatic choriocarcinoma. Occurrence of MPFLH in a pediatric patient is of especial interest because it forces a reassessment of a recent suggestion that MPFLH represents benign metastasizing uterine leiomyomas.3
INDEX WORDS: Multiple pulmonary fibroleiomyomatous harmartoma.
In December, 1972, a 9-yr-old white female developed a nontender, slowly growing epigastric, subcutaneous nodule. The clinical diagnosis was an abscess for which she was treated with antibiotics. When the lesion did not resolve, local excision was performed 2 mo later. Histologically the nodule was diagnosed as embryonal rhabdomyosarcoma, and the patient was referred to James Whitcomb Riley Children's Hospital, at Indiana University Medical Center, for further evaluation and therapy. In March, 1973, a metastatic survey including bone and liver-spleen scintiscans, chest roentgenograms, inferior vena cavograms, intravenous pyelogram, upper and lower gastrointestinal barium roentgenograms, and bone marrow biopsy was normal. The patient underwent wide reexcision and was started on Vincristine, Actinomycin-D, and Cytoxan. Histologically no residual tumor was apparent. Postoperatively she remained stable until the discovery of microhematuria in September, 1973. Chest roentgenograms at that time revealed an 8 mm, noncalcified nodule lying within the anterior segment of the right middle lobe. (Figs. 1 and 2) This lesion was not present on previous studies and was believed to represent metastatic rhabdomyosarcoma. In light of the apparent solitary nature of the lesion a thoracotomy was performed. At surgery, three discrete intrapulmonary nodules were identified and locally excised. Two nodules, each measuring 8 mm, were located in the right lower lobe, and a third nodule, measuring 9 mm was situated in the right middle lobe. Each had the characteristic histologic appearance of MPFLH (Figs. 3 and 4). During the ensuing 36 mo, the patient remained free of disease. However, in March, 1976, chest roentgenograms demonstrated two new noncalcified, pulmonary nodules, one in the right upper lobe, and one in the left upper lobe. Roentgenographically, metastatic rhabdomyosarcoma could not be differentiated from new MPFLH. Aside from these nodules, there were no other lesions suggestive of metastases. In light of this patient's history of MPFLH and because she had remained free of metastatses 24 mo following resection of her primary rhabdomyosarcoma, it was elected to treat the new pulmonary lesions as MPFLH and closely follow them by serial roentgenograms. She has demonstrated no progression of these lesions for 24 mo.
PULMONARY fibroleiomyoM ULTIPLE matous hamartomata (MPFLH) occur uncommonly, and their etiology and pathogenesis remain unknown. To date approximately 15 cases of MPFLH T M have been reported in the American and European literature. These have been reviewed recently by Horstmann et al. 3 Some ultrastructural aspects have been described) 3 The individual lesions are composed of an admixture of mature tissue native to the lung, including smooth muscle, collagenous fibrous tissue and glandular elements. Interestingly, MPFLH has been described in females only and prior to the present report the age range has been 3 0 - 7 4 yr. 3
MPFLH is of particular clinical interest because its presentation often simulates pulmonary metastases of a malignant neoplasm. Many previous cases have occurred in patients following hysterectomy for apparently benign uterine leiomyomas, thus igniting fears of occult leio-
From the Division of Pediatric Pathology, Department of Clinical Pathology and Pathology, and the Section of Pediatric Surgery, Department of Surgery, Indiana University School of Medicine, and the James Whitcomb Riley Hospital for Children, Indianapolis, Ind. Address reprint requests to Meredith T. Hull, M.D., Department of Clinical Pathology, William N. Wishard Memorial Hospital, Indiana University School of Medicine, Indianapolis, Ind. 46202. 9 1979 by Grune & Stratton, Inc. 0022-3468/79/1404~006501.00/0 428
CASE REPORT
Journal of Pediatric Surgery, Vol. 14, No. 4 (August), 1979
PULMONARY HAMARTOMATA
429
alveoli. Both mesenchymal and epithelial elements were present. A large number of glands and slit-like spaces were lying within a dense matrix of smooth muscle and collagenous fibrous tissue. The glands were lined by a single layer of large, vacuolated cuboidal cells containing a single, darkly staining, eccentric nucleus. The slit-like spaces were lined by smaller cuboidal cells containing vacuolated, eosinophilic cytoplasm. The admixture of smooth muscle and coUagenous tissue was confirmed by Mallory's trichrome stain. Mitoses and nuclear atypia were not present.
Fig. 1, Chest roentogenogram demonstrates 1 of the 3 nodules present in the right lung (arrows). The other t w o hamartomas are not visible by roentgenogram.
MICROSCOPY
Sections of lung demonstrated three unencapsulated nodules lying within normal lung parenchyma (Figs. 3 and 4). Their margins were well-demarcated, slightly compressing adjacent
Fig. 3. Photomicrograph shows one of the nodules that is composed of an admixture of glandular and fibromuscular tissue. The adjacent pulmonary parenchyma is compressed (Hematoxylin and eosin: 60 X).
Fig. 2. Chest tomogram shows the same nodule in Fig. 1. Note the solid nature of the lesion and the lack of calcification.
430
HULL, GONZALEZ-CRUSSI, AND GROSFELD
Fig. 4. Photomicrograph shows the same nodule in Fig. 3 and illustrates the spindle-shaped muscle fibers traversing between glandular elements (Hematoxylin and eosin: 320 X).
DISCUSSION
In view of this patient's history of rhabdomyosarcoma, the tendency of MPFLH to clinically simulate a metastatic neoplasm was greatly enhanced. Roentgenographically, these two lesions are indistinguishable, thus requiring tissue sampling for definitive diagnosis. The possible relationship between MPFLH and rhabdomyosarcoma in this patient appears remote, however. Histologically, the soft tissue tumor and the lung lesions were quite dissimilar. The pulmonary nodules demonstrated no anaplasia and the rhabdomyosarcoma contained no foci of mature tissue. We are unaware of any reported overlap in histologic appearance of
either of these two lesions, nor has there been any documentation of progressive "maturation" or differentiation of metastatic lesions in either treated or untreated cases of rhabdomyosarcoma of childhood. Moreover, the presence of metastases confined to the lung would be unlikely in the clinical setting described. But most importantly, the histologic structure of the lung lesions was that of hamartoma and not of a uniform malignant tumor. The natural history of MPFLH appears related to the patients' hormonal status. 3 The lesions have a greater growth potential when they occur in premenopausal patients and, conversely, a slower growth rate in postmenopausal and postoophorectomy patients. 3 This interrelationship between smooth muscle neoplasms and estrogen stimulation has been established in the case of uterine leiomyomata;~7'18it seems reasonable to speculate that a similar estrogen-dependent growth rate might also be operational in other lesions composed, at least in part, of smooth muscle. A possible relationship between MPFLH and benign metastasizing uterine leiomyomata has been proposed? However, repeated examinations of our patient have failed to demonstrate smooth muscle lesions at any site other than the lungs, and the patient's age--10 yr at the time of diagnosis of MPFLH--argues against the presence of benign uterine leiomyomata with subsequent metastases to the lungs.
REFERENCES
1. Castleman B, Kibbee BA: Case records of Massachusetts General Hospital. N Engl J Med 268:550-557, 1963 2. Eggimann P, Woltz B: Adenoleiomyomas, multiples, des deux poumons. Radiol Clin (Basel) 18:335-343, 1949 3. Horstmann JP, Pietra GG, Harman JA, et al: Spontaneous regression of pulmonary leiomyomas during pregnancy. Cancer 39:314-321, 1977 4. Kaplan C, Katoh A, Shamato M, et al: Multiple leiomyomas of the lungs: Benign or malignant. Am Rev Resp Dis 108:656-659, 1973 5. Keers RY, Smith FA: A case of multiple pulmonary hamartomata of unusual type. Br J Dis Chest 54:349-352, 1960 6. Laustela E: Myomatosis of the lung--Report of one case. Acta Chir Scand 127:311-313, 1964 7. Logan WD, Rohde FC, Abbott, OA, et al: Multiple pulmonary fibroleiomyomatous Hamartomas--Report of a case and review of the literature. Am Rev Resp Dis 91:101103, 1965
8. Madani MA, Dafoe CS, Ross CA: Multiple hamartomata of the lung. Thorax 21:468-472, 1966 9. Del Pozo E, Mattei IR: Multiple pulmonary leiomatous hamartomas. A case report. Am Rev Resp Dis 100:388-390, 1969 10. Ramchand S, Baskerville L: Multiple hamartomas of the lung. Am Rev Resp Dis 99:932-935, 1969 11. Rondez R: Adenomyomatose der lungen. Pathol Microbiol 24:245-248, 1961 12. Sargent EN, Barnes RA, Schwinn CP: Multiple pulmonary fibroleiomyomatous hamartomas--Report of a case and review of the literature. Am J Roentgenol Radium Ther Nucl Med 110:694-700, 1970 13. Silverman JF, Kay Saul: Multiple pulmonary leiomyomatous hamartomas. Report of a case with ultrastructure examination. Cancer 38:1199-1204, 1976 14. Spotnitz M, Hopeman AR: Roentgenogram of the month. Dis Chest 51:645-646, 1967 15. Stanulla H, Scheel W: Beitrag zu multiplem Fehlbil-
PULMONARY HAMARTOMATA
dungen der Lunge (benigne Adenofibromyomat~se Hamartomatose). Thoraxchirurgie 17:15-22, 1969 16. Sulser H, Buhler H: Multiple leiomyomatose hamartom~ der lunge. Schweiz Med Wochenschr 105:56-60, 1975 17. Farber M, Conrad S, Heinricbs WL, et al: Estradiol
431
binding by fibroid tumors and normal myometrium. Obstet Gynecol 40:479-486, 1972 18. John AH, Martin R: Growth of leiomyomata with estrogen-progesterone therapy. J Reprod Med 6:56 58, 1971
9 A 9-yr-old girl with a history of rhabdomyosarcoma developed multiple pulmonary fibroleiomyomatous hamartomata. This clinical setting illustrates the tendency of these hamartomata to clinically mimic metastatic tumors. Further, this case represents the first description of multiple pulmonary fibroleiomyomatous hamartomata in a pediatric age group, and finally, in this clinical setting, supports the concept that these hamartomata represent a distinct entity apart from benign metastasizing uterine leiomyomata.
myosarcoma. In one case? MPFLH manifested during pregnancy, and the disease was clinically interpreted as metastatic choriocarcinoma. Occurrence of MPFLH in a pediatric patient is of especial interest because it forces a reassessment of a recent suggestion that MPFLH represents benign metastasizing uterine leiomyomas.3
INDEX WORDS: Multiple pulmonary fibroleiomyomatous harmartoma.
In December, 1972, a 9-yr-old white female developed a nontender, slowly growing epigastric, subcutaneous nodule. The clinical diagnosis was an abscess for which she was treated with antibiotics. When the lesion did not resolve, local excision was performed 2 mo later. Histologically the nodule was diagnosed as embryonal rhabdomyosarcoma, and the patient was referred to James Whitcomb Riley Children's Hospital, at Indiana University Medical Center, for further evaluation and therapy. In March, 1973, a metastatic survey including bone and liver-spleen scintiscans, chest roentgenograms, inferior vena cavograms, intravenous pyelogram, upper and lower gastrointestinal barium roentgenograms, and bone marrow biopsy was normal. The patient underwent wide reexcision and was started on Vincristine, Actinomycin-D, and Cytoxan. Histologically no residual tumor was apparent. Postoperatively she remained stable until the discovery of microhematuria in September, 1973. Chest roentgenograms at that time revealed an 8 mm, noncalcified nodule lying within the anterior segment of the right middle lobe. (Figs. 1 and 2) This lesion was not present on previous studies and was believed to represent metastatic rhabdomyosarcoma. In light of the apparent solitary nature of the lesion a thoracotomy was performed. At surgery, three discrete intrapulmonary nodules were identified and locally excised. Two nodules, each measuring 8 mm, were located in the right lower lobe, and a third nodule, measuring 9 mm was situated in the right middle lobe. Each had the characteristic histologic appearance of MPFLH (Figs. 3 and 4). During the ensuing 36 mo, the patient remained free of disease. However, in March, 1976, chest roentgenograms demonstrated two new noncalcified, pulmonary nodules, one in the right upper lobe, and one in the left upper lobe. Roentgenographically, metastatic rhabdomyosarcoma could not be differentiated from new MPFLH. Aside from these nodules, there were no other lesions suggestive of metastases. In light of this patient's history of MPFLH and because she had remained free of metastatses 24 mo following resection of her primary rhabdomyosarcoma, it was elected to treat the new pulmonary lesions as MPFLH and closely follow them by serial roentgenograms. She has demonstrated no progression of these lesions for 24 mo.
PULMONARY fibroleiomyoM ULTIPLE matous hamartomata (MPFLH) occur uncommonly, and their etiology and pathogenesis remain unknown. To date approximately 15 cases of MPFLH T M have been reported in the American and European literature. These have been reviewed recently by Horstmann et al. 3 Some ultrastructural aspects have been described) 3 The individual lesions are composed of an admixture of mature tissue native to the lung, including smooth muscle, collagenous fibrous tissue and glandular elements. Interestingly, MPFLH has been described in females only and prior to the present report the age range has been 3 0 - 7 4 yr. 3
MPFLH is of particular clinical interest because its presentation often simulates pulmonary metastases of a malignant neoplasm. Many previous cases have occurred in patients following hysterectomy for apparently benign uterine leiomyomas, thus igniting fears of occult leio-
From the Division of Pediatric Pathology, Department of Clinical Pathology and Pathology, and the Section of Pediatric Surgery, Department of Surgery, Indiana University School of Medicine, and the James Whitcomb Riley Hospital for Children, Indianapolis, Ind. Address reprint requests to Meredith T. Hull, M.D., Department of Clinical Pathology, William N. Wishard Memorial Hospital, Indiana University School of Medicine, Indianapolis, Ind. 46202. 9 1979 by Grune & Stratton, Inc. 0022-3468/79/1404~006501.00/0 428
CASE REPORT
Journal of Pediatric Surgery, Vol. 14, No. 4 (August), 1979
PULMONARY HAMARTOMATA
429
alveoli. Both mesenchymal and epithelial elements were present. A large number of glands and slit-like spaces were lying within a dense matrix of smooth muscle and collagenous fibrous tissue. The glands were lined by a single layer of large, vacuolated cuboidal cells containing a single, darkly staining, eccentric nucleus. The slit-like spaces were lined by smaller cuboidal cells containing vacuolated, eosinophilic cytoplasm. The admixture of smooth muscle and coUagenous tissue was confirmed by Mallory's trichrome stain. Mitoses and nuclear atypia were not present.
Fig. 1, Chest roentogenogram demonstrates 1 of the 3 nodules present in the right lung (arrows). The other t w o hamartomas are not visible by roentgenogram.
MICROSCOPY
Sections of lung demonstrated three unencapsulated nodules lying within normal lung parenchyma (Figs. 3 and 4). Their margins were well-demarcated, slightly compressing adjacent
Fig. 3. Photomicrograph shows one of the nodules that is composed of an admixture of glandular and fibromuscular tissue. The adjacent pulmonary parenchyma is compressed (Hematoxylin and eosin: 60 X).
Fig. 2. Chest tomogram shows the same nodule in Fig. 1. Note the solid nature of the lesion and the lack of calcification.
430
HULL, GONZALEZ-CRUSSI, AND GROSFELD
Fig. 4. Photomicrograph shows the same nodule in Fig. 3 and illustrates the spindle-shaped muscle fibers traversing between glandular elements (Hematoxylin and eosin: 320 X).
DISCUSSION
In view of this patient's history of rhabdomyosarcoma, the tendency of MPFLH to clinically simulate a metastatic neoplasm was greatly enhanced. Roentgenographically, these two lesions are indistinguishable, thus requiring tissue sampling for definitive diagnosis. The possible relationship between MPFLH and rhabdomyosarcoma in this patient appears remote, however. Histologically, the soft tissue tumor and the lung lesions were quite dissimilar. The pulmonary nodules demonstrated no anaplasia and the rhabdomyosarcoma contained no foci of mature tissue. We are unaware of any reported overlap in histologic appearance of
either of these two lesions, nor has there been any documentation of progressive "maturation" or differentiation of metastatic lesions in either treated or untreated cases of rhabdomyosarcoma of childhood. Moreover, the presence of metastases confined to the lung would be unlikely in the clinical setting described. But most importantly, the histologic structure of the lung lesions was that of hamartoma and not of a uniform malignant tumor. The natural history of MPFLH appears related to the patients' hormonal status. 3 The lesions have a greater growth potential when they occur in premenopausal patients and, conversely, a slower growth rate in postmenopausal and postoophorectomy patients. 3 This interrelationship between smooth muscle neoplasms and estrogen stimulation has been established in the case of uterine leiomyomata;~7'18it seems reasonable to speculate that a similar estrogen-dependent growth rate might also be operational in other lesions composed, at least in part, of smooth muscle. A possible relationship between MPFLH and benign metastasizing uterine leiomyomata has been proposed? However, repeated examinations of our patient have failed to demonstrate smooth muscle lesions at any site other than the lungs, and the patient's age--10 yr at the time of diagnosis of MPFLH--argues against the presence of benign uterine leiomyomata with subsequent metastases to the lungs.
REFERENCES
1. Castleman B, Kibbee BA: Case records of Massachusetts General Hospital. N Engl J Med 268:550-557, 1963 2. Eggimann P, Woltz B: Adenoleiomyomas, multiples, des deux poumons. Radiol Clin (Basel) 18:335-343, 1949 3. Horstmann JP, Pietra GG, Harman JA, et al: Spontaneous regression of pulmonary leiomyomas during pregnancy. Cancer 39:314-321, 1977 4. Kaplan C, Katoh A, Shamato M, et al: Multiple leiomyomas of the lungs: Benign or malignant. Am Rev Resp Dis 108:656-659, 1973 5. Keers RY, Smith FA: A case of multiple pulmonary hamartomata of unusual type. Br J Dis Chest 54:349-352, 1960 6. Laustela E: Myomatosis of the lung--Report of one case. Acta Chir Scand 127:311-313, 1964 7. Logan WD, Rohde FC, Abbott, OA, et al: Multiple pulmonary fibroleiomyomatous Hamartomas--Report of a case and review of the literature. Am Rev Resp Dis 91:101103, 1965
8. Madani MA, Dafoe CS, Ross CA: Multiple hamartomata of the lung. Thorax 21:468-472, 1966 9. Del Pozo E, Mattei IR: Multiple pulmonary leiomatous hamartomas. A case report. Am Rev Resp Dis 100:388-390, 1969 10. Ramchand S, Baskerville L: Multiple hamartomas of the lung. Am Rev Resp Dis 99:932-935, 1969 11. Rondez R: Adenomyomatose der lungen. Pathol Microbiol 24:245-248, 1961 12. Sargent EN, Barnes RA, Schwinn CP: Multiple pulmonary fibroleiomyomatous hamartomas--Report of a case and review of the literature. Am J Roentgenol Radium Ther Nucl Med 110:694-700, 1970 13. Silverman JF, Kay Saul: Multiple pulmonary leiomyomatous hamartomas. Report of a case with ultrastructure examination. Cancer 38:1199-1204, 1976 14. Spotnitz M, Hopeman AR: Roentgenogram of the month. Dis Chest 51:645-646, 1967 15. Stanulla H, Scheel W: Beitrag zu multiplem Fehlbil-
PULMONARY HAMARTOMATA
dungen der Lunge (benigne Adenofibromyomat~se Hamartomatose). Thoraxchirurgie 17:15-22, 1969 16. Sulser H, Buhler H: Multiple leiomyomatose hamartom~ der lunge. Schweiz Med Wochenschr 105:56-60, 1975 17. Farber M, Conrad S, Heinricbs WL, et al: Estradiol
431
binding by fibroid tumors and normal myometrium. Obstet Gynecol 40:479-486, 1972 18. John AH, Martin R: Growth of leiomyomata with estrogen-progesterone therapy. J Reprod Med 6:56 58, 1971
