help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rivera, J. A.
Right arrow Articles by Trifiro, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rivera, J. A.
Right arrow Articles by Trifiro, M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Medline Plus Health Information
*Lung Cancer
*Uterine Cancer
*Uterine Fibroids
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 7 3183-3188
Copyright © 2004 by The Endocrine Society

CLINICAL CASE SEMINAR

Hormonal Manipulation of Benign Metastasizing Leiomyomas: Report of Two Cases and Review of the Literature

J. A. Rivera, S. Christopoulos, D. Small and M. Trifiro

Division of Endocrinology (J.A.R., S.C.), McGill University Health Centre, Montréal, Québec H3A 1A1, Canada; and Division of Respirology (D.S.) and Lady Davis Institute and Division of Endocrinology (M.T.), SMBD Jewish General Hospital, Montréal, Québec H3T 1E2, Canada

Address all correspondence and requests for reprints to: Dr. Juan-Andres Rivera, Royal Victoria Hospital, 687 Pine Avenue West, Room M3.15, Montréal, Québec H3A 1A1, Canada. E-mail: juan.rivera{at}mcgill.ca.


   Abstract
Top
 Abstract
Introduction
 Discussion
 References
 
Benign metastasizing leiomyomas (BMLs) occur predominantly in women during reproductive years. The condition is characterized by uterine leiomyomas associated with the development, typically years later, of slow-growing metastatic lesions. The most commonly affected organs are the lungs, but BMLs have been reported in lymph nodes, deep soft tissues, mesentery, bones, the central nervous system, and the heart. In many cases, these lesions have an indolent course and are discovered rather incidentally. However, occasionally they can present with debilitating symptoms or even life-threatening complications. The presence of estrogen and progesterone receptors in these tumors supports their origin from uterine smooth muscle and, more importantly, makes them amenable to hormonal manipulation. Radical interventions, such as extensive tumor debulking and oophorectomy for hormonal control, although effective in many cases, are not always possible or desirable and carry significant morbidity. Here we present two cases of BMLs to illustrate the role of newer therapeutic agents, the estrogen receptor modulators and the aromatase inhibitors, in the hormonal manipulation of these tumors.


   Introduction
Top
 Abstract
 Introduction
Discussion
 References
 
UTERINE LEIOMYOMAS HAVE been reported in association with extrauterine benign-appearing smooth muscle tumors. This condition has been described mainly in women of reproductive age but can occur at any age. It has been referred to in the literature as benign metastasizing leiomyoma (BML). This term was introduced in 1939 by Steiner (1) in his report of a case of a 36-yr-old woman who died after massive pulmonary and hilar lymphatic metastases of a uterine leiomyoma. The interest of this condition to endocrinologists is its susceptibility to the hormonal milieu. Knowledge of this susceptibility may lead to effective clinical control of this metastasizing tumor by hormonal manipulation. We report two cases of BML in which hormonal manipulation with LHRH agonists, antiestrogens, and aromatase inhibitors (AIs) caused alleviation of symptoms and regression of the metastatic lesions.

Case 1

A 47-yr-old Caucasian woman consulted because of recurrent left subscapular pain that presented every few weeks with spontaneous resolution within a few days. Her complaint was initially attributed to cervical arthrosis and treated with analgesics. Three years later she developed numbness over her left hand, and a firm mass of about 5 cm was noticed in the left supraclavicular area (Fig. 1Go). A magnetic resonance image (MRI) revealed a large paraspinal tumor involving the brachial plexus and extending into the vertebral canal (Fig. 2Go). C5-T1 laminectomies, debulking of the extraspinal, and near complete removal of the intraspinal component was carried out. Pathological evaluation revealed a well-differentiated leiomyosarcoma [1–3 mitoses per 10 high-power fields (HPFs) and no necrosis] with bony involvement (Fig. 3Go).



View larger version (107K):
[in this window]
[in a new window]
  		FIG. 1. A 5 x 4 cm left supraclavicular mass was evident at simple inspection as shown in this picture taken before the first surgery in case 1.

 


View larger version (95K):
[in this window]
[in a new window]
  		FIG. 2. MRI in case 1 showing the tumor and its invasion of the left brachial plexus, vertebral bones, and the spinal canal at C6-C7. Note the spinal cord compression.

 


View larger version (93K):
[in this window]
[in a new window]
  		FIG. 3. Histological appearance of the paraspinal tumor in case 1; counterstained with hematoxylin and eosin, these high-power views show negative immunostaining for S-100 (neural tissue marker) and positive immunostaining (brown staining) for desmin (smooth muscle marker).

 
Radiotherapy was planned but the patient refused it. Shortly afterward she began experiencing cervical pain unrelieved by opioid analgesia, with a similar cyclical pattern to her previous pain; this prompted consultation to endocrinology. Her past medical history was remarkable for a total hysterectomy at age 36 yr for a 6-cm uterine leiomyoma. The histological blocks were retrieved and reexamined; the new report described a tumor with ill-defined infiltrative borders, areas of coagulative necrosis, mitotic rate of 4/10 HPFs, and few pathological mitotic figures but no significant cytological atypia. The conclusion was smooth muscle tumor of low malignant potential (2). The histological appearance of the paraspinal tumor was reported to be similar to that of the uterine leiomyoma, and the immunohistochemistry was moderate to strongly positive for estrogen (ERs) and progesterone receptors (PRs).

Sequential serum levels of estradiol, progesterone, LH, and FSH showed normal premenopausal cycles and synchrony between pain crisis and midcycle LH-FSH-estrogen peaks (Fig. 4Go). Additionally, a short course of tamoxifen 20 mg daily clearly reproduced her symptoms.



View larger version (72K):
[in this window]
[in a new window]
  		FIG. 4. Sequential measurement of LH, FSH, estradiol, and progesterone in case 1 shows synchrony of midcycle hormonal surges and an episode of pain. The units have been adjusted to make them comparable in a single graph. For conversion to SI units, multiply FSH (international units/liter) by 0.045, LH (international units/liter) by 0.09, estradiol (picomoles/liter) by 3.67, and progesterone (nanomoles/liter) by 0.318.

 
A new MRI showed significant growth of tumor remnants that prompted another surgical intervention followed by radiotherapy. The long-acting GnRH agonist, leuprolide acetate, was also initiated immediately with significant symptomatic relief. Five months later an MRI showed persistence of remnant tumor and anastrozole, an AI at a dose of 1 mg daily was added. Thereafter the patient has remained symptom free, and successive MRI showed regression of tumor remnants with no evidence of regrowth 5 yr after the initial diagnosis. In the meantime, the patient has undergone natural menopause, which allowed the discontinuation of leuprolide injections.

Case 2

A 37-yr-old Haitian woman was referred to the respirology department for progressive shortness of breath. Her past medical history was remarkable for a large uterine leiomyoma discovered 7 yr previously that led to total hysterectomy at age 34 yr. Cells from the 22 x 16 x 10 cm intramural leiomyoma stained strongly positive for both ER and PR.

Her history revealed progressive dyspnea of a few months duration that appeared to be worse for a few days, occurring at midcycle, and improving over the course of the month. Her chest radiographs showed multiple diffuse nodules (Fig. 5Go). A thoracoscopic lung biopsy was performed and the pathology reported as that of a benign smooth muscle tumor that stained strongly for ER and PR (Fig. 6Go), compatible with BML. The patient refused all hormonal treatment modalities, including oophorectomy. Her dyspnea, radiographic appearance, and pulmonary function tests slowly worsened over the ensuing 10 yr.



View larger version (140K):
[in this window]
[in a new window]
  		FIG. 5. Chest radiograph of case 2 demonstrating multiple bilateral nodules in the parahilar and the lower third areas.

 


View larger version (150K):
[in this window]
[in a new window]
  		FIG. 6. High-power view of a lung lesion in case 2 immunostained for ER (brown staining) with light hematoxylin counterstain (blue). Moderate nuclear positivity of most tumor cells. Asterisk indicates lumen of a bronchiole; note that bronchiolar lining cells do not express ER.

 
At age 47 yr, she presented to the emergency department with a 3-d history of progressive severe shortness of breath. She admitted to a marked deterioration over the course of the preceding 6 months. She was admitted to the intensive care unit with acute respiratory failure and needed urgent noninvasive ventilation. A chest radiograph revealed multiple diffuse pulmonary nodules and a large left pleural effusion. A pleural tube drained 3 liters of serosanguinous fluid. A small pericardial effusion was also documented on ultrasound but without evidence of hemodynamic compromise. Two days later she was still dependent on noninvasive ventilation for adequate oxygenation. Considering the potential benefit of reducing hyperemia and proliferation in estrogen sensitive lesions by blocking estrogen stimulation (3), the endocrinology consultant decided to initiate raloxifene 60 mg and anastrozole 1 mg daily. She progressively improved over the course of 3 d and was discharged home on these two medications while an elective oophorectomy was being planned. FSH and LH hormone levels were requested and confirmed the patient’s premenopausal status. However, the patient refused the addition of an LHRH agonist.

On follow-up a month after discharge, the patient had discontinued her medications and described worsening dyspnea. She was convinced to restart raloxifene 120 mg daily and anastrozole 2 mg daily, and she experienced a marked improvement of her clinical status within a few days. Ten weeks later a bilateral oophorectomy was performed. Raloxifene and anastrozole were continued, and she has remained clinically well for over 2 yr. She has not reaccumulated pleural fluid, and mild radiological improvement of the pulmonary nodules has been documented.


   Discussion
Top
 Abstract
 Introduction
 Discussion
References
 
Uterine leiomyomas, the most common gynecological neoplasms in women of reproductive age, have a prevalence of about 50% above the age of 30 yr and result from clonal proliferation of uterine smooth muscle tissue (4, 5). The great majority of these tumors are benign with the relative frequency of leiomyosarcomas estimated between 0.13 and 6% (6). Very rarely, benign uterine leiomyomas display bizarre growth patterns including intravascular leiomyomatosis, disseminated peritoneal leiomyomatosis, and the so-called BML (6).

BMLs are uterine leiomyomas that histologically appear benign with a low mitotic rate but are associated with the development of similar tumors (metastases) in distant locations. In our cases as in most previously reported, there was an interval of several years between the surgical removal of the uterine lesions and the discovery of the extrauterine tumors. This indolent clinical behavior with late and slow-growing metastases, common to other benign metastasizing tumors such as the benign metastasizing meningioma (7), distinguishes these tumors from true sarcomas, their malignant counterpart. However, there is still controversy as to where the line between benign and malignant leiomyomas should be drawn histologically. Among many different pathological features, it is now recognized that the mitotic index, the degree of cytological atypia, and the presence or absence of coagulative necrosis are the most important predictors of tumor behavior (2). Uterine leiomyomas with less than 5 mitoses per 10 HPFs, with no cellular atypia or necrosis, are considered benign. On the other hand, a mitotic index greater than 10, marked cellular atypia, and coagulative tumor cell necrosis characterizes overt leiomyosarcomas. For tumors with characteristics between these extremes, the term, "leiomyoma of uncertain malignant potential" is reserved (2, 6).

The pathogenesis of BMLs has been object of controversy. Several hypotheses have been proposed, but vascular dissemination is at present the most widely accepted. The majority of women with these tumors have a prior dilatation and curettage, myomectomy, or hysterectomy. This raises the possibility of surgically induced vascular spread. However, some cases have been described in which the uterine tumor is discovered simultaneously (8) or even after the metastases (9). A multifocal origin has been advocated in some cases with unusual distribution of metastatic lesions (10, 11, 12). Smooth muscle neoplasm can in fact develop de novo in virtually any location (from vascular smooth muscle). However, extrauterine leiomyomas are uniformly ER negative, and only few (13%) extrauterine leiomyosarcomas show weak and focal ER immunoreaction (13, 14). In contrast, most BMLs are ER positive. Moreover, genomic hybridization and X-chromosome inactivation analysis demonstrated a balanced karyotype and identical X-chromosome inactivation pattern consistent with a monoclonal origin of pulmonary and uterine tumors in one case of BML (15). Some investigators have suggested that the primary lesions could actually be low-grade sarcomas with metastatic potential, and that sampling error may account for their deceivingly benign appearance (12). Still others have suggested that the tumor metastases might have undergone maturation (16). However, as pointed out before, the clinical course in BML is much less aggressive than in true leiomyosarcomas. In fact, these tumors are often asymptomatic, and metastatic lesions in the lungs have sometimes been found incidentally in routine chest x-rays (17).

In most reported cases, pulmonary involvement is present. In 1996 Jautzke et al. (17) reviewed 74 cases of BML reported until then in which pulmonary lesions was the common denominator. A review of the more recent medical literature reveals that at least 31 new cases have since been reported, with lung involvement in 18 of them. Extrapulmonary lesions have been documented in lymph nodes (18, 19), deep soft tissues (10, 12, 20, 21, 22), omentum and mesentery (10, 12), bone (23, 24, 25), skull base and spine (23), and heart (26, 27).

Several facts support the hormonal dependency of BML. The presence of ERs and PRs has been clearly documented (10, 15, 17, 22, 28, 29). Jautzke et al. (17) reported five cases of BML in which ERs were positive in four and PRs in all five. Evans et al. (22) reported high PR levels, whereas ER levels were low in a metastatic leiomyoma arising from the muscles of the thigh. In our case, immunohistochemistry was positive for both ERs and PRs in both patients. On the other hand, regression of metastatic lesions has been demonstrated in situations in which estrogen levels fall significantly, such as after termination of pregnancy (18, 30, 31) and after menopause (17, 24, 28).

In accordance with these observations, a review of the literature reveals advancing efforts to control gonadal hormone secretion in patients with BML. Bilateral oophorectomy has been reported to be effective in controlling tumor growth (9, 22, 29). However, the possibility of medical castration attracts more interest because of its reversibility, and its potential to obviate the need for a surgical procedure, or to allow symptom control when surgical management is not possible, needs to be postponed or has been ineffective. The use of long-acting GnRH analogs, which suppress the endogenous gonadotropin secretion necessary for gonadal steroid production, has been described with good results in several reports (23, 25, 32, 33, 34, 35). The response to leuprolide, one of such agents, was only partial in our case 1, probably because a significant source of estrogens in these situations is the peripheral aromatization of androgens, which is not affected by LHRH agonists.

Progesterone treatment has also been shown to be effective in both the prophylaxis against recurrences (36) and the regression of the leiomyomatous tumors (17, 18, 37). Cho et al. (12) reported a 17-yr-old woman with multiple metastases in the posterior mediastinum, deep soft tissues of the neck, paravertebral region, incisional scar, and mesentery, who failed to respond to bilateral oophorectomy but in whom progesterone provided symptomatic relief. The basis for the use of progestins lies in their ability to suppress the hypothalamic-pituitary-gonadal axis, thereby reducing ovarian estrogen synthesis. Progesterone also acts to increase the rate of enzymatic inactivation of estradiol by increasing its conversion to estrone through an increase in the activity of an oxidative type 17ß-hydroxysteroid dehydrogenase enzyme and enhancing estrogen sulfation through activation of estrogen sulfotransferase (38). In addition, progesterone has been shown to reduce aromatase activity by up to 30% (39). The direct effect of progesterone on leiomyoma cells has also been studied. In cultures of leiomyoma cells, both estradiol (10 ng/ml) and progesterone (100 ng/ml) increase the expression of the proliferating cell nuclear antigen, a marker for cell proliferation; in contrast, estradiol but not progesterone augmented proliferating cell nuclear antigen expression in cultures of normal myometrial cells (40). This may explain why in some BML patients, progestins were ineffective (22) or caused worsening and further tumor spread (36).

Progesterone antagonists have been used with success in the treatment of uterine myomas (41, 42, 43). In a patient with low-grade osteolytic leiomyosarcoma expressing PRs, there was prolonged remission during long-term administration of the antiprogestin RU486 (42). However, to the best of our knowledge, these agents have not yet been used in BML. In addition, progesterone antagonists should probably not be used alone because of their potential to induce up-regulation of ERs (44).

We report two cases that illustrate the role of newer agents used for medical castration to either obviate the need for oophorectomy and create a bridge to menopause (case 1) or as adjuvant therapy to allow symptom control as a bridge to an oophorectomy that needed to be postponed (case 2). The novelty of our cases lies in the successful use of anastrozole, an AI, and raloxifene, a selective estrogen receptor modulator (SERM) in the treatment of BML.

In our first patient, an LHRH analog failed to control tumor progression. When anastrozole was given, an excellent clinical response and radiological regression of the tumor were documented. Our second case depicts a patient who showed remarkable clinical response to raloxifene and anastrozole that permitted to successfully postpone the oophorectomy given the patient’s acute state of illness. In contrast with previously used agents and surgical castration, these compounds block sexual steroids synthesis and actions directly at the target tissue level.

Raloxifene, a synthetic nonsteroidal SERM, acts on the skeleton, cardiovascular system, and central nervous system as an estrogen agonist, whereas it exhibits weak estrogenic antagonist effect on the breast and uterus. This profile is particularly useful in clinical situations like uterine leiomyomas and in BML. Preclinical studies have demonstrated that raloxifene inhibits proliferation of leiomyoma-derived cell lines in vitro and reduces the incidence of leiomyomas in Eker rats (45). Clinical data have shown in recent years that raloxifene induces a significant reduction in leiomyoma size after 1 yr of treatment in postmenopausal women (46). A randomized, placebo-controlled trial showed that the addition of raloxifene in patients treated with an LHRH agonist for uterine leiomyomas induces a greater reduction of leiomyoma sizes (47). Furthermore, the addition of raloxifene prevents LHRH agonist treatment-related bone loss in premenopausal women with uterine leiomyomas (48). There are no reports in the literature on the efficacy of raloxifene in BML; however, a similar biology of BML and uterine myomas predicted a favorable response of BML to ER modulation with raloxifene.

Interestingly, before the use of raloxifene, we were able to document synchrony between serum hormonal peaks and the episodes of pain in case 1 (Fig. 4Go). When a trial with tamoxifen was attempted, there was a clear worsening of symptoms that further supported the hormonal susceptibility of the tumor. Tamoxifen, a SERM with predominantly agonistic activity in uterine tissue, is known to induce increased myometrial volume and growth of uterine myomas (49).

Aromatase-P450, the enzyme responsible for the last step in estrogen biosynthesis, is widely distributed throughout the body. Anastrozole and other selective nonsteroidal inhibitors of this enzyme lower estradiol concentrations by acting both in the gonads and peripheral and tumor tissues. They are effective and increasingly used in ER-positive metastatic breast cancer. Interestingly, it has been shown that aromatase-P450 overexpression in uterine leiomyomas may be responsible for their growth advantage over the surrounding myometrium (50, 51). However, except for one case report describing the successful treatment with anastrozole of a symptomatic uterine leiomyoma in a perimenopausal woman (52) and the brief mention of its use in an asymptomatic patient with pulmonary BML (53), to the best of our knowledge, there are no other data in the literature about the use of AIs in leiomyomas or BML.

Our report is the first to describe a role for anastrozole and raloxifene in the treatment of BML. We believe that, just like LHRH agonists and progesterone, AIs and SERMs should find their place in the armamentarium of hormonal manipulations of BML. AIs decrease estrogen production from extragonadal sources, whereas SERMs antagonize estrogen actions in target tissues; this makes them a reasonable treatment option even in postmenopausal women. The exact place for each of these medications in the algorithmic treatment of BML is not known. Given the rarity of this entity, a randomized, controlled trial is not feasible. Combination therapy appears scientifically sound, given that all of the above-mentioned treatment options have different mechanisms of action and would thus exert a synergistic effect. Furthermore, raloxifene may provide the additional benefit of counteracting the detrimental effect of long-term LHRH agonism on bone.


   Acknowledgments
 
We thank Dr. Steffen Albrecht for providing the pathology pictures. We also thank Dr. Line Jacques for providing pictures of the tumor in case 1.


   Footnotes
 
This work was supported in part by awards (to J.A.R.) from the Research Institute of the McGill University Health Centre and the Fundacion Gran Mariscal de Ayacucho (Venezuela).

Abbreviations: AI, Aromatase inhibitor; BML, benign metastasizing leiomyoma; ER, estrogen receptor; HPF, high-power field; MRI, magnetic resonance image; PR, progesterone receptor; SERM, selective estrogen receptor modulator.

Received November 19, 2003.

Accepted March 4, 2004.


   References
Top
 Abstract
 Introduction
 Discussion
 References
 

  1. Steiner PE 1939 Metastasizing fibroleiomyoma of the uterus-a report of a case and review of the literature. Am J Pathol 15:89–109
  2. Bell SW, Kempson RL, Hendrickson MR 1994 Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases. Am J Surg Pathol 18:535–558[Medline]
  3. Hyder SM, Stancel GM 1999 Regulation of angiogenic growth factors in the female reproductive tract by estrogens and progestins. Mol Endocrinol 13:806–811[Free Full Text]
  4. Prayson RA, Hart WR 1995 Pathologic considerations of uterine smooth muscle tumors. Obstet Gynecol Clin North Am 22:637–657[Medline]
  5. Kjerulff KH, Langenberg P, Seidman JD, Stolley PD, Guzinski GM 1996 Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis. J Reprod Med 41:483–490[Medline]
  6. Robboy SJ, Bentley RC, Butnor K, Anderson MC 2000 Pathology and pathophysiology of uterine smooth-muscle tumors. Environ Health Perspect Suppl 5:779–784
  7. Pramesh CS, Saklani AP, Pantvaidya GH, Heroor AA, Naresh KN, Sharma S, Deshpande RK 2003 Benign metastasizing meningioma. Jpn J Clin Oncol 33:86–88[Abstract/Free Full Text]
  8. Yoshitomi A, Sato A, Imokawa S, Suganuma H, Tamura R, Suda T, Yagi T, Iwata M, Hayakawa H, Chida K 1994 A case of so-called benign metastasizing leiomyoma. Nihon Kyobu Shikkan Gakkai Zasshi 32:373–377[Medline]
  9. Banner AS, Carrington CB, Emory WB, Kittle F, Leonard G, Ringus J, Taylor P, Addington WW 1981 Efficacy of oophorectomy in lymphangioleiomyomatosis and benign metastasizing leiomyoma. N Engl J Med 305:204–209[Medline]
  10. Horiuchi K, Yabe H, Mukai M, Morioko H, Udagawa Y, Nozowa S, Yabe Y 1998 Multiple smooth muscle tumors arising in deep tissue of lower limbs with uterine leiomyomas. Am J Surg Pathol 22:897–901[CrossRef][Medline]
  11. Groeneveld AB, Bosma A, Ceelen TL, Kouwenhoven TJ, Meuwissen SG 1986 Progressive and fatal course of a patient with a multifocal leiomyomatous tumor. Am J Gastroenterol 81:702–707[Medline]
  12. Cho KR, Woodruff JD, Epstein JI 1989 Leiomyoma of the uterus with multiple extrauterine smooth muscle tumors: a case report suggesting multifocal origin. Human Pathol 20:80–83[CrossRef][Medline]
  13. McGinley KM, Bryant S, Kattine AA, Fitzgibbon JF, Googe PB 1997 Cutaneous leiomyomas lack estrogen and progesterone receptor immunoreactivity. J Cutan Pathol 24:241–245[CrossRef][Medline]
  14. Rao UNM, Finkelstein SD, Jones MW 1999 Comparative immunohistochemical and molecular analysis of uterine and extrauterine leiomyosarcomas. Mod Pathol 12:1001–1009[CrossRef][Medline]
  15. Tietze L, Gunther K, Horbe A, Pawlik C, Klosterhalfen B, Handt S, Merkelbach-Bruse S 2000 Benign metastasizing leiomyoma: a cytogenetically balanced but clonal disease. Hum Pathol 31:126–128[CrossRef][Medline]
  16. Wolff M, Silva F, Kaye G 1979 Pulmonary metastases (with admixed epithelial elements) from smooth muscle neoplasms. Report of nine cases, including three males. Am J Surg Pathol 3:325–342[Medline]
  17. Jautzke G, Müller-Ruchholtz E, Thalmann U 1996 Immunohistological detection of estrogen and progesterone receptors in multiple and well differentiated leiomyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases. Pathol Res Pract 192:215–223[Medline]
  18. Cramer SF, Meyer JS, Kraner JF, Camel M, Mazu MT, Tenenbaum MS 1980 Metastasizing leiomyoma of the uterus. S-phase fraction, estrogen receptor and ultrastructure. Cancer 45:932–937[CrossRef][Medline]
  19. Abell MR, Littler ER 1975 Benign metastasizing uterine leiomyoma. Multiple lymph nodal metastases. Cancer 36:2206–2213[Medline]
  20. Konomoto T, Fukuda T, Hayashi K, Kumazawa J, Tsuneyoshi M 1998 Leiomyosarcoma in soft tissue: examination of p53 status and cell proliferating factors in different locations. Hum Pathol 29:74–81[CrossRef][Medline]
  21. Sentinelli S, Covello R, Benevolo M, Licci S, Perrone Donnorso R 2002 Benign metastasizing pulmonary leiomyoma: description of a case and review of the literature. Pathologica 94:253–256[CrossRef][Medline]
  22. Evans AJ, Wiltshaw E, Koshanowski SJ, Macfarlane A, Sears RT 1986 Metastasizing leiomyoma of the uterus and hormonal manipulations. Case report. Br J Obstet Gynaecol 93:646–648[Medline]
  23. Alessi G, Lemmerling M, Vereecken L, De Waele L 2003 Benign metastasizing leiomyoma to skull base and spine: a report of two cases. Clin Neurol Neurosurg 105:170–174[CrossRef][Medline]
  24. Giove S, Scappaticci E, Baldi S, Ricci C, Minetto E 1984 Benign metastasizing uterine leiomyoma. Case report. Minerva Med 75:1819–1821[Medline]
  25. Nakanishi S, Nakano K, Hiramoto T, Shimizu M, Nakamura K, Yamane N 1999 So-called benign metastasizing leiomyoma of the lung presenting with bone metastases. Nihon Kokyuki Gakkai Zasshi 37:146–150[Medline]
  26. Takemura G, Takatsu Y, Kaitani K, Ono M, Ando F, Tanada S, Niwa H, Tankawa H, Fujiwara T, Yamabe H 1996 Metastasizing uterine leiomyoma. A case with cardiac and pulmonary metastasis. Pathol Res Pract 192:622–629[Medline]
  27. Nayar AC, McAleer EP, Tunick PA, Applebaum RM, Colvin SB, Kronzon I 2002 Benign metastasizing leiomyomatosis diagnosed by echocardiography. Echocardiography 19:571–572[CrossRef][Medline]
  28. Esteban JM, Allen WM, Schaerf RH 1999 Benign metastasizing leiomyoma of the uterus. Histologic and immunohistochemical characterization of primary and metastatic lesions. Arch Pathol Lab Med 123:960–962[Medline]
  29. Uchida T, Tokumaru T, Kojima H, Nakagawaji K, Imaizumi M, Abe T 1992 A case of multiple leiomyomatous lesions of the lung: an analysis of flow cytometry and hormone receptors. Surg Today 22:265–268[CrossRef][Medline]
  30. Boyce CR, Buddhdev HN 1973 Pregnancy complicated by metastasizing leiomyoma of the uterus. Obstet Gynecol 42:252–258[Medline]
  31. Horstmann JP, Pietra GG, Harman JA, Cole NG, Gunspan S 1977 Spontaneous regression of pulmonary leiomyomas during pregnancy. Cancer 39:314–321[CrossRef][Medline]
  32. Maheux R, Samson Y, Farid NR, Parent JG, Jean C 1987 Utilization of luteinizing hormone-releasing hormone agonist in pulmonary leiomyomatosis. Fertil Steril 48:315–317[Medline]
  33. Hague WM, Abdulwahid NA, Jacobs HS, Craft I 1986 Use of LHRH analogue to obtain reversible castration in a patient with benign metastasizing leiomyoma. Br J Obstet Gynecol 93:455–460[Medline]
  34. Sabatini R, Ferreri R, Distante G, Loizzi V, Loizzi P 2002 Benign metastasizing leiomyoma in the lung: a case report. Eur J Gynaecol Oncol 23:445–446[Medline]
  35. Nardo LG, Iyer L, Reginald PW 2003 Benign pulmonary metastasizing leiomyomatosis in pregnancy: a rare complication after cesarean section. Acta Obstet Gynecol Scand 82:770–772[CrossRef][Medline]
  36. Pawlik C, Wildberger JE, Tietze L, Matern S, Busch N 2001 Benign metastasizing leiomyoma of the lung—a rare differential diagnosis of pulmonary space-occupying lesions. Dtsch Med Wochenschr 126:551–555[CrossRef][Medline]
  37. Uchida T, Nakakawaji K, Sakamoto J, Kojima H, Murakami H, Kato J, Yasue M 1996 The effectiveness of medroxyprogesterone in the treatment of multiple metastasizing leiomyosarcomas: report of a case. Surg Today 26:138–141[CrossRef][Medline]
  38. Yang S, Fang Z, Gurates B, Tamura M, Miller J, Ferrer K, Bulun SE 2001 Stromal PR mediate induction of 17ß-hydroxysteroid dehydrogenase type 2 expression in human endometrial epithelium: a paracrine mechanism for inactivation of E2. Mol Endocrinol 15:2093–2105[Abstract/Free Full Text]
  39. Perel E, Daniilescu D, Kharlip L, Blackstein M, Killinger DW 1988 Steroid modulation of aromatase activity in human cultured breast carcinoma cells. J Steroid Biochem 29:393–399[CrossRef][Medline]
  40. Maruo T, Matsuo H, Samoto T, Shimomura Y, Kurachi O, Gao Z, Wang Y, Spitz IM, Johansson E 2000 Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids 65:585–592[CrossRef][Medline]
  41. Eisinger SH, Meldrum S, Fiscella K, le Roux HD, Guzick DS 2003 Low-dose mifepristone for uterine leiomyomata. Obstet Gynecol 101:243–250[CrossRef][Medline]
  42. Cadepond F, Ulmann A, Baulieu EE 1997 RU486 (mifepristone): mechanisms of action and clinical uses. Annu Rev Med 48:129–156[CrossRef][Medline]
  43. Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SS 1993 Regression of uterine leiomyomata in response to the antiprogesterone RU486. J Clin Endocrinol Metab 76:513–517[Abstract]
  44. Glasier AF, Wang H, Davie JE, Kelly RW, Critchley HO 2002 Administration of an antiprogesterone up-regulates estrogen receptors in the endometrium of women using Norplant: a pilot study. Fertil Steril 77:366–372[CrossRef][Medline]
  45. Walker CL, Burroughs KD, Davis B, Sowell K, Everitt JI, Fuchs-Young R 2000 Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma. J Soc Gynecol Investig 7:249–256[CrossRef][Medline]
  46. Palomba S, Sammartino A, Di Carlo C, Affinito P, Zullo F, Nappi C 2001 Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 76:38–43[CrossRef][Medline]
  47. Palomba S, Russo T, Orio F, Tauchmanova L, Zupi E, Benedetti Panici PL, Nappi C, Colao A, Lombardi G, Zullo F 2002 Effectiveness of combined GnRH analogue plus raloxifene administration in the treatment of uterine leiomyomas: a prospective, randomized, single-blind, placebo-controlled clinical trial. Hum Reprod 12:3213–3219
  48. Palomba S, Orio F, Morelli M, Russo T, Pellicano M, Zupi E, Lombardi G, Nappi C, Panici PL, Zullo F 2002 Raloxifene administration in premenopausal women with uterine leiomyomas: a pilot study. J Clin Endocrinol Metab 87:3603–3608[Abstract/Free Full Text]
  49. Kedar RP, Bourne TH, Powles TJ, Collins WP, Ashley SE, Cosgrove DO, Campbell S 1994 Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343:1318–1321[CrossRef][Medline]
  50. Bulun SE, Simpson ER, Word RA 1994 Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. J Clin Endocrinol Metab 78:736–743[Abstract]
  51. Shozu M, Murakami K, Segawa T, Kasai T, Inoue M 2003 Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman with a nonsteroidal aromatase inhibitor. Fertil Steril 79:628–631[CrossRef][Medline]
  52. Sumitani H, Shozu M, Segawa T, Murakami K, Yang HJ, Shimada K, Inoue M 2000 In situ estrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism. Endocrinology 141:3852–3861[Abstract/Free Full Text]
  53. Abramson S, Gilkeson RC 1999 Multiple pulmonary nodules in an asymptomatic patient. Chest 116:245–247 [Comment in Chest 2000;117:921–922][Free Full Text]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
H. Ishikawa, V. Fencki, E. E. Marsh, P. Yin, D. Chen, Y.-H. Cheng, S. Reisterd, Z. Lin, and S. E. Bulun
CCAAT/Enhancer Binding Protein {beta} Regulates Aromatase Expression via Multiple and Novel Cis-Regulatory Sequences in Uterine Leiomyoma
J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 981 - 991.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. G. Imir, Z. Lin, P. Yin, S. Deb, B. Yilmaz, M. Cetin, A. Cetin, and S. E. Bulun
Aromatase Expression in Uterine Leiomyomata Is Regulated Primarily by Proximal Promoters I.3/II
J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1979 - 1982.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rivera, J. A.
Right arrow Articles by Trifiro, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rivera, J. A.
Right arrow Articles by Trifiro, M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Medline Plus Health Information
*Lung Cancer
*Uterine Cancer
*Uterine Fibroids

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals