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Lymphangioleiomyomatosis (LAM) is the result of disorderly smooth muscle proliferation throughout the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways (leading to pulmonary cyst formation and pneumothorax) and lymphatics (leading to chylous pleural effusion). LAM occurs in a sporadic form, which only affects females, who are usually of childbearing age. LAM also occurs in patients who have tuberous sclerosis. more...

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The cause of the sporadic form of LAM is unknown. This type only affects women.

The proliferating smooth muscle that occurs the type of LAM seen in patients with tuberous sclerosis (TSC-LAM) has been shown to represent clones of the smooth muscle in those patients' renal angiomyolipomas, and thus is believed to represent metastases of this "benign" tumor. There is a female properandence to TSC-LAM. (reference: Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes, Chromosomes & Cancer. Dec. 2003. 38(4):376-81)


With LAM, there is diffuse replacement of the pulmonary parenchyma by thin-walled cysts measuring 2-20 mm in diameter, with equal involvement of upper and lower lung zones. On chest X-rays, superimposition of the cysts gives a reticulonodular pattern of interstitial lung disease. High-resolution CT of the chest is both more specific for the diagnosis, as well as better able to assess the degree of pulmonary involvement.


Without lung transplant, there is a 50-80% 5-year survival rate.


  • Worsening pulmonary insuffiency
  • Pneumothorax, secondary to rupture of a cyst into the pleural space
  • Chylous pleural effusions


The association of LAM with women of childbearing age suggests that hormonal stimulation plays a role in the disease process, and several approaches to treatment involve diminishing the effect of estrogen. At one time or another, therapeutic approaches have included

  • progesterone
  • oophorectomy
  • tamoxifen
  • gonadotropin-releasing hormone (GnRH) agnonists
  • androgen therapy

No therapy is clearly efficacious, and all have undesirable side-effects.

When pulmonary function deteriorates to the point where oxygenation is inadequate, lung transplantation is usually performed. Following lung transplant (usually unilateral), LAM patients have survival curves similar to other lung transplant patients.


The drug Sirolimus (also known as Rapamycin) is being investigated in clinical trials as a possible treatment. It has been shown to shrink angiomyolipomas in animals. For more information see this interview.


LAM Action (UK)

The LAM Foundation (US)


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Localized retroperitoneal lymphangioleiomyomatosis mimicking malignancy: A case report and review of the literature
From Archives of Pathology & Laboratory Medicine, 7/1/03 by Jaiswal, Vilkesh R

* Lymphangioleiomyomatosis (lymphangiomyomatosis [LAM]), a rare disease of unknown etiology that is seen only in women usually in the reproductive period, generally presents with features of pulmonary involvement. Extrapulmonary involvement, such as angiomyolipomas and retroperitoneal adenopathy, can occur in up to 75% of cases. It is very rare, however, for patients to present with features of extrapulmonary LAM. We present an unusual, localized case of LAM presenting with neurologic symptoms related to a retroperitoneal mass in a 51-year-old woman. Magnetic resonance imaging showed that the mass involved retroperitoneal lymph nodes, and a clinical diagnosis of atypical sarcoma (possibly from a uterine primary) was made. The mass was resected, and a total abdominal hysterectomy was performed. On pathologic examination, the mass showed classic histologic features of LAM with spread along lymphatic channels in the lymph nodes. Intralymphatic projections simulated lymphatic metastasis; however, the cytologic features were benign. Immunostains revealed the tumor to be positive for smooth muscle actin and desmin, but negative for HMB-45. The uterus was unremarkable, except for a subserosal leiomyoma. Although intratumoral variability for HMB-45 has recently been described, to the best of our knowledge, this is the first documented case of HMB-45-negative, histologically classic LAM. Because of the presence of several atypical features in this case, such as age, location, compressive neurologic presentation, radiologic impression of atypical sarcoma, and HMB-45 negativity, we feel that this case may represent a distinct, as yet uncharacterized variant of LAM.

(Arch Pathol Lab Med. 2003;127:879-882)

Lymphangioleiomyomatosis (lymphangiomyomatosis [LAM]) is a rare disorder that has been reported in more than 375 cases to date.1 It is thought to have a worldwide incidence of about 100 cases per year. In Europe and the United States, the incidence is estimated to be about 1 in 1 million people.2 The disease is characterized by a proliferation of morphologically distinguishable smooth muscle in the lymphatics and lymph nodes of the pulmonary parenchyma in most cases. However, the disease has also been reported elsewhere in the mediastinum, as well as in the retroperitoneum. Lymphangioleiomyomatosis occurs almost exclusively in women, usually during their reproductive years.3 It has also been associated with tuberous sclerosis, an autosomal dominant, tumor suppressor gene syndrome characterized by seizures, mental retardation, and tumors in the brain, heart, and kidney (angiomyolipoma).2,4 The typical presenting symptoms of the more common pulmonary form of LAM include progressive dyspnea, pneumothorax, and chylous pleural effusion.2,5 We report an unusual case of a primary localized form of LAM limited to the retroperitoneum that was not associated with any stigmata of tuberous sclerosis and was negative for HMB-45.


A 51-year-old woman presented to a clinic with a chief complaint of back pain for more than 1 year. The patient was initially diagnosed with sciatica and treated. However, she developed numbness and tingling in her left lower limb. A magnetic resonance imaging study revealed a left distal periaortic and proximal left common iliac region retroperitoneal mass that had radiologic characteristics suggestive of a "soft tissue" mass. The dimensions of the mass were 12.3 cm superior to inferior, 3.5 cm side to side, and 2.0 cm anterior to posterior. On Ti imaging, the mass was hypointense, and on T2 imaging it was homogenously hyperintense (Figure 1). The aortic and iliac vessels appeared uninvolved. Additional studies revealed a small serosal uterine mass. The radiologic differential diagnosis included a lymphvascular lesion and an atypical leiomyosarcoma, possibly metastatic from a uterine primary. The mass was in the expected location of the left ureter; however, no ureteral obstruction was noted. No pelvic adenopathy was identified. The patient underwent an exploratory laparotomy for the removal of the retroperitoneal mass, as well as total abdominal hysterectomy, bilateral salpingo-oophorectomy, and gynecologic/oncologic staging procedures. The patient had an unremarkable postoperative course and is well several months after her procedure. A computed tomographic scan of the abdomen demonstrated no evidence of disease 6 months after the procedure.


A needle biopsy performed at an outside institution and diagnosed as a "soft tissue lesion, favor low-grade leiomyosarcoma" was reviewed and a diagnosis of "vascular smooth muscle neoplasm, favor vascular leiomyoma" was made. Immunostains on the biopsy showed the cells to be positive for caldesmon and negative for cytokeratin, CD34, epithelial membrane antigen, factor XIII, S100, and Bcl-2. An endometrial biopsy and endocervical curettage specimen revealed only benign tissue.

Pathologic examination of the retroperitoneal resection specimen showed 2 masses, measuring 5.0 cm and 4.0 cm and consisting of irregular segments of matted lymph nodes. A frozen section showed lymph node tissue involved by a spindle cell neoplasm. The hysterectomy/salpingectomy specimen consisted of a 72-g uterus with attached bilateral fallopian tubes and ovaries. There was a single, 0.3-cm, white, rubbery, subserosal nodule on the uterus. No other masses were identified in the hysterectomy/salpingectomy specimen. The remainder of the lymph nodes submitted as part of the staging procedure showed no distinguishing gross abnormalities.

Microscopically, sections from the retroperitoneal masses consisted of spindle cell proliferation involving the lymph node and extending into adjoining soft tissue (Figure 2). The bundles of uniform spindle cells were separated by large numbers of thin-walled and variably dilated vascular channels. The individual cells had a bland morphology, oval to elongated vesicular nuclei, and abundant pink cytoplasm. No mitotic figures were identified (Figure 3). There was variable focal involvement of the lymph nodes included in the mass in the form of smooth muscle proliferation involving the subcapsular sinuses, as well as deep-seated lymphatic spaces. In some areas, there were intralymphatic projections simulating lymphatic tumor emboli, but on closer scrutiny these were found to be bland smooth muscle extensions from the thickened lymphatic channel walls (Figure 4). In addition to the 2 large masses in the retroperitoneum, focal involvement of the right iliac and left pelvic nodes was also noted.

Immunostains revealed the tumor cells to be diffusely positive for smooth muscle actin (Dako Corporation, Carpinteria, Calif) and desmin (Dako). The vascular network was highlighted by stain for CD34. The tumor cells, however, were negative for CD34 (Signet, Dedham, Mass), 5100 (Dako), PGP9.5 (Biogenesis, Brentwood, NH), chromogranin (Dako), and HMB-45 (Dako). The MIB-1 (Dako) proliferation marker labeled less than 5% of the tumor nuclei. Immunohistochemistry followed by image analysis quantitation revealed that the Ki-67 (MIB-1) proliferation index was 4%, whereas the analysis was negative for estrogen and progesterone receptors and CD117. Medium positive expression for Cox-2 was noted.


Lymphangioleiomyomatosis is a rare disorder that presents in women at a mean age of 37 years (range, 18-89 years), predominantly with pulmonary symptoms. The typical presenting symptoms include dyspnea (67%), pneumothorax (25%), hemoptysis (12%), cough (12%), and chest pain (10%).2,6 In addition, LAM can be divided into a sporadic form, as in this case, or a tuberous sclerosis-- associated form.2,4 Although LAM most commonly involves the pulmonary system, it can secondarily involve the retroperitoneum. Our case exhibited no clinical features of lung involvement; the primary involvement was of the retroperitoneum, presenting as back pain. The clinical and pathologic findings of patients with clinically significant extrapulmonary LAM are summarized in the Table.

The typical histology of LAM shows a proliferation of smooth muscle arranged in fascicular, trabecular, and papillary patterns associated with slitlike vascular channels. The proliferating smooth muscle cells can vary from small, spindle-shaped cells to large epithelioid cells.2,3 In this case, the tumor cells were spindle shaped and involved both the periphery and the central portions of the lymph nodes. There were small spindle cell nodules, as well as proliferating bundles along the lymphatics extending deeper into the lymph nodes. Occasionally, the tumor formed intraluminal projections, which could be confused with vascular invasion.

A critical issue in this case was the clinical, radiologic, and to some extent histologic differential diagnosis with a metastatic sarcoma. As evident from the Table, none of the reported cases in the literature had compressive neurologic presentation, as was seen in the current case. Radiologically, the mass had the appearance of a soft tissue lesion; however, no ureteral compression or local infiltration was noted. Histologically, the pattern of spread along lymphatic spaces and intralymphatic projections simulating lymphatic tumor emboli were features more common in malignant neoplasms; however, the uniformly bland morphology favored a benign proliferation. Also, the absence of mitoses and the low MIB-1 proliferation index were not consistent with a diagnosis of leiomyosarcoma. The overall histologic picture was typical for LAM. The uterine mass, which was clinically suspected to be a leiomyosarcoma, was histologically found to be a typical leiomyoma. The presence of marked vascularity in the retroperitoneal mass raised the differential of vascular leiomyomatosis. However, the involvement of lymph nodes outside the main masses and absence of vascular involvement on magnetic resonance angiography ruled out that possibility. Other differential diagnoses included intranodal leiomyoma, but this disease is reported only in male patients with AIDS,7 whereas LAM is seen almost exclusively in women.2,3 The possibilities of paraganglioma and nerve sheath tumor were ruled out by the absence of staining for chromogranin, S100, and PGP9.5.

In a recent report of 12 extrapulmonary LAM cases,8 HMB-45 positivity was noted in 11 cases, and in 1 case the lesion was reported to be HMB-45 negative. However, because adequate tissue for immunostaining was not available, the reported negativity could not be confirmed.8 In this case, however, the proliferating smooth muscle cells did not stain with HMB-45. Immunostaining for HMB-45 is a highly sensitive way to identify LAM cells and cells of angiomyolipomas. The antibody is more often used to recognize a 100-kd glycoprotein localized in premelanosomes in melanocytic lesions. The etiology of HMB-45 positivity in LAM is not known. It has recently been shown that the percentage of HMB-45-positive LAM cells can vary among patients from 17% to 67%, and the percent positivity may be inversely related to cellular proliferation.9 Moreover, HMB-45 positivity has been described to be stronger in epithelioid cells at the periphery of the lesion.2 The current case was completely negative for HMB-45 expression, despite having a typical histologic picture of LAM. To the best of our knowledge, this is the first documented case of HMB-45-negative LAM. Absence of HMB-45 staining in the current case may correlate with tumor cellularity and absence of epithelioid cells. In addition to smooth muscle markers, LAM cells have also been shown to variably express estrogen and progesterone receptors.10 The current case was also negative for these hormone receptors.

Although the exact pathogenesis is unclear, LAM occurs only in women, usually during their reproductive years. Since the disease onset or exacerbation is often preceded by pregnancy or hormone therapy, a hormonal cause has been suggested.9 A proportion of cases are associated with tuberous sclerosis.2,4 There now appears to be genetic evidence for this link. It has been shown that there is loss of heterozygosity of the TSC2 gene on chromosome 16 in both sporadic LAM and LAM from patients with tuberous sclerosis.2,4 This finding may provide a pathogenetic mechanism for LAM and possibly lead to novel therapeutic approaches. Currently, however, resection remains a common therapeutic approach. Patients with retroperitoneal LAM have been reported to develop pulmonary LAMB; therefore, close follow-up is recommended.

To conclude, we present an unusual case of localized retroperitoneal LAM in a 51-year-old woman who presented with sciatica. Magnetic resonance imaging revealed a mass involving retroperitoneal lymph nodes, giving the impression of an atypical sarcoma, likely with metastasis and possibly from a uterine primary. Pathologic examination revealed it to be a histologically classic LAM that was completely negative for HMB-45. The atypical features in the current case include the patient's age, localized retroperitoneal disease, neurologic presentation, radiologic differential with a sarcoma, and HMB-45 negativity. We believe that because of the presence of these atypical features, this case may represent a distinct clinicopathologic subtype or variant of LAM.


1. Johnson SR, Tattersfield AE. Clinical experience of lymphangioleiomyomatosis in the UK. Thorax. 2000;55:1052-1057.

2. Johnson SR, Tattersfield AE. Lymphangioleiomyomatosis. Semen Respir Crit Care Med. 2002;23:85-92.

3. Weiss S, Goldblum JR. Soft Tissue Tumors. 4th ed. St Louis, Mo: Mosby; 2001:973-981.

4. Yu J, Astrinidis A, Henske E. Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis. Am J Resp Crit Care Med. 2001;164(8 pt 1):1537-1540.

5. Johnson S, Davey D, Cibull M, Schwartz R, Strodel W. Lymphangiomyomatosis. Am Surg. 1993;59:395-399.

6. Kelly J, Moss J. Lymphangiomyomatosis. Am J Med Sci. 2001;321:17-25.

7. Starasoler L, Vuitch F, Albores-Saavedra J. Intranodal leiomyoma. Ami Clin Pathol. 1991;95:858-862.

8. Matsui K, Tatsuguchi A, Valencia J, et al. Extrapulmonary lymphangiomyomatosis (LAM): clinicopathologic features in 22 cases. Hum Pathol. 2000;31: 1242-1248.

9. Chu SC, Horiba K, Usuki J, et al. Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis. Chest. 1999;115:1041-1052.

10. Torres VE, Bjornsson J, King BF, et al. Extrapulmonary lymphangioleiomyomatosis and lymphangiomatous cysts in tuberous sclerosis complex. Mayo Clin Proc. 1995;70:641-648.

11. Bhattacharyya AK, Balogh K. Retroperitoneal lymphangiomyomatosis: a 36-year benign course in a postmenopausal woman. Cancer. 1985;56:11441146.

12. Chan J, Tsang W, Pau M, et al. Lymphangiomyomatosis and angiomyolipoma: closely related entities characterized by hamartomatous proliferation of HMB-45 positive smooth muscle. Histopathology 1993;22:445-455.

13. Gawad KA, Knoefel WT, Izbicki JR, Schroder S, Broelsch CE. Generalized lymphangiomyomatosis presenting as a retroperitoneal tumor. Eur] Surg. 1996; 162:583-585.

14. Lack E, Dolan M, Finisio J, et al. Pulmonary and extrapulmonary lymphangiomyomatosis. Am J Surg Pathol. 1986;10:650-657.

Vilkesh R. Jaiswal, MD; Julie Baird, MD; Jason Fleming, MD; David Scott Miller, MD; Suash Sharma, MD; Kyle Molberg, MD

Accepted for publication February 26, 2003.

From the Departments of Pathology (Drs Jaiswal, Baird, Sharma, and Molberg), Surgery (Dr Fleming), and Gynecologic Oncology (Dr Miller), University of Texas Southwestern Medical Center, Dallas.

Reprints: Suash Sharma, MD, Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9073 (e-mail:

Copyright College of American Pathologists Jul 2003
Provided by ProQuest Information and Learning Company. All rights Reserved

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