Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2

Tuberous sclerosis (TSC) is a rare, genetically determined disorder / familial tumor syndrome, currently diagnosed using specific clinical criteria proposed by Gomez, including the presence of multiorgan hamartomas. Pulmonary involvement in TSC is well known as pulmonary lymphangioleiomyomatosis (LAM), which has an incidence of 1-2.3% in TSC patients. LAM has immunohistochemical expression of both smooth-muscle actin and a monoclonal antibody specific for human melanoma, HMB-45. It has recently been reported that multifocal micronodular pneumocyte hyperplasia (MMPH) associated with TSC should be considered as a distinct type of lung lesion, whether it occurs with or without LAM. Two predisposing genes have been found in families affected by TSC; approximately half of the families show linkage to TSC1 at 9q34.3, and the other half show linkage to TSC2 at 16p13.3. TSC genes are considered to be tumor suppressor genes, and mutations in them may lead to abnormal differentiation and proliferation of cells. Tuberin, the TSC2 gene product, has recently been found to be expressed in LAM and MMPH. In this article we discuss the histogenesis and genetic abnormalities of neoplastic lesions associated with TSC, and we review the current understanding of the pathogenesis of pulmonary hamartomatous lesions such as LAM and MMPH in TSC.     

Multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis with a TSC2 gene.

A 45-year-old woman with a long-standing diagnosis of tuberous sclerosis (TSC) is presented. She has multifocal micronodular pneumocyte hyperplasia (MMPH) and lymphangioleiomyomatosis (LAM) of the lung, together with the detection of TSC2 gene mutation. During surgery for spontaneous pneumothorax, an open-lung biopsy was performed. Micronodules were well defined, measuring approximately 4 mm in diameter. These MMPHs were histologically composed of papillary proliferation of Type II pneumocytes, with positive immunoreactivity of keratin and surfactant apoprotein. The cystlike spaces, with dilatation and destruction of air spaces, were diffusely formed, and the walls were composed of the spindle cells. Such LAM showed positive immunoreactivity for HMB-45 (a monoclonal antibody specific for human melanoma) and tuberin (the gene product of TSC2). On germline mutation analysis using leukocytes of the present patient, a TSC2 gene mutation was confirmed as a deletion of G (or g) on Exon 9 by polymerase chain reaction-single-strand conformational polymorphism. However, no mutation was detected in her son. With microdissection analysis using paraffin-embedding lung tissues, LOH of the TSC2 gene preliminarily was detected in a LAM lesion but not in MMPH. It is suggested that MMPH, in addition to LAM, could be another pulmonary lesion in TSC patients and that the detection of TSC2 and/or TSC1 gene could essentially be useful for the pathogenesis of MMPH and LAM in TSC patients.     

Glutamine synthetase interpretation in hepatocellular adenoma

Lymphangioleiomyomatosis (LAM) of the lung is a rare low-grade malignancy affecting primarily women of childbearing age. LAM is characterized by the proliferation of SMA and HMB-45 positive spindle-shaped and epithelioid cells throughout the lung in the form of discrete lesions causing cystic destruction and ultimately respiratory insufficiency. LAM occurs sporadically or in patients with tuberous sclerosis complex (TSC) and is etiologically linked to mutations in the TSC1 and TSC2 genes. Although LAM cells are known to express estrogen and progesterone receptors (ER and PR, respectively), their respective expression level was never determined. Therefore, here we measured the immunohistochemical expression of ERs and PRs in a large series of pulmonary LAM cases using the Aperio Spectrum Analysis Platform. Our case series comprised open lung biopsy specimens from 20 LAM patients and lungs explanted during the course of lung transplant from 24 patients. All cases were positive for ER and PR. PR expression was statistically significantly higher than ER in 80 % of the biopsies while ER predominated only in one case. Specimens from explanted cases of LAM had relatively fewer PR-positive nuclei. As a result, PR expression was significantly higher than ER in 38 % of the cases, whereas ER predominated in 33 %. Overall, PR expression predominated in 57 % of cases and ER in 21 %. These data indicate that PR frequently prevails over ER in pulmonary LAM. LAM is unusual in its high PR/ER ratio; other female neoplasms show a definite prevalence of ER. Our findings therefore warrant further study of PR function in LAM.     

Leiomyomatosis-like lymphangioleiomyomatosis of the colon in a female with tuberous sclerosis.

Smooth muscle lesions of the large bowel, excluding the rectum, are generally rare, and diffuse smooth muscle lesions, termed leiomyomatosis, are even rarer. In this report, we document, for the first time, leiomyomatosis-like lymphangioleiomyomatosis (LAM) of the ascending, transverse, and descending colon in association with bilateral renal angiomyolipoma (AML) in a 30-year-old Chinese female with tuberous sclerosis complex (TSC). She presented with protracted constipation for which a colectomy was performed. Histology disclosed multiple confluent nodular CD34 and CD117 negative smooth muscle proliferation within the large bowel wall, whereas the renal biopsy revealed typical features of AML. Interestingly, the epithelioid smooth muscle cells of both the colonic and renal lesions were HMB45 positive, suggesting that leiomyomatosis-like LAM of the colon, pulmonary LAM and AML are closely related entities. The patient remained free of complications for the last five years after surgery. Leiomyomatosis-like LAM of the large bowel probably represents another manifestation of the tendency of TSC to be associated with proliferative lesions.     

Multifocal micronodular pneumocyte hyperplasia in a postmenopausal woman with tuberous sclerosis

We report a peculiar case of multifocal micronodular pneumocyte hyperplasia (MMPH) without association of pulmonary lymphangioleiomyomatosis (LAM) in a 56-year-old postmenopausal woman with tuberous sclerosis. This case is surmised to be a forme fruste of tuberous sclerosis. Computed tomography demonstrated multiple micronodules, measuring up to 5 mm in size, present in the bilateral lung fields, but no cystic changes. A proliferation of pleomorphic type-II pneumocytes lining the thickened alveolar septa in an adenomatoid pattern, with an associated increase in alveolar macrophages, was observed without typical nuclear atypia. In fully developed lesions, the ingrowth of more proliferating type-II pneumocytes into the thickened alveolar septa and macrophages filling the alveolar lumens were characteristic findings. Proliferation of immature smooth muscle cells suggesting LAM was not observed. Positive immunohistochemical stains for cytokeratin, epithelial membrane antigen, and surfactant apoproteins A and B, and negative staining for HMB45, alpha-1 smooth muscle actin, desmin, and carcinoembryonic antigen confirmed the characteristics of alveolar lining cells in each MMPH lesion. MMPH associated with tuberous sclerosis in the postmenopausal woman appears to be similar to that described in premenopausal women. The present case is familial rather than sporadic and suggests no relationship between the development of MMPH and the underlying hormonal state. Received: 15 June 1999 / Accepted: 19 October 1999     

PEComas: the past,the present and the future

The perivascular epithelioid cell (PEC) is a cell type constantly present in a group of tumors called PEComas. PEC expresses myogenic and melanocytic markers, such as HMB45 and actin. Recently, recurrent chromosomal alterations have been demonstrated in PEC. At present, PEComa is a widely accepted entity. In the past 10 years, the use of this term has allowed to report and describe numerous cases permitting to start highlighting the biology of this group of lesions. PEComas are related to the genetic alterations of tuberous sclerosis complex (TSC), an autosomal dominant genetic disease due to losses of TSC1 (9q34) or TSC2 (16p13.3) genes which seem to have a role in the regulation of the Rheb/mTOR/p70S6K pathway. There are some open questions about PEComas regarding its histogenesis, the definition of epithelioid angiomyolipoma and the identification of the histological criteria of malignancy. An innovative therapeutic trial using rapamycin is under way for tumors occurring in TSC such as renal angiomyolipoma and lymphangioleiomyomatosis. Its success could provide the rationale for the use of the same drug in other lesions composed of PECs, especially in the malignant ones.     

β-Catenin is a useful adjunct immunohistochemical marker for the diagnosis of pulmonary lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease leading to cystic destruction of the lung parenchyma and is associated with abnormal smooth muscle proliferation affecting airways, lymphatics, and blood vessels. LAM occurs sporadically or in association with the tuberous sclerosis complex (TSC). Recent evidence demonstrates the role of aberrant β-catenin signaling in TSC. To further understand the pathogenesis of LAM and to examine the diagnostic usefulness of β-catenin, we examined protein expression in 28 pulmonary LAM cases and 10 cases of renal angiomyolipoma resected from patients with sporadic LAM. Immunohistochemical analysis was performed for established markers of LAM cells (HMB45, estrogen receptor [ER]-α, and progesterone receptor [PR]) and β-catenin. All LAM cases were positive for β-catenin and demonstrated high specificity with overall immunoreactivity superior to HMB45, ER-α, and PR. Similar expression was demonstrated in renal angiomyolipoma. Our results indicate that β-catenin is a useful marker of LAM and may be clinically useful in the diagnostic setting.     

Pulmonary choriostoma in a case of tuberous sclerosis complex

A 52 years old lady was diagnosed to have Tuberous Sclerosis Complex (TSC) on the basis of 2 major and one minor criterion. She had family history of similar complaints in her sister and two sons. There was involvement of kidney in the form of angiomyolipoma, skin in the form of facial angiofibroma and teeth with a dental pit. She had an unusual lung involvement in the form of multiple small choristomas. Choristoma was diagnosed on transbronchial lung biopsy and was present in the form of disorganised striated muscles. The reported pulmonary manifestations of TCS i.e. lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH) are types of hamartomas. Hamartomas and choristomas are both types of disorganized tissue. ‘Choristoma’of lung in TSC however is not reported. Clinopathological correlation of pulmonary hamartoma and choristoma, and treatment in TSC has been discussed.KEY WORDS: Tuberous sclerosis, choristoma, hamartoma     

Metastasis of benign tumor cells in tuberous sclerosis complex

Lymphangiomyomatosis (LAM) is a life-threatening lung disease affecting almost exclusively young women. Histologically, LAM is characterized by the diffuse, bilateral proliferation of abnormal smooth muscle cells and cystic degeneration of the lung parenchyma. LAM can occur as an isolated disorder (sporadic LAM), or in women with tuberous sclerosis complex (TSC-LAM). Patients with both sporadic LAM and TSC-LAM often have benign renal angiomyolipomas. The smooth muscle cells within the angiomyolipomas are very similar to the smooth muscle cells in pulmonary LAM. Genetic data suggest that pulmonary LAM is the result of a highly unusual disease mechanism: the metastasis of benign cells. If LAM is the result of metastasis, it is remarkable that the metastasis occurs in women, but not in men. In this review, I discuss the genetic data supporting this metastatic model for LAM. The implications of the model for the functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, will also be considered. Hamartin and tuberin may play functional roles in the suppression of cell migration and/or metastasis, possibly through their regulation of the small GTPase Rho.     

Association of lymphangioleiomyomatosis (LAM) with endosalpingiosis in the retroperitoneal lymph nodes: report of two cases

We report 2 patients in whom pulmonary lymphangioleiomyomatosis (LAM) affected the retroperitoneal lymph nodes and was associated with endosalpingiosis. These lesions were large, encapsulated masses with multiple cysts containing chylous fluid. Both were characterized by proliferating LAM cells that formed fascicles separated by slit-like channels. Some cysts were lined by ciliated epithelium resembling that of Fallopian tubes. Other cysts were lined either by flattened endothelial cells or by a mixture of these cells and epithelial cells. Many LAM cells gave a positive reaction with HMB-45 antibody. Most LAM cells in fascicles were reactive for alpha-smooth muscle actin and desmin. In 1 patient, many of the epithelial cells and some of the subjacent LAM cells were positive for estrogen and progesterone receptors. In conclusion, immunostaining with HMB-45 antibody and markers for smooth muscle cells can be helpful in the evaluation of problems in the differential diagnosis of lesions of extrapulmonary LAM, particularly those involving the genital system.     

Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis

Pulmonary lymphangioleiomyomatosis (LAM) is a destructive lung disease characterized by a diffuse hamartomatous proliferation of smooth muscle cells (LAM cells) in the lungs. Pulmonary LAM can occur as an isolated form (sporadic LAM) or in association with tuberous sclerosis complex (TSC) (TSC-LAM), a genetic disorder with autosomal dominant inheritance with various expressivity resulting from mutations of either the TSC1 or TSC2 gene. We examined mutations of both TSC genes in 6 Japanese patients with TSC-LAM and 22 patients with sporadic LAM and identified six unique and novel mutations. TSC2 germline mutations were detected in 2 (33.3%) of 6 patients with TSC-LAM and TSC1 germline mutation in 1 (4.5%) of 22 sporadic LAM patients. In accordance with the tumor-suppressor model, loss of heterozygosity (LOH) was detected in LAM cells from 3 of 4 patients with TSC-LAM and from 4 of 8 patients with sporadic LAM. Furthermore, an identical LOH or two identical somatic mutations were demonstrated in LAM cells microdissected from several tissues, suggesting LAM cells can spread from one lesion to another. Our results from Japanese patients with LAM confirmed the current concept of pathogenesis of LAM: TSC-LAM has a germline mutation but sporadic LAM does not; sporadic LAM is a TSC2 disease with two somatic mutations; and a variety of TSC mutations causes LAM. However, our study indicates that a fraction of sporadic LAM can be a TSC1 disease; therefore, both TSC genes should be examined, even for patients with sporadic LAM. Received: August 30, 2001 / Accepted: November 2, 2001     

Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: Role for tumor suppressor TSC2

The TSC1 and TSC2 proteins, which function as a TSC1/TSC2 tumor suppressor complex, are associated with lymphangioleiomyomatosis (LAM), a genetic disorder characterized by the abnormal growth of smooth muscle-like cells in the lungs. The precise molecular mechanisms that modulate LAM cell growth remain unknown. We demonstrate that TSC2 regulates LAM cell growth. Cells dissociated from LAM nodules from the lungs of five different patients with LAM have constitutively activated S6K1, hyperphosphorylated ribosomal protein S6, activated Erk, and increased DNA synthesis compared with normal cells from the same patients. These effects were augmented by PDGF stimulation. Akt activity was unchanged in LAM cells. Rapamycin, a specific S6K1 inhibitor, abolished increased LAM cell growth. The full-length TSC2 was necessary for inhibition of S6 hyperphosphorylation and DNA synthesis in LAM cells, as demonstrated by co-microinjection of the C-terminus, which contains the GTPase activating protein homology domain, and the N-terminus, which binds TSC1. Our data demonstrate that increased LAM cell growth is associated with constitutive S6K1 activation, which is extinguishable by TSC2 expression. Loss of TSC2 GAP activity or disruption of the TSC1/TSC2 complex dysregulates S6K1 activation, which leads to abnormal cell proliferation associated with LAM disease.     

Tissue-specific renin-angiotensin system in pulmonary lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM), a multisystem disease found in middle-aged women, is characterized by cystic lung destruction and abdominal tumors (e.g., angiomyolipomas, lymphangioleimyomas), resulting from proliferation of abnormal-appearing, smooth muscle-like cells (LAM cells). The LAM cells, in combination with other cells, form nodular structures within the lung interstitium and in the walls of the cysts. LAM cells contain mutations in the tuberous sclerosis complex TSC1 and/or TSC2 genes, which lead to dysregulation of the mammalian target of rapamycin, affecting cell growth and proliferation. Proliferation and migration of vascular smooth muscle cells and production of angiogenic factors are regulated, in part, by angiotensin II. To determine whether a LAM-specific renin-angiotensin system might play a role in the pathogenesis of LAM, we investigated the expression of genes and gene products of this system in LAM nodules. mRNA for angiotensinogen was present in RNA isolated by laser-captured microdissection from LAM nodules. Angiotensin I-converting enzyme and chymase-producing mast cells were present within the LAM nodules. We detected renin in LAM cells, as determined by the presence of mRNA and immunohistochemistry. Angiotensin II type 1 and type II receptors were identified in LAM cells by immunohistochemistry and immunoblotting of microdissected LAM nodules. Angiotensin II is localized in cells containing alpha-smooth muscle actin (LAM cells). A LAM-specific renin-angiotensin system appears to function within the LAM nodule as an autocrine system that could promote LAM cell proliferation and migration, and could represent a pharmacologic target.     

肾混合性上皮间质肿瘤和成人囊性肾瘤的临床病理学观察

目的 探讨肾混合性上皮间质肿瘤(MEST)和成人囊性肾瘤的临床病理学特点、免疫表型和鉴别诊断.方法 通过HE和免疫组织化学染色(EnVision法)分析5例MEST和4例囊性肾瘤,并复习有关文献.结果 5例MEST均为女性,中位年龄45岁;囊性肾瘤中男性3例,女性1例,中位年龄41岁;临床表现为腰痛或血尿.大体观察:MEST界清无包膜,切面未见明显出血坏死,其中3例旱实性,1例呈囊实性,另1例呈多囊性其间为厚的纤维分隔;囊性肾瘤有包膜,切面呈多囊性,囊壁薄,无实区和坏死厌.镜下观察:MEST由不等量增生、囊性扩张的腺上皮与不同排列方式的梭形间质细胞混合组成,两种细胞成分无明显异形,2例局部衬覆子宫内膜样或输卵管样上皮;囊性肾瘤为多房囊腔组织,囊壁薄,内衬单层上皮.免疫表型:9例上皮细胞CKpan、上皮细胞膜抗原(EMA)均呈阳性表达;MEST间质梭形细胞波形蛋白(5/5)、平滑肌肌动蛋白(SMA,3/5)、结蛋白(4/5)、CD10(5/5)、ER(4/5)和PR(4/5)呈阳性表达,HMB45、CD34、CD117和S-100蛋白呈阴性;囊性肾瘤间质成分波形蛋白(4/4)、SMA(4/4)、结蛋白(1/4)阳性,ER(3/4)和PR(1/4)少量细胞阳性,CDIO、HMB45、CD34、CDll7和S-100蛋白呈阴性.结论 (1)MEST和囊性肾瘤均是少见的肾脏肿瘤,大多为良性.(2)MEST间叶细胞呈不同程度的平滑肌或肌纤维母细胞分化;2例有MaUerian管上皮分化特征.(3)MEST和成人囊性肾瘤在形态学和免疫表型上有很多相似性,可能为位于同一肿瘤谱系两端的肿瘤.     

Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases

We describe the lesions of extrapulmonary lymphangioleiomyomatosis (LAM) affecting the lymph nodes of the mediastinum and retroperitoneum in 22 women (mean age +/- SD, 42.4+/-10.5 years). In most of these patients, the diagnosis of extrapulmonary LAM preceded that of pulmonary LAM, usually by 1 to 2 years. Eleven patients had distinct symptoms, including chylous pleural effusion and/or ascites, abdominal pain, and palpable abdominal masses. In the other 11 patients, the masses caused no symptoms. Well-circumscribed, encapsulated masses, measuring up to 20 cm in size, occurred in the mediastinum in 2 patients, the upper retroperitoneum in 15, extensive areas of the retroperitoneum in 2, and the pelvis in 3. The masses exceeding 3 cm in diameter contained large, multiple cysts filled with yellow-tan chylous fluid. Histologically, the masses were characterized by a proliferation of smooth muscle cells (LAM cells) arranged in fascicular, trabecular, and papillary patterns, which were associated with slit-like vascular channels. The LAM cells varied from small, spindle-shaped cells to large epithelioid cells. Immunohistochemical studies showed a strong reactivity of most LAM cells for alpha-smooth muscle actin and smooth muscle myosin heavy chain and a weak to moderate reactivity of a lesser number of cells for desmin and nonmuscle myosin heavy chain II-B. A reaction for HMB-45 and estrogen and progesterone receptors was observed mainly in epithelioid LAM cells. These patterns of reactivity are similar to those observed in pulmonary LAM. However, the chylous cysts are not a feature of pulmonary LAM and are thought to result from obstruction of lymphatics.     

Selected case from the Arkadi M. Rywlin International Pathology Slide Seminar: Sporadic lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a systemic, progressive, and fatal condition affecting almost exclusively women in their reproductive years. LAM most often occurs as a sporadic disease, but also occurs in women with tuberous sclerosis complex (TSC) (syndromic LAM). There are no pathologic differences between sporadic and syndromic LAM. Sporadic LAM is a rare disease with prevalence of approximately 1 to 2 cases per million women in the United States and among populations of white descent, and is even rarer among Asian and African individuals. Syndromic LAM affects 4% to 5% of women with TSC. Sporadic LAM is often found also in association with renal angiomyolipoma, the most common sign of TSC, but LAM associated with angiomyolipoma does not define TSC. Although LAM is not diagnostic for TSC either in isolation or in association with angiomyolipoma, still it is considered by some researchers as an incomplete expression (forme fruste) of TSC. LAM may involve the lungs and the axial lymphatics and lymph nodes of the thorax and retroperitoneum. In sporadic LAM, thoracic, intraabdominal, and cervical lymph nodes can be involved with or without lung involvement. The diagnosis of LAM is often delayed. A case of LAM in a young lady, which was complicated with pleural and peritoneal chylous effusions, is presented. The diagnosis was first made on a retroperitoneal lymph node biopsy. The patient had a prolonged prior history of respiratory problems owing to lung involvement, and eventually died 2 years after diagnosis. Focus on the clinicopathologic diagnosis of TSC is also made.     

Lymphangioma and congenital pulmonary lymphangiectasis: a histologic, immunohistochemical, and clinicopathologic comparison.

Lymphangioma (LA) and congenital pulmonary lymphangiectasis (CPL) are part of a spectrum of lymphatic disorders less well characterized than other vascular tumors and malformations. Recent studies showed proliferative and involutional growth phases for hemangiomas that distinguish them from malformations. We investigated immunohistochemical reactivity and proliferative activity to determine whether a similar diagnostically/prognostically useful pattern exists for LA, comparing LA with CPL as a malformative lesion. Immunohistochemical tests for vimentin, Factor VIII-related protein, CD31, CD34, CD45RO, smooth muscle actin, Type IV collagen, MIB-1, bcl-2, and topoisomerase IIalpha were performed on 20 LAs and 10 cases of CPL. Giemsa staining was also performed to quantitate mast cells. Clinicopathologic correlation was performed by medical record review. LA and CPL shared a similar immunohistochemical profile for vimentin, Factor VIII-related protein, CD31, CD34, smooth muscle actin, CD34, and, to a lesser extent, CD45RO. CD31 and CD34 displayed the most uniform pattern of endothelial reactivity, although CD34 had high background staining. bcl-2 was negative. Four LAs exhibited focal low reactivity for MIB-1 and topoisomerase IIalpha; recent infection and thrombosis were associated conditions. LAs displayed seven-fold more mast cells and more reactive T lymphocytes than did cases of CPL. LA and CPL had similar immunohistochemical profiles; LA resembled vascular malformations more than hemangiomas. CD31 and CD34 were useful for detection of small lymphatics at resection margins of LA, a feature associated with recurrence. MIB-1 and topoisomerase IIalpha expression were associated with inflammatory, thrombotic, or reactive processes and were not diagnostically useful. Abundant mast cells, which also were noted in other soft tissue neoplasms, prompt speculation concerning their role in the growth of LAs.     

Cystic pulmonary metastases of endometrial stromal sarcoma of the uterus, mimicking lymphangiomyomatosis: A case report with immunohistochemistry of HMB45

A case of endometrial stromal sarcoma (ESS) showed cystic pulmonary metastases mimicking lymphangiomyomatosis (LAM). A 58-year-old female, who had undergone total hysterectomy for low-grade ESS 16 years previously, had repeated bouts of pneumothorax. Multiple then-walled cysts in the perlpheral lung were revealed by radiological examinations. In an open-lung blopsy specimen, cystlc lesions were surrounded by layers of spindle-shaped cells of varying thickness that resembled LAM. However, In addltion to subtle histological differences from LAM, HMB45 (antimelanoma antibody) showed positive In LAM (n=3), but was negative in ESS (M) and the cystlc leslons of this case. Using myogenic markers (desmin and α-smooth muscle actin), metastatlc ESS could be immunohistochemically differentiated from mesenchymal cystlc hamartoma (n=1). HMB45 Immunohistochemistry is useful in the differential diagnosis of cystic puimonary lesions.     

Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis

The loss of TSC2 function is associated with the pathobiology of lymphangioleiomyomatosis (LAM), which is characterized by the abnormal proliferation, migration, and differentiation of smooth muscle-like cells within the lungs. Although the etiology of LAM remains unknown, clinical and genetic evidence provides support for the neoplastic nature of LAM. The goal of this study was to determine the role of tumor suppressor TSC2 in the neoplastic potential of LAM cells. We show that primary cultures of human LAM cells exhibit increased migratory activity and invasiveness, which is abolished by TSC2 re-expression. We found that TSC2 also inhibits cell migration through its N-terminus, independent of its GTPase-activating protein activity. LAM cells show increased stress fiber and focal adhesion formation, which is attenuated by TSC2 re-expression. The small GTPase RhoA is activated in LAM cells compared with normal human mesenchymal cells. Pharmacologic inhibition of Rho activity abrogates LAM cell migration; RhoA activity was also abolished by TSC2 re-expression or TSC1 knockdown with specific siRNA. These data demonstrate that TSC2 controls cell migration through its N-terminus by associating with TSC1 and regulating RhoA activity, suggesting that TSC2 may play a critical role in modulating cell migration and invasiveness, which contributes to the pathobiology of LAM.