LAM is lymphangiomyomatosis. This fascinating but rare tumor occupies a place in favorite test questions for medical students who are presented with a young woman with a history of repeated pneumothorax. In addition to pneumothorax, there may be shortness of breath, cough, hemoptysis, and chylous pleural effusions. This tumor has been associated with tuberous sclerosis. It typically occurs in the lungs of young women and is associated with a chylous pleural effusion, a condition where milky lymphatic fluid is released into the pleural cavities.
The importance of this diagnosis lies with its close association with tuberous sclerosis. Indeed, in fully expressed cases of tuberous sclerosis, tumors having histologically similar appearances in the kidney (angiomyolipomas), abdominal or thoracic lymphatic ducts, and lymph nodes may occur. This has led some to speculate that LAM is a limited or forme fruste expression of tuberous sclerosis.
Under the microscope, there is a lacy proliferation of smooth muscle bundles within the interstitial spaces, extending around bronchi, bronchioles, and blood vessels. The smooth muscle cells may have an optically clear cytoplasm filled with glycogen. Bronchiolar obstruction by the smooth muscle may lead to air trapping and overdistension leading to cystic blebs and pneumothorax. Obstruction of the veins and lymphatic flow may lead to hemorrhage and lymphatic cysts which may rupture causing chylous effusions. An interesting characteristic of the smooth muscle is the immunopositivity for HMB-45 and estrogen and progesterone receptors. Some patients have multifocal proliferations of alveolar type II pneumocytes called micronodular pneumocyte hyperplasia. These proliferations are negative for HMB-45 and hormone receptors.
The pathologist must distinguish this disorder from benign metastasizing leiomyomas which are localized smooth muscle proliferations and not diffuse. Metastatic endometrial stromal sarcomas to the lung may be cystic and must be distinguished. Diffuse pulmonary lymphangiomatosis are seen in all ages and sexes. There are prominent lymphatic vessels in the pleura and connective tissue septa with smooth muscle proliferation. Unlike LAM, there are no cysts, pneumothorax, or HMB-45 positivity. Chylothorax may occur.
Disease Associations Pathogenesis Gross Appearance and Clinical Variants Histopathological Features and Variants Prognosis Treatment Commonly Used Terms Internet Links
DISEASE ASSOCIATIONS CHARACTERIZATION TUBEROUS SCLEROSIS
PATHOGENESIS CHARACTERIZATION PROGRESSION
- Lymphangiogenesis-Mediated Shedding of LAM Cell Clusters as a Mechanism for Dissemination in Lymphangioleiomyomatosis.
Kumasaka T, Seyama K, Mitani K, Souma S, Kashiwagi S, Hebisawa A, Sato T, Kubo H, Gomi K, Shibuya K, Fukuchi Y, Suda K.
From the Departments of *Pathology and daggerRespiratory Medicine, Juntendo University, School of Medicine, Tokyo, Japan; double daggerDivision of Clinical Pathology, Tokyo Medical Center, Tokyo, Japan; section signHMRO, Graduate School of Medicine, Kyoto University, Kyoto, Japan; parallelDepartment of Pathology, Yokohama City University Medical Center, Yokohama, Japan; and paragraph signDepartment of Pathology, Toho University, School of Medicine, Tokyo, Japan. Drs. T. Kumasaka and K. Seyama have equally contributed to this work.
Am J Surg Pathol. 2005 Oct;29(10):1356-1366. Abstract quote
Lymphangioleiomyomatosis (LAM) affects exclusively women of reproductive age, involves the lungs and axial lymphatic system, and is frequently complicated with renal angiomyolipomas. LAM lesions are generated by the proliferation of LAM cells with mutations of one of the tuberous sclerosis complex (TSC) genes. Recent studies indicate that LAM cells can migrate or metastasize to form new lesions in multiple organs, although they show a morphologically benign appearance. In the previous study, we reported LAM-associated lymphangiogenesis and implicated its role in the progression of LAM.
In this study, we further focused on the lymphatic abnormalities in LAM: LAM-associated chylous fluid (5 pleural effusion and 2 ascites), surgically resected diaphragm (1 patient), and axial lymphatic system including the thoracic duct, lymph nodes at various regions, and diaphragmatic lymphatic system (5 autopsy cases). We demonstrated that LAM cell clusters enveloped by lymphatic endothelial cells (LCC) in all chylous fluid examined.
We identified LAM lesion in the diaphragm (2 of 5 autopy cases and one surgical specimen), thoracic duct (5 of 5), and lymph nodes (retroperitoneal (5 of 5), mediastinal (4 of 5), left venous angle (5 of 5) with total positive rate of 68% to 88% at each region of the lymph node, but less frequent or none at remote lymph nodes located away from the axial lymph trunk (cervical [1 of 5] and axillary [0 of 5]). LCCs were identified in intra-LAM lesional lymphatic channels where LAM cells proliferate along lymphatic system. In in vitro culture system, LCC can fragment into each proliferating LAM cell.
These findings suggest that LAM-associated lymphangiogenesis demarcates LAM lesion into bundle- or fascicle-like structure and eventually shed LCC into the lymphatic circulation and that LCCs play a central role in the dissemination of LAM lesion.
Lymphangiogenesis in Lymphangioleiomyomatosis: Its Implication in the Progression of Lymphangioleiomyomatosis.
Kumasaka T, etal.
Am J Surg Pathol. 2004 Aug;28(8):1007-1016. Abstract quote
Lymphangioleiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lungs, lymph nodes, and/or other organs.
We examined lymphangiogenesis using immunohistochemistry for Flt-4 (VEGFR-3), a new specific marker for lymphatic endothelial cells, as well as the expression of vascular endothelial growth factor (VEGF)-C in LAM. Specimens were obtained from 6 autopsy cases, a single lung transplant case, and 8 surgical cases for analyses.
We demonstrated that lymphatics were extremely abundant in both pulmonary and extrapulmonary LAM and that lymphatic endothelial cells not only proliferated encompassing LAM foci but also infiltrated the intra-LAM foci, and that in advanced LAM, lymphangiogenesis involved vascular walls and interstitium surrounding the area where LAM cells proliferate. In contrast, angiogenesis, confirmed with CD31 immunostaining, was observed less in the LAM foci. LAM cells demonstrated positive reactivity against anti-VEGF-C antibody at varying intensities. Significant correlation (P < 0.001) was noted between the degree of lymphangiogenesis in LAM or VEGF-C expression on LAM cells and lymphagioleiomyomatosis histologic score (LHS), which represents the histologic severity of pulmonary LAM and has been reported to have prognostic significance.
Our study is likely to provide a novel point of view on the pathophysiologic significance of lymphangiogenesis in LAM.
CHARACTERIZATION General VARIANTS EXTRAPULMONARY DISEASE-GENERAL Hum Pathol 2000;31:1242-1248
Tumors arising within the lymph nodes of the mediastinum and retroperitoneum in 22 women
Leiomyomatosis-Like Lymphangioleiomyomatosis of the Colon in a Female with Tuberous Sclerosis
Seng Geok Nicholas Goh, M.B.B.S., Jean May Sian Ho, F.R.C.Path., Khoon Leong Chuah, F.R.C.P.A., Puay Hoon Tan, F.R.C.P.A., Wee Teng Poh, F.R.C.P.A. and Robert H. Riddell, F.R.C.Path.
Department of Pathology (SGNG, JMSH, KLC, PHT, WTP), Singapore General Hospital, Singapore; and Department of Anatomic Pathology (RHR), McMaster University Medical Center, Hamilton, Ontario, Canada
Mod Pathol 2001;14:1141-1146 Abstract quote
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.
CHARACTERIZATION General VARIANTS FOCAL CHANGES
Regional proliferation of HMB-45-positive clear cells of the lung with lymphangioleiomyomatosislike distribution, replacing the lobes with multiple cysts and a nodule.
Hironaka M, Fukayama M.
Department of Pathology, Jichi Medical School, Tochigi, Japan.
Am J Surg Pathol 1999 Oct;23(10):1288-93 Abstract quote
The authors report a case of a localized lesion of the lung presenting as multiple cysts and as a tumor in the right upper and middle lobes, consisting of a diffuse proliferation of clear cells with intralysosomal glycogen granules and human melanin black (HMB)-45 immunoreactivity.
A 33-year-old woman complained of dyspnea because of the enlargement of bullae in the right upper and middle lung fields without stigmata of tuberous sclerosis. Resection showed multiple, various-size air-filled cysts and a tumor. The cysts in the resected lungs were reminiscent of lymphangioleiomyomatosis (LAM), accompanied by the diffuse proliferation of clear cells in the interstitium. The tumor, 1.8 cm in diameter, resembled a clear cell tumor of the lung (CCTL) and showed proliferation of clear cells with sinusoidlike vascular spaces.
Both forms of proliferation were continuous spatially, and both constituent cells showed diffuse HMB-45 immunoreactivity. The cells that comprised a nodule revealed ultrastructurally abundant cytoplasmic glycogen, which was in the form of free and membrane-bound glycogen granules.
This case may represent a particular pulmonary lesion consisting of CCTL-LAM hybrid cells, which share the cytologic features with CCTL cells on one hand, and the proliferative pattern and potential with LAM cells on the other.
Multifocal Micronodular Pneumocyte Hyperplasia and Lymphangioleiomyomatosis in Tuberous Sclerosis with a TSC2 Gene
Hiroshi Maruyama, M.D., Kuniaki Seyama, M.D., Junko Sobajima, M.D., Kazumichi Kitamura, M.D., Tooru Sobajima, M.D., Tomokazu Fukuda, Ph.D., Kaoru Hamada, M.D., Masahiro Tsutsumi, M.D., Okio Hino, M.D. and Yoichi Konishi, M.D.
Departments of Pathology (HM), Internal Medicine (JS, KK), and Thoracic Surgery (TS), Hoshigaoka Koseinenkin Hospital, Hirakata, Japan; Department of Respiratory Medicine (KS), School of Medicine, Juntendo University, Tokyo, Japan; Department of Experimental Pathology (TF, OH), Cancer Institute, Tokyo, Japan; and Second Department of Internal Medicine (KH) and Department of Oncological Pathology (MT, KY), Cancer Center, Nara Medical University, Kashihara, Japan
Mod Pathol 2001;14:609-614 Abstract quote
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.
PROGNOSIS AND TREATMENT CHARACTERIZATION Prognostic Factors
Prognostic Significance of Pulmonary Lymphangioleiomyomatosis Histologic Score
Kazuhiro Matsui, etal.
Am J Surg Pathol 2001;25:479-484 Abstract quote
Correlations were made between clinical and follow-up data and histopathologic findings in 105 women (mean age ± standard deviation, 38.3 ± 9.0 years) with pulmonary lymphangioleiomyomatosis (LAM).
The actuarial survival (to pulmonary transplantation or death) of the patients from the time of lung biopsy was 85.1% and 71.0% after 5 and 10 years respectively.
The histologic severity of LAM, graded as a LAM histologic score (LHS), was determined on the basis of semiquantitative estimation of the percentage of tissue involvement by the two major features of LAM: the cystic lesions and the infiltration by abnormal smooth muscle cells (LAM cells) in each case: LHS-1, <25%; LHS-2, 25% to 50%; and LHS-3, >50%. Analysis using the Kaplan-Meier method revealed significant differences in survival for patients with LHS-1, -2, and -3 (p = 0.01). The 5-and 10-year survivals were 100% and 100% for LHS-1, 81.2% and 74.4% for LHS-2, and 62.8% and 52.4% for LHS-3. Increased degrees of accumulation of hemosiderin in macrophages also were associated with higher LHS scores (p = 0.029) and a worse prognosis (p = 0.0012).
Thus, the current study suggests that the LHS may provide a basis for determining the prognosis of LAM.
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