Diagnostic usefulness of transbronchial lung cryobiopsy in two patients mildly affected with pulmonary lymphangioleiomyomatosis

Transbronchial lung biopsy is a non-invasive technique used primarily for the pathological diagnosis of lymphangioleiomyomatosis (LAM). However, some cases, particularly those with early-stage lung lesions, are difficult to diagnose because of the specimen size and presence of artifacts. Herein, we present two cases of LAM with relatively mild cystic changes in the lungs and slight impairment seen in pulmonary function tests. Both patients were diagnosed pathologically through transbronchial lung cryobiopsy. These cases indicate that transbronchial lung cryobiopsy is a useful tool for diagnosing early-stage pulmonary LAM owing to its appropriate specimen size for detecting LAM cells and few crush artifacts.     

Pulmonary lymphangiomyomatosis (LAM) developing chylothorax

We describe a case of pulmonary lymphangiomyomatosis (LAM) with chylothorax that developed in a 46-year-old Japanese woman. This patient exhibited clinical symptoms of dyspnea and chest X-ray showed right pleural effusion. Thoracocentesis demonstrated chylous effusion. Chest computed tomography (CT) scan revealed multiple cystic lesions. Subsequent thoracoscopy revealed the chylorrhea from swelled vessels on the diaphragm. The clinical diagnosis, based on histological examinations with biopsy specimens obtained by thoracoscopy, was pulmonary LAM. Although the hormone therapy was not effective, chylous effusion was improved by the pleurodesis. Pulmonary LAM developing chylothorax is rare in Japan.     

A patient with TSC1 germline mutation whose clinical phenotype was limited to lymphangioleiomyomatosis

BACKGROUND: Lymphangioleiomyomatosis (LAM) can occur as in isolated form (sporadic LAM) or as a pulmonary manifestation of tuberous sclerosis complex (TSC) (TSC-associated LAM). Recent studies, however, revealed that both forms of LAM are genetically related but that sporadic LAM is a distinct clinical entity caused by somatic mutations of TSC2 (not TSC1) rather than a forme fruste of TSC carrying either of the TSC1 or TSC2 germline mutations. METHOD: Case presentation and in-depth molecular and histopathological examinations. A 34-year-old Japanese woman was diagnosed as having pulmonary lymphangioleiomyomatosis (LAM) when bilateral pneumothoraces were surgically treated in 1992. Although slowly progressive renal disfunction was observed due to bilateral multiple renal cysts during the past 4 years, she had no other clinical features of TSC and was diagnosed as having sporadic LAM with multiple renal cysts of undetermined aetiology. Her subsequent clinical course was complicated by an endobrochial carcinoid tumour, which eventually resulted in her death in June 1999 due to massive haemoptysis. RESULTS: Postmortem examination revealed the presence of LAM lesions in the lungs, mediastinal lymph nodes, kidneys and uterus. Diffuse renal LAM lesions are presumed to generate multiple renal cysts by constricting the nephron rather than epithelial hyperplasia obstructing lumina, which is analysis of the TSC genes demonstrated that she did not have TSC2/PKD1 contiguous gene syndrome but had a TSC1 germline mutation (Sato T et al. J Hum Genet 2002; 47: 20-8) that had occured de novo. CONCLUSION: This patient therefore illustrates that clinical manifestations of TSC are sufficiently diverse as to allow a forme fruste of TSC that mimics sporadic LAM and that TSC1 mutation can cause multiple renal cysts resulting in renal failure.     

Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated disorder (sporadic LAM) or in association with tuberous sclerosis complex. Renal angiomyolipomas, which are found in most tuberous sclerosis patients, also occur in 60% of sporadic LAM patients. We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and TSC could have a common genetic basis. In this study, we report the identification of somatic TSC2 mutations in five of seven angiomyolipomas from sporadic LAM patients. In all four patients from whom lung tissue was available, the same mutation found in the angiomyolipoma was present in the abnormal pulmonary smooth muscle cells. In no case was the mutation present in normal kidney, morphologically normal lung, or lymphoblastoid cells. Our data demonstrate that somatic mutations in the TSC2 gene occur in the angiomyolipomas and pulmonary LAM cells of women with sporadic LAM, strongly supporting a direct role of TSC2 in the pathogenesis of this disease.     

Pneumothorax in a female with renal angiomyolipoma

Spontaneous pneumothorax occurs less in females than in males, in contrast to the relatively more commonly and incidentally found renal angiomyolipoma (AML). We report a renal AML in a 23-year-old female patient, which presented as right palpable abdominal mass. This renal tumor was removed owing to enlargement and internal hemorrhage and AML was proved by pathological examination. Three years later, she experienced a life-threatening spontaneous tension pneumothorax and pulmonary lymphangioleiomyomatosis (LAM), which was diagnosed by chest computed tomography. Clinically, she did not have tuberous sclerosis. Pulmonary LAM and renal AML are related lesions and both of these proliferative lesions occur in sporadic patients without family history and at much higher frequency in patients with tuberous sclerosis. Because of the nonspecific symptoms and high rate of complications, we should consider the possibility of LAM in patients diagnosed with AML. The association between renal AML and pulmonary LAM is reviewed.     

Tuberous sclerosis with pulmonary involvement

Pulmonary involvement in tuberous sclerosis (pTS) is very rare and seems to be associated with a more benign course, compared to tuberous sclerosis without pulmonary manifestation (TS). Furthermore, pTS seems to be related to lymphangiomyomatosis (LAM). We present the case of a 33-year-old woman in whom the overlap of TS, pTS and LAM is demonstrated. Treatment with medroxyprogesterone was initiated, but without success.     

Acute right ventricular infarction secondary to massive pulmonary embolism

Isolated right ventricular infarction has been found in casesof right ventricular hypertrophy, but there are no reports onright ventricular infarction secondary to massive pulmonaryembolism. Six autopsied patients with massive pulmonary embolismand pure right ventricular infarction, suspected to be secondaryto the embolism, were selected from a population of 216 autopsies.Pulmonary embolism was the suspected diagnosis in five casesdue to typical clinical, electrocardiographic and haemodynamicdata. Right ventricular infarction was a post-mortem finding,not previously diagnosed. In every case the thickness of theright ventricular myocardium was normal. The necrosis of theright ventricle was transmural in four cases and subendcardialin two and the entire right ventricular wall (anterolateralas well as posterior) was involved. No mural thrombi were presentand in no case did the necrosis involve the left ventricle.In one case the coronary arteries were normal, in the otherfive significant lesions of the right or the left coronary arterieswere observed. These lesions may have been, in part, responsiblefor the necrosis of the right ventricle when the massive pulmonaryembolism was added. We conclude that right ventricular infarctionmay be secondary to pulmonary hypertension in the setting ofmassive pulmonary embolism, even in the absence of right ventricularhypertrophy and with normal or stenotic coronary arteries.     

Rare lung diseases I �C Lymphangioleiomyomatosis

The present article is the first in a series that will review selected rare lung diseases. The objective of this series is to promote a greater understanding and awareness of these unusual conditions among respirologists. Each article will begin with a case that serves as a focal point for a discussion of the pathophysiology and management of the particular condition. The first article is on lymphangioleiomyomatosis (LAM); subsequent articles will focus on pulmonary alveolar proteinosis, alpha-1-antitrypsin deficiency and primary ciliary dyskinesia.LAM is a rare, progressive and (without intervention) often fatal interstitial lung disease that predominantly affects women of childbearing age. LAM is characterized by progressive interstitial infiltration of the lung by smooth muscle cells, resulting in diffuse cystic changes of the lung parenchyma. The molecular basis of this disorder has been delineated over the past five years and LAM is now known to be a consequence of mutations in the tuberous sclerosis genes. This knowledge, combined with advances in our understanding of the signalling pathways regulated by these genes, has given rise to potential molecular therapies that hold great promise for treating this devastating disease.     

Procoagulant (thromboplastin) activity in human bronchoalveolar lavage fluids is derived from alveolar macrophages

Fibrin deposition in the alveolar space and the lung interstitium is a prominent feature of many types of inflammatory pulmonary diseases. Cells of the monocyte/macrophage line are the primary cells supplying procoagulant activity in inflammatory lesions. In the present study we found that both lung alveolar macrophages (LAM) and bronchoalveolar lavage fluids (BALF) from humans contained procoagulant activities. The procoagulant in BALF was associated with membrane vesicles which sedimented at 100,000 g for 1 h. By electron microscopy the BALF ultrasediment was seen to consist almost exclusively of membrane material and this was confirmed by monitoring the content of different marker enzymes for specific subcellular structures. Using macrophage membrane markers, at least part of the BALF-ultrasediment was shown to be derived from LAM. On the basis of phospholipase C sensitivity, antibody neutralization and the site of action of the procoagulant in the sequential activation of coagulation factors, both the LAM-associated and the BALF-associated procoagulant activity was identified as thromboplastin (tissue factor) or thromboplastin-factor VII complexes. This suggests that alveolar macrophages and the LAM-derived thromboplastin-containing microvesicles may contribute to intraalveolar and interstitial fibrin deposition in vivo and probably also have consequences for the development of pulmonary fibrosis.     

Thrombolytic therapy of massive pulmonary embolism during prolonged cardiac arrest using recombinant tissue-type plasminogen activator

Cardiac arrest caused by massive pulmonary embolism is highly refractory to conventional resuscitation. Emergency surgical embolectomy has been considered the only effective intervention. We present the case of a 33-year-old woman who suffered a massive pulmonary embolism with circulatory arrest refractory to one half hour of aggressive CPR. A 10-mg bolus of recombinant tissue-type plasminogen activator was administered through a central line followed by a further 90-mg IV infusion over two hours. Rapid hemodynamic and clinical improvement followed the bolus dose. The patient was discharged later without neurological or other sequelae. This is the first reported case of successful thrombolytic therapy of massive pulmonary embolism during prolonged CPR.     

Pulmonary lymphangioleiomyomatosis. Description and course of 2 cases

Pulmonary lymphangioleiomyomatosis (LAM) is a rare, serious, chronic disease whose etiology is unknown and which affects young women almost exclusively. It produces typical clinical and radiological characteristics. Diagnosis is confirmed on finding histological evidence of irregular proliferation of the smooth muscle cells of the lungs. Treatment is not usually effective and there is rapid worsening of the pulmonary function leading to serious respiratory failure which often results in the patients death. We present two cases of LAM in women, one of whom was 33 and the other 38. In the first case the patient had all the pulmonary findings described in the literature, while the second also had bilateral renal angiomyolipomas. We discuss the histological, radiological and clinical characteristics and evolution of both cases, as well as the treatment given. We also review the literature. It is concluded that LAM should be suspected in young women who have dyspnea, cough and/or hemoptysis and an interstitial radiological pattern, especially when associated with a pleural effusion or pneumothorax.     

肺淋巴管肌瘤病并肺母细胞瘤1例临床分析并文献复习

目的 加强肺淋巴管肌瘤病（LAM）合并恶性肿瘤的临床、影像、病理特点的认识,提高对该病的早期认识和治疗水平.方法 分析2013年3月收治的1例肺LAM并肺母细胞瘤患者临床资料及诊治经过,并结合相关文献进行复习.截止至2014年2月,以“Lymphangiomyomatosis、cancer”为检索词,在PubMed检索系统进行检索,论著3篇,综述1篇;在万方数据库中以“淋巴管肌瘤病、恶性肿瘤”为检索词进行检索,病例报告1篇.结果 患者,女,37岁,慢性病程,主要症状为咳嗽、咯血、胸痛3个月,既往有“双肾错构瘤”史,曾行右肾错构瘤切除术,术后病理示血管平滑肌脂肪瘤,左肾未予处理.曾有“自发性气胸”病史.胸部高分辨率CT示右中下肺巨大肿块并纵隔淋巴结肿大,考虑恶性病变;肺LAM.血清血管内皮生长因子D为1 092.61 ng/L.免疫组化示CD56灶（＋）,Vim小细胞（＋）,Syn（＋）,CD99（＋/-）,组织改变考虑为肺母细胞瘤.复习国内外文献,尚无LAM合并肺母细胞瘤的病例报道.结论 近十年来,随着LAM分子发病机制的深入研究,LAM目前可定义为低度恶性转移性肿瘤.本例患者为LAM合并高度恶性肿瘤肺母细胞瘤,在国内外尚属首例报道.但究其机制,是LAM细胞癌变为肺母细胞瘤,或是二者同时存在,目前尚无定论.     

Expression of human telomerase reverse transcriptase in lymphangioleiomyomatosis

Telomerase synthesizes nucleotide hexameric repeats (telomeres) at the ends of chromosomes, replacing base sequences that are lost from these sites during each mitotic cycle and protecting these ends against the action of exonucleases and ligases. Therefore, telomerase is essential for maintaining cellular replication. To evaluate the role of telomerase in the proliferation of abnormal smooth muscle cells (lymphangioleiomyomatosis [LAM] cells) in LAM, we performed immunostaining and in situ hybridization studies to identify telomerase protein and messenger RNA (mRNA), respectively, in pulmonary (n = 18) and extrapulmonary (n = 4) lesions from 22 women with LAM (14 untreated and 8 treated with progesterone or tamoxifen). Immunoreactivity and hybridization signals for telomerase were observed in 5 to 20% of LAM cells, mostly of the spindle-shaped type, in 21 of the 22 patients, and were less intense in the treated group. Other types of cells were unreactive in both groups. Telomerase colocalized in the same cells with alpha-smooth muscle actin, but only rarely with HMB-45 antibody (a marker for epithelioid LAM cells); colocalization with proliferating cell nuclear antigen was incomplete. The telomerase-positive LAM cells may constitute the sources of renewal of LAM cells. Modulation of telomerase may be involved in the control of LAM cell proliferation.     

Massive pulmonary embolism: a remarkable case and review of treatment

Although the clinical syndrome following pulmonary embolism (PE) may be subtle, in the case of massive PE the severity of the clinical presentation typically makes the picture more obvious. If more than two lobar pulmonary arteries become obstructed, the hemodynamic and respiratory consequences are severe, and may be life threatening. We present an unusual case where a patient experienced transient hemodynamic collapse during valsalva, and a massive saddle pulmonary embolus was discovered incidentally. Current treatment options for massive PE are then discussed.     

Surgical treatment of chylothorax caused by lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare progressive disease caused by infiltration of smooth muscle-like cells in lymph vessels as well as the lung. We report a case of pulmonary LAM in a 22-year-old female with shortness of breath, recurrent pneumothorax and chylous pleural effusions. Multiple ligation of thoracic in lower part of thoracic duct was performed and biopsy of thoracic duct confirmed the diagnosis of LAM. The operation was successful and the patient was discharged. Although the thoracic duct involvement is extensive, multiple ligation in lower part of thoracic duct may be a good choice.     

Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex

The true prevalence of pulmonary lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex (TSC) is unknown. The prevalence of LAM, radiological features, and lung function in patients with TSC was measured. The presence of LAM, as defined by the presence of cysts by high-resolution chest computed tomography (HRCT) scan, was determined in patients with TSC without prior pulmonary disease (Group 1). To determine the significance of early detection, severity of disease in screened patients (Group 1) was compared with that in patients with TSC with a prior diagnosis of LAM (Group 2). Forty-eight patients with TSC and no prior history of LAM were screened. Of the 38 females, 13 (34%) had LAM; LAM was absent in males. Lung function was preserved in patients with TSC who were found to have LAM by screening. In patients previously known to have LAM, FEV(1) and DL(CO) correlated inversely with severity of disease as assessed by CT scan. The prevalence of LAM in women with TSC was 34%, approximately 10-fold that previously reported, consistent with a large hitherto unrecognized subclinical population of patients at risk for pulmonary complications.     

Lymphangioleiomyomatosis (LAM): a rare cause of ascites and pleural effusion

HISTORY AND CLINICAL FINDINGS: A 45 year old woman presented at our hospital for further evaluation of intermittent abdominal pain. The patient reported that she had suffered a spontaneous pneumothorax 8 years and a pleural effusion 3 years before. DIAGNOSTIC FINDINGS AND THERAPY: Abdominal ultrasound showed abdominal fluid which proved to be chylous ascites by diagnostic paracentesis. Radiologic (lymphangiography) findings were consistent with lymphangioleiomyomatosis (LAM). Remarkably, lymphangiography resulted in an immediate disappearance of the ascitic fluid. CONCLUSION: This report depicts a case of LAM which involved both pulmonary and intestinal symptoms. Previous pulmonary problems gave a hint towards the right diagnosis. Though lymphangiography is rarely performed in these days, the method was both diagnostic and therapeutic in the case presented.     

Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations

OBJECTIVE:

Lymphangioleiomyomatosis (LAM) is a rare disease that is currently considered a low-grade neoplasm with metastatic potential and variable progression. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have recently become a treatment option for LAM patients, especially those with extrapulmonary manifestations. The objective of the present study was to describe a case series of four patients with LAM in Brazil who showed significant improvement, particularly in their extrapulmonary manifestations, after treatment with sirolimus (at 1-4 mg/day).

METHODS:

We describe four cases of LAM patients with different extrapulmonary manifestations who were treated with sirolimus.

RESULTS:

After treatment with sirolimus for 12 months, one patient presented resolution of severe chylothorax; one had a significant reduction in renal angiomyolipoma volume; and one showed significant regression of retroperitoneal lymphangioleiomyomas and abdominal lymph node enlargement. After treatment with sirolimus for 6 months, the remaining patient had a significant reduction in the volume of a massive retroperitoneal lymphangioleiomyoma.

CONCLUSIONS:

Our findings confirm that mTOR inhibitors are beneficial for patients with LAM, especially those with extrapulmonary manifestations, such as renal angiomyolipoma, lymphangioleiomyomas, and chylous effusions. However, certain aspects, such as the optimal dose, duration of treatment, and long-term adverse effects, have yet to be sufficiently clarified for mTOR inhibitors to be incorporated into LAM management protocols.     

Right Ventricular Outflow Tract Tumor Mimicking a Thrombus in the Main Pulmonary Artery

Primary sarcomas of the pulmonary artery and right 'ventricle are rare, and their presentation is unusual in clinical practice; therefore, their diagnosis is often missed or delayed. The progression of the obstruction from the outflow tract of the right ventricle to the pulmonary artery resembles massive pulmonary embolism. We present a case of one of these tumors which mimicked transesophageal echocardiography (TEE), a massive pulmonary embolism. We conclude that TEE represents a non-invasive method of diagnosis and evaluation when the suspicion is massive pulmonary thromboembolism or a heart tumor.     

CT diagnosis of appendicitis. Report of a case and review of the literature

Diagnosis of appendicitis has been historically supported in clinical findings. Imaging studies such as US and CT have been used mainly in cases where clinical diagnosis of appendicitis is uncertain. CT techniques have ranged between full abdominopelvic examinations after administration of oral and intravenous contrast media and unhenhanced scanning limited to the right bowel quadrant. We present the case report of an 18-year-old male patient with recurrent abdominal pain, with clinical suspicion of appendicitis; an abdominopelvic CT examination was performed that showed a suggestive image of appendicitis. This diagnosis was confirmed with the results of surgery and pathologic examination of the appendix.