Lymphangioleiomyomatosis: A Monogenic Model of Malignancy.

Lymphangioleiomyomatosis (LAM) is a rare, low-grade, metastasizing neoplasm that arises from an unknown source, spreads via the lymphatics, and targets the lungs. All pulmonary structures become infiltrated with benign-appearing spindle and epithelioid cells (LAM cells) that express smooth-muscle and melanocyte-lineage markers, harbor mTOR-activating mutations in tuberous sclerosis complex (TSC) genes, and recruit abundant stromal cells. Elaboration of lymphangiogenic growth factors and matrix remodeling enzymes by LAM cells enables their access to lymphatic channels and likely drives the cystic lung remodeling that often culminates in respiratory failure. Dysregulated cellular signaling results in a shift from oxidative phosphorylation to glycolysis as the preferred mode of energy generation, to allow for the accumulation of biomass required for cell growth and tolerance of nutrient-poor, anaerobic environments. Symptomatic LAM occurs almost exclusively in females after menarche, highlighting the central but as yet poorly understood role for sex-restricted anatomical structures and/or hormones in disease pathogenesis. LAM is an elegant model of malignancy because biallelic mutations at a single genetic locus confer all features that define cancer upon the LAM cell-metabolic reprogramming and proliferative signals that drive uncontrolled growth and inappropriate migration and invasion, the capacity to exploit the lymphatic circulation as a vehicle for metastasis and access to the lungs, and destruction of remote tissues. The direct benefit of the study of this rare disease has been the rapid identification of an effective FDA-approved therapy, and the collateral benefits have included elucidation of the pivotal roles of mTOR signaling in the regulation of cellular metabolism and the pathogenesis of cancer.

Clinical Course of Histologically Proven Multifocal Micronodular Pneumocyte Hyperplasia in Tuberous Sclerosis Complex: A Case Series and Comparison with Lymphangiomyomatosis.

BACKGROUND: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of tuberous sclerosis complex (TSC). Because of its rarity, no previous study has described the detailed clinical course of this disease. OBJECTIVES: This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH. METHODS: Nine patients with MMPH diagnosed at Hokkaido University Hospital were retrospectively analyzed. Changes in computed tomography findings and pulmonary function were compared during the follow-up period. Serum levels of KL-6, surfactant protein (SP)-A, and SP-D were measured to clarify their potentials as blood biomarkers of the disease. Fourteen cases of lymphangiomyomatosis (LAM) were also included to compare their clinical characteristics with those of subjects with MMPH. RESULTS: Of the 9 patients, 7 were female and 2 were male. The median age at diagnosis was 43 years (range, 19-56), and all cases were diagnosed following incidental abnormal radiographic findings. During the follow-up, 1 patient died of lung cancer, but others were radiographically stable and had stable pulmonary function. Serum levels of SP-A in 5 patients (mean, 146.4 ng/mL) and SP-D in 6 patients (mean, 337.3 ng/mL) were elevated in subjects with MMPH, whereas KL-6 levels were within the reference range (mean, 230 U/mL) in all patients. Levels of SP-A and SP-D were significantly higher in subjects with MMPH than those with LAM (p < 0.05). CONCLUSIONS: Radiographic findings and pulmonary function were stable in all cases of MMPH. Serum SP-A and SP-D, but not KL-6, may be useful markers for suspicion of the presence of MMPH in patients with TSC.

Resection of Extrapulmonary Lymphangiomyoma and Post-Operative Management Considerations.

Background: Lymphangiomyomatosis is a rare disease involving the lymph vessels, causing obstruction and cystic formation with an incidence of 3-8 per million women. The disease might be sporadic or inherited. Lymphangiomyomatosis mostly affects the pulmonary system, whereas extrapulmonary Lymphangiomyomatosis may present in various site, occasionally as a localized abdominal mass. The diagnostic process might entail surgical resection to obtain a specimen for pathology that may also help to achieve a long-term control of the disease. Methods: Herein, we present a case of a 45 years old female, who suffered from pulmonary symptoms, and during her workup an abdominal mass was found. The patient underwent exploratory laparotomy with resection of a left retroperitoneal bilobar mass. Results: Histopathological report revealed Lymphangiomyoma. She had a complication of a lymphatic leakage that required a second laparotomy with satisfactory clinical outcome. Conclusions: Surgeons should be aware of the pathological lymphatics and manage post-operative complications by a trial of conservative.

Retroperitoneal Cystic Adenopecoma with Genetic Analysis: A Rare Neoplasm.

Lymphangiomyomatosis is a member of the PEComa family, and usually involves the pulmonary parenchyma of middle-aged females. Infrequently, it may involve abdominal and retroperitoneal lymph nodes, and rarely it has been described to be associated with fallopian tube-type ciliated epithelium co-existing in one neoplasm. To increase our understanding of this unusual tumor, we describe the morphology and genetics of one case and review the literature. We present the case of a 50-year-old female found to have 12.5 and 7.7 cm cystic retroperitoneal masses, describe its unique pathological features and review the literature on the previously reported cases. Based on its unique morphological, immunohistochemical, and molecular features we propose the term adenoPEComa to represent this entity. This case represents a rare example of adenoPEComa with lymphangiomyomatosis of the lymph nodes. It is the first example that has undergone next-generation sequencing revealing a mutation in TSC2 making it a confirmed member of the PEComa family of tumors.

Tuberous sclerosis complex: a complex case.

Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the TSC1 (hamartin) or more frequently TSC2 (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic TSC2 mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms' tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's TSC2 alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the TSC2 locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2 Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.

The Impact of TSC-1 and -2 Mutations on Response to Therapy in Malignant PEComa: A Multicenter Retrospective Analysis.

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy. METHODS: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations. RESULTS: No significant differences in survival were identified between TSC-1 and TSC-2 mutated PEComa or TSC-1/-2 versus other mutations. No significant difference was seen in progression-free survival (PFS) after first-line therapy between mTOR inhibition versus other systemic therapies. CONCLUSIONS: We were unable to detect differences in survival based on genomic alterations or PFS between mTOR inhibition versus other systemic therapies. Future studies should seek to identify other drivers of TSC-1/-2 silencing that could predict response to mTOR inhibition.

Pelvic Lymph Node Lymphangiomyomatosis Found During Surgery for Gynecological Fallopian Tube Cancer: A Case Report and Literature Review.

Background: Lymphangioleiomyomatosis (LAM) is a rare low-grade metastatic tumor with an unknown origin that spreads through lymphatic vessels. It is characterized by the proliferation of smooth muscle-like or epithelioid tumor cells in the lung and axial lymphatic system. Extrapulmonary LAM is a localized disease with a low incidence rate, and the location of the related lesions is atypical. It is difficult to diagnose. The LAM of pelvic lymph nodes is hidden. It is usually found through gynecological oncology surgery. Case presentation: We report a 57-year-old postmenopausal woman with a pelvic mass and vaginal bleeding as the main symptoms. The patient had no history of pulmonary LAM, tuberous sclerosis complex (TSC), or renal angiomyolipoma and had not used exogenous hormones. We performed a total hysterectomy, bilateral adnexectomy, greater omentum resection, and pelvic lymphadenectomy under laparoscopy. The postoperative pathology confirmed high-grade serous carcinoma of the left fallopian tube, and four lymph nodes were found in the pelvic lymph nodes, suggesting lymphangiomyomatosis. Immunohistochemical results also showed that these cells could express markers of smooth muscle cells and melanoma cells. The patient was treated with chemotherapy after the operation. Chest CT did not suggest lung LAM during the postoperative follow-up, and there was no tumor recurrence. Conclusion: The diagnosis of this disease is challenging. At the same time, due to insufficient clinical samples, it is still unknown whether there is a potential relationship between pelvic and peritoneal lymph node LAM found in the surgical staging of gynecological tumors and lung LAM and/or TSC. There is no evidence that pelvic and peritoneal lymph node LAM will increase the risk of pulmonary LAM. Therefore, additional clinical data are required to analyze and summarize the relationship between pelvic and peritoneal lymph node LAM, pulmonary LAM, and the source of LAM. We present a case of pelvic lymph node LAM and propose a hypothesis that the pathogenesis of endometriosis can be used for reference in the study of this disease.

Rapamycin nanoparticles improves drug bioavailability in PLAM treatment by interstitial injection.

BACKGROUND: Pulmonary lymphangiomyomatosis (PLAM) is a rare interstitial lung disease characterized by diffuse cystic changes caused by the destructive proliferation of smooth muscle-like cells or LAM cells. PLAM is more common in young women than other people, and a consensus is lacking regarding PLAM treatment. The clinical treatment of PLAM is currently dominated by rapamycin. By inhibiting the mTOR signaling pathway, rapamycin can inhibit and delay PLAM's occurrence and development. However, the application of rapamycin also has shortcomings, including the drug's low oral bioavailability and a high binding rate to hemoglobin, thus significantly decreasing the amount of drug distributed to the lungs. METHODS AND RESULTS: Here, we developed a new mode of rapamycin administration in which the drug was injected into the intrathecal space after being nanosized; the directional flow characteristics of the liquid in the intrathecal space were exploited to increase the drug content in the interstitial fluid to the greatest extent possible. We studied the rapamycin content in the interstitial fluid and blood after intervaginal space injection (ISI). Compared with oral administration, ISI significantly increased the drug concentration in the lung interstitial fluid. CONCLUSIONS: These results provided new ideas for treating PLAM and optimizing the dosing regimens of drugs with similar characteristics to rapamycin.

Perivascular epithelioid cell tumor (PEComa) of abdominal cavity from falciform ligament: a case report.

We present a case of perivascular epithelioid cell tumors (PEComas) in the abdominal cavity at the falciform ligament. A 30-yr-old Korean man visited to hospital for the evaluation of a growing, palpable abdominal mass. He had felt the mass growing over 6 months. There was no family or personal history of tuberous sclerosis. The resected specimen showed a mass of 8.0x7.0x5.5 cm in size. Histological examination showed sheets of spindle-to-epithelioid cells with clear-to-eosinophilic cytoplasm. Immunohistochemically, tumor cells were positive for HMB-4 (gp100) and smooth muscle actin. They were also positive for the S-100, which is a marker of neurogenic and melanocytic tumors. Patient was treated with radical resection of tumor without any adjuvant therapy. He is well and on follow-up visits without tumor recurrence.

A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis.

RATIONALE: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. OBJECTIVES: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. METHODS: Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF-D) were measured at baseline and at 3-month intervals. RESULTS: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was -3 ± 3 ml/mo (P = 0.4), and for serum VEGF-D, the rate of change was -0.024 ± 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (-0.029 ± 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF-D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole-treated-placebo-treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole-treated patients. CONCLUSIONS: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209).

Lymphangioleiomyomatosis Presenting with Perirenal Hemorrhage.

Lymphangioleiomyomatosis (LAM) is a rare debilitating disease of unknown etiology, classically described as almost exclusively affecting women of childbearing age. The disease most commonly involves the lungs and is characterized by hamartomatous smooth muscle cell proliferations along blood vessels, airways and lymphatics. Most patients present with pulmonary symptoms, including shortness of breath, recurrent pneumothorax and pleural effusions. Extrapulmonary manifestations of LAM as the initial presentation of the disease are highly unusual. We present the case of a patient in whom LAM was incidentally discovered when the patient presented with retroperitoneal hemorrhage from a ruptured renal angiomyolipoma.

Recurrent pneumothorax in a young female with pulmonary lymphangiomyomatosis: a case report and overview of literature.

Lymphangiomyomatosis (LAM) is a rare cystic interstitial lung disease that exclusively affects women of child bearing age and is associated with vascular proliferation of smooth muscle cells in the lung. We report a case of young female with pulmonary LAM presenting with recurrent pneumothorax.

Lymphangiomyomatosis discovered by massive hemoptysis during general anesthesia -A case report-.

Lymphangiomyomatosis (LAM) is a rare lung disease that is characterized by the progressive proliferation of atypical smooth muscle-like cells, which leads to severe respiratory impairment and death. Dyspnea, cough, recurrent pneumothorax, and hemoptysis are the most common clinical symptoms of LAM. We report a 29-year-old female patient with massive hemoptysis during laparoscopic gynecologic surgery under general anesthesia, who was diagnosed with pulmonary LAM.

Gastric Adenocarcinoma in Association with Tuberous Sclerosis: Case report.

We report the first case of gastric cancer in association with tuberous sclerosis. Tuberous sclerosis is an autosomal dominant disorder which presents with a constellation of signs including benign tumours in the brain and in other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioural problems, skin abnormalities, and lung and kidney disease. It is caused by mutations on either of two genes, tuberous sclerosis genes, TSC1 or TSC2, which encode for the proteins hamartin and tuberin respectively. These proteins act as tumour growth suppressor agents that regulate cell proliferation and differentiation. Tuberous sclerosis has been associated with hamartomatous growths and angiomyolipomas, an association with gastric cancer has not been reported; however, this could be a co-incidental finding and further cases need to be reported.