Recently, several studies have reported that dysfunctions in protein phosphatase 2A (PP2A) caused by alterations in protein phosphatase 2 regulatory subunit A, alpha (PPP2R1A) are responsible for ...tumorigenesis and tumor progression in several types of cancers. The impact of PPP2R1A mutations remains unknown in gastrointestinal stromal tumors (GISTs), although mutations in KIT and PDGFRA, which result in constitutive activation of the receptor tyrosine kinase pathway, are important in GIST tumorigenesis. In this study, we performed mutation analysis of PPP2R1A to examine the frequency of PPP2R1A mutations and their clinicopathological correlation in 94 GIST cases. In addition, we performed an in vitro analysis to investigate the effects of PPP2R1A mutations on cell proliferation and kinase phosphorylation in GIST cells. Seventeen GIST cases (18%) harbored mutations in PPP2R1A. All but one of these 17 cases harbored a KIT, PDGFRA, HRAS, NRAS, or KRAS mutation as the oncogenic driver mutation, and the remaining case was immunohistochemically negative for succinate dehydrogenase B (SDHB). Multivariate analysis showed that larger tumor size, higher mitotic rate, and PPP2R1A mutation are independent prognostic factors for overall survival; however, PPP2R1A mutation was not an independent prognostic factor for disease-free survival. The transduction of GIST cells with mutant PPP2R1A induced an accelerated growth rate via increased phosphorylation of Akt1/2, ERK1/2, and WNK1, a kinase associated with angiogenesis. In addition, the transduction of GIST cells with mutant PPP2R1A caused increased c-kit phosphorylation, suggesting that c-kit is also a target of PP2A, reinforcing the tumorigenic capabilities of c-kit. Furthermore, the transducing GIST cells with wild-type PP2A dephosphorylated mutant c-kit. This study provides a new insight into the biology of GISTs and their phosphatase activity, and activated PP2A could be a therapeutic target in GISTs.
Multifocal micronodular pneumocyte hyperplasia is a rare pulmonary manifestation of tuberous sclerosis complex (TSC) that is a tumor suppressor gene disorder characterized by many hamartomas. A ...purported mechanism of hamartomatous proliferation in TSC is constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway dysregulated by a functional loss of TSC genes. Although multifocal micronodular pneumocyte hyperplasia develops locally as self-limited, benign lesions, it is morphologically similar to the preinvasive lesion of pneumocytes that characterize atypical adenomatous hyperplasia or bronchioloalveolar carcinoma. Frequently both conditions include a loss of heterozygosity on TSC. The goal of this study was to determine whether multifocal micronodular pneumocyte hyperplasia is neoplastic. Loss of heterozygosity on TSC genes and immunohistochemistry for mTOR-related proteins (phospho-mTOR, phospho-p70S6K, phospho-S6, and phospho-Akt) were analyzed in 42 lesions: 16 multifocal micronodular pneumocyte hyperplasia (7 patients with TSC, 1 TSC not confirmed), 14 atypical adenomatous hyperplasia, and 12 bronchioloalveolar carcinoma (9 and 12 patients, respectively). The results showed that at least one of two multifocal micronodular pneumocyte hyperplasia lesions from each patient had loss of heterozygosity on TSC1 or TSC2 (15 or 50%) and were frequently immunopositive for phospho-mTOR (88%), phospho-p70S6K (100%), and phospho-S6 (100%) but not phospho-Akt (14%), an upstream regulatory protein of mTOR. Loss of heterozygosity of TSC was found in the preinvasive lesions of pneumocytes, equal to or less than multifocal micronodular pneumocyte hyperplasia. In contrast, phospho-Akt was expressed in the preinvasive lesions of pneumocytes more frequently than multifocal micronodular pneumocyte hyperplasia, but the other mTOR-related proteins were less frequently expressed in the former than in the latter. These outcomes suggest that functional loss of TSCs and consequent hyperphosphorylation of mTOR-related proteins in multifocal micronodular pneumocyte hyperplasia may cause its benign neoplastic proliferation of pneumocytes.
We have previously shown that galectin-4 expression is an independent predictor for lymph node metastasis and serves as an adverse prognostic indicator in patients with acinar adenocarcinoma of the ...lung. In contrast, thyroid transcription factor-1 (TTF-1) expression in non-small cell lung carcinoma has been shown to be associated with a favorable prognosis. In the present study, 208 cases of acinar adenocarcinoma of the lung and 36 cases with distant metastatic lesions of lung adenocarcinoma were immunohistochemically examined for expression of galectin-4 and TTF-1 to elucidate their correlation with clinicopathological factors. TTF-1 expression was observed in 145 cases (69.7%) and associated with smaller tumor size, infrequent pleural invasion, and lower TNM stage. Galectin-4 expression was observed in 86 cases (41.3%). Furthermore, galectin-4-positive carcinoma cells and TTF-1-positive carcinoma cells existed exclusively within the same lesion. Expressions of TTF-1 and galectin-4 were favorable and adverse prognostic factors, respectively. Approximately 40% (15/36 cases) of lung adenocarcinoma at the distant metastatic sites were immunohistochemically negative for TTF-1. Four out of five galectin-4-positive metastatic lesions were negative for TTF-1. We found an inverse correlation between galectin-4 and TTF-1 expressions in acinar adenocarcinoma, and this phenomenon was also found to be present in metastatic sites. These findings suggest that we should not exclude the possibility of metastatic adenocarcinoma of the lung, even if the tumor cells are immunohistochemically negative for TTF-1 in the primary unknown tumor, because aggressive lung adenocarcinomas often lack TTF-1 expression.
Lymphangioleiomyomatosis (LAM) (MIM #606690) is a rare lung disorder leading to respiratory failure associated with progressive cystic destruction due to the proliferation and infiltration of ...abnormal smooth muscle-like cells (LAM cells). LAM can occur alone (sporadic LAM, S-LAM) or combined with tuberous sclerosis complex (TSC-LAM). TSC is caused by a germline heterozygous mutation in either
TSC1
or
TSC2
, and TSC-LAM is thought to occur as a result of a somatic mutation (second hit) in addition to a germline mutation in
TSC1
or
TSC2
(first hit). S-LAM is also thought to occur under the two-hit model involving a somatic mutation and/or loss of heterozygosity in
TSC2
. To identify
TSC1
or
TSC2
changes in S-LAM patients, the two genes were analyzed by deep next-generation sequencing (NGS) using genomic DNA from blood leukocytes (
n
= 9), LAM tissue from lung (
n
= 7), LAM cultured cells (
n
= 4), or LAM cell clusters (
n
= 1). We identified nine somatic mutations in six of nine S-LAM patients (67 %) with mutant allele frequencies of 1.7–46.2 %. Three of these six patients (50 %) showed two different
TSC2
mutations with allele frequencies of 1.7–28.7 %. Furthermore, at least five mutations with low prevalence (<20 % of allele frequency) were confirmed by droplet digital PCR. As LAM tissues are likely to be composed of heterogeneous cell populations, mutant allele frequencies can be low. Our results confirm the consistent finding of
TSC2
mutations in LAM samples, and highlight the benefit of laser capture microdissection and in-depth allele analyses for detection, such as NGS.
Lymphangioleiomyomatosis in a Male Wakida, Kazuhiro; Watanabe, Yui; Kumasaka, Toshio ...
The Annals of thoracic surgery,
09/2015, Volume:
100, Issue:
3
Journal Article
Peer reviewed
Open access
We report a 17-year-old male with a histopathologic diagnosis of lymphangioleiomyomatosis after surgery for a pneumothorax. In general, lymphangioleiomyomatosis has been considered a female-specific ...disease. However, there are a few lymphangioleiomyomatosis cases reported in males, and our patient is the youngest case reported. Spontaneous pneumothorax occurs most commonly in males in their late teens and early twenties. Histopathologic diagnosis cannot always be performed in young males with pneumothorax. However, simple diagnosis should be avoided, and lymphangioleiomyomatosis should be considered as an underlying disease. This remarkable case provides new and valuable clinical insights into young male pneumothorax.
Summary Lymphangioleiomyomatosis (LAM), a rare progressive disease that almost exclusively affects women, is characterized by pulmonary cysts and neoplastic proliferation of smooth muscle–like cells ...(LAM cells). Airflow obstruction is a physiologic consequence that is commonly observed in LAM and has been attributed to narrowing of peripheral airways. However, histopathologic examinations of the entire airway have been precluded by the limited availability of such specimens. Here, we used explanted lung tissues from 30 LAM patients for a thorough histologic analysis with a special emphasis on the bronchi. We found bronchial involvement by LAM cells and lymphatics in all patients examined. Furthermore, a moderate to severe degree of chronic inflammation (73%), goblet cell hyperplasia (97%), squamous cell metaplasia (83%) of the epithelium, and thickening of basal lamina (93%) were identified in the bronchi. Because LAM cells are transformed by the functional loss of the TSC genes leading to a hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, we confirmed the expression of phospho-p70S6K, phospho-S6, phospho–4E-BP1, and vascular endothelial growth factor (VEGF)-D in LAM cells from all of the patients examined. In contrast, no protein expression of hypoxia-inducible factor 1α, a downstream molecule indicative of mTORC1 activation and leading to VEGF production, was detected in any patient. Our study indicates that late-stage LAM patients commonly have bronchi involved by the proliferation of both LAM cells and lymphatics and that chronic inflammation complicated their disease. Furthermore, the up-regulation of hypoxia-inducible factor 1α, a common event in mTORC1-driven tumor cells, does not occur in LAM cells and plays no role in VEGF-D expression in LAM cells.
This report describes two patients with sporadic lymphangioleiomyomatosis complicated by protein-losing enteropathy (PLE). Imaging studies indicated retroperitoneal lymphangioleiomyomas and ...abnormalities of the adjacent digestive tract. Endoscopic mucosal biopsy revealed colonic lymphangiectasia in one patient; whereas the site in the other patient was intestinal. Treatment with sirolimus led to the complete resolution of PLE within several months; additionally, marked shrinkage was observed in the lymphangioleiomyomas of both cases. These findings suggest that colonic or intestinal lymphatic congestion due to neighboring lymphangioleiomyomas was the mechanism for the development of PLE. At the time of writing this report, the beneficial effect of sirolimus has lasted for more than 3 years.
Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease in which abnormal smooth muscle-like cells (LAM cells) proliferate in the lungs and along the axial lymphatic systems, including the lymph ...nodes and thoracic ducts. LAM cells are transformed due to loss-of-function type mutations of either the TSC1 or TSC2 tumor suppressor genes. The pathological features include the proliferation of benign-looking LAM cells and the existence of abundant lymphatic vessels that are associated with clinical conditions such as chyle leakage. LAM cells produce potent lymphangiogenic growth factors (VEGF-C and VEGF-D) and the lymphatic vessel density within LAM lesions correlates with the histologic severity of LAM. The serum VEGF-D level increases in LAM, especially in patients with lymphatic involvement. LAM cell clusters (LCCs), which are postulated pathologically to be generated by lymphangiogenesis-mediated fragmentation and subsequent shedding into the lymphatic circulation, are observed in both chylous effusion and LAM-associated lymphatics within LAM tissue specimens. The identification of LCCs in chylous effusion together with the characteristic clinical manifestations can therefore be an alternative for a lung biopsy if LAM patients are complicated with chylous effusion.
LAM appears to be a disease involving a dysfunction of the lymphatic system and a fascinating model of tumor dissemination that is exclusively lymphangitic. LAM-associated lymphangiogenesis that mediates the shedding of LCCs seems to play a central role in the dissemination of LAM cells and progression in LAM and it may also be a potential therapeutic target as well as the dysregulated mTOR signaling pathway.
Babingtonite, Ca
2
Fe
2+
Fe
3+
Si
5
O
14
(OH) (
Z
= 2, space group
P
1
¯
) from Yakuki mine (Japan), Grönsjöberget (Sweden), Kandivali Quarry (India), Baveno Quarry (Italy), Bråstad Mine (Norway), ...and Kouragahana (Japan), and manganbabingtonite, Ca
2
(Mn
2+
, Fe
2+
)Fe
3+
Si
5
O
14
(OH), from Iron Cap mine (USA) were studied using electron-microprobe analysis (EMPA),
57
Fe Mössbauer analysis and single-crystal X-ray diffraction methods to determine the cation distribution at M1 and M2 and to analyze its effect on the crystal structure of babingtonite. Although all studied babingtonite crystals are relatively homogeneous, chemical zonation due to mainly Fe ↔ Mn substitution is observed in manganbabingtonite. Mössbauer spectra consist of two doublets with isomer shift (
I.S.
) = 1.16–1.22 mm/s and quadrupole splitting (
Q
.
S
.) = 2.33–2.50 mm/s and with
I.S.
= 0.38–0.42 mm/s and
Q.S.
= 0.82–0.90 mm/s, assigned to Fe
2+
and Fe
3+
at the M1 and M2 octahedral sites, respectively. The determined ratio of Fe
2+
/total Fe in manganbabingtonite (0.26) was smaller than that in the others (0.35–0.44) because of high Mn
2+
content instead of Fe
2+
. The unit-cell parameters of babingtonite are
a
= 7.466–7.478,
b
= 11.624–11.642,
c
= 6.681–6.690 Å,
α
= 91.53–91.59,
β
= 93.86–93.94,
γ
= 104.20–104.34º, and
V
= 560.2–562.3 Å
3
, and those of manganbabingtonite are
a
= 7.4967(3),
b
= 11.6632(4),
c
= 6.7014(2) Å,
α
= 91.602(2),
β
= 93.989(2),
γ
= 104.574(3)º, and
V
=565.09(5) Å
3
. Structural refinements converged to
R
1
values of 1.64–3.16 %. The distance was lengthened due to the substitution of large octahedral cations such as Mn
2+
for Fe
2+
. The increase of the M1-O8, M1-O8’ and M1-O13 lengths with mean ionic radii is slightly more pronounced than of the other M1-O
i
lengths. The lengthened M1-O13 distance leads the positive correlation between Si5-O15-Si1 angle and M1-O13 distance. The increase of Si2-O3-Si1 and Si5-O12-Si4 angles due to the increase of mean ionic radius of M2 is also observed.
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