Comparison of locoregional recurrence risk among nipple-sparing mastectomy, skin-sparing mastectomy, and simple mastectomy in patients with ductal carcinoma in situ: a single-center study.

BACKGROUND: In invasive breast cancer, there are no differences among the mid- and long-term oncological safety results of nipple-sparing mastectomy (NSM), skin-sparing mastectomy (SSM), and simple mastectomy (SM). There are several reports comparing NSM and SSM with SM in the context of ductal carcinoma in situ (DCIS); however, the eligibility criteria vary among institutions, and there are no reports that compare all three surgical methods simultaneously within the same institution. This study aimed to compare the local recurrence and survival rates of the three techniques (NSM, SSM, and SM) in Japanese patients undergoing mastectomy for DCIS. METHODS: Patients undergoing NSM, SSM, or SM at our institution between 2006 and 2015 were identified, and their outcomes were analyzed. RESULTS: The mean follow-up period was 80.4 months (standard deviation [SD]: 37.1 months). NSM was performed in 152 cases, SSM in 49, and SM in 44. Five of 245 patients developed local recurrences. Four of these patients had invasive cancer. The primary endpoints of 5-year cumulative local recurrence were 2.4% (95% confidence interval [CI]: 0.0-5.0) for NSM, 2.2% (95% CI: 0.0-6.3) for SSM, and 0% (95% CI: 0.0-0.0) for SM. There were no significant differences among the 5-year local recurrence rates. CONCLUSIONS: In this single-center, retrospective study, the oncological safety of SSM and NSM for DCIS was comparable to that of conventional SM.

Pulmonary Tumor Thrombotic Microangiopathy Mimicking Inhalation Lung Injury.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a complication characterized by dyspnea, pulmonary hypertension, and occasionally sudden death. We encountered a man who developed PTTM and had an inhalation history of chemical herbicides and abnormal findings on chest computed tomography, mimicking chemical inhalation lung injury. He was diagnosed with PTTM with adenocarcinoma by a transbronchial lung biopsy and received chemotherapy and anticoagulant therapy. He survived for one month. An autopsy revealed primary gastric cancer with PTTM that can have a presentation similar to diffuse pulmonary diseases, including chemical inhalation lung injury. The examination of a biopsy specimen is crucial in such patients.

Oestrogen receptor-negative/progesterone receptor-positive phenotype of invasive breast carcinoma in Japan: re-evaluated using immunohistochemical staining.

BACKGROUND: The existence of progesterone receptor (PgR) expression in oestrogen receptor (ER)-negative breast carcinoma is controversial. Here, we re-evaluated ER-negative/PgR-positive (ER-/PgR+) carcinoma cases by immunohistochemical staining (IHC). MATERIALS AND METHODS: We selected patients who underwent surgery for primary breast carcinoma from our databases at Dokkyo Medical University Hospital and Kameda General Hospital. Among the 9844 patients, the largest series in Japan, 27 (0.3%) were initially diagnosed as ER-/PgR+ breast carcinomas and we re-evaluated by IHC. RESULTS: The re-evaluated IHC showed that of the 27 patients with the initial results of ER-/PgR+, 12 were ER+/PgR+, 8 were ER-/PgR-, and 7 were ER-/PgR+. ER was negative in 12 of 27 patients (44.4%), and PgR was positive in 8 of 27 patients (29.6%). In our seven re-evaluated and confirmed as ER-/PgR+ cases, the staining proportions of tumor cells were 0% in ER and 1-69% (average 15.8%) in PgR. The average staining proportion of PgR in the re-evaluated ER-/PgR+ phenotype was lower than the initial diagnosis. Histological grading was as follows: grade I, one case; grade II, two cases; grade III, four cases. There were two lymph-node-positive cases. CONCLUSIONS: The ER-/PgR+ phenotype was confirmed after re-evaluation of ER and PgR assessment by a different pathologist. We recommend that pathologists discuss with clinicians, or re-test and re-evaluate ER/PgR expression, particularly in low-grade carcinoma and with a high staining proportion of PgR in the ER-/PgR+ phenotype.

Preoperative breast MRI: reproducibility and significance of findings relevant to nipple-areolar complex involvement.

BACKGROUND: Eligibility of nipple-sparing mastectomy has been expanded. The purpose of this study was to evaluate interobserver agreement regarding magnetic resonance imaging (MRI) descriptors important in determining eligibility for mastectomy, and to investigate the significance of enhancement extending to the areola concerning nipple-areolar complex (NAC) involvement. METHODS: Fifty-one cases with histologically confirmed NAC involvement and 54 cases with negative NAC were enrolled. Two radiologists assessed the following factors: lesion morphology (mass or non-mass enhancement); intra-nipple bright signal; enhancement extending to the areola; abnormal nipple enhancement; and tumor-nipple distance. Factors that showed a significant association with outcome in the univariate analysis were assessed by means of multivariate analysis using a logistic regression model. Interobserver agreement between observers was assessed by calculating κ values (dichotomous variables), or intraclass correlation coefficients (ICCs; continuous variables). RESULTS: In multivariate analysis of the results from the two observers, tumor-nipple distance (observer 1: odds ratio [OR] 0.93; 95% confidence interval [CI] 0.88-0.99; observer 2: OR 0.89; 95% CI 0.83-0.95) and enhancement extending to the areola (observer 1: OR 17.9; 95% CI 1.97-162.2; observer 2: OR 24.0; 95% CI 2.62-219.7) were found to be significant predictors of NAC involvement. A substantial agreement (κ = 0.64-0.71) for every dichotomous variable and an almost perfect agreement (ICC = 0.86) for continuous variable were observed. CONCLUSIONS: Findings of breast MRI for NAC preservation had good interobserver agreement. Enhancement extending to the areola, together with tumor-nipple distance, was significant factors for NAC involvement.

Breast MRI as a Problem-solving Study in the Evaluation of BI-RADS Categories 3 and 4 Microcalcifications: Is it Worth Performing?

RATIONALE AND OBJECTIVES: We aimed to investigate the utility of problem-solving breast magnetic resonance imaging (MRI) for mammographic Breast Imaging Reporting and Data System (BI-RADS) categories 3 and 4 microcalcifications. MATERIALS AND METHODS: Between January 1, 2010 and December 31, 2011, 138 women with 146 areas of categories 3 and 4 microcalcifications without sonographic correlates underwent breast MRI and had a stereotactic core biopsy using an 11-gauge needle or follow-up at least for 24 months. Positive predictive value (PPV), negative predictive value, sensitivity, and specificity were calculated on the basis of BI-RADS category, with categories 1-3 being considered benign and categories 4 and 5 being considered malignant. RESULTS: Twenty-four cases (16.4%) were malignant (18 ductal carcinoma in situ, 6 invasive). MRI increased PPV and specificity from 43% to 68% and from 80% to 93% (P = .054 and .005) compared to mammography. Within 102 category 3 microcalcifications, 5 carcinomas were assessed correctly as category 4 by MRI. Within 44 category 4 microcalcifications, a correct diagnosis was made by MRI in 77% (34 of 44) as opposed to 43% (19 of 44) by mammography, and 80% (20 of 25) of unnecessary biopsies could have been avoided. Within the 24 carcinomas, 5 were negative at MRI. MRI-negative carcinomas have a significantly higher possibility of being low grade (ductal carcinoma in situ or invasive) (P = .0362). CONCLUSIONS: Breast MRI has the potential to improve the diagnosis of category 3 or 4 microcalcifications and could alter indications for biopsy. Breast MRI could help predict the presence or absence of higher-grade carcinoma for category 3 or 4 microcalcifications.

Single focus on breast magnetic resonance imaging: diagnosis based on kinetic pattern and patient age.

Background Because of its small size, a focus in breast magnetic resonance imaging (MRI) must be evaluated on the basis of characteristics other than morphologic features. Patient-related factors including patient age, in conjunction with lesion-related factors, could be useful for decision-making. Purpose To assess the probability of malignant foci based on both lesion- and patient-related factors, and to propose a relevant decision-making method. Material and Methods Foci in our breast MRI database dating from April 2006 to June 2013 were retrospectively identified and analyzed. A Fisher's exact test or a Mann-Whitney U test were performed for univariate analyses, and factors that showed a significant association with outcome in the univariate analyses were subjected to multivariate analysis using a logistic regression model. A decision tree was then drawn using the significant predictors confirmed by multivariate analysis. Results In total, 184 foci (168 benign, 16 malignant) in 184 patients were analyzed in our study. The presence of a washout pattern and older age were found to be significant predictors of malignancy ( P < 0.0001; odds ratio [OR], 17.8; P = 0.021; OR, 1.1, respectively). The main decisive node on the decision tree was the presence of a washout pattern, followed by whether the patient's age was >63 years. Conclusion An enhancing focus showing a washout pattern, especially in older patients, may warrant immediate biopsy rather than short-interval follow-up.

NUT midline carcinoma mimicking a germ cell tumor: a case report.

BACKGROUND: NUT midline carcinoma (NMC) is a rare and highly aggressive malignancy. Although more information on NMC has been recently accumulating in the literature, most oncologists and pathologists remain unfamiliar with the clinical and pathologic features of this disease. The clinical features of NMC sometimes mimic those of other malignancies, and NMC can therefore be overlooked if the diagnosis is not suspected. We present the case of a young male with NMC arising in the mediastinum with elevated serum alpha-fetoprotein levels suggestive of an extragonadal nonseminomatous germ-cell tumor. CASE PRESENTATION: A 28-year-old Japanese male presented with cough and left-sided chest pain for 6 weeks. The patient had a mediastinal tumor with metastases to the right lung, lymph nodes, and bones at initial presentation. Nonseminomatous germ cell tumor was suspected due to the young age, location of the tumors, and elevated serum alpha-fetoprotein. However, biopsy confirmed the diagnosis of NMC with immunohistochemistry. The tumor briefly responded to cytotoxic chemotherapy but subsequently progressed and became refractory to the chemotherapy regimen. External beam radiotherapy was administered with dramatic shrinkage of the tumor and a metabolic response on 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan. However, the patient died 4.5 months after the diagnosis of NMC. CONCLUSIONS: Serum levels of alpha-fetoprotein may be elevated in patients with NMC. Regardless of the level of tumor markers, immunohistochemistry for NUT should be performed in cases of poorly differentiated carcinomas without glandular differentiation arising in the midline structures. 18F-FDG PET/CT is useful for staging and assessing responses to therapy.

Local recurrence following treatment for breast cancer with an endoscopic nipple-sparing mastectomy.

PURPOSE: Endoscopic nipple-sparing mastectomy (E-NSM) has been reportedly associated with smaller scars and greater patient satisfaction; however, long-term results of this procedure have not been made. The purpose of this retrospective study was to investigate the local recurrence (LR) rate and factors associated with it after E-NSM and to examine the oncologic safety of this procedure. METHODS: We reviewed the medical records of a total of 421 breasts in 404 patients who underwent E-NSM to investigate the LR rate and the factors associated with it. The clinico-pathological features and the treatment and outcomes of the patients with LRs were also examined. RESULTS: Eleven breasts (2.6 %) in 11 patients presented with LR as the first site of recurrence after a median follow-up time of 61 months. Among the 11 LRs, 9 patients presented with LR only, 1 patient exhibited regional lymph node recurrence, and 1 patient exhibited distant metastasis. The median time from surgery until LR was 25 months. Eight LRs developed near the original tumor site. The risk factors for LR in a multivariate analysis were a younger age of less than 40 years (p = 0.02), Stage III tumor (p = 0.01), and an inadequate surgical margin (p = 0.001). After the treatment, 6 patients had no evidence of disease, 2 patients died from metastatic disease, 2 patients experienced repeat LR, and the remaining patient who rejected excision exhibited a persistent LR. CONCLUSIONS: E-NSM is an oncologically safe procedure and an acceptable method in selected patients requiring a mastectomy.

Neuroendocrine tumor arising from tailgut cyst with spinal cord tethering: case report and literature review.

BACKGROUND CONTEXT: Neuroendocrine tumors (NETs) from tailgut cysts are rare; only 15 cases have been reported until now. A tailgut cyst with spinal cord tethering has not been previously reported, although both diseases are congenital anomalies in the early stage of gestation. PURPOSE: To report a rare case of NET from tailgut cyst associated with spinal cord tethering and review the literature. STUDY DESIGN: Case report and literature review. METHODS: We describe the clinical course of a 53-year-old man, who presented with gluteal pain and bladder dysfunction. Magnetic resonance images showed that a tumor of the sacral spinal canal extended into the retrorectal space and connected to a thickened fatty filum terminale, which was tethering the spinal cord. RESULTS: Because of tumor malignancy on a computed tomography-guided biopsy and the imaging data of involvement of presacral lymph nodes, we performed total removal of the tumor. Pathologic examination revealed NET (Grade 2) arising from a tailgut cyst. The patient received somatostatin analog therapy after surgery, followed by local radiation because of the further enlargement of the lymph nodes. Later, we started everolimus therapy for the metastases to the retroperitoneal lymph nodes. He presented with no local recurrence or further disease progression at 28 months after surgery. The review indicated that tumors in Grade 2 or 3 showed progressive clinical course after surgery and three of seven patients with biopsy were misdiagnosed. CONCLUSIONS: The correct preoperative diagnosis of NETs from tailgut cysts is difficult, but extremely important because Grade 2 or 3 tumors show disease progression even after surgery. Presacral congenital tumors, such as tailgut cysts, have the potential of malignant transformation into neuroendcrine tumors or adenocarcinomas. Comorbidity of spinal cord tethering and tailgut cyst suggests some relationship to common developmental errors in embryogenesis.

A case of primary pancreatic lymphoblastic lymphoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration.

Pancreatic involvement is an extremely rare manifestation of lymphoblastic lymphoma (LBL), and only a few cases have been reported. We report a case of LBL arising from the pancreas that was diagnosed using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). The patient was a 57-year-old female who had suffered from abdominal pain for 2 weeks. A physical examination revealed an upper abdominal mass, but did not detect peripheral lymphadenopathy. Imaging studies including computed tomography (CT) and (18)F-fluorodeoxy glucose (FDG)-positron emission tomography-CT revealed an enlarged pancreatic body, which was positive for FDG uptake. EUS-FNA detected medium-sized proliferating atypical lymphocytes, and immunohistochemical staining demonstrated that these cells were positive for CD20, CD10, PAX5, and terminal deoxynucleotidyl transferase. A bone marrow examination was negative for lymphoma infiltration, and a diagnosis of LBL arising from the pancreas was made. The patient was successfully treated with a combination of chemotherapy and pancreatic irradiation.

Is MRI useful for the prediction of nipple involvement?

BACKGROUND: The purpose of this retrospective study was to examine the usefulness of MRI for predicting nipple involvement. METHODS: A retrospective review was performed of 81 breasts in 78 breast cancer patients who had undergone nipple or nipple-areolar complex resections during surgery. The enhancement patterns of the nipple on MRI were compared to the contralateral side and were categorized as no enhancement, bilateral enhancement, and unilateral enhancement. The physical examination results, MRI findings, and pathological findings were assessed. RESULTS: Nipple involvement was observed in 17 of 81 nipples (21%), of which one exhibited infiltration of invasive ductal carcinoma, 12 exhibited ductal carcinoma in situ, and four exhibited Paget's disease. The nipples with no enhancement or with bilateral enhancement on MRI showed a lower rate of nipple involvement than the nipples with unilateral enhancement (0/48 vs. 17/33, p < 0.001). Among the unilaterally enhanced nipples, those with continuous enhancement from the index lesion showed a higher rate of nipple involvement than those without continuous enhancement (16/26 vs. 1/7, p = 0.03). When the enhancement characteristics of the unilaterally enhanced nipples were categorized, the findings with relatively high positive predictive values for nipple involvement were diffuse enhancement (100%, 2/2), unilateral skin enhancement (100%, 2/2), rim enhancement (86%, 6/7), and periductal enhancement (80%, 4/5). CONCLUSIONS: MRI was useful for predicting nipple involvement. Unilateral enhancement of the nipple with continuous enhancement from the index lesion may suggest the possibility of nipple involvement.

A case of focal autoimmune pancreatitis (AIP) mimicking an intraductal papillary mucinous neoplasm (IPMN).

The present case involved a 76-year-old man with a cystic mass in the head of his pancreas. The cystic lesion, which measured 17.7 × 9.8 mm, was first detected by ultrasonography (US) at the age of 72 years. Follow-up endoscopic ultrasonography (EUS) performed at 4 years after the lesion had first been detected revealed a mural nodule measuring 14.0 × 8.4 mm in the cyst. Endoscopic retrograde pancreatography (ERP) imaging revealed that the main pancreatic duct was in communication with the cyst and that there was no irregular narrowing of the main pancreatic duct. On the basis of these results, the patient was diagnosed with an intraductal papillary mucinous neoplasm (IPMN), and stomach-preserving pancreaticoduodenectomy was performed. A histopathological examination revealed that the interior of the cystic part of the lesion was lined by a pancreatic ductal epithelium. A pathological examination of the nodular lesion detected storiform fibrosis, severe lymphoplasmacytic infiltration, and hyperplasia in the pancreatic duct epithelium together with a small amount of mucus. On immunohistological staining, the infiltrating lymphoplasmacytes were found to be positive for IgG4. Accordingly, the patient was diagnosed with focal autoimmune pancreatitis (AIP). In conclusion, we reported a case of focal AIP mimicking IPMN. This case showed neither enlargement of the pancreas nor irregular narrowing of the main pancreatic duct.

Granular cell tumor of the common bile duct: a Japanese case.

Granular cell tumor (GCT) of the biliary system is rare. It is reported that it occurs more commonly in young black women. We report here our seldom experience of a Japanese case in whom icterus was found as a first symptom just after a caesarean operation. A 36-year-old Japanese woman developed icterus after delivery by the Caesarean operation. A surgical operation was performed without can deny that there was a tumor-related change in a bile duct as a result of examination for various images. As a result of pathological evaluation, GCT was diagnosed. By the preoperative organization biomicroscopy result, it was not able to be attachd a right diagnosis. It was thought that this tumor, although rare, should be considered as one of the causes of biliary stenosis in the younger population.

Parotid Gland Metastasis of Breast Cancer: Case Report and Review of the Literature.

BACKGROUND: Parotid gland metastasis in breast cancer is extremely rare, and only 14 cases have been reported between 1982 and 2010. CASE REPORT: A 67-year-old female patient was diagnosed with invasive lobular carcinoma of the left breast. Although clinical staging was T1N3M1 (stage IV), the tumor experienced a complete response to chemotherapy. We therefore performed a mastectomy followed by radiotherapy, and continued administration of trastuzumab. However, 11 months later, the patient complained of a swelling in the left parotid gland. Histology following a partial parotidectomy revealed a parotid gland metastasis from the breast. CONCLUSION: Treatment with capecitabine in addition to trastuzumab, which is one of the strategies applied in HER2-positive breast cancer, was effective in our patient. Analysis of the 14 cases of parotid gland metastasis from the breast reported between 1982 and 2010 revealed that the metastasis may occur not by direct lymphatic but by hematogenous spread.

Lymphomatoid gastropathy: a distinct clinicopathologic entity of self-limited pseudomalignant NK-cell proliferation.

Diagnostic errors in distinguishing between malignant and reactive processes can cause serious clinical consequences. We report 10 cases of unrecognized self-limited natural killer-cell proliferation in the stomach, designated as lymphomatoid gastropathy (LyGa). This study included 5 men and 5 women (age, 46-75 years) without any gastric symptoms. Gastroscopy showed elevated lesion(s) (diameter, ∼ 1 cm). Histologically, medium-sized to large atypical cells diffusely infiltrated the lamina propria and, occasionally, the glandular epithelium. The cells were CD2(+/-), sCD3(-), cCD3(+), CD4(-), CD5(-), CD7(+), CD8(-), CD16(-), CD20(-), CD45(+), CD56(+), CD117(-), CD158a(-), CD161(-), T cell-restricted intracellular antigen-1(+), granzyme B(+), perforin(+), Epstein-Barr early RNA(-), T-cell receptor αß(-), and T-cell receptor γδ(-). Analysis of the 16 specimens biopsied from 10 patients led to a diagnosis of lymphoma or suspected lymphoma in 11 specimens, gastritis for 1 specimen, adenocarcinoma for 1 specimen, and LyGa or suspected LyGa for 3 specimens. Most lesions underwent self-regression. Three cases relapsed, but none of the patients died. According to conventional histopathologic criteria, LyGa is probably diagnosed as lymphoma, especially as extranodal natural killer/T-cell lymphoma, nasal type. However, LyGa is recognized as a pseudomalignant process because of its clinical characteristics. The concept of LyGa should be well recognized.

[A case of duodenal gangliocytic paraganglioma with lymph node metastasis].

A 28-year-old man complained of tarry stool. A series of examinations showed a submucosal tumor with bleeding at the papilla of Vater and a swollen # 17b lymph node, both of which indicated a hypervascular tumor. The pathological findings of the enucleated tumor specimens revealed gangliocytic paraganglioma with metastasis to the # 17b lymph node. Additional pancreaticoduodenectomy revealed another # 17b lymph node metastasis 7-mm in diameter. Although the majority of gangliocytic paragangliomas are benign, 7% of reported cases have lymph node metastases, as shown in the present case. These findings are important in treating patients with gangliocytic paraganglioma.

1H MR spectroscopy of invasive ductal carcinoma: correlations with FDG PET and histologic prognostic factors.

OBJECTIVE: The purpose of this article is to assess the histologic prognostic relevance of choline levels obtained using (1)H MR spectroscopy with a 1.5-T MR unit in patients with invasive breast cancer and to compare the observed choline levels with the standardized uptake value obtained using FDG PET. MATERIALS AND METHODS: Single-voxel (1)H MR spectroscopy and PET/CT were performed for 50 patients with invasive ductal carcinoma (1.5-3 cm in size). The normalized choline signal was calculated using an external standard method. RESULTS: Proton MR spectroscopy detected the presence of choline in 44 cases. The average normalized choline signal was 1.1 (range, 0-3.9). The average standardized uptake value was 6.5 (range, 1.1-23). The correlation (r) between the normalized choline signal and the standardized uptake value was 0.52 (p < 0.0001). The normalized choline signal was significantly correlated with nuclear grade (p = 0.0002), triple-negative breast cancer status (p = 0.0009), and estrogen receptor negativity (p = 0.007). The standardized uptake value was significantly correlated with nuclear grade (p = 0.0002), estrogen receptor negativity (p = 0.002), and triple-negative breast cancer status (p = 0.009). No significant differences were found between the progesterone receptor-positive and negative groups or between the human epidermal growth factor receptor 2-positive and negative groups. CONCLUSION: The choline levels obtained using (1)H MR spectroscopy with a 1.5-T unit were well correlated with the standardized uptake value obtained using PET/CT and with the histologic prognostic parameters (nuclear grade, estrogen receptor status, and triple-negative lesion status).

Ultrasound-guided cryoablation of invasive ductal carcinoma inside the MR room.

One disadvantage of ultrasound (US)-guided cryoablation of breast cancer is the difficulty in visualizing the area behind the ice ball because of acoustic shadowing. We performed US-guided cryoablation with the patient in prone position inside the MR room. The lumpectomy specimen after cryoablation revealed dense fibrosis without residual viable cancer cells. The combination of needle insertion under US guidance with planning and verification using magnetic resonance imaging may be a feasible and promising treatment protocol.

LKB1 protein expression in neuroendocrine tumors of the lung.

During a recent investigation of LKB1 gene abnormality in lung lesions, strong expression of LKB1 protein in normal neuroendocrine (NE) cells of the bronchial epithelium was found. Because LKB1 functions as a tumor suppressor gene, the question of whether alteration of LKB1 expression is related to the development of pulmonary NE tumors of various grades was investigated. LKB1 immunohistochemistry was examined in a total of 68 primary pulmonary NE tumors consisting of 30 specimens of small cell lung carcinoma (SCLC), 23 large cell neuroendocrine carcinomas (LCNEC), two atypical carcinoids, and 13 typical carcinoids. Loss or low expression (<20% immunoreactive cells) of LKB1 protein expression was more frequently observed in high-grade NE tumors (SCLC and LCNEC; 45/53, 84.9%) than in typical and atypical carcinoids (3/15; 20%). The difference in LKB1 immunoreactivity between the high-grade NE tumors and the carcinoid group was statistically significant (P < 0.0001). In conclusion, marked reduction of LKB1 expression in high-grade NE tumors of the lung suggests a possible role of LKB1 inactivation in its tumorigenesis. Although a few previous studies indicated rare genetic alterations of LKB1 in SCLC, further studies including analysis of other NE tumors and focusing on epigenetic abnormalities of LKB1 gene are warranted.