Multifocal Adenocarcinoma Research Articles

MAX germline mutation-associated pheochromocytoma-paraganglioma syndrome: multiple endocrine neoplasia type 5

The individualized precision management of hereditary pheochromocytoma (PHEO) and paraganglioma (PGL) syndromes (PPGLs) based on molecular diagnosis and molecular subtype is becoming more popular. The newly discovered MAX germline mutation-associated PPGLs are autosomally dominant and rare. To raise awareness and explore the effective management of individual diagnosis and treatment, the relevant literature published between January 2011 and February was systematically reviewed. There were a total of 101 patients in the 77 families, involving all 5 exons, containing 44 types of MAX germline mutations and mostly concentrated in exons 3 and 4 (64.4%), the main mutations were nonsense mutations and missense mutations (72.3%), and some were large fragment deletions or insertions, intron variant, gene fusion mutations were relatively infrequent. Furthermore, about 10% of the patients had a paternal parent-of-origin effect. Among the 101 patients, 96 (95.0%) developed PHEO including 15 metastatic PHEO, 61 bilateral PHEO and 35 unilateral PHEO. The age of diagnosis was (31.7±10.9) years (range: 13 to 80 years). The male to female ratio was 1.2∶1. Eleven were accompanied with chest and abdominal PGL. Eight (7.9%) were accompanied by functional pituitary adenoma. And 12 (11.9%) developed other neuroendocrine tumors (NET), of which 8 were accompanied by PHEO, including 4 hyperparathyroidism, 1 gangliocytoma and neuroblastoma, 1 pancreatic NET, 1 medullary thyroid carcinoma and 1 C cell hyperplasia. Six presented concomitant non-NET, including 1 tongue squamous cell carcinoma, 1 papillary thyroid carcinoma, 1 prostate cancer, 1 renal oncocytoma, 1 breast cancer with renal oncocytoma, and 1 thoracic chondrosarcoma with multifocal adenocarcinoma of lung. The remaining 5 cases (5.0%), including 4 other NET (2 ganglioblastoma, 1 abdominal neuroblastoma and 1 pancreatic NET) and 1 asymptomatic child, did not present PHEO. The MAX germline mutation may cause a novel multiple endocrine neoplasia, which can be described as type 5. A comprehensive baseline assessment of neural crest cell-derived diseases such as PPGL, pituitary adenoma, hyperparathyroidism, and/or gangliocytoma (neuroblastoma) was recommended for all people with MAX germline mutations, and the risk of bilateral and/or metastatic PHEO should also be considered. In contrast, patients with PPGLs combined with other NET, such as functional pituitary adenoma, should undergo genetic testing and pedigree screening that includes at least the MAX gene.

Multifocal biliary carcinoma; whether synchronous or metastatic: A need to conquer

Multiple synchronous primary carcinoma involving gall bladder, liver and common bile duct are rare and difficult to differentiate with hepatic and extrahepatic bile duct metastasis from single primary. Radiological features, molecular landscape, and even integrated mutational profiling are not of much help. We describe a case of 48-year-old male who presented with jaundice and follow up CT scan raised the suspicion of gall bladder carcinoma with hepatic metastasis. Peroperative frozen section examination revealed adenocarcinoma with involvement of cystic duct margin; however revised common duct margin was free from tumor invasion. Final histopathology on resected gall bladder revealed multifocal adenocarcinoma, while histomorphology of hepatic nodule was consistent with cholangiocarcinoma. Common bile duct a one focus had also revealed adenocarcinoma while cut margins were negative form malignancy. In view of different morphology of gall bladder and hepatic tumor, no continuity of three tumors and single large, firm, non umblicated hepatic nodule, diagnosis of multiple synchronous carcinoma was suggested.

Synchronous Primary Adenocarcinoma of Distal Common Bile Duct and Gall bladder.

Synchronous primary cancer of the gall bladder and distal common bile duct is rare. There are only few case reports and case series available of these synchronous cancers. Management of this tumor is individualized in these case reports and series based upon the presentation. We present a case of a patient who had multifocal adenocarcinoma involving distal common bile duct and gall bladder. Keywords: Distal common bile duct cancer; gall bladder cancer; synchronous primary.

Mixed epithelial and stromal tumours of the kidney with malignant transformation: a clinicopathological study of four cases

Mixed epithelial and stromal tumour of the kidney is a complex benign neoplasm in which malignancy rarely arises. In this study, we report four mixed epithelial and stromal tumours in which sarcoma or carcinoma developed. In the first, a multifocal adenocarcinoma arose and areas of transition from benign to malignant epithelium were observed. Oestrogen and progesterone receptors were diffusely present in the nuclei of the spindle cell stroma of the benign component. The second was a sarcoma in which benign epithelial elements were intermixed. Outside the renal parenchyma, clusters of small benign glands surrounded by oestrogen receptor-positive benign stroma were present, supporting the diagnosis of mixed epithelial and stromal tumour. Fluorescence in situ hybridisation for SYT-SSX translocation and immunohistochemical results, specifically TLE1 -ativity, argued against primary renal synovial sarcoma. The patient died 24 months after surgery. The third tumour consisted of small blue round cells, positive for epithelial membrane antigen, BCL2, CD99, and FLI1. Throughout the tumour, the presence of benign appearing branching tubules in fibromuscular stroma, reactive for smooth muscle actin, desmin and progesterone receptor, supported the diagnosis of mixed epithelial and stromal tumour in which a small round blue cell sarcoma with EWSR1 rearrangement arose. In the fourth tumour, adenocarcinoma with papillary architecture arose in a typical mixed epithelial and stromal tumour. In summary, we present four cases of mixed epithelial and stromal tumour with malignant transformation, two showing carcinomatous and the other two with sarcomatous transformation. Identification of typical benign looking elements and the absence of SYT-SSX translocation are helpful in recognition of this entity.

Analysis of the gastric microbiome in gastric cancer patients and in non-tumorous patients.

349 Background: Gastric cancer is the fifth most common cancer worldwide and it is the most commonly diagnosed cancer in Korea. The most clearly known microbiologic risk factor is Helicobacter pylori infection. Chronic inflammation of gastric mucosa accelerates a cascade of chronic active gastritis, multifocal atrophy intestinal metaplasia, gastric dysplasia and gastric adenocarcinoma. Studies proved H. pylori reduces microbial diversity, but it is reversible with H. pylori eradication. Thus, we could assume gastric carcinogenesis may not solely depend on H. pylori. In this study, we analyzed and compared gastric microbiome in gastric cancer patients and non-cancer patients to find changes between the two groups. Additionally, we analyzed microbial diversity of cancerous lesions and para-cancerous lesions in the cancer group in an effort to reveal the role of microbiome in carcinogenesis. Methods: Gastric mucosa collected by biopsy during esophagogastroduodenoscopy (EGD) from 10 patients with gastric cancer and 18 non-cancer patients. Gastric biopsies were obtained from the margin of cancer and para-cancerous lesions in cancer patients. In control group, samples were obtained from antrum with normal mucosal morphology. DNA was extracted from the gastric mucosal tissues and 16s rRNA genes were amplified. Then they were analyzed by microbiome analysis program. Results: Higher number of species was detected in the control group (average of 97.75 species) compared to the cancer group (average of 73.4 species). The gastric cancer microbiome was showed reduced microbial diversity compared to that of control group. Fusobacteria was more dominant in cancer group and Rhodobacterales was found more prominent in control group. We compared microbial diversity of the cancer lesion and the para-cancerous lesion within the cancer group and higher number of species was detected in non-tumorous lesion. Conclusions: Gastric microbiome of non-tumorous patients was more diverse and the composition of species was different between the two groups. These results suggest that microbial dysbiosis may be involved in gastric carcinogenesis. Further studies should include more detailed analysis of spatial and temporal composition and the comparison between different pathologic types and tumor location are necessary. Better understanding of microbial differences and changes in healthy and gastric cancer patients could verify the carcinogenesis of gastric cancer.

External Beam Radiation Therapy for Metastatic Tumor to the Iris: A Case Report and Brief Literature Review

Tumor metastases involving the iris are rare and represent about 3% of metastases to the uveal tract. The typical presentation is a patient with a known history of carcinoma who develops blurry vision, ocular pain, and/or eye redness, which may be erroneously diagnosed as uveitis. In this case, we report the workup, diagnosis, and treatment of a 76 year old man with a history of node negative multi-focal adenocarcinoma of the lung who was found to have a left iris metastasis. He presented with blurry vision and left eye pain. Exam revealed a 7 x 7 mm amelanotic ciliary body mass, which was ultimately biopsied and found to be consistent with his lung primary. He was treated with external beam radiation therapy, 3000cGy in 10 fractions, to the left globe. His three and nine-month follow up MRIs showed good treatment response and he is clinically without disease progression. EBRT is a safe and effective modality for the treatment of iris metastases.

The surgical management of early-stage lung adenocarcinoma: is wedge resection effective?

BackgroundThe aim of the study was to explore the outcomes of wedge resection on patients with early-stage lung adenocarcinoma (LUAD) and further identify potential prognostic factors for these patients.MethodsA retrospective cohort of 190 patients (99 solitary LUAD and 91 multifocal LUAD) undergone wedge resection from October 2014 to September 2015 was established. Cox proportional-hazards model was used to evaluate the significant clinical prognostic factors. Further, data on patients with multifocal adenocarcinoma after segmentectomy were retrieved and propensity score matching was used to compare the outcomes of patients with multiple pulmonary nodules (MPNs) after wedge resection and segmentectomy.ResultsThe 5-year overall survival (OS), progression-free survival (PFS), and lung cancer specific survival of the 190 patients after wedge resection were 95.5%, 87.9%, and 97.7%, respectively. Multivariable analysis showed that MPN [hazard ratio (HR) 3.07; 95% confidence interval (CI), 1.05–8.98] and solid-dominant lesions (HR 15.87; 95% CI, 2.38–105.84) were independently associated with worse PFS. Further, propensity score matching analysis showed that MPN patients had better PFS after segmentectomy compared with wedge resection (94% vs. 80.9%, P=0.008). MPN patients were more likely to perform systematic mediastinal nodal sampling (95.6% vs. 59.3%, P<0.001) after segmentectomy compared to patients who underwent wedge resection.ConclusionsWedge resection is a practical option for appropriately selected early-stage LUAD where tumor size is less than 2 cm and has a consolidation-to-tumor ratio ≤0.5. However, for MPNs, wedge resection may be not reliable and alternative procedures such as segmentectomy should be used.

Treatment options for pulmonary multifocal ground glass opacity type adenocarcinoma: Surgery combine thermal ablation?

ObjectivesTo retrospectively analyze the clinical results of the treatment of pulmonary multifocal adenocarcinoma presenting as ground glass opacity (GGO) by surgery and thermal ablation. Methods87 GGO-type pulmonary adenocarcinomas of 48 patients (14 males and 34 females; mean age: 59.7 years old ±9.9, range: 33–79 years old) had been treated from March 2015 to March 2019. Treatment means included 43 wedge resections, 7 segmentectomy, 17 lobectomies, and 20 thermal ablations. The indication selected for treatment means, safety, and local tumor progression rate were evaluated. ResultsNo operation-related death occurred in all patients. 42 times of surgery were performed and 67 carcinomas were resected in 42 patients. 23 times of single-port Video-assisted thoracoscopic surgery (VATS), 8 times of two-port VATS and 11 times of three-port VATS were performed in total. There were 2 cases of air leak (exceeding 1 week), 1 case of chylothorax and 1 case of massive pleural effusion. Time duration of surgery was between 60 and 300mins (mean: 167mins). Intra-operative blood loss was between 5 and 300 ​mL (mean: 44 ​mL). Time of chest drainage was between 2 and 23d (mean 4.9d). Chest drainage volume was between 14 and 4633 ​mL (mean: 872 ​mL). Post-operation LOS (length of stay) was between 3 and 25d (mean: 6.2d). 15 times of thermal ablation were performed (1 case of air leak) and 20 carcinomas were ablated in 14 patients. The ablation time was between 30 and 120min (mean: 43min); post-operation LOS was between 1 and 10d (mean: 3.5d). During the mean follow-up period (16 months ​± ​13) (range: 5–60 months), no local tumor progression occurred. ConclusionsSurgery and thermal ablation are safe and effective options for the treatment of pulmonary multifocal GGO-type adenocarcinoma.

Concomitant EGFR mutation and ALK rearrangement in multifocal lung adenocarcinoma: a case report

BackgroundThe prevalence of EGFR/ALK co-alterations in patients with NSCLC was low. The several previous studies focused on the simultaneous occurrence of EGFR mutations and ALK rearrangements in a unifocal lung cancer. However, the incidence of multifocal pulmonary adenocarcinomas was increasingly encountered in clinical practice, due to the increased availability and improvement of the thoracic imaging. The clinical relevance of EGFR/ALK co-alterations in multifocal adenocarcinomas required detailed investigation as well.Case presentationWe present the case of a 57-year-old woman with solid nodule in the left upper lung and a ground glass nodule in the left lower lobe, who underwent radical operation. Pathological examination confirmed multifocal adenocarcinoma, molecular tests revealed that the left upper lung lesion was positive for ALK rearrangement but the left lower lobe displayed EGFR mutation positive separately. The patient pulmonary lesions were well controlled by adjuvant chemotherapy and radiation therapy. When brain metastases occurred, EGFR-TKI was not effective after firstly administration, while subsequent ALK inhibitors were efficient. We retrospective evaluated the oncogenic status of metastatic lymph nodes and found that the driver gene was ALK rearrangement rather than EGFR mutation.ConclusionsThe status of the oncogenic mutations in lymph node metastasis may provide some effective hints for metastasis lesion in other organ or tissue. Therefore, it is recommended to fully evaluate the driver genes in lymph node metastasis after radical resection.

Concomitant EGFR Mutation and EML4-ALK Rearrangement in Lung Adenocarcinoma Is More Frequent in Multifocal Lesions

BackgroundThe coexistence of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement in patients with multifocal lung adenocarcinomas (LUAC) constitutes a rare molecular subtype of lung cancer. We aimed to investigate the intertumoral heterogeneity of pathologic and genetic characteristics of multifocal LUAC with EGFR/ALK co-alterations. Patients and MethodsA total of 1059 LUAC patients who underwent resection were investigated to screen for EGFR or ALK alterations using amplification refractory mutation system polymerase chain reaction and immunohistochemistry/fluorescence in situ hybridization. Molecular testing was extensively performed in patients with synchronous multifocal LUAC. Clonal evolution analysis was implemented using next-generation sequencing. ResultsA total of 97 multiple synchronous lesions were observed among 1059 LUAC patients. Patients with at least 1 sample harboring EGFR mutation or ALK rearrangement were 62.89% (61/97) and 14.43% (14/97), respectively. Patients with concomitant EGFR and ALK alterations were 4.71% (4/97). Comparatively, patients with unifocal LUAC harboring EGFR mutation, ALK rearrangement, and EGFR/ALK co-alterations were 58.25% (570/962), 6.44% (62/962), and 0.83% (8/962), respectively. The prevalence of EGFR/ALK co-alterations in the multifocal LUAC was significantly higher than that in the unifocal LUAC (4.71% (4/97) vs. 0.83% (8/962)). Furthermore, we present 4 cases of EGFR/ALK co-altered multifocal LUAC with different morphological and molecular patterns. In addition to radiographic, pathological, and molecular testing results, clonal evolutional analysis could also be used to distinguish intertumoral heterogeneity. ConclusionThe results highlight the importance of distinguishing synchronous primary tumors from intrapulmonary metastases, and of assessing the relative abundance of EGFR mutation and ALK rearrangement in patients with multifocal adenocarcinomas with EGFR/ALK co-alterations.

The Clinical and Molecular Characteristics of Adenocarcinoma Presented by Multi-focal GGO

随着人们对肺癌早期筛查的重视，肺多发磨玻璃影（multiple ground glass opacities, GGOs）的检出率逐年增高，以GGOs为表现的多灶肺腺癌也逐渐成为临床研究热点。其更多见于女性、非吸烟者，且无论是自然病程还是手术后的患者均有极佳预后。独特的临床特征提示其很可能是相对独立的一种疾病形式。从分子遗传学路径对其的探究发现，同一个体内的多个病灶间极可能有截然不同的克隆性特征，因此遗传异质性（genetic heterogeneity）是以GGOs为表现多灶肺腺癌最显著的分子遗传学特征。此特征可辅助原发多灶肺腺癌与肺癌肺内转移的鉴别诊断，也提示了对病灶进行分子遗传学检测的治疗意义。部分呈现出遗传相似性的GGOs病灶为气腔播散转移（spread through air spaces, STAS）理论提供了新的证据。

PS02.26 Multifocal Adenocarcinoma of the Lung: Factors Predictive for Local Therapy: Topic: Medical Oncology

PS02.26 Multifocal Adenocarcinoma of the Lung: Factors Predictive for Local Therapy: Topic: Medical Oncology

Cholangiocarcinoma with concurrent ovarian adenocarcinoma in a green iguana (Iguana iguana)

Green iguanas with gastrointestinal, hepatic, and reproductive disease may present to the veterinary clinic displaying non-specific clinical signs, necessitating a thorough clinical evaluation. A 15-year-old intact female green iguana (Iguana iguana) presented with a 3-week history of decreased appetite and coelomic distension. A complete blood count and plasma biochemistry analysis showed anaemia and leukopenia with an absolute lymphopenia; decreased sodium and chloride concentrations; and increased phosphorus, potassium, aspartate transaminase, and uric acid concentrations. Whole body radiographs revealed a large, round, homogenous soft tissue opacity structure in the coelom. Ultrasonography confirmed a thin-walled cystic structure located in the cranial coelomic cavity. An exploratory coeliotomy revealed a large hepatic cyst, diffusely abnormal hepatic parenchyma, and cysts on the right ovary. The right ovary and hepatic cyst were surgically excised, however the iguana died under general anesthesia. Histopathology provided a diagnosis of multifocal cholangiocarcinoma and ovarian papillary adenocarcinoma. This case report alerts the clinician to the clinical presentation, anaesthetic protocol, surgical intervention, and challenges associated with the diagnosis of a large cystic cholangiocarcinoma in a pet green iguana.

Germline T790M mutation of the epidermal growth factor receptor (EGFR) in a case of multifocal adenocarcinoma of the lung without exposure to Tyrosine Kinase Inhibitors (TKI): A Case Report

Germline T790M mutation of the epidermal growth factor receptor (EGFR) in a case of multifocal adenocarcinoma of the lung without exposure to Tyrosine Kinase Inhibitors (TKI): A Case Report

Lung Adenocarcinoma with Miliary Metastases and Left Femur Pathologic Fracture: an Unusual Case Mimicking Disseminated Tuberculosis

Lung adenocarcinoma can have a varied appearance at presentation. Solid, ground-glass, or part-solid and part-ground-glass nodules are commonly seen [1]. Multifocal areas of consolidation that are peribronchovascular and contain air bronchograms may also be identified [3]. Multiple discrete nodules, or the so-called miliary pattern, are rare, with few cases reported in the literature [3, 10, 12, 14]. This pattern is more commonly reported as multifocal or diffuse adenocarcinoma, and detailed data regarding the incidence has not yet been studied in depth. However, in one case report of 73 patients with adenocarcinoma, 14 presented with multifocal disease, though only one had innumerable discrete nodules [19, 22]. In another study examining 548 patients with non-small cell lung cancer, 504 patients presented with a dominant lesion (stage I disease) and 44 with multifocal disease. Of the 44 patients, 18 had multifocal adenocarcinoma [2]. Some have suggested that the miliary pattern of adenocarcinoma may be produced by bone or liver metastases that continually seed the lung, though this has yet to be verified [10]. Because the miliary pattern is much less common, it may be confused for other entities, such as tuberculosis. Non-small cell lung cancer metastasizes to the bone in approximately 15–40% of cases, mostly involving the axial skeleton [11, 16]. Appendicular metastases are more common proximal to the knee and elbow, though more distal involvement is reported [5, 9, 11, 15, 18, 20, 21]. Extremity metastases are often initially misdiagnosed as benign entities such as infection due to presenting symptoms of local redness, pain, and swelling. Generally, a bony metastasis on radiograph appears as a lytic lesion and may be centered in the cortex (cookie-bite lesion). There may or may not be a demonstrable soft tissue mass [7]. Tuberculous and malignant involvement of the bone is often indistinguishable on imaging, particularly in the spine, where MRI findings can be similar [4, 13, 17, 23]. Diagnosis of tuberculous spread to the bone in general is often difficult, with an average delay in diagnosis of 16–19 months [4]. The musculoskeletal system is involved in 1–3% of cases of tuberculosis. The femur, tibia, and small bones of the hands and feet are often affected [6]. Typically, the metaphyses are involved, with radiographic features that include osteopenia and poorly defined lytic lesions with minimal surrounding sclerosis [4]. Our goal is to highlight the importance of maintaining a broad differential when evaluating a patient with confounding risk factors and imaging findings. Premature diagnoses may lead to delays in appropriate management [13]. Ultimately, tissue sampling may be necessary in providing a definitive, timely diagnosis.

Clinical implications of genetic heterogeneity in multifocal pulmonary adenocarcinomas.

Multifocal pulmonary adenocarcinomas are increasingly encountered in clinical practice, in part due to the increased availability and improvement in the thoracic imaging. Recognized as a distinct entity in the upcoming 8th edition of American Joint Commission on Cancer (AJCC) staging system, multifocal adenocarcinomas exhibit several unique features such as the characteristic appearance of multiple ground glass opacities or nodules in computerized tomography (CT). Recent studies have suggested that the vast majority of these malignant lesions are genetically independent even when occurring synchronously in a single patient. For instance, the pattern of epidermal growth factor receptor (EGFR) mutations in multifocal pulmonary adenocarcinomas can vary from one lesion to another. This observation has several important clinical implications. These include the potential need to perform multiple molecular tests on multiple lesions, the possible role of molecular marker such as EGFR mutation in the staging of questionable multiple lung cancers, and the justification for empirical use EGFR inhibitors for multifocal adenocarcinomas among high-prevalence population when no known mutation has been detected.

Primary adenocarcinoma of the renal pelvis, ureter and the urinary bladder: A case report and review of the literature.

Primary adenocarcinoma is a rare type of urological neoplasm. The present study reports the case of a 55-year-old man with multifocal adenocarcinoma of the renal pelvis, ureter and urinary bladder that occurred in association with a large cystic calculus and perinephric abscess. The patient had suffered from gross hematuria for 2 years and right flank pain for 2 months. Following a series of investigations, a large cystic calculus with multiple tumors in the renal pelvis and ureter was identified. Multifocal tumors and a large calculus were located in the bladder using a cystoscope. The pathological report of 3 individual biopsies revealed a moderately differentiated tubular adenocarcinoma. Right nephrectomy, ureterectomy, radical cystectomy and left ureterocutaneostomy were performed. The pathological investigation revealed a moderately differentiated adenocarcinoma of the renal pelvis, ureter and urinary bladder. No additional treatment was administered and the patient remains alive at follow-up without disease recurrence or metastasis. Although uncommon, the development of a tumor is possible in patients that possess long-standing urolithiasis, particularly when accompanied by hydronephrosis or infection.

폐의 분화와 폐암에서 SRC-3와 TTF-I의 역할

Steroid receptor coactivators (SRC) are transcriptional coactivators. Among SRCs, SRC-3 is the most studied in relation to different types of tumors. However, the role of SRC-3 in early lung development and lung cancer has not been well studied. The expression profiles of SRC-3 showed that SRC-3 contributed to bronchial and alveolar development in embryonic lung development. SRC-3 was strongly expressed in Clara cells and type II alveolar cells during fetal lung development (E17.5- E18.5), and SRC-3 was expressed in both cell types in the adult lung. TTF-1 was expressed in the lungs of heterozygote SRC-3 mice and Clara cell-specific-CCSP-TAg tumor mice, along with SRC-3 expression. The expression of TTF-1 was localized at transformed Clara cells and multifocal adenocarcinomas in lung cancer mice. However, SRC-3 was not expressed in the multifocal adenocarcinomas, suggesting that SRC-3 might not be involved in the invasiveness of lung cancer. Cotransfection of TTF-1 in Clara cell-specific mtCC cell lines resulted in significant activation of CCSP expression. However, cotransfection of SRC-3 had no significant effects on transient transfection. These in vivo and in vitro results suggest that SRC-3 does not play a significant role in lung tumor progression. In conclusion, SRC-3 is involved in bronchial and alveolar development in fetal and adult lungs, but it does not play an important role in the progression of Clara cell-derived lung cancer.

Abstract A085: miR-222/221 in aggressive breast cancer

Abstract MicroRNAs (miRNAs) are small non coding RNAs that regulate gene expression at post-transcriptional level through translational inhibition and/or degradation of mRNA target genes. Recent evidence points to a widespread role for miRNAs in the initiation and progression of tumorigenesis in a plethora of tissues including the mammary gland. Aberrant miRNA expression profiles have been described in breast cancer specimens compared to normal tissues, discriminating breast tumors with different clinico-biological phenotypes. In our previous publications, we have demonstrated that miR-222/221 cluster is highly expressed in aggressive breast cancer and high levels of miR-222/221 may confer a proliferation advantage to cancer cells and resistance to therapeutic agents by repressing several genes such as ERα;, CDKN1B, BIM, FOXO3, CAV1, PTEN. To demonstrate the in vivo role of miR-222/221 cluster in breast cancer initiation and progression, we have genetically deleted miR-222/221 gene in the MMTV-PyVT mouse model that develops multifocal mammary adenocarcinoma and lung metastatic lesions in 80% of the population. The tumor latency and multiplicity were assessed and none of these parameters were significantly affected by miR-222/221 ablation. Interestingly, lack of miR-222/221 impairs the development of lung metastasis with a reduction of the metastatic load of the lung. Moreover, metastases arising from miR-222/221 deficient cells present a greater cytoarchitectural similarity and a reduced rate of mitosis and apoptosis. We also show that loss of miR-222/221 modulates the transcriptome and miRNA expression profiles of mouse breast tumors and cancer cells, stimulating a stronger estrogen receptor alpha transcriptional network and a suppression of the cancer stem cells population. Citation Format: Gianpiero Di Leva, Claudia Piovan, Douglas Cheung, Daniel Briskin, Arpan Kumar, Gerard Nuovo, Matteo Fassan, Vincenzo Coppola, Michela Garofalo, Carlo Croce. miR-222/221 in aggressive breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A085.

Malignancies Incidentally Detected at Lung Transplantation: Radiologic and Pathologic Features

The purpose of this study was to assess the CT-pathologic features of cancer incidentally detected at lung transplantation. Our lung transplant registry was reviewed over 7 years for incidental malignancy. Patient demographics, diffuse lung disease, surgical procedure, histopathology, and chest CT were recorded. We correlated lesion size, morphology, multiplicity, and location with surgical and pathology reports and histopathology. Cancers were pathologically staged. Of 759 lung transplant recipients, cancer was incidentally detected in 22 (2.9%). Half (11 of 258) or 4.3% were detected within the past 2 years. Four patients had a history of treated malignancy, and three had recurrence. Patients had emphysema (chronic obstructive pulmonary disease [COPD]) (n = 10), fibrosis (n = 10), or combined COPD and fibrosis (n = 2). Histopathology revealed 13 solitary lung carcinomas, four multifocal adenocarcinomas, three metastases, and two lymphoproliferative diseases. Lung cancer (n = 17) stages were I or II (n = 13), IIIA (n = 2), or IV (n = 2). Metastases (n = 3) and lymphoproliferative disease (n = 2) represented advanced disease. The interval between CT and surgery was a mean of 4 months. CT-positive cases (n = 10) represented lung cancer (n = 9) and posttrans-plantation lymphoproliferative disease (n = 1). Cases with no CT findings of malignancy (n = 12) included lung cancer (n = 8), metastases (n = 3), and lymphoma (n = 1). Ten cases (45%) had other histologically benign CT abnormalities that mimicked cancer. Detection of incidental malignancy at lung transplantation has increased over the past 2 years. Malignancies were typically stage I or II lung cancers that were occult or indeterminate on CT. Diffuse lung disease, multiple CT abnormalities, and a delay between CT and transplantation compromise the preoperative diagnosis of cancer.