Multiple Tumor Nodules Research Articles

Pathology of Surgically Resected Lung Cancers Following Neoadjuvant Therapy.

In around 30% of patients, non-small cell lung cancer is diagnosed at an advanced but resectable stage. Adding systemic therapy has shown clear benefit over surgery alone in locally advanced disease, and currently, chemo-immunotherapy in the adjuvant or neoadjuvant setting is the new standard for patients without targetable mutations. One major advantage of the neoadjuvant approach is the possibility of an immediate evaluation of the treatment effect, highlighting the role of pathology as an important contributor at the forefront of clinical decision-making and research. This review provides a summary and an update on current guidelines for histological evaluation of treatment effect after neoadjuvant therapy, also known as regression grading, and discusses newer data focusing on areas of evolving questions and controversies, such as the gross examination of the tumor and tumor bed, weighted versus unweighted evaluation approaches, discussion of histologic tumor type-specific cut-offs for major pathologic response, assessment of lymph nodes and regression grading after immunotherapy and targeted therapy. As no data or recommendations exist on regression grading of multiple tumor nodules, a practical approach is recommended. Lastly, we will touch on additional tissue biomarkers and summarize recent advances in the ardently discussed field of using circulating tumor DNA for the evaluation of treatment response.

Targeting CD20-expressing malignant melanoma cells augments BRAF inhibitor killing.

Mutant BRAF targeted therapies remain a standard of care for the treatment of metastatic malignant melanoma (MM); however, high initial response rates are tempered by the persistence of residual MM cells that eventually lead to disease recurrence and mortality. As MM recurrence during targeted therapy can present with the simultaneous occurrence of multiple tumour nodules at the original body sites, we hypothesized the presence of an intrinsically resistant MM cell subpopulation. To identify an MM cell subpopulation that is intrinsically resistant to targeted therapy and possibly responsible for MM recurrence. Using melanoma cell lines, we defined culture conditions for the reproducible three-dimensional growth of melanospheres to investigate putative cancer stem cell populations. We undertook RNA sequencing and bioinformatic analysis to characterize cell populations between adherent and nonadherent culture, and cells expressing or not expressing CD20. Furthermore, we defined an in vitro assay to evaluate the killing of melanoma cancer stem cells as a therapeutic test using combination therapies targeting driver mutation and CD20. We described the culture conditions that promote MM cells to form melanospheres with a reproducible colony-forming efficiency rate of 0.3-1.3%. RNA sequencing of melanosphere vs. conventional MM cell cultures (n = 6), irrespective of the BRAF mutation status, showed that melanosphere formation was associated with growth and differentiation transcriptional signatures resembling MM tumours. Importantly, melanosphere formation also led to the emergence of a CD20+ MM cell subpopulation, similar to that observed in primary human MM tumours. CD20+ MM cells were resistant to BRAF inhibitor therapy and, consistent with this finding, demonstrated a Forkhead box protein M1 transcriptomic profile (n = 6). Combining BRAF inhibitor and anti-CD20 antibody treatment led to the additional killing of previously resistant CD20+ BRAF mutant MM cells. In patients with MM that harbour a CD20+ subpopulation, combined therapy with BRAF inhibitor and anti-CD20 antibody could potentially kill residual MM cells and prevent disease recurrence.

Intraoperative diagnosis of facial schwannomas: a multicenter summation of clinical experience, preoperative avoidance, and intraoperative management protocol.

Preoperative differentiation of facial nerve schwannoma (FNS) from vestibular schwannoma (VS) can be challenging, and failure to differentiate between these two pathologies can result in potentially avoidable facial nerve injury. This study presents the combined experience of two high-volume centers in the management of intraoperatively diagnosed FNSs. The authors highlight clinical and imaging features that can distinguish FNS from VS and provide an algorithm to help manage intraoperatively diagnosed FNS. Operative records of 1484 presumed sporadic VS resections between January 2012 and December 2021 were reviewed, and patients with intraoperatively diagnosed FNSs were identified. Clinical data and preoperative imaging were retrospectively reviewed for features suggestive of FNS, and factors associated with good postoperative facial nerve function (House-Brackmann [HB] grade ≤ 2) were identified. A preoperative imaging protocol for suspected VS and recommendations for surgical decision-making following an intraoperative FNS diagnosis were created. Nineteen patients (1.3%) with FNSs were identified. All patients had normal facial motor function preoperatively. In 12 patients (63%), preoperative imaging demonstrated no features suggestive of FNS, with the remainder showing subtle enhancement of the geniculate/labyrinthine facial segment, widening/erosion of the fallopian canal, or multiple tumor nodules in retrospect. Eleven (57.9%) of the 19 patients underwent a retrosigmoid craniotomy, and in the remaining patients, a translabyrinthine (n = 6) or transotic (n = 2) approach was used. Following FNS diagnosis, 6 (32%) of the tumors underwent gross-total resection (GTR) and cable nerve grafting, 6 (32%) underwent subtotal resection (STR) and bony decompression of the meatal facial nerve segment, and 7 (36%) underwent bony decompression only. All patients undergoing subtotal debulking or bony decompression exhibited normal postoperative facial function (HB grade I). At the last clinical follow-up, patients who underwent GTR with a facial nerve graft had HB grade III (3 of 6 patients) or IV facial function. Tumor recurrence/regrowth occurred in 3 patients (16%), all of whom had been treated with either bony decompression or STR. Intraoperative diagnosis of an FNS during a presumed VS resection is rare, but its incidence can be reduced further by maintaining a high index of suspicion and undertaking further imaging in patients with atypical clinical or imaging features. If an intraoperative diagnosis does occur, conservative surgical management with bony decompression of the facial nerve only is recommended, unless there is significant mass effect on surrounding structures.

Liver Transplantation for Hepatocellular Carcinoma in Patients with Inherited Metabolic Liver Diseases: A Single-Center Analysis.

Liver transplantation is an acceptable treatment for some selected hepatocellular carcinoma. We report our experience of 6 patients with liver transplantation for hepatocellular carcinoma with background inherited metabolic disease. This is a single-center retrospective, descriptive study. Consecutive patients who underwent liver transplantation for hepatocellular carcinoma with background inherited metabolic disease were included in the study. The record of the patients was accessed, and the following data were extracted: sociodemographic variables, type of metabolic disease, date of liver transplantation, tumor characteristics, laboratory parameters, Model for End-Stage Liver Disease score, immediate- and long-term outcome after transplantation, disease-free survival, and overall survival. Data were analyzed using Statistical Package for the Social Sciences version 25.0. Six patients received liver transplantation for hepatocellular carcinoma with background inherited metabolic liver disease. The median age was 4.5 years. The median Model for End-Stage Liver Disease score was 29.30. The median maximum tumor diameter was 2.15 cm. Three patients had multiple tumor nodules. Half of the patients had microvascular invasion. Four of the patients had a moderately differentiated tumor. Progressive familial intrahepatic cholestasis type II is the commonest inherited metabolic disease seen in 3 patients. Median follow-up is 46.1 months. Half of the patients are currently more than 5 years post liver transplantation with no features of recurrence. The estimated survival rates at 1, 3, and 5 years are 100%, 83.3%, and 83.3%, respectively. Liver transplant for these categories of patients is associated with good disease-free and overall survival, even in the presence of some seemingly poor prognostic features.

Transcriptomic Analysis of Cirrhosis-Like Hepatocellular Carcinoma Reveals Distinct Molecular Characteristics and Pathologic Staging Implications.

Cirrhosis-like hepatocellular carcinoma (CL-HCC) is a rare hepatocellular malignancy characterized by multiple tumor nodules that clinically, radiologically, macroscopically, and microscopically mimic cirrhosis. We aimed to elucidate the molecular biology of CL-HCC and determine tumor nodule clonality. We performed RNA sequencing on formalin-fixed, paraffin-embedded tissue from confirmed CL-HCC cases (n = 6), along with corresponding nonneoplastic hepatic tissue (n = 4) when available. Transcriptomes from our previous work on steatohepatitic hepatocellular carcinoma and The Cancer Genome Atlas (TCGA) were used for comparison purposes. Histologically, CL-HCC displayed innumerable nodules and extensive vascular invasion. Intratumoral nodule comparison indicated that the multiple nodules were all clonally related, not independent primaries. The unique histomorphologic appearance corresponded with a distinct transcriptome compared with other HCCs, including fibrolamellar HCC (n = 6), steatohepatitic HCC (n = 8), and conventional HCC in TCGA (n = 424). Tumor-normal gene expression analysis revealed consistent overexpression of several genes involved in degradation of tissue matrix. No recurrent translocations or point mutations were identified. CL-HCC showed a gene expression profile indicative of zone 2 hepatocytes. CL-HCC's distinctive clinicopathologic features correspond to a unique gene expression profile, increased expression of invasive markers, features of zone 2 hepatocytes, and features suggestive of intratumoral nodule monoclonality.

Long-term survival in colorectal liver metastasis.

Liver resection is the best treatment option for patients with resectable colorectal liver metastasis (CRLM). A 10-year follow-up can reflect the true curative potential of resection. This retrospective study investigated factors for long-term survival of CRLM patients. Data of patients who underwent liver resection for CRLM without extrahepatic disease from 1990 to 2012 at our hospital were reviewed. Patients who survived for > 10years were compared with those who survived for < 10years. Totally, 315 patients were included in the study. They were divided into 2 groups: < 10-year group and > 10-year group. Patients in the < 10-year group had more tumor nodules (P = 0.016), more bilobar involvement (P = 0.004), narrower resection margin (P < 0.001), and worse disease-free and overall survival (P < 0.001). On multivariate analysis, low preoperative hemoglobin level, large number of tumor nodules, and bilobar involvement were poor prognostic factors for overall survival, while adjuvant chemotherapy was a favorable factor. Further analysis of patients with bilobar disease showed that perioperative blood transfusion was a poor prognostic factor for overall survival while adjuvant chemotherapy was a favorable one. In patients with multiple bilobar tumor nodules, adjuvant chemotherapy had a positive impact on disease-free survival and overall survival. Patients who survived for > 10years after liver resection for CRLM tended to have normal preoperative hemoglobin level, unilobar disease, fewer tumor nodules, and have received adjuvant chemotherapy. Adjuvant chemotherapy favorably affected long-term survival of CRLM patients.

Transglutaminase 3 expression in hepatocellular carcinoma patients: Correlation with tumor features and survival profile

BackgroundTransglutaminase 3 (TGM3) regulates multiple oncogene pathways (GSK-3β/β-catenin pathway, Akt/ERK pathway, etc.) to promote hepatocellular carcinoma (HCC) cell proliferation, migration and invasion, however, its clinical value for HCC management is still limited. Therefore, we conducted this study to compare the TGM3 expression between tumor tissue and paired adjacent noncancerous tissue, aiming to explore the clinical application of TGM3 in HCC patients. MethodsTotally, 208 HCC patients were enrolled and their clinicopathological features were collected. Then, 208 pairs of HCC specimens and adjacent noncancerous specimens were used to detect TGM3 protein expression by IHC assay and assessed by a semi-quantitative scoring method. Besides, 157 pairs were proposed to detect TGM3 mRNA expression by RT-qPCR. ResultsBoth TGM3 protein (P<0.001) and mRNA (P<0.001) levels were increased in HCC specimens compared to adjacent noncancerous specimens. Besides, TGM3 high protein expression correlated with multifocal tumor nodules (P<0.001), advanced Barcelona Clinic Liver Cancer (BCLC) stage (P = 0.006), higher carcinoembryonic antigen (P = 0.038) and alpha-fetoprotein (AFP) (P<0.001). While TGM3 high mRNA expression correlated with multifocal tumor nodules (P = 0.025), largest tumor size ≥ 5.0 cm (P = 0.042) and higher AFP (P = 0.019). Furthermore, both TGM3 protein (P = 0.002) and mRNA (P = 0.028) high expressions correlated with shorter overall survival (OS). While after adjustment by multivariant Cox's regression, TGM3 protein high expression (vs. low) independently predicted worse OS (P = 0.004). ConclusionsTMG3 expression is increased in tumor tissue, also its high expression correlates with multiple tumor nodules, higher BCLC stage, abnormal AFP and reduced OS in HCC patients.

Efficacy of traditional herbal medicine versus transcatheter arterial chemoembolization in postsurgical patients with hepatocellular carcinoma: A retrospective study

BackgroundRecurrence is a major obstacle to improve the prognosis of hepatocellular carcinoma (HCC) patients. Transcatheter arterial chemoembolization (TACE) has been routinely used as an adjuvant therapy in treating HCC, but efficacy of TACE in preventing the recurrence of HCC remains unsatisfactory. This study aimed to compare the efficacy of a traditional herbal medicine (THM) therapy and TACE in preventing tumor recurrence and improving survival in postsurgical patients with HCC. Materials and methodsA total of 1506 HCC patients were enrolled from January 2008 to June 2017, including 262 patients who received THM therapy and 1244 patients who were treated with TACE. All patients were followed up until the occurrence of outcome event or June 30th, 2019. The recurrence-free survival (RFS) and overall survival (OS) were calculated by the Kaplan-Meier method, and the differences of RFS and OS between THM group and TACE group were analyzed by the log-rank test. Factors affecting the RFS or OS among these patients were assessed by the Cox proportional hazard regression model. A nomogram was built with the factors based on the Cox regression analysis to predict the prognosis. ResultsThe 1-, 3-, and 5-year RFS were 91.0%, 68.3%, and 49.7%, respectively, in the THM group and 79.4%, 38.6%, and 19.3%, respectively, in the TACE group. The RFS in the THM group was significantly higher than that of the TACE group (P = 6.2 × 10−11). The 1-, 3-, and 5-year OS were significantly improved in the THM group as compared to those in the TACE group (94.3%, 65.2%, and 41.4% vs. 82.7%, 46.0%, and 25.4%, P = 2.2 × 10−11). Multivariate analysis revealed that serum AFP level ≥400 ng/mL, HBV DNA load ≥500 copies/mL, TNM stage III-IV, tumor diameter ≥5 cm, presence of MVI, and multiple tumor nodules were independent risk factors for RFS, while complete tumor encapsulation and THM therapy were protective factors for RFS and OS. The nomogram demonstrated good accuracy in predicting RFS and OS, with the adjusted C-index of 0.748 and 0.796, respectively. ConclusionThe efficacy of THM therapy was superior to that of TACE in preventing recurrence and improving survival for HCC patients after hepatectomy.

P02.25 Coexistence of Invasive Adenocarcinoma, Minimally Invasive Adenocarcinoma and Atypical Adenomatous Hyperplasia: A Case Report

Multiple small nodular lung cancer (MSLC) refers to multiple tumor nodules on the same or different lobes of the lungs. These nodules are affected by the same germline characteristics and environmental exposure factors that occur simultaneously in one individual. Invasive adenocarcinoma (inv ADC), minimally invasive adenocarcinoma (MIA) and atypical adenomatous hyperplasia (AAH) are regarded as the “three-steps” in the evolution of lung adenocarcinoma. A fifty-year-old Asian female patient without a history of smoking was hospitalized due to three ground-glass nodules (GGNs) in the right upper lobe of the lung, which were detected in March 2017. Three nodules revealed by chest CT were each pathologically diagnosed as ADC, MIA and AAH. To further confirm the correlations and differences among these types, we performed whole-exome sequencing on the three lesions followed by a comparative analysis at the genetic level to determine the major genes that may play an important role in the progression of these “three-steps” in lung adenocarcinoma. The TMB of the three lesions was relatively low, especially in AAH.(Fig 2C) The three lesions were found to share a common gene (BAGE2).(Fig 2B) We found that MAP3K14, MAP2K1, and EGFR, which are three major genes of the EGFR-MAPK pathway, may play an important role in AAH, MIA and inv ADC, respectively.(Fig 2D) The C>T alteration was the primary change observed in the three nodules of the patient. C>A was increased in the ADC nodule and decreased in the MIA nodule, but was rare in AAH.(Fig 2E, F) We found that MAP3K14, MAP2K1, and EGFR were three dominant factors that exist as part of “three-steps” and that might act as new specific targets for the treatment of this disease type. However, the relationship among MAP2K1, MAP3K14 and EGFR still requires more verification in more samples.

Unusual radiologic presentations of malignant peritoneal mesothelioma.

BACKGROUNDMalignant peritoneal mesothelioma is an unusual disease process characterized radiologically by ascites and infiltration of the peritoneum by multiple small tumor nodules. Both parietal and visceral peritoneum are involved by the multiple malignant tumor nodules. Computed tomography (CT) has been used to identify the anatomic pathology induced by the progression of this malignant process. AIMTo identify and then describe unusual CT images in patients with malignant peritoneal mesothelioma. Recognition of these unusual radiologic findings can cause the radiologist to be suspicious of this rare malignant process.METHODSIn 100 patients who were to undergo definitive treatment of malignant peritoneal mesothelioma, the findings on preoperative CT scans were catalogued. Many of these changes were repeatedly noted on the CT scans. Other pathologic CT images were less common. These unusual radiologic presentations were specially studied in this manuscript. RESULTSEight unusual radiologic presentations of malignant peritoneal mesothelioma were selected for study. These unusual findings included a mass occurring within a Spigelian hernia, infiltration of the splenic parenchyma by spherical mesothelioma masses, infiltration of the lower mediastinum by tumor, a mesothelioma mass within a left inguinal canal, enlarged cardiophrenic angle lymph nodes, pleural plaques associated with the progression of malignant peritoneal mesothelioma, splenic notches caused by disease surrounding the spleen, and a mass greater than 5 cm associated with the proximal jejunum and directly adjacent to the anatomic location of the Treitz ligament.CONCLUSIONThere are unusual radiologic presentations of malignant peritoneal mesothelioma that are important to recognize in order to accurately diagnose this disease by CT.

Intrapulmonary inoculation of multicellular spheroids to construct an orthotopic lung cancer xenograft model that mimics four clinical stages of non-small cell lung cancer

IntroductionLung cancer leads in mortality among all types of cancer in US and Non-small cell lung cancer (NSCLC) is the major type of lung cancer. Mice models of lung cancer based on subcutaneous or orthotopic inoculation of cancer cell suspension do not adequately mimic the progression of lung cancer in clinic. MethodsA549-iRFP cells (human NSCLC adenocarcinoma) were cultured to form multicellular spheroids (MCS), which were then inoculated intrapulmonarily into male athymic nude mice. The xenograft cancer development was monitored by in vivo fluorescent imaging and validated by open-chest anatomy, ex vivo fluorescent imaging, and histological studies. ResultsThe newly developed orthotopic xenograft model of lung cancer simulated all four clinical stages of NSCLC progression over one month: Stage 1) localized tumor at the inoculation site, Stage 2) multiple tumor nodules or larger tumor nodule on the same side of the lung, Stage 3) cancer growth on heart surface, and Stage 4) metastatic cancer on both sides of the lung. The model yielded high rates of postoperative survival (100%) and parenchymal tumor establishment (88.9%). The roughness of the inoculated MCS associated negatively with the time needed to develop metastatic cancer (p = .0299). DiscussionThis new orthotopic xenograft model of NSCLC would facilitate the development of medications to treat lung cancer.

Clonal Origin Evaluated by Trunk and Branching Drivers and Prevalence of Mutations in Multiple Lung Tumor Nodules.

Differentiation between intrapulmonary metastasis (IPM) and multiple primary lung cancers (MPLC) in patients with synchronous or metachronous lung tumor nodules is critical but challenging. We proposed an algorithm to evaluate clonal origin based on trunk (initiating) versus branching drivers and the prevalence of mutations in lung adenocarcinomas. Driver mutations were examined using next-generation sequencing in five trunk driver genes (BRAF, EGFR, ERBB2, KRAS, and NRAS) and three branching driver genes (ATK1, PIK3CA, and TP53). Mutational profiling supported same clonality and likely same clonality, respectively, in 39 and 14 of 66 pairs of specimens with known identical clonal origin. Discordance of TP53 mutations (branching drivers) was observed in three pairs. Subsequent analyses of 30 pairs of synchronous or metachronous lung tumor nodules revealed different clonality and likely different clonality in 17 and 2 pairs, respectively, including three pairs with similar histomorphology; same clonality and likely same clonality in three and five pairs, respectively, including two pairs with different histomorphology; and inconclusive or noninformative results in three pairs. While discordance of trunk drivers indicated MPLC in patients with synchronous or metachronous lung tumor nodules, discordance of branching drivers did not exclude IPM. Concordance of uncommon drivers supported IPM, whereas concordance of common drivers did not exclude MPLC. Additional recommendations from official organizations are needed to guide applications of molecular markers in defining clonality of multiple lung tumor nodules.

Plexiform Schwannoma of the Oral Cavity: Report of Eight Cases and a Review of the Literature.

Plexiform schwannoma represents an unusual schwannoma variant, characterized by multinodular growth grossly and/or microscopically. A review of the English-language literature reveals only 28 previously reported cases involving the oral cavity, and herein we present 8 additional cases. Among these 36 patients, the average age at diagnosis was 28 years (range 5 to 62 years), with a female-to-male ratio of 1.4:1. The most frequently involved sites were the tongue (n = 13) and lip (n = 11). Lesion duration prior to presentation averaged 5.3 years (range, 6 weeks to 26 years). The average lesion size was 2.1 cm (range, 0.3 to 16 cm). The typical clinical presentation was a painless mass, although infrequent findings included pain/discomfort, paresthesia, difficulty chewing, and limited buccal mobility. All cases clinically appeared as a solitary mass or localized cluster of tumor nodules, with the exception of one patient who had neurofibromatosis 2 (NF2) and exhibited two distinct nodules on the tongue and buccal mucosa. In addition, extraoral neural neoplasms were evident in four patients, including three with NF2. Typical microscopic findings included multiple well-circumscribed tumor nodules, each surrounded by a perineurium-derived capsule with immunoreactivity for epithelial membrane antigen. The nodules contained characteristically bland and diffusely S-100-positive spindle cells arranged in Antoni A and B patterns; however, modest nuclear pleomorphism was evident in three cases. Most patients (n = 23) were treated by excision or enucleation and curettage, and three patients experienced recurrence. Unlike plexiform neurofibromas, plexiform schwannomas exhibit only a weak association with neurofibromatosis and have no known malignant potential.

Peritoneal mesothelioma: PSOGI/EURACAN clinical practice guidelines for diagnosis, treatment and follow-up

Peritoneal mesothelioma (PM) is a rare and aggressive primary peritoneal malignancy characterized by widespread multiple metastatic tumour nodules originating from the peritoneum. The conventional classification distinguishes diffuse malignant peritoneal mesothelioma (DMPM) and border-line forms: multicystic peritoneal mesothelioma (MCPM) and well-differentiated papillary peritoneal mesothelioma (WDPPM). Despite the novel achievements in the management of PM, there is difficulty in conducting randomized trials due to its rarity and aggressive biology in many cases.

Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis

BackgroundPeritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat...

Preoperative PET-CT is useful for predicting recurrent extrahepatic metastasis of hepatocellular carcinoma after resection

PurposeIn recent years, it has been reported that use of 18F-FDG PET-CT can reveal the degree of hepatocellular carcinoma malignancy. We evaluate the ability of a preoperative 18F-FDG PET-CT to predict the recurrence of extrahepatic metastasis of HCC after surgery. MethodsWe retrospectively examined 67 patients who received 18F-FDG PET-CT prior to curative hepatic resection for HCC between April 2010 and March 2016. Multivariate Cox regression analysis was performed to identify the factors associated with recurrence of extrahepatic metastasis of HCC after surgery. We also evaluated the sensitivity, specifity, positive predictive value, negative predictive value and accuracy of diagnosis of 18F-FDG PET-CT for recurrent extrahepatic metastasis of HCC after surgery. ResultsThe multivariate analysis identified a tumor-to-normal liver standardized uptake value ratio (TNR) ≥ 1.53 (hazard ratio [HR], 0.037; P = 0.003), multiple tumor nodules (HR, 0.121; P = 0.007), and presence of microvascular invasion (HR, 0.094; P = 0.003) as independent predictors of distant metastasis recurrence. A TNR ≥ 1.53 showed a sensitivity of 91.7 %, specificity of 76.4 %, positive predictive value of 45.8 %, negative predictive value of 97.7 %, and accuracy of 79.1 % for diagnosing distant metastasis recurrence of HCC. In a binomial logistic regression analysis of tumor factors associated with a TNR ≥ 1.53, poor tumor differentiation and large tumor size were significant factors. Conclusion18F-FDG PET-CT and microvascular invasion may be useful for predicting the recurrence of extrahepatic metastasis of HCC after surgery.

Living donor liver transplantation for combined hepatocellular-cholangiocarcinoma: A case series of four patients

IntroductionCombined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma whose components include both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Indications for liver transplantation for cHCC-CCA remain controversial. Case presentationsFour patients underwent living donor liver transplantation (LDLT) for cHCC-CCA. All patients had multiple tumor nodules preoperatively diagnosed as HCC. Postoperative pathological examinations revealed that one of the tumors was cHCC-CCA. Cases 1 and 2 underwent LDLT for cirrhosis with HCC tumors that met Milan criteria. Case 3 underwent LDLT for recurrent HCC tumors with nonalcoholic steatohepatitis. Although the preoperative examinations showed that the patient met the Kyoto, but not Milan criteria, postoperative pathological examinations revealed that the patient did meet Milan criteria. The three patients who met Milan criteria on postoperative pathological examination had no recurrences after LDLT. Case 4 had multiple tumors with alcoholic liver cirrhosis. Although the preoperative examinations showed that the patient did not meet Milan criteria—but did meet Kyoto criteria—, on postoperative pathological examinations, the patient met neither Millan nor Kyoto criteria. He died of tumor recurrence 15 months after LDLT. Discussion and conclusionsOur experiences suggested that patients who meet Millan or Kyoto criteria experienced acceptable outcomes of LDLT for cHCC-CCA. By itself, cHCC-CCA is not contraindication for liver transplantation.

ES12.01 Multiple Lung Nodules

Advanced imaging techniques resulted in increased detection of multiple tumors of the lung. Distinguishing synchronous primary lung cancers from intrapulmonary metastases (separate nodules) is important because treatments are very different. In addition, patients with independent primary tumors are expected to have better prognosis. Staging of such tumors as independent primary tumors or intrapulmonary metastases is often challenging, particularly in squamous cell carcinomas. Martini and Melamed modified criteria were used as the main approach for many decades with the idea that morphology of metastases should match the primary tumor, while different morphology supports classification of tumors as unrelated separate primaries. The 8th edition of the AJCC staging of the lung cancer pretty much has replaced this classification by establishing a multidisciplinary approach to these tumors as a standard of care and by promoting the tools such as comprehensive histologic assessment, imaging studies and molecular characterization either by CGH or biomarker testing. Comprehensive histologic assessment is based on the 2015 WHO classification of lung cancers and includes determination of the main histologic tumor type, quantitative subtyping particularly of lung adenocarcinomas, and assessment of cytologic and stromal characteristics. This approach can be relatively easily applied in lung adenocarcinomas, while squamous cell carcinoma remains a great challenge. A recent study conducted by the IASLC Pathology committee showed a good agreement (κ score 0.60) among thoracic pathologists in the histologic assessment of independent primary tumors from intrapulmonary metastasis. Despite a good agreement, there were cases with split opinions supporting a need for ancillary studies. Over the past decade many studies reported different molecular approaches to analysis of multiple lung tumor nodules including DNA microsatellite analysis, CGH/aCHG and most recently next generation sequencing. The data from published reports indicate a highly variable percentage of multifocal tumors identified as clonally related (up to 70%). Discrepancy between clinical and molecular classification of originally presumed cases of multiple primary lung cancers ranged in different series from 18% to 30%. Recent recommendations for routine molecular profiling of lung adenocarcinoma resulted in a widespread use of targeted mutational profiling for oncogenic mutations (i.e. EGFR, KRAS, BRAF etc) and gene rearrangements (i.e.ALK, ROS1) which results can be used in staging of multiple lung cancers. A different mutation profile in oncogenic mutations strongly indicates two separate primary tumors. However, the presence of a common driver mutation does not necessarily indicate tumors of similar origin. Therefore, limited molecular panels may not be sufficient in some cases. The detection of shared identical breakpoints by whole genome sequencing has been recently proposed as potentially more accurate and specific for lineage determination than the analysis of driver mutations alone. Also whole exome and whole genome sequencing approaches have been reported, but these assays may be technically challenging and turnaround time may not be suitable for routine clinical use.

Comparison of the 7th and 8th Edition of the UICC/AJCC TNM Staging System in Primary Resected Squamous Cell Carcinomas of the Lung-A Single Center Analysis of 354 Cases.

Background: The AJCC/UICC TNM (tumor, node, metastasis) classification is a standardized system for the description of anatomical extent and stage grouping of solid malignant tumors and is regularly updated. We aimed at testing the new 2017 8th edition of the TNM classification (TNM8) compared to the former 2009 7th edition (TNM7), in pulmonary squamous cell carcinomas (pSQCC).Methods: We analyzed a clinico-pathologically well-annotated Western single-center cohort of 354 consecutive pSQCC, resected 2000–2013, without previous neoadjuvant therapy. Patients with a clinical history of SQCC of other organs were excluded to reliably exclude lung metastases. Patients in whom TNM was unclear due to multiple tumor nodules were excluded. We reevaluated all pathological records and slides and retrospectively validated pleural invasion for all cases. Raw data of our cohort are provided as Supplementary Material.Results: The stage distribution according to TNM7 was as follows: IA (2009): 59 (16.7%), IB: 75 (21.2%), IIA: 71 (20.1%), IIB: 53 (15.0%), IIIA: 79 (22.3%), IIIB: 7 (2.0%), IV: 10 (2.8%). Staging the cases according to TNM8, 7/354 (2.0%) cases were down-staged, 154 (43.5%) were upstaged; most pronounced between stages IIA(TNM7) and IIB(TNM8), and IIB(TNM7) and IIIA(TNM8). Both staging systems showed significant prognostic impact for overall survival, disease free and disease specific survival and time to recurrence, without significant differences regarding goodness-of-fit criteria (Akaike Information Criterion and Schwarz Bayesian Criterion).Conclusion: In conclusion, we show a significant stage migration between tumors staged using TNM7 and TNM8, without benefit regarding prognostication in our cohort of primary resected pSQCC.

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) are known to promote tumourigenesis through various mechanisms. Fibroblast growth factor (FGF)/FGF receptor (FGFR)-dependent lung cancers have been described. We have developed a mouse model of lung adenocarcinoma that was constructed through the induction of Fgf9 overexpression in type 2 alveolar cells. The expression of Fgf9 in adult lungs resulted in the rapid development of multiple adenocarcinoma-like tumour nodules. Here, we have characterised the contribution of CAFs and the Fgf/Fgfr signalling pathway in maintaining the lung tumours initiated by Fgf9 overexpression. We found that CAF-secreted Fgf2 contributes to tumour cell growth. CAFs overexpressed Tgfb, Mmp7, Fgf9, and Fgf2; synthesised more collagen, and secreted inflammatory cell-recruiting cytokines. CAFs also enhanced the conversion of tumour-associated macrophages (TAMs) to the tumour-supportive M2 phenotype but did not influence angiogenesis. In vivo inhibition of Fgfrs during early lung tumour development resulted in significantly smaller and fewer tumour nodules, whereas inhibition in established lung tumours caused a significant reduction in tumour size and number. Fgfr inhibition also influenced tumour stromal cells, as it significantly abolished TAM recruitment and reduced tumour vascularity. However, the withdrawal of the inhibitor caused a significant recurrence/regrowth of Fgf/Fgfr-independent lung tumours. These recurrent tumours did not possess a higher proliferative or propagative potential. Our results provide evidence that fibroblasts associated with the Fgf9-induced lung adenocarcinoma provide multiple means of support to the tumour. Although the Fgfr blocker significantly suppressed the tumour and its stromal cells, it was not sufficient to completely eliminate the tumour, probably due to the emergence of alternative (resistance/maintenance) mechanism(s). This model represents an excellent tool to further study the complex interactions between CAFs, their related chemokines, and the progression of lung adenocarcinoma; it also provides further evidence to support the need for a combinatorial strategy to treat lung cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.