Immunohistochemistry of p53 surrogates TP53 mutation as an accurate predictor for early-relapse of surgically resected stage I-III lung adenocarcinoma.

Introduction: TP53 is a strong tumor suppressor gene; its deactivation contributes to carcinogenesis and influences clinical outcomes. However, the prognostic influence of p53 deactivation on early relapse in patients with surgically resected non-small cell lung cancer remains unclear. Materials and methods: A cohort of 170 patients with primary stage I through III lung adenocarcinoma (LADC) and lung squamous cell carcinoma who underwent complete resection at Tokyo Medical and Dental University was screened for TP53 mutations using panel testing, and association studies between TP53 mutations and clinical data, including histology and postoperative recurrence, were performed. The association between TP53 mutations and postoperative recurrence was validated using data from 604 patients with MSK-IMPACT from The Cancer Genome Atlas. Additional immunohistochemistry for p53 was performed on some subsets of the Tokyo Medical and Dental University population. Results: Mutations in TP53 were recurrently observed (35.9%; 61 out of 170) in the Tokyo Medical and Dental University cohort. In the histology-stratified analysis, patients with LADC histology showed TP53 mutations that were associated with poor relapse-free survival (log-rank test; P = .020), whereas patients with lung squamous cell carcinoma histology showed TP53 mutations that were not (P = .99). The poor prognosis of TP53 mutation-positive LADCs was validated in The Cancer Genome Atlas-LADC cohort (log-rank test; P = .0065). Additional immunohistochemistry for p53 in patients with LADC histology in the Tokyo Medical and Dental University cohort showed a significant correlation between TP53 mutations and abnormal IHC pattern of p53 (Cramer's correlation coefficient V = 0.67). Conclusions: TP53 mutation is a potential marker for worse prognosis in surgically resected LADC; immunohistochemistry for p53 could be a surrogate method to identify patients with LADC with a worse prognosis.

Prognostic Impact and Genomic Backgrounds of Renal Parenchymal Infiltration or Micronodular Spread in Nonmetastatic Clear Cell Renal Cell Carcinoma.

A subset of clear cell renal cell carcinomas (ccRCCs) exhibits various growth patterns that infiltrate the normal renal parenchyma; however, our understanding of its association with cancer aggressiveness is incomplete. Here, we show that the morphology of the tumor interface with normal renal parenchyma is robustly associated with cancer recurrence after surgery, even when compared with the TNM staging system or the World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade in nonmetastatic ccRCC. Hematoxylin and eosin-stained slides of whole tissue sections from surgical specimens were analyzed using a cohort of 331 patients with nonmetastatic ccRCC treated with radical nephrectomy. The patients were classified into 10 subgroups based on our classification algorithms for assessing the tumor interface with normal renal parenchyma. Among the 10 subgroups, 4 subgroups consisting of 40 patients (12%) were identified to have aggressive forms of nonmetastatic ccRCC associated with poor prognosis and unified as renal parenchymal infiltration or micronodular spread (RPI/MNS) phenotypes. Multivariable analyses showed that RPI/MNS phenotypes were robustly associated with shorter disease-free survival, independently of existing pathological factors including the TNM staging system and WHO/ISUP nuclear grade. The hazard ratio was highest for RPI/MNS (4.62), followed by WHO/ISUP grades 3 to 4 (2.11) and ≥pT3a stage (2.05). In addition, we conducted genomic analyses using next-generation sequencing of infiltrative lesions in 18 patients with RPI/MNS and tumor lesions in 33 patients without RPI/MNS. Results showed that alterations in SETD2 and TSC1 might be associated with RPI/MNS phenotypes, whereas alterations in PBRM1 might be associated with non-RPI/MNS phenotypes. These data suggest that RPI/MNS may be associated with aggressive genomic backgrounds of ccRCC, although more comprehensive analyses with a larger sample size are required. Future studies may further elucidate the clinical implications of RPI/MNS, particularly for deciding the indication of adjuvant treatment after nephrectomy.

Granulomatous hepatitis with Crohn's disease: a case report.

A 45-year-old man who was regularly followed up for Crohn's disease (CD) and maintained clinical remission with vedolizumab (VDZ). At 37 years old, he was diagnosed CD from longitudinal ulcers in the distal ileum by balloon-assisted enteroscopy (BAE). During the follow-up, liver enzyme elevation, splenomegaly and thrombocytopenia were in progress. Esophagogastric varices suggested chronic liver disease and portal hypertension. Magnetic resonance elastography (MRE) showed liver stiffness of 3.4 kPa and proton density fat fraction (PDFF) of 1.86%. He was diagnosed with granulomatous hepatitis based on a liver biopsy. The hepatic venous pressure gradient (HVPG) was mildly elevated at 7 mmHg, consistent with the pre-sinusoidal portal hypertension due to granulomatous hepatitis. We report a rare case with granulomatous hepatitis diagnosed from liver injury and portal hypertension, despite the stable intestinal symptoms of CD.

The possibility of mutations of RAS signaling genes and/or TP53 in combination as a negative prognostic impact on pathological stage I non-small cell lung cancer.

BACKGROUND: The recurrence rate of non-small cell lung cancer (NSCLC) is as high as 30%, even in the cancer with pathological stage I disease. Therefore, identifying factors predictive of high-risk pathological recurrence is important. However, few studies have examined the genetic status of these tumors and its relationship to prognosis. MATERIALS AND METHODS: A cohort of 328 cases of primary lung cancer that underwent complete resection at Tokyo Medical and Dental University (TMDU) was screened for 440 cancer-associated genes using panel testing. Further analyses included 92 cases of pathological stage I NSCLC who did not receive adjuvant chemotherapy. Ridge regression was performed to identify association studies mutational status and postoperative recurrence. These data were then validated using clinical and genetic data from 56 patients in The Cancer Genome Atlas (TCGA). RESULTS: Mutations in TP53, RAS signaling genes KRAS and HRAS, and EGFR were recurrently detected. Ridge regression analysis relevant to recurrence, as well as survival analysis, performed using data from the TMDU cohort revealed significantly shorter relapse-free survival (RFS) for patients with RAS signaling or TP53 gene mutations than for those without (log-rank test, p = 0.00090). This statistical trend was also suggested in the TCGA cohort (log-rank test, p = 0.10). CONCLUSION: Mutations in RAS signaling genes and/or TP53 could be useful for the prediction of shorter RFS of patients with stage I NSCLC.

Spontaneous splenic rupture due to occult signet-ring cell gastric cancer accompanied by a bulky splenic vein thrombosis and postoperative brain infarction: A case report.

Background: Splenic rupture because of metastasis from a distant organ is extremely rare. Case Presentation: An 80-year-old man presented with left flank pain. A computed tomography (CT) demonstrated a poorly enhanced enlarged spleen with bulky thrombus in the splenic vein without extravasations. A CT on the following day showed increased intraperitoneal hemorrhage; therefore, an emergency laparotomy was performed. The spleen was enlarged and ruptured with lacerations on its surface. Macroscopic examination showed congestion with a thrombus in the splenic vein around the hilum. Pathology revealed signet-ring cell carcinoma. On the third postoperative day, a massive cerebral infarction in the left middle cerebral artery was revealed. Endoscopic examination demonstrated normal gastric mucosa except for some erosions, for which biopsies were performed, and two of five specimens encompassed signet-ring cell carcinoma in the lamina propria. Conclusion: Occult cancer could result in a drastic manifestation of its metastasis accompanying systemic thrombotic events.

Succinate dehydrogenase-deficient malignant paraganglioma complicated by succinate dehydrogenase-deficient renal cell carcinoma.

Introduction: SDH Gene mutation is known to be a common cause of pheochromocytoma/paraganglioma and renal cell carcinoma. Here, we report a case of succinate dehydrogenase B-deficient paraganglioma, which has a high risk of metastasis and recurrence, complicated by succinate dehydrogenase-deficient renal cell carcinoma, which is rare and accounts for approximately 0.1% of all renal cell carcinomas. Case presentation: A 50-year-old man underwent en bloc resection of a retroperitoneal tumor and the right kidney for retroperitoneal paraganglioma and right renal tumor. Both tumors showed negative expressions of succinate dehydrogenase B in immunostaining. The patient was diagnosed with succinate dehydrogenase-deficient paraganglioma and succinate dehydrogenase-deficient renal cell carcinoma. Seventeen months later, retroperitoneal lymphadenectomy revealed lymph node metastasis of the paraganglioma. Deletion of the SDHB gene was revealed by genome sequencing of the lymph node. Conclusion: This is the first reported case of synchronously diagnosed succinate dehydrogenase-deficient paraganglioma and succinate dehydrogenase-deficient renal cell carcinoma.

PHOX2B is a Sensitive and Specific Marker for the Histopathological Diagnosis of Pheochromocytoma and Paraganglioma.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are non-epithelial neuroendocrine neoplasms originating from the adrenal medulla and paraganglion of the sympathetic and parasympathetic nervous system, respectively. PCCs and PGLs show histological similarities with other epithelial neuroendocrine neoplasms and olfactory neuroblastomas (ONBs), and the differential diagnosis of PGLs is particularly difficult. Therefore, we compared the sensitivity of PHOX2A, PHOX2B, and tyrosine hydroxylase (TH) in the histopathological diagnosis of PCCs and PGLs immunohistochemically using the tissue microarrays of 297 neoplasms including PCCs, PGLs, neuroblastomas, ganglioneuromas, epithelial neuroendocrine neoplasms, and ONBs. Using cutoff values of 25%, 5%, and 5% of tumor cells expressing PHOX2A, PHOX2B, and TH, respectively, as positive, 40 of 51 PCCs, 32 of 33 parasympathetic/head and neck PGLs (HNPGLs), 17 of 19 sympathetic/thoracoabdominal PGLs (TAPGLs), and 12 of 152 epithelial neuroendocrine neoplasms, including 123 well-differentiated and 29 poorly differentiated neuroendocrine neoplasms, were PHOX2A-positive. All 51 PCCs, 33 HNPGLs, and 19 TAPGLs were PHOX2B-positive, while all 152 epithelial neuroendocrine neoplasms were PHOX2B-negative. Moreover, 50 of 51 PCCs, 13 of 33 HNPGLs, all TAPGLs, and 12 of 152 epithelial neuroendocrine neoplasms were TH-positive. All ONBs were negative for PHOX2A, PHOX2B, and TH. PHOX2B was the most sensitive and specific diagnostic marker for PCCs and PGLs among PHOX2A, PHOX2B, and TH. PHOX2B can facilitate identification of PCCs and PGLs from epithelial neuroendocrine neoplasms and ONBs, especially in the case of HNPGLs, in which TH is often negative.

Clinical utility of comprehensive genomic profiling in Japan: Result of PROFILE-F study.

INTRODUCTION: Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme. RESULTS: The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor. CONCLUSIONS: Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved.

Immune subtypes and neoantigen-related immune evasion in advanced colorectal cancer.

Elimination of cancerous cells by the immune system is an important mechanism of protection from cancer, however, its effectiveness can be reduced owing to development of resistance and evasion. To understand the systemic immune response in advanced untreated primary colorectal cancer, we analyze immune subtypes and immune evasion via neoantigen-related mechanisms. We identify a distinctive cancer subtype characterized by immune evasion and very poor overall survival. This subtype has less clonal highly expressed neoantigens and high chromosomal instability, resulting in adaptive immune resistance mediated by the immune checkpoint molecules and neoantigen presentation disorders. We also observe that neoantigen depletion caused by immunoediting and high clonal neoantigen load are correlated with a good overall survival. Our results indicate that the status of the tumor microenvironment and neoantigen composition are promising new prognostic biomarkers with potential relevance for treatment plan decisions in advanced CRC.

Integrative genome-wide analyses reveal the transcriptional aberrations in Japanese esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a malignant disease. At present, the genomic profiles of ESCC are known to a considerable extent, and DNA methylation and gene expression profiles have been mainly used for the classification of ESCC subtypes, but integrative genomic, transcriptomic, and epigenomic analyses remain insufficient. Therefore, we performed integrative analyses using whole-exome sequencing, DNA methylation, and RNA sequencing (RNA-seq) analyses of Japanese patients with ESCC. In cancer-related genes, such as NOTCH family genes, RTK/PI3K pathway genes, and NFE2L2 pathway genes, variants and copy number amplification were detected frequently. Japanese ESCC cases were clustered into two mutational signatures: an APOBEC-associated signature and an age-related signature. In imprinted genes, DNA methylation was aberrant in gene promoter regions and correlated well with gene expression profiles. Nonsynonymous single-nucleotide variants and allelic expression imbalance were detected frequently in FAT family genes. Our integrative genome-wide analyses, including DNA methylation and allele-specific gene expression profiles, revealed altered gene regulation of imprinted genes and FAT family genes in ESCC.

A Pilot Study Analyzing the Clinical Utility of Comprehensive Genomic Profiling Using Plasma Cell-Free DNA for Solid Tumor Patients in Japan (PROFILE Study).

BACKGROUND: The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic profiling by liquid biopsy in a Japanese population. METHODS: In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360. RESULTS: Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were TP53 (53.9%, 46/102), KRAS (25.5%, 26/102), PIK3CA (19.6%, 20/102), and EGFR (17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (P = 0.010). CONCLUSIONS: The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients.

Acute Spinal Cord Infarction with Preferential Involvement of Ventral Gray Matter: An Autopsy Report.

Herein, we report abdominal aortic thrombosis as a rare cause of acute spinal cord infarction. A 78-year-old man with multiple vascular risk factors developed acute paraplegia with sensory and urinary disturbances and signs of ischemia in both lower limbs. The post-mortem study done 3 days after the onset of symptoms revealed a large coagulum in the abdominal aorta, distal to the renal arteries and extending to bilateral common iliac arteries; in addition, marked atherosclerosis was present in most large blood vessels. Premature incomplete necrotic foci were seen in the ventral gray matter of the spinal cord from T6 through S5; the surrounding white matter and dorsal gray matter were spared. Considering our autopsy case, spinal cord gray matter may be more vulnerable to ischemia than the white matter.

Notable response to nivolumab during the treatment of SMARCA4-deficient thoracic sarcoma: a case report.

SMARCA4-deficient thoracic sarcoma is a rare tumor typically presenting as a mediastinal mass. The prognosis is estimated to be poor, and no effective treatment has been established. We present a case of a 76-year-old man who was diagnosed with SMARCA4-deficient thoracic sarcoma. The provisional diagnosis was carcinoma of unknown primary but subsequently corrected to SMARCA4-deficient thoracic sarcoma based on the panel-based cancer gene screening and immunohistochemistry. Cytotoxic chemotherapy as the first- and second-line did not reveal enough therapeutic effects but third-line therapy using nivolumab showed marked tumor regression, which was sustained. This is the first case report of SMARCA4-deficient thoracic sarcoma showing a good response to nivolumab. Immune checkpoint inhibitor might be therapeutic candidates for this type of tumor.

Comprehensive genetic analysis of cholangiolocellular carcinoma with a coexistent hepatocellular carcinoma-like area and metachronous hepatocellular carcinoma.

AIM: The genetic profile of cholangiolocellular carcinoma (CLC) and its origin in relation to hepatocellular carcinoma (HCC) remain unclear. To elucidate the genetic profile of CLC, a comprehensive analysis of genetic mutations was carried out in a case of CLC with an HCC-like focal area and metachronous HCC. METHOD: Liver tissue was obtained from CLC, a co-existent HCC-like area, and metachronously developed HCC by laser capture microdissection of formalin-fixed paraffin-embedded specimens obtained by hepatectomy. Gene mutational profiles were analyzed comprehensively by next-generation sequencing and digital PCR. Relationships among gene profiles, immunohistochemistry, and clinicopathological findings were investigated. RESULTS: Mutations in EGFR, PTEN, RB1, TP53, and ERBB2 were found in CLC, whereas mutations in KIT, BRAF, PTEN, TP53, and SMAD4 were found in the coexistent HCC-like area. Only the mutation in PTEN has a common Catalogue of Somatic Mutations in Cancer ID in the CLC and coexistent HCC-like area, and is related to the kinase-RAS module. In contrast, no cancer-related mutations were found in the metachronous HCC. No TERT mutations were found in any of the regions by digital PCR. Immunohistochemical staining for p53 was negative in CLC, although ≤10% positive in the coexistent HCC-like area. Immunostaining of C-kit, HER2, PTEN, and SMAD4 were negative. CONCLUSION: The genomic features of CLC and the focal area of an HCC-like region differ, but are related to the kinase-RAS module. The development of carcinogenesis in the CLC and HCC-like areas in this case might differ, following a common PTEN mutation, although alteration of the kinase-RAS module is the most common molecular event in CLC.

Clinical outcome of primary giant cell tumor of bone after curettage with or without perioperative denosumab in Japan: from a questionnaire for JCOG 1610 study.

BACKGROUND: Giant cell tumor of bone (GCTB) is an intermediate tumor known to be locally aggressive, but rarely metastasizing. To plan a prospective study of GCTB, we performed a questionnaire survey for institutions participating in the Bone and Soft Tissue Tumor Study Group (BSTTSG) in the Japan Clinical Oncology Group (JCOG) in 2015. METHODS: We reviewed 158 consecutive patients with primary GCTB treated with curettage without perioperative denosumab from 2008 to 2010 in Japan. We investigated local and distant recurrence rates after definitive curettage. We also investigated the recurrence rate after treatment with preoperative and/or postoperative denosumab with curettage in recent years. There were 40 patients treated with perioperative denosumab, and the factors affecting recurrence in them were investigated. RESULTS: Answers were available from 24 of 30 institutions (80.0%) participating in JCOG BSTTSG. Thirty (19.0%) and 4 (2.5%) of 158 patients developed local and distant recurrence after curettage without perioperative denosumab from 2008 to 2010, respectively. Campanacci grade and embolization before surgery were significantly associated with increasing incidence of local recurrence after curettage (p = 0.034 and p = 0.022, respectively). In patients treated with perioperative desnosumab, 120 mg denosumab was administered subcutaneously for a median 6 (2-41) and 6 (1-14) times in preoperative and postoperative settings, respectively. The recurrence rates were 6 of 21 (28.6%), 2 of 9 (22.2%), and 0 of 10 (0.0%) in the preoperative, postoperative, and both pre- and postoperative denosumab treatment groups, respectively. With all of the preoperative treatments, administration exceeding five times was significantly associated with a decreased incidence of local recurrence after curettage (p < 0.001). CONCLUSION: The recurrence rate of GCTB was still high after curettage, especially in Campanacci grade III, and improvements in the therapeutic strategy are needed in this cohort. There is a possibility that a sufficient dose of preoperative denosumab can reduce recurrence after curettage. Recently, we have started a clinical trial, JCOG1610, to investigate the efficacy of preoperative denosumab in patients who can be treated with curettage in GCTB.

Phenotypic Variation in 46,XX Disorders of Sex Development due to the NR5A1 p.R92W Variant: A Sibling Case Report and Literature Review.

Recently, a heterozygous missense mutation in NR5A1, p.R92W, was identified as a cause of 46,XX testicular/ovo-testicular disorders of sexual development (DSD). We report a sibling pair with 46,XX DSD due to an NR5A1 mutation with distinct phenotypes, including external and internal genitalia and gonads, for whom different rearing sexes were selected. Thus, the phenotypes of p.R92W vary, even within a family. The father of the patients showed oligozoospermia with the p.R92W mutation, suggesting that in 46,XY individuals, the mutation would cause various gonadal phenotypes. We review and discuss the general role of the R92W mutation in sexual development.

Hepatocellular Carcinoma Histological Grade Prediction: A Quantitative Comparison of Diffusion-Weighted, T2-Weighted, and Hepatobiliary-Phase Magnetic Resonance Imaging.

OBJECTIVES: This study aimed to compare quantitative assessments for predicting hepatocellular carcinoma (HCC) histological grades using magnetic resonance imaging. METHODS: We retrospectively reviewed magnetic resonance imaging data from 49 patients with 54 surgically resected HCCs (11 well differentiated, 29 moderately differentiated, and 14 poorly differentiated). We measured the lesion-to-liver relative contrast ratio (RCR) on diffusion-weighted (DW), T2-weighted (T2W), and ethoxybenzyl-hepatobiliary images. We also evaluated contrast-to-noise ratio (CNR) on DW images, and the apparent diffusion coefficient. We compared the feasibility of these parameters in predicting HCC histological grade. RESULTS: Areas under the receiver operating characteristic curves of both the DW RCR (97%) and DW CNR (97%) were significantly greater compared with those of the apparent diffusion coefficient (79%), T2W RCR (81%), and ethoxybenzyl-hepatobiliary RCR (80%) (P < 0.05, 0.001, and 0.001, respectively). CONCLUSIONS: The DW RCR and DW CNR might represent accurate predictors of HCC histological grade.

Dual-time-point FDG-PET/CT Imaging of Temporal Bone Chondroblastoma: A Report of Two Cases.

Temporal bone chondroblastoma is an extremely rare benign bone tumor. We encountered two cases showing similar imaging findings on computed tomography (CT), magnetic resonance imaging (MRI), and dual-time-point (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT. In both cases, CT images revealed temporal bone defects and sclerotic changes around the tumor. Most parts of the tumor showed low signal intensity on T2-weighted MRI images and non-uniform enhancement on gadolinium contrast-enhanced T1-weighted images. No increase in signal intensity was noted in diffusion-weighted images. Dual-time-point PET/CT showed markedly elevated (18)F-FDG uptake, which increased from the early to delayed phase. Nevertheless, immunohistochemical analysis of the resected tumor tissue revealed weak expression of glucose transporter-1 and hexokinase II in both tumors. Temporal bone tumors, showing markedly elevated (18)F-FDG uptake, which increases from the early to delayed phase on PET/CT images, may be diagnosed as malignant bone tumors. Therefore, the differential diagnosis should include chondroblastoma in combination with its characteristic findings on CT and MRI.

Adrenal cortical adenoma arising from an adrenohepatic union.

Although the observation of an adrenohepatic union is not a rare occurrence during autopsies, cases associated with this clinical entity are rarely described. We report a case with an adrenal cortical adenoma arising from adrenohepatic union tissue in a patient with a past history of a liver mass.