Clinical utility of rapid on-site evaluation of brush cytology during bronchoscopy using endobronchial ultrasound with a guide sheath.

Previous studies have shown that rapid on-site evaluation (ROSE) improves the diagnostic yield of bronchoscopy using endobronchial ultrasound with a guide sheath (EBUS-GS) for peripheral pulmonary lesions (PPL). While ROSE of imprint cytology from forceps biopsy has been widely discussed, there are few reports on ROSE of brush cytology. This study investigated the utility of ROSE of brush cytology during bronchoscopy. We retrospectively analyzed data from 214 patients who underwent bronchoscopy with EBUS-GS for PPL. The patients in the ROSE group had significantly higher diagnostic sensitivity through the entire bronchoscopy process than in the non-ROSE group (96.8% vs. 83.3%, P = 0.002). The use of ROSE significantly increased the sensitivity of brush cytology with Papanicolaou staining (92.9% vs. 75.0%, P < 0.001). When ROSE was sequentially repeated on brushing specimens, initially negative ROSE results converted to positive in 79.5% of cases, and the proportion of specimens with high tumor cell counts increased from 42.1 to 69.0%. This study concludes that ROSE of brush cytology improves the diagnostic accuracy of bronchoscopy and enhances specimen quality through repeated brushing.

Clinical Implications of the Degree of Pancreatic Invasion in Ampulla of Vater Carcinoma.

BACKGROUND: Ampulla of Vater carcinoma (AVC) stage T3 was subdivided according to the degree of pancreatic invasion into T3a (≤ 0.5 cm) and T3b (> 0.5 cm) by the 8th edition of the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) cancer staging system. However, the differences in clinicopathological features and survival outcomes between the two categories have not been well discussed. PATIENTS AND METHODS: We retrospectively analyzed 133 consecutive patients who underwent pancreatoduodenectomy for AVC at our institution between 2002 and 2020. Clinicopathological features and survival outcomes of patients with AVC were analyzed, with a focus on the depth of pancreatic invasion. In addition, the survival outcomes of patients with T3 AVC were compared with those of patients with resectable pancreatic head carcinoma (R-PhC) who underwent pancreatoduodenectomy during the same period. RESULTS: The overall survival (OS) in patients with T3b AVC (n = 12) was significantly worse than that in patients with T3a AVC (n = 39) [median survival time (MST) 9.2 vs. 74.5 months, p < 0.001). A multivariate analysis identified T3b tumor (hazard ratio 5.64, p = 0.009) as an independent prognostic factor. The OS of patients with T3a AVC was significantly better than that of patients with R-PhC who received adjuvant chemotherapy (n = 276, MST 35.0 months, p = 0.007). In contrast, the OS of patients with T3b AVC tended to be worse than that of patients with R-PhC managed without adjuvant chemotherapy, although this difference was not statistically significant (n = 163; MST, 17.5; p = 0.140). CONCLUSIONS: AVC with > 0.5 cm invasion into the pancreas was associated with poor survival and represented advanced tumor progression to systemic disease.

Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols.

BACKGROUND: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach. METHODS: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed. RESULTS: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001). CONCLUSIONS: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Japanese classification of pancreatic carcinoma by the Japan Pancreas Society: Eighth edition.

In 2023, the Japan Pancreas Society (JPS) published the new eighth edition of the Japanese classification of pancreatic carcinoma. We present here an excerpted version in English, based on the latest edition. The major changes in this revision are as follows: In the eighth edition of the Union for International Cancer Control (UICC), the T category was changed to be based on tumor size; however, the eighth edition of the Japanese classification retains the previous T category based on local invasion factors. Lymph nodes have been renamed, and regional lymph nodes have been defined by location. Peritoneal cytology, which was not previously included in distant metastasis (M), has now been included in the M category. Moreover, significant additions have been made regarding the pathological diagnosis of endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) and criteria for histological assessment of the effects after chemotherapy and radiation therapy. Although this classification is aimed at carcinoma originating in the pancreas, not in the bile duct or duodenum, if the differentiation of the primary organ is difficult, this classification should be applied. It is also desirable to describe tumors other than carcinoma and metastatic tumors to the pancreas in accordance with this classification.

Subdivision of pT1N0 (American Joint Committee on Cancer 8th edition) distal cholangiocarcinoma for adjuvant chemotherapy consideration.

BACKGROUND: The adjuvant S-1 trial affirmed adjuvant chemotherapy for biliary tract cancer but excluded pT1N0 distal cholangiocarcinoma (DCC) according to the seventh edition of the American Joint Committee on Cancer (AJCC) classification. The introduction of tumor depth of invasion (DOI) for T-classification in the eighth edition complicates identifying DCC patients less likely to benefit from adjuvant chemotherapy. METHODS: Our cohort consisted of 185 patients with DCC who underwent pancreaticoduodenectomy between 2002 and 2019. We compared clinicopathological factors and survival outcomes between pT1N0 patients in the seventh edition and those in the eighth edition. New DOI cutoffs for subdividing pT1N0 (8th edition) patients were evaluated to identify patients less likely to benefit from adjuvant chemotherapy. RESULTS: Transitioning to the eighth edition increased in pT1N0 cases from eight to 46. The 5-year cumulative recurrence rates of them were 14.3% for the seventh edition and 28.3% for the eighth edition. We proposed a DOI cutoff of <2 mm, at which the 5-year cumulative recurrence rate was 11.5%. CONCLUSION: The eighth AJCC classification revealed that a significant proportion of pT1N0 DCC patients were at risk for recurrence. A DOI cutoff of <2 mm may be considered to potentially improve patient selection for adjuvant chemotherapy.

Investigation of the usefulness of a bile duct biopsy and bile cytology using a hyperspectral camera and machine learning.

To improve the efficiency of pathological diagnoses, the development of automatic pathological diagnostic systems using artificial intelligence (AI) is progressing; however, problems include the low interpretability of AI technology and the need for large amounts of data. We herein report the usefulness of a general-purpose method that combines a hyperspectral camera with machine learning. As a result of analyzing bile duct biopsy and bile cytology specimens, which are especially difficult to determine as benign or malignant, using multiple machine learning models, both were able to identify benign or malignant cells with an accuracy rate of more than 80% (93.3% for bile duct biopsy specimens and 83.2% for bile cytology specimens). This method has the potential to contribute to the diagnosis and treatment of bile duct cancer and is expected to be widely applied and utilized in general pathological diagnoses.

The response of pancreatic acinar cell carcinoma to platinum and olaparib therapy in a germline BRCA2 variant carrier: case report and literature review.

A 73-year-old Japanese man with a history of distal biliary cancer treated by pancreatoduodenectomy developed pancreatic acinar cell carcinoma (PACC) treated by remnant pancreatectomy and adjuvant chemotherapy. Thirteen months after surgery, multiple liver metastases developed and FOLFOX chemotherapy was initiated. Based on the PACC diagnosis and a positive family history for breast and ovarian cancer genetic testing was performed which revealed a pathogenic germline BRCA2 variant (c.8629G > T, p.Glu2877Ter). Olaparib therapy was initiated and the metastases responded well (partial response). PACC is a BRCA2-associated cancer which may respond well to PARP inhibitors.

High-grade Solid Pseudopapillary Neoplasms of the Pancreas: Distinct Clinicopathological Malignant Features With Intriguing Gene Alterations through a Comparison With the Conventional Type.

Pancreatic solid pseudopapillary neoplasm (SPN) is a low-grade malignant neoplasm with a good prognosis. Clinically aggressive SPNs have rarely been reported but have not been analyzed in detail. In this study, we referred to this highly malignant type of SPN as high-grade SPN (HG-SPN) and compared its clinicopathological and genetic characteristics with conventional SPN (C-SPN) using immunohistochemistry and gene panel analyses. Five HG-SPNs and 15 C-SPNs were evaluated in this study. HG-SPNs share many pathologic characteristics: macroscopically, solid/cystic appearances, microscopically, pseudopapillary/pseudorosette pattern (100%), tumor cell loose cohesiveness (100%), thin/delicate vasculature (100%), tumor cell cytoplasmic vacuolization (100%), immunohistochemical positivity for ß-catenin (nuclear expression) (100%), CD10 (80%), CD56 (80%), and vimentin (100%). Conversely, HG-SPNs showed distinct malignant features compared with C-SPNs: mean tumor size (11.7 vs. 2.9 cm, P <0.001); true necrosis (100% vs. 0%, P <0.001); high-grade nuclear atypia (100% vs. 0%, P <0.001); lymphatic and/or venous invasion (100% vs. 20%, P =0.004); mean mitotic count (4.38 vs. 0.05/high-power field, P <0.001); and mean Ki-67 labeling index (33.9% vs. 3.4%, P <0.001). All HG-SPN patients died of primary disease 3 to 36 months after surgery, while all C-SPN patients were alive without disease. Genetic studies have shown that all analyzed HG-SPNs have CTNNB1 mutations. Two HG-SPN cases showed RB1 mutations with altered immunohistochemical findings for RB1 and p16. Two HG-SPN cases had TP53 mutation and/or p53 overexpression. In conclusion, HG-SPNs show distinct malignant features and some genetic alterations that differ from C-SPNs, indicating the importance of differentiating between these 2 subtypes.

A Japanese Family Meeting the Clinical Diagnostic Criteria for MEN1 with a MEN1 Variant of Uncertain Significance.

Multiple gastroenteric, pancreatic, and pituitary neuroendocrine neoplasms (NENs) were diagnosed in a 74-year-old man with a history of primary hyperparathyroidism (PHPT). Germline testing demonstrated a variant of MEN1 (c.1694T>A, p.L565Q), whose pathogenicity was classified as a variant of uncertain significance (VUS) according to the ACMG/AMP guidelines. The same germline variant was detected in the patient's son and daughter, who also showed PHPT or hypercalcemia and met the clinical diagnostic criteria for multiple endocrine neoplasia type 1 (MEN1). During surveillance of the son, multiple pancreatic tumors suggestive of NENs were detected. The pathogenicity of the current MEN1 variant was re-evaluated as likely pathogenic, based on additional family data.

Tumor vascularity on contrast-enhanced computed tomography as a predictive marker of metastatic potential for small nonfunctioning pancreatic neuroendocrine tumors.

BACKGROUND: Although surgical resection is generally suggested for nonfunctioning pancreatic neuroendocrine tumors, observation can be proposed for carefully selected patients with small tumors. However, the indications for observation remain unclear. METHODS: This retrospective study included 77 patients with nonfunctioning pancreatic neuroendocrine tumors, including small tumors (≤2.0 cm, n = 41), who received pancreatectomy. The ratio of the mean computed tomography value of a tumor in the late arterial/equilibrium phase (computed tomography a/e ratio) was used to evaluate tumor vascularity. Pathologic examinations of small tumors were conducted. The associations among the computed tomography a/e ratio, pathologic findings, and survival outcomes were investigated. RESULTS: Small tumors were pathologically categorized by the degree of fibrosis as follows: medullary (n = 20), intermediate (n = 11), and fibrotic (n = 10). The fibrotic type had significantly lower computed tomography a/e ratios than the medullary type (median, 1.42 vs 2.03, P < .001). The median number of vessels with microscopic venous invasion was significantly higher in the fibrotic type than in the medullary type (4.5 vs 0.0, P < .001). The cutoff value of the computed tomography a/e ratio for predicting microscopic venous invasion was determined to be 1.54 by the receiver operating characteristic curve (area under the curve, 0.832; sensitivity, 80.0%; specificity, 83.9%; accuracy, 82.9%). Microscopic venous invasion was an independent prognostic factor for relapse-free survival in overall patients (hazard ratio 5.18, P = .017). CONCLUSION: The computed tomography a/e ratio may be a useful predictor of the metastatic potential of nonfunctioning pancreatic neuroendocrine tumors and may help decide the indications of observation for small nonfunctioning pancreatic neuroendocrine tumors.

Interobserver agreement of pathologic classification and grading of tumoral intraductal pre-invasive neoplasms of the bile duct.

Current WHO terminology and recent publications have classified tumoral (grossly visible) intraductal pre-invasive neoplasms of bile duct (TIDN) into three categories: intraductal papillary neoplasm of bile duct (IPNB), intraductal papillary oncocytic neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN). A total of 227 cases of TIDN and related lesions ≥3 mm in height were examined by 10 biliary pathologists referring to these 3 categories and two pathologic gradings: two-tiered system (low- and high-grade dysplasia) and modified types 1 and 2 subclassification. Among them, IPNB was the most frequent (183 cases), followed by IOPN (28 cases), while ITPN was rare (2 cases), and interobserver agreement in this classification was "substantial" (κ-value, 0.657). The interobserver agreement of two-tiered grading system of TIDN was "slight" (κ-value, 0.201), while that of modified types 1 and 2 subclassification was "moderate" (κ-value, 0.515), and 42 % were of type 1, and 58 % were of type 2. Type 1 TIDN showed occasional stromal invasion (6.7 %), whereas type 2 TIDN was frequently associated with stromal invasion (49.6 %) (p < 0.01). In conclusion, the classification of TIDN into three categories and modified types 1 and 2 subclassification are a practically applicable classification and grading system for TIDN.

A case of synchronous IgG4-associated pleuritis and type 1 autoimmune pancreatitis.

A 50-year-old man presented to the emergency department with left chest pain, epigastralgia, and low-grade fever for several days. A CT scan showed left pleural effusion, ground-glass opacities in the lower lobes of both lungs, and a capsule-like rim in the pancreas. ERCP showed narrowing of the main pancreatic duct. EUS-FNA was performed, but pathological findings showed no IgG4-positive cells. A thoracoscopic biopsy was performed, and pathological findings showed many IgG4-positive cells. A diagnosis of autoimmune pancreatitis and IgG4-associated pleurisy was made according to international diagnostic criteria. After that, oral steroid therapy was started, and left pleural effusion and pancreatic enlargement improved.

Long-term Follow-up of Small Nonfunctioning Pancreatic Neuroendocrine Tumors Diagnosed Using Endoscopic Ultrasound-guided Fine-needle Aspiration.

Objective Clinical practice guidelines in Japan recommend surgery for all nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs), regardless of their size or associated symptoms. Because pancreatic resection is highly invasive, follow-up for small NF-PNETs is often chosen in clinical practice. However, the natural history of NF-PNET remains poorly understood. We aimed to examine the natural history of pathologically confirmed NF-PNET. Methods This single-center retrospective case series investigated NF-PNETs that were pathologically diagnosed using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) at our hospital between 2014 and 2018. Patients who were followed up without treatment due to their general condition or their wish were included in the study. Patients' background characteristics, imaging findings, pathological findings, and long-term prognoses were investigated using medical records. Results Overall, 26 patients were diagnosed with NF-PNET by EUS-FNA during the observation period. Of these, 9 patients (3 men and 6 women; median age: 64 years old) were followed up without treatment. All of these patients were asymptomatic, and localization was noticed in 3 cases in the head, body, and tail (1 each), with a median size of 12 (range: 4-18) mm. Neuroendocrine tumor (Grade 1 [G1]) was pathologically diagnosed in all patients with EUS-FNA. The median observation period was 63 (range: 26-90) months. Tumor growth and distant metastasis were not observed in any of the nine patients who remained asymptomatic. Conclusion Follow-up is a feasible option for asymptomatic NF-PNET ≤20 mm in size with a pathological grade of G1.

Molecular genetic positioning of small intestine and papilla of Vater carcinomas including clinicopathological classification.

BACKGROUND: Small intestine carcinoma (SIC) cases in Japan have recently been treated with chemotherapy according to colorectal carcinoma classification, while papilla of Vater carcinoma (PVC) cases according to cholangiocarcinoma (CHC) classification. However, few research reports support the molecular genetic validity of these therapeutic choices. PATIENTS AND METHODS: Here, we investigated the clinicopathological and molecular genetic factors of SIC and PVC. We used the data from the Japanese version of The Cancer Genome Atlas. Additionally, molecular genetic data on gastric adenocarcinoma (GAD), colorectal adenocarcinoma (CRAD), pancreatic ductal adenocarcinoma (PDAC), and CHC were also referred to. RESULTS: This study consisted of tumor samples from 12 patients of SIC and three patients of PVC treated from January 2014 to March 2019. Among them, six patients had pancreatic invasion. t-Distributed stochastic neighbor embedding analysis showed that the gene expression pattern of SIC was similar not only to those of GAD and CRAD, but also to that of PDAC in the pancreatic invasion patients. In addition, PVC resembled the GAD, CRAD, and PDAC, rather than the CHC. The molecular genetic characteristics of the six patients with pancreatic invasion were: one had high microsatellite instability, two had a TP53 driver mutation, and three had tumor mutation burden values <1 mutation/Mb with no driver mutation. CONCLUSIONS: In this study, the extensive gene expression profiling of organ carcinomas newly suggests that SIC or PVC may resemble GAD, CRAD, and PDAC. In addition, the data demonstrate that pancreatic invasive patients may be classified into several subtypes using molecular genetic factors.

Clinical significance of immunocytochemical staining for peritoneal lavage cytology in pancreatic cancer.

BACKGROUND: Peritoneal lavage cytology for pancreatic ductal adenocarcinoma is conducted with both an intraoperative rapid diagnosis by Papanicolaou staining (cytology-rapid) and a final diagnosis by immunocytochemical staining at a later date (cytology-final) in our hospital. However, the clinical significance of cytology-final has not yet been elucidated. METHODS: A total of 675 pancreatic ductal adenocarcinoma patients who underwent pancreatectomy and cytology between 2002 and 2018 were retrospectively reviewed. Diagnostic results of cytology-rapid and cytology-final and survival outcomes were analyzed. RESULTS: A total of 43 patients (6.4%) were diagnosed as cytology-rapid (+), and all of them were ultimately diagnosed as cytology-final (+). Among the 632 patients with cytology-rapid (-), 19 (3.0%) were eventually diagnosed as cytology-final (+). The overall survival of patients with cytology-rapid (+) and that of patients with cytology-rapid (-) did not differ to a statistically significant extent (median survival time 26.4 vs 32.9 months; P = .106). In contrast, the overall survival of patients who were diagnosed as a false-negative result by cytology-rapid was significantly worse than that of patients diagnosed as a true negative (18.7 vs 34.8 months; P = .031). The overall survival of patients with cytology-final (+) was significantly worse than that of patients with cytology-final (-) (23.6 vs 34.8 months; P = .012). A multivariate analysis showed that cytology-final (+) was an independent prognostic factor for the OS (hazard ratio = 1.43; P = .049), whereas cytology-rapid (+) was not. CONCLUSION: Immunocytochemical staining may be a useful complement to a diagnosis of cytology by conventional Papanicolaou staining in pancreatic ductal adenocarcinoma patients.

Pancreatic hamartoma: detection of harbouring NAB2::STAT6 fusion gene.

Hamartomas in the pancreas are rare and are often histologically and morphologically similar to solitary fibrous tumours (SFTs). We examined the differences between hamartomas and SFTs at the molecular level. METHODS AND RESULTS: Thirteen patients histopathologically diagnosed with pancreatic hamartoma were included in the study. We also performed STAT6 immunohistochemistry (IHC), which is used in the diagnosis of SFT. Furthermore, for the three cases in which RNA was extracted, reverse transcription polymerase chain reaction to search for NAB2::STAT6 fusions was used. Macroscopically, 13 patients had well-demarcated tumour lesions. Histologically, no islets of Langerhans were observed in the lesions, acinar tissue and ducts were unevenly distributed and elastic fibres were not observed around the ducts by Elastica van Gieson staining. One case contained a lipomatous hamartoma composed mainly of adipose tissue. Seven of the 13 cases demonstrated expression of STAT6 in the nuclei of intervening spindle cells. NAB2::STAT6 fusions were observed in two of the three cases in which RNA was extracted. These two cases also demonstrated STAT6 expression in spindle cells using STAT6 IHC. In one case of lipomatous hamartoma, we did not confirm NAB2::STAT6 fusion or STAT6 expression in STAT6 IHC. CONCLUSION: Of the 13 patients histopathologically diagnosed with hamartoma, two demonstrated NAB2::STAT6 fusions, suggesting the existence of pancreatic hamartomas with molecular-level components identical to those of SFT.