Pathology of Treated Pancreatic Ductal Adenocarcinoma and Its Clinical Implications

Abstract

Context:

Pre-operative neoadjuvant therapy has been increasingly used to treat patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant therapy often induces extensive fibrosis in tumor, adjacent pancreatic parenchyma and peripancreatic tissue. Histopathologic evaluations and tumor regression grading of post-therapy pancreatectomy specimens are very difficult and challenging. Studies on prognostic significance of post-therapy pathologic staging, optimal tumor regression grading system, and other pathologic parameters in treated PDAC patients are limited.

Objective:

This review is to provide a timely update of the prognostic values of post-therapy pathologic staging, tumor regression grading, and other pathologic parameters in PDAC patients who received neoadjuvant therapy and pancreas resection.

Data Sources:

Systemic review of major studies on pathologic evaluation and its clinicopathologic implications in treated PDAC patients.

Conclusions:

Systemic pathologic examination, histologic tumor regression grading, pathologic evaluation of the margins, tumor involvement of superior mesenteric vein/portal vein, accurate pathologic staging and reporting of post-therapy pancreatectomy specimens provide highly valuable prognostic information for post-operative patient care. Our findings suggest for the first time that tumor size of 1.0 cm, instead of 2.0 cm, is a better cut-off for ypT2 in PDAC patients. The newly proposed three-tier MD Anderson (MDA) tumor regression grading system has not only proved to be an independent prognostic marker for PDAC patients who received neoadjuvant therapy and pancreatectomy, but also improves the inter-observer agreement among the pathologists in evaluation of tumor regression/response. This grading system should be considered in future editions of the CAP protocol for pancreatic ductal adenocarcinoma.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year survival rate of 8.5%¹. The prognosis and survival for patients with PDAC have not changed significantly in the past four decades despite significant advances in surgical oncology and developments in new oncologic therapeutic strategies, such as targeted therapy and immunotherapy^2,3.

Pre-operative neoadjuvant therapy has been increasingly used to treat patients with potentially resectable PDAC. Neoadjuvant therapy has been shown to improve resectability in patients with borderline resectable PDAC and to provide a survival benefit in patients with locally advanced disease⁴. At MD Anderson Cancer Center, a multidisciplinary neoadjuvant approach is routinely used to treat all patients who have potentially resectable PDAC, except those who had contraindications to or refused neoadjuvant therapy. The potential advantages of neoadjuvant therapy approach for patients with PDAC are listed in Table 1. Neoadjuvant therapy approach provides a window of 3–6 months to observe the tumor behavior/biology while the patients are being treated with chemotherapy or chemoradiation therapy. The tumor responses to neoadjuvant therapy are clinically evaluated by comparing the pre- and post-therapy computerized tomography (CT) scans or magnetic resonance imaging (MRI). Only patients who have no evidence of disease progression or metastasis and no contraindications to major surgery are selected to receive pancreatic resection with curative intent. Therefore, the selected patients may benefit the most from pancreatectomy.

Table 1.

Potential Benefits of Neoadjuvant Therapy for Pancreatic Cancer

Selection for patients who would benefit the most from surgery

Better tolerance by patients compared to post-operative adjuvant therapy

Increased resectability of borderline resectable tumors

Providing early treatment of micrometastasis

Potential reduction in tumor volume, and increase of likelihood of resectability/complete resection

Systemic pathologic examination and reporting of post-therapy pancreatectomy specimens are not only important for the post-operative care, but also for the prognosis of PDAC patients^5–13. Because neoadjuvant therapy often induces extensive fibrosis in the adjacent pancreatic parenchyma and peripancreatic soft tissue, histopathologic evaluations of post-therapy pancreatectomy specimens, such as pathologic stage based on the current American Joint Committee on Cancer (AJCC) Staging Manual, tumor regression grading, tumor involvement of superior mesenteric vein/portal vein (SMV/PV), and status of resection margins, etc., are often very difficult and challenging. In this review, we will focus on the prognostic values of these histopathologic parameters and the challenges in pathologic evaluations of post-therapy pancreatectomy specimens.

Prognostic significance of the post-therapy pathologic stage in PDAC patients

The current AJCC staging system for PDAC (8^th edition) uses only tumor size in maximum dimension for pT1 to pT3: pT1 tumor ≤ 2 cm (subdivided into pT1a ≤ 0.5 cm, pT1b > 0.5 cm and < 1 cm, and pT1c ≥ 1 cm and ≤ 2 cm), pT2 tumor > 2 cm and ≤ 4 cm, pT3 tumor > 4 cm. The pT4 definition remains the same as the 7^th edition and is defined as tumor involving the celiac axis, superior mesenteric artery and/or common hepatic artery, irrespective of tumor size¹⁴. The current AJCC staging system also subclassifies N stage into N0 (no lymph nodes [LN] involved), N1 (1–3 positive LNs) and N2 (≥4 positive LNs). However, both the current and previous AJCC staging systems are based on the clinical and survival data from PDAC patients who did not receive neoadjuvant therapy. Few studies have examined the prognostic significance of post-therapy pT and pN stages of PDAC. Using a large cohort of 240 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy, Estrella et al. showed that post-therapy T stage based on the 7^th AJCC staging system is an important prognostic factor in their patient population⁹. In addition, they subclassified lymph node positive patients into two groups: one with 1–3 positive LNs, and the other with 4 or more positive LNs. They found that the group with 1–3 positive LNs had better disease-free and overall survival than those with 4 or more positive LNs by univariate and multivariate analyses⁹. Their findings have been incorporated into the pN classification for PDAC in the 8^th AJCC Cancer Staging Manual. Recently Chatterjee et al. showed that the 8^th AJCC ypT and ypN stages are independent factors for both disease-free and overall survival in a large cohort of 398 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy¹⁵. Similar to the findings from the patient populations who did not receive neoadjuvant therapy, they reported that the 8^th AJCC ypT stage performed better in predicting patient survival than the 7^th AJCC ypT stage^15,16. More importantly, Chatterjee et al. showed that patients with ypT1c had shorter survival than those with ypT1a and ypT1b, but similar survival to those with ypT2¹⁵. Their findings suggest for the first time that tumor size of 1.0 cm, instead of 2.0 cm, is a better cut-off for ypT2 in PDAC patients. More studies are needed to confirm their findings.

It is important to note that accurate tumor size measurement (ypT stage) in post-therapy pancreatectomy specimens is extremely difficult and may be impossible in some cases. Neoadjuvant therapy induces extensive fibrosis in both tumor and adjacent pancreatic tissue, which often makes the gross identification of tumor border and gross measurement of tumor size inaccurate, especially for those patients who had good responses to neoadjuvant therapy. In addition, residual viable PDAC cells often invade into the adjacent pancreatic/peripancreatic tissue beyond the treated tumor area/tumor bed identified grossly. Thus the gross measurement of tumor size may be either larger or smaller than the actual tumor size. The current College of American Pathologists (CAP) cancer protocol recommends that gross measurement of tumor size be validated by microscopic examination for PDAC. In order to validate the tumor size by histology, systemic tumor mapping across the largest possible tumor/tumor bed area and generous sampling of the possible tumor area are highly recommended. When no tumor is grossly identified in a pancreatectomy specimen, systemic submission of the entire pancreas with peripancreatic soft tissue, bile duct, ampulla of Vater and peripancreatic duodenal wall is ideal to rule out any microscopic residual carcinoma. In cases which have major pathologic responses, the tumor bed is often overrun by fibrosis with only scattered microscopic foci of residual viable tumor cells defined as tumor cells that has intact cytoplasmic membrane, cytoplasm and intact nuclei based on histologic examination on hematoxylin and eosin (H & E) stained slides. For these cases, some investigators proposed to measure the maximal linear dimension of each tumor focus and then calculate the sum of the maximal linear dimension as the final tumor size. However there are no reported criteria or minimal distance to define separate microscopic tumor foci in the same treated tumor bed. Based on the study by Deyali et al., a practical approach for the tumor size in these cases is to measure the largest dimension of the entire area of treated tumor bed that is bound by viable tumor cells (Figure 1A–1C)¹⁵. This approach was adopted from the recommendations of an international working group for the standardized pathologic evaluation of post-neoadjuvant breast cancer¹⁷, and is in line with the recommendation from the current CAP cancer protocol for pancreatic exocrine tumor (https://documents.cap.org/protocols).

Figure 1.

Schematic illustration of the tumor size measurement for treated pancreatic ductal adenocarcinoma. A. The largest linear dimension of the viable tumor focus on H&E slide should be used as the final tumor size when only single focus of viable residual tumor is present. B. When two or more foci of viable residual tumor are present, the largest linear dimension of the entire area involved by viable residual tumor cells including the intervening stroma should be used as the tumor size. C. If residual tumor involves the pancreatic parenchyma or peripancreatic soft tissue beyond the tumor bed area, the largest dimension of the entire area involved by viable residual tumor including the intervening stroma, pancreas or peripancreatic soft tissue should be used as the final tumor size. Of note, sizable acellular mucin pools in the treated tumor bed, if present, should not be interpreted as viable tumor.

The current AJCC N stage is a robust prognostic factor for survival in both treated and treatment-naïve PDAC patient populations. The number of examined LN (ELN) and the ratio of number of positive LN to ELN have also shown to be prognostic factors in PDAC patients in previous studies^18–20. The importance of examining adequate number of LNs from pancreatectomy specimens for accurate N stage cannot be overemphasized^18,20. For accurate N stage, a minimum of 12 LNs from pancreatectomy specimens should be examined according to the 8^th AJCC Staging Manual and CAP protocol, while the International Study Group on Pancreatic Surgery (ISGPS) recommends that a minimum of 15 be examined. Since neoadjuvant therapy often shrinks peripancreatic LNs, dissecting adequate number of LNs in post-therapy pancreatectomy specimens may be difficult. Careful examination and complete submission of the peripancreatic fat and retroperitoneal soft tissue should be performed to maximize the number of LNs in pancreatectomy specimens. Some institutions used the orange-peeling method to increase the yield of LN harvest in pancreatoduodenectomy specimens²¹.

Tumor Regression Grading of Tumor Response to Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma

PDAC is characterized by extensive desmoplastic stroma and often infiltrates into adjacent pancreatic tissue beyond the grossly identifiable tumor area. Among patients with untreated PDAC, there is significant variation in the percentage of PDAC tumor cells and the ratio of the tumor cells to stroma. In addition, neoadjuvant therapy-induced fibrosis in the tumor and adjacent pancreatic tissue obscures the boundary of treated tumor bed. Therefore histopathologic evaluation of tumor response to neoadjuvant therapy (tumor regression grading, TRG) for treated PDAC is often subjective and very difficult. There are several major grading systems of tumor regression/response for PDAC in post-treatment pancreatectomy specimens (Table 2)^22–25. The current CAP TRG system for PDAC is adopted from a modified Ryan scheme, which was originally proposed for treated rectal cancer. The same grading scheme and criteria are also used for reporting tumor response/regression of all carcinomas of the gastrointestinal tract, including carcinoma of the esophagus, esophagogastric junction, stomach, rectum and anus. The clinical significance of this grading system has not been validated in PDAC patients who received preoperative neoadjuvant therapy. Recently Chatterjee et al. examined the clinical and prognostic significance of TRG in 223 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy using both Evans grading system and CAP grading system²⁶. They found that patients with complete pathologic response (CAP grade 0 or Evans grade IV) or minimal residual tumor (CAP grade I or Evans grade III) had better disease-free and overall survivals than those with CAP grades 2 and 3, or Evans grades IIa, IIb and I. However, there were no difference in either disease-free survival or overall survival between the patients with CAP grade 2 and those with grade 3²⁶. There were also no differences in either disease-free survival or overall survival among the patients with Evans grades I, IIa and IIb. Although the number of patients who had complete pathologic response (CAP grade 0) was small in their study, patients with CAP grade 0 response had better disease-free survival and overall survival than those with CAP grade 1 response (P < .01). Based on their findings, they proposed a new three-tier MD Anderson (MDA) grading system (modified CAP grading system): Grade 0, no residual carcinoma; Grade 1, patients with minimal residual carcinoma (single cells or small groups of cancer cells, <5% residual carcinoma cells in the treated tumor bed); and Grade 2, patients with 5% or more residual carcinoma cells in the treated tumor bed (Figure 2A–2D)²⁶. The clinical and prognostic significance of this newly proposed three-tier MDA grading system has been validated by Lee et al. in another large cohort of 167 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy⁶. The disease-free and overall survival curves stratified by CAP and MDA TRG of 398 treated PDAC patients, which combined the cohorts from above-mentioned studies are shown in Figure 3A–3D. The new MDA TRG system correlated significantly with the ypT and ypN stages, resection margin status and tumor recurrence after resection^6,26. A recent study of pathologic tumor response in borderline resectable PDAC patients from Cleveland Clinic Foundation showed similar results although the correlation of TRG and overall survival was not statistically significant, which may be due to a small patient population²⁷.

Table 2.

Major Tumor Regression Grading Systems for Treated Pancreatic Ductal Adenocarcinoma

Grading System Proposed by Ishikawa et al. based on the percentage of severely degenerative cancer cells (SDCC) 23

Grade 1: One third or less of SDCC

Garde 2: One-third to two-thirds of SDCC

Grade 3: Greater than two-thirds of SDCC

Evans Grading System based on the percentage of tumor cell destruction 22

Grade I: Little (<10%) or no tumor cell destruction

Grade IIa: Destruction of 10%–50% of tumor cells

Grade IIb: Destruction of 51%–90% of tumor cells

Grade III: Few (<10%) viable-appearing tumor cells

Grade IV: No viable tumor cells

Grading System Proposed by White et al. based on the percentage of viable tumor cells 25

Large: >90% viable tumor cells.

Moderate, 10% to 90% viable tumor cells

Small, <10% residual tumor cells, scattered foci of tumor cells or no residual tumor cells

CAP Grading System based on the degree of radiation-induced fibrosis and regressive changes in the tumor 24

Grade 0: No viable cancer cells (complete response)

Grade 1: Single cells or rare small groups of cancer cells (near complete response)

Grade 2: Residual cancer with evident tumor regression, but more than single cells or rare small groups of cancer cells (partial response)

Grade 3: Extensive residual cancer with no evident tumor regression (poor or no response)

MD Anderson Grading System based on the percentage of viable tumor cells 26

Grade 0: No viable cancer cells (complete response)

Grade 1: Minimal residual carcinoma (single cells or small groups of cancer cells, <5% viable residual carcinoma in the treated tumor bed)

Grade 2: 5% or more viable residual carcinoma cells in the treated tumor bed

Figure 2.

A, Representative micrograph shows extensive fibrosis in the tumor bed, but no viable carcinoma cells present [College of American Pathologists (CAP) grade 0 and MD Anderson (MDA) grade 0]; B, Tumor bed with extensive fibrosis and rare individual tumor cells and one small tumoral gland (CAP grade 1 and MDA grade 1); C, Residual cancer with evident tumor regression, but more than single cells or rare small groups of cancer cells (>5% viable tumor cells in treated tumor bed, CAP grade 2 and MDA grade 2); D. Extensive residual cancer with no evident tumor regression (>5% viable tumor cells in treated tumor bed, CAP grade 3 and MDA grade 2). A-D, hematoxylin and eosin (H & E) stain; magnifications: 40x for A, B, and D; 20x for C.

Figure 3.

Correlations of CAP and MDA tumor regression grading with disease-free and overall survival in 398 patients who received neoadjuvant therapy and pancreaticoduodenectomy. The survival curves are constructed using the Kaplan-Meier method and the log-rank test is used to evaluate the statistical significance of differences. Kaplan-Meier curves for disease-free survival (A and C) and overall survival (B and D) are stratified by CAP tumor regression grading (A and B) and by MDA tumor regression grading (C and D). There is no difference in either disease-free survival (P = .94) or overall survival (P = .84) between the group with CAP grade 2 response and that with CAP grade 3 response. Patients with CAP grade 0 or 1 response have significantly better disease-free survival (P < .001) and overall survival (P < .001) than those with CAP grade 2 or 3.

Reliability and reproducibility of a tumor regression grading system is very important for daily practice. The MDA tumor regression grading has not only proved to be a highly valuable prognostic factor for clinical care of patients, but also improves the inter-observer agreement among pathologists. Recently, N Kalimuthu et al. examined the inter-observer concordance rate among four gastrointestinal pathologists using CAP, Evans and the new MDA grading system. They found a concordant grading in 11 of 14 cases (79%) using the MDA grading system, compared to 2/14 (14%) for CAP grading system, and 1/14 (7%) for Evans grading system²⁸. Therefore, the new three-tier MDA grading system is simple and easy to apply by pathologists, and produces a more consistent and reproducible histologic grading for tumor response in pancreatectomy specimens from patients who have received neoadjuvant therapy.

Recently Panni et al. examined the prognostic value of residual tumor index (RTI), which is calculated as a product of the percentage of residual viable tumor and tumor bed size in centimeters, in a cohort of 105 PDAC patients who received neoadjuvant therapy and pancreatectomy. They subgrouped their patients into RTI-low, -mid, and -high using RTI cutoffs of 0.2 and 2.0, respectively. They found that RTI is a predictive marker for both recurrence-free survival and overall survival in their patient populations²⁹. However accurate measurement of RTI is difficult, and RTI may have a limited use in routine pathologic reporting given the above-mentioned difficulties in accurate measurement of tumor size and the percentage of residual viable tumor for treated PDAC.

Another important issue is how to measure the tumor regression of metastatic PDAC in LNs. Tumor regression of LN metastasis alone or in combination with tumor regression of primary PDAC may prove to be a valuable parameter in measuring overall response to neoadjuvant therapy, and this may affect the prognosis of PDAC patients who received neoadjuvant therapy. Future studies to integrate tumor regression grade of primary PDAC and nodal metastasis are needed.

Prognostic significance of Superior Mesenteric Artery (SMA) Margin in Post-therapy pancreaticoduodenectomy specimens

Microscopically negative resection margins (R0 resection) are important indicators of high-quality surgery. PDAC patients with R1 resection [microscopically positive resection margin(s)] have shorter survival than those with an R0 resection^30,31. The pancreatic resection margin and the common bile duct margin are routinely submitted en face and often evaluated by intra-operative frozen sections in most institutions. However, the method to evaluate the SMA margin (also known as uncinate or retroperitoneal margin margin) varies among different institutions. Some submit representative section(s) of SMA margin either en face or perpendicularly, while others submit the entire SMA margin for histologic examination. Moreover, some authors/studies include the posterior free surfaces as a margin as well. At MD Anderson Cancer Center, we routinely submit the entire SMA margin using perpendicular sections for all pancreaticoduodenectomy specimens because microscopic tumor invasion into fibroadipose tissue or perineural spaces close to the SMA margin cannot be reliably identified by gross examination. In our practice, the SMA margin is strictly defined as the uncinated surgically-dissected margin, not including the non-uncinated posterior free surface, which is in line with the current CAP cancer protocol for pancreas exocrine.

Local recurrence of PDAC after pancreaticoduodenectomy often occurs in the area corresponding to the SMA margin. For patients who underwent pancreatectomy for treatment-naïve PDAC, positive SMA margin is associated with increased risk of local recurrence and distant metastasis³¹. In a study of a large cohort of 411 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy, Liu et al. showed that patients with positive margins had median disease-free and overall survival of 11.9 months and 24.1 months, respectively, which are significantly shorter than those with negative margins (median disease-free and overall survival of 15.9 months and 37.3 months, respectively)¹¹. Among the 379 margin-negative patients in this study, there was no difference in either disease-free or overall survival between the margin-positive group and those with a SMA margin of 0 to 1.0 mm. This data supports the CAP and European definition of a positive SMA margin as the presence of tumor cells at 1 mm or less from the SMA margin. They also showed that patients with a SMA margin of > 5.0 mm survived longer than those with an SMA margin of 1.0 to 5.0 mm and that longer distance of SMA margin correlated with smaller tumor size, lower ypT and AJCC stages, better tumor response grading to neoadjuvant therapy, less frequent lymph node metastases and recurrences¹¹. Similar findings have been reported in a recent study of 531 patients from US and European Cancer Centers that show patients with a SMA margin of ≥ 1 mm have better survival compared to those with 0 mm clearance [hazard ratio (HR) 0.71, P < .01]. But there was no difference in survival between patients with a margin clearance of < 1 mm and those with 0 mm SMA margin clearance (HR: 0.93, P = .60)³¹. Therefore, complete examination of perpendicular sections of the SMA margin and accurate microscopic measurement of the distance of tumor clearance to SMA margin are important for post-operative management and prognosis of PDAC patients. A SMA margin clearance of ≥ 1 mm is a better predictor of a complete margin-negative resection in PDAC patients who underwent pancreaticoduodenectomy.

Clinical Implications of Tumor Involvement of Superior Mesenteric Vein/Portal Vein (SMV/PV)

The current National Comprehensive Cancer Network (NCCN) guideline recommends neoadjuvant chemotherapy and/or radiation therapy before surgery for patients with borderline resectable PDAC, which is defined based on the potential tumor resectability as tumor abutment or short segment occlusion of the SMV/PV, short-segment involvement of the hepatic artery or its branches or < 180° abutment of the superior mesenteric artery (SMA)³². Therefore it is not uncommon to have simultaneous segmental or tangential/patch resection of SMV/PV with pancreaticoduodenectomy in PDAC patients who received neoadjuvant therapy. However, there is no standardized protocol for the histologic evaluation of tumor involvement of resected SMV/PV, and in some cases the status of vein involvement may be overlooked and not reported in the final pathology report. In these cases, due to close proximity of the tumor to the vein wall, therapy-induced fibrosis involving the tunica adventitia of SMV/PV is often present and difficult to be differentiated from the fibrosis of treated tumor bed after neoadjuvant therapy. Therefore, a clear definition of histologic tumor involvement of SMV/PV is needed, especially for those cases with tumor cells invading the perivascular soft tissue of SMV/PV. In a study by Wang et al., the tumor involvement of the tunica adventitia of SMV/PV is defined as tumor cells invading perivascular soft tissue at ≤ 1.0 mm from the tunica media of the vein with fibrosis extending to the tunica media of the vein¹³. In their cohort of 225 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy, 85 patients had SMV/PV resection and 57 (67%) had histologic tumor involvement of SMV/PV (18 patients with tumor involving the tunica adventitia, 35 with tumor invasion into the tunica media or intima, and 4 with tumor invasion into the lumen of SMV/PV). Histologic tumor involvement of SMV/PV was associated with significant shorter disease-free and overall survival (9.2 and 27.6 months, respectively), compared to those with no tumor involvement of SMV/PV (15.9 and 35.7 months, respectively). In addition, histologic SMV/PV involvement by tumor is also associated with more blood loss during surgery, larger tumor size, and higher frequencies of margin-positive resection, more frequent recurrence and distant metastasis compared to those who had no SMV/PV involvement. By multivariate analysis, histologic tumor involvement of SMV/PV was an independent predictor of both disease-free and overall survivals in their cohort. These findings have been recently validated by two large independent studies, a multicenter study of 406 patients and a study of 127 patients who underwent pancreatectomy with vein resection. Both studies showed similar adverse association between histologic tumor involvement of SMV/PV and patient survival^33,34. In contrast to previous studies, which reported that the depth of tumor invasion into SMV/PV was associated with survival^35,36, no significant difference in survival among patients with tumor invasion of the tunica adventitia, vein wall, or lumen of the SMV/PV was observed by Wang et al. Their findings are similar to the findings from a recent meta-analysis of 310 patients who had the reported depth of tumor invasion into SMV, in which the depth of tumor invasion into SMV/PV was not found to be associated with patient survival after pancreaticoduodenectomy³⁷.

Based on the discussion above, it is critically important for pathologists to pay close attention to the vein groove of the pancreaticoduodenectomy specimen during gross examination to identify the resected SMV/PV and the vein margins, which may be tiny and not marked or labeled in the specimen. At MD Anderson Cancer Center, the resected segment or patch of SMV/PV is entirely submitted for all cases with the underlying tumor to document tumor involvement of the vein. The vein margins are carefully inked. For segmental vein resection, the superior and inferior vascular margins are submitted en face, and the rest of the vein is submitted using cross section of the vein perpendicular to the tumor. For vein patch resection, the tips of the vein are submitted separately after inking, and the rest of the vein patch with perpendicular vein margin and underlying tumor are submitted in a fashion similar to a skin ellipse. Histologic evidence of tumor cell invasion of SMV/PV is reported as present or absent. If present, invasion to which layer of the vessel: lumen, tunica media, or perivascular soft tissue (tunica adventitia), which is defined as tumor invasion to ≤1.0 mm from tunica media, and margin status of vein resection are also reported in the final pathology report. Recently Prakash et al. examined the significance of tumor cells present at vein edge/margin in 127 patients who underwent pancreatectomy with vein resection, of which 114 (90%) received neoadjuvant therapy. They found that the presence of tumor cells at the vein edge/margin was not associated with survival and local recurrence³³. It is possible that the presence of tumor cells at the inked vein margin may not reflect the true positive margins of veins due to retraction artifact of the muscular wall of the vein after incision. More studies are needed to examine the optimal way for vein margin evaluation and to determine the clinical importance of vein resection margin.

In summary, systemic pathologic examination, histologic tumor regression grading, pathologic evaluation of the margin status, tumor involvement of SMV/PV, accurate pathologic staging and reporting of post-therapy pancreatectomy specimens provide highly valuable prognostic information for post-operative patient care. Our findings suggest for the first time that tumor size of 1.0 cm, instead of 2.0 cm, is a better cut-off for ypT2 in PDAC patients¹⁵. The newly proposed three-tier MDA tumor regression grading system has not only proved to be an independent prognostic marker for PDAC patients who received neoadjuvant therapy and pancreatectomy, but also improves the inter-observer agreement among pathologists in evaluation of tumor regression/response. This grading system should be considered in future editions of the CAP protocol for pancreatic ductal adenocarcinoma.