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Infiltration pattern predicts metastasis and progression better than the T-stage and grade in pancreatic neuroendocrine tumors: a proposal for a novel infiltration-based morphologic grading

Modern Pathology volume 35, pages 777–785 (2022)Cite this article

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Abstract

The advancing edge profile is a powerful determinant of tumor behavior in many organs. In this study, a grading system assessing the tumor-host interface was developed and tested in 181 pancreatic neuroendocrine tumors (PanNETs), 63 of which were <=2 cm. Three tumor slides representative of the spectrum (least, medium, and most) of invasiveness at the advancing edge of the tumor were selected, and then each slide was scored as follows. Well-demarcated/encapsulated, 1 point; Mildly irregular borders and/or minimal infiltration into adjacent tissue, 2 points; Infiltrative edges with several clusters beyond the main tumor but still relatively close, and/or satellite demarcated nodules, 3 points; No demarcation, several cellular clusters away from the tumor, 4 points; Exuberantly infiltrative pattern, scirrhous growth, dissecting the normal parenchymal elements, 5 points. The sum of the rankings on the three slides was obtained. Cases with scores of 3–6 were defined as “non/minimally infiltrative” (NI; n = 77), 7–9 as “moderately infiltrative” (MI; n = 68), and 10–15 as “highly infiltrative” (HI; n = 36). In addition to showing a statistically significant correlation with all the established signs of aggressiveness (grade, size, T-stage), this grading system was found to be the most significant predictor of adverse outcomes (metastasis, progression, and death) on multivariate analysis, more strongly than T-stage, while Ki-67 index did not stand the multivariate test. As importantly, cases <=2 cm were also stratified by this grading system rendering it applicable also to this group that is currently placed in “watchful waiting” protocols. In conclusion, the proposed grading system has a strong, independent prognostic value and therefore should be considered for integration into routine pathology practice after being evaluated in validation studies with larger series.

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Fig. 1: Diagram illustrating different infiltration patterns and respective points designated.
Fig. 2: Tumor infiltration pattern scored as 1 point.
Fig. 3: Tumor infiltration pattern scored as 1 point:
Fig. 4: Tumor infiltration pattern scored as 2 points:
Fig. 5: Tumor infiltration pattern scored as 3 points:
Fig. 6: Tumor infiltration pattern scored as 4 points:
Fig. 7: Tumor infiltration pattern scored as 5 points:
Fig. 8

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was presented in part at the 110th annual meeting of the United States and Canadian Academy of Pathology in March 2021.

Funding

The authors received no specific funding for this work.

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Authors and Affiliations

  1. Department of Pathology, Koc University School of Medicine and Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey

    Orhun Cig Taskin, Ayse Armutlu, Burcu Saka, Yersu Kapran & Volkan Adsay

  2. Department of Pathology, Emory University, Atlanta, GA, USA

    Michelle D. Reid, Serdar Balci & Yue Xue

  3. Department of Pathology, Marmara University School of Medicine, Istanbul, Turkey

    Pelin Bagci & Emine Bozkurtlar

  4. Koc University School of Medicine, Istanbul, Turkey

    Deniz Demirtas

  5. Department of Pathology, Dokuz Eylul University School of Medicine, Izmir, Turkey

    Burcin Pehlivanoglu

  6. Department of Pathology, Sisli Hamidiye Etfal Research and Training Hospital, Istanbul, Turkey

    Bahar Memis

  7. Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey

    Can Berk Leblebici & Cenk Sokmensuer

  8. Department of Pathology, Spitalul Clinic Sfânta Maria, Bucuresti, Romania

    Adelina Birceanu

  9. Department of Surgery, Koc University School of Medicine and Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey

    Mert Erkan

  10. Department of Statistics, Koc University School of Medicine and Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey

    Arzu Baygul

  11. Department of Diagnostics and Public Health, Section of Pathology and ARC-NET Research Centre, University of Verona, Verona, Italy

    Aldo Scarpa & Claudio Luchini

  12. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Olca Basturk

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Contributions

V. A., A. S., C. L., and O. B. conceptualized and designed the study; V. A., P. B., M. D. R., and C. S. devised the scoring protocol. M. D. R., P. B., B. P., Y. X., O. C. T., A. A., C. S., and V. A. identified the patients; D. D., A. B., E. B., A. B., B. M., C. B. L, B. P., and Y. X. compiled and organized the data; O. C. T., M. D. R., P. B., B. S., Y. X., Y. K., C. S., and V. A. reviewed histopathology. S.B. and A.B. performed statistical analyses. S. B., O. C. T, O. B., and V. A. analyzed data. O. C. T., M. D. R., B. P., O. B., and V. A. wrote the manuscript. D. D, E. B., B. P., and O. C. T. organized the figures and the tables. All the authors critically read, edited, and approved the final manuscript.

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Correspondence to Volkan Adsay.

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This study was performed in accordance with the Declaration of Helsinki.

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Taskin, O.C., Reid, M.D., Bagci, P. et al. Infiltration pattern predicts metastasis and progression better than the T-stage and grade in pancreatic neuroendocrine tumors: a proposal for a novel infiltration-based morphologic grading. Mod Pathol 35, 777–785 (2022). https://doi.org/10.1038/s41379-021-00995-4

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