Histomorphology of immunomodulation and PD1 expression in breast cancer tumor draining lymph nodes Determinants of Breast Cancer Screening

Suma Nayek (1), Sourav Sau (2), Kaushik Majumdar (3), Anupam Basu (4), Arghya Bandyopadhyay (5)
(1) Department of Pathology, Burdwan Medical College, Burdwan, India, India,
(2) Department of Radiotherapy, Burdwan Medical College, Burdwan,India, India,
(3) Specialist Pathology, Al Sabah Hospital, Kuwait, Kuwait,
(4) Department of Zoology, University of Burdwan , India , India,
(5) Department of Pathology, Burdwan Medical College, Burdwan, India, India


Background: Metastasis in tumor draining lymph nodes (TDLNs) is correlated with poor prognosis in breast cancers. It is associated with local immune suppression, which can be partly due to the higher expression of check point inhibitors in immune cells. The morphological manifestation of the underlying immunomodulation of TDLNs has been less investigated. Here, we present the histomorphological changes and PD1 expression pattern in metastatic and non-metastatic TDLNs in breast cancer patients.

Methods: A total of 248 metastatic or non-metastatic TDLNs from 50 breast carcinoma samples were examined histologically and for PD1 expression in the present study. We assessed the immune response in these TDLNs  as per histomorphological patterns on H&E stained slides, categorizing them into lymphocyte predominance, germinal center predominance and an un-stimulated pattern. Anti-PD1 immunohistochemistry was performed on all lymph nodes. The results were analyzed using SPSS version 23 and P value <0.05 was considered to be significant.

Results: The lymph node metastasis in breast carcinoma was significantly higher at younger age, patients with higher tumor grade and lympho-vascular invasion in the primary tumor. The metastatic lymph nodes showed significantly higher densities of germinal centers with abnormal shapes, as compared to non-metastatic ones. There was significantly higher expression of PD1 in the immune cells of metastatic TDLNs.

Conclusion: The identification of PD1 immunohistochemical profile along with histological changes of TDLNs should therefore be considered as a possible prognostic and predictive marker for lymph node metastasis. The patients with higher densities of germinal center with abnormal shape and increased PD1 expression should benefit from immune-check point inhibitor therapy.

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Heer E, Harper A, Escandor N, Sung H, McCormack V, Fidler-Benaoudia MM. Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study. Lancet Glob Health. 2020 ;8(8):e1027-e1037. doi: 10.1016/S2214-109X(20)30215-1.

Pereira ER, Jones D, Jung K, Padera TP. The lymph node microenvironment and its role in the progression of metastatic cancer. Semin Cell Dev Biol. 2015;38:98-105. doi: 10.1016/j.semcdb.2015.01.008.

Seidl M, Bader M, Vaihinger A, Wellner UF, Todorova R, Herde B et al. Morphology of Immunomodulation in Breast Cancer Tumor Draining Lymph Nodes Depends on Stage and Intrinsic Subtype. Sci Rep. 2018; 8(1):5321. doi: 10.1038/s41598-018-23629-3.

Willard-Mack CL. Normal structure, function, and histology of lymph nodes. Toxicol Pathol. 2006;34(5):409-24. doi: 10.1080/01926230600867727.

Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008; 26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331.

Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev. 2014 ;23(12):2965-70. doi: 10.1158/1055-9965.EPI-14-0654.

Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009 ;114(8):1537-44. doi: 10.1182/blood-2008-12-195792.

Yuan C, Liu Z, Yu Q, Wang X, Bian M, Yu Z et al. Expression of PD-1/PD-L1 in primary breast tumours and metastatic axillary lymph nodes and its correlation with clinicopathological parameters. Sci Rep. 2019 ;9(1):14356.doi: 10.1038/s41598-019-50898-3.

Muenst S, Soysal SD, Gao F, Obermann EC, Oertli D, Gillanders WE. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2013 ;139(3):667-76. doi: 10.1007/s10549-013-2581-3.

Berlinger NT, Tsakraklides V, Pollack K, Adams GL, Yang M, Good RA. Immunologic assessment of regional lymph node histology in relation to survival in head and neck carcinoma. Cancer. 1976 ;37(2):697-705. doi: 10.1002/1097-0142(197602)37:2<697::aid-cncr2820370214>3.0.co;2-i.

Tsakraklides V, Olson P, Kersey JH, Good RA. Prognostic significance of the regional lymph node histology in cancer of the breast. Cancer. 1974 ;34(4):1259-67.doi: 10.1002/1097-0142(197410)34:4<1259::aid-cncr2820340436>3.0.co;2-y.

Yadav ST, Madhu Shankari GS, Chatura K, Dhanuja RJ, Rashmi M. Immunomorphological assessment of regional lymph nodes for predicting metastases in oral squamous cell carcinoma. Indian J Dent Res. 2012 ;23(1):121-2. doi: 10.4103/0970-9290.99059.

Unger S, Seidl M, Schmitt-Graeff A, Böhm J, Schrenk K, Wehr C et al. Ill-defined germinal centers and severely reduced plasma cells are histological hallmarks of lymphadenopathy in patients with common variable immunodeficiency. J Clin Immunol. 2014 ;34(6):615-26.doi: 10.1007/s10875-014-0052-1.

Núñez NG, ToselloBoari J, Ramos RN, Richer W, Cagnard N, Anderfuhren CD et al. Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients. Nat Commun. 2020 ;11(1):3272.doi: 10.1038/s41467-020-17046-2.

Yenidunya S, Bayrak R, Haltas H. Predictive value of pathological and immunohistochemical parameters for axillary lymph node metastasis in breast carcinoma. Diagn Pathol. 2011 ;6:18. doi: 10.1186/1746-1596-6-18.

Rivadeneira DE, Simmons RM, Christos PJ, Hanna K, Daly JM, Osborne MP. Predictive factors associated with axillary lymph node metastases in T1a and T1b breast carcinomas: analysis in more than 900 patients. J Am Coll Surg. 2000 ;191(1):1-6. doi: 10.1016/s1072-7515(00)00310-0.

Ze-Yu Shuang, Yi-Ze Mao, Yong-Cheng Liu, Guo-He Lin, Jun-Cheng Wang, Jun Wang et al.The tumor-draining lymph nodes are immunosuppressed in patients with hepatocellular carcinoma. Transl Cancer Res. 2017; 6(6):1188-1196. doi: 10.21037/tcr.2017.11.14.

Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ et al. Expression of indoleamine 2,3-

dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest. 2004 ;114(2):280-90. doi: 10.1172/JCI21583.

Kojima M, Kashimura M, Itoh H, Noro M, Matsuda H, Tsukamoto N et al. Infectious mononucleosis lymphoadenitis showing histologic findings indistinguishable from toxoplasma lymphadenitis. A report of three cases. Pathol Res Pract. 2010;206(6):361-4.doi: 10.1016/j.prp.2009.12.010.

Gujral S, Gandhi JS, Valsangkar S, Shet TM, Epari S, Subramanian PG. Study of the morphological patterns and association of Epstein-Barr virus and human herpes virus 8 in acquired immunodeficiency deficiency syndrome

related reactive lymphadenopathy. Indian J Pathol Microbiol. 2010 ;53(4):723-8. doi: 10.4103/0377-4929.72055.

Turner RR, Levine AM, Gill PS, Parker JW, Meyer PR. Progressive histopathologic abnormalities in the persistent generalized lymphadenopathy syndrome. Am J Surg Pathol. 1987;11(8):625-32. doi: 10.1097/00000478-198708000-00006.

Maier H, Isogawa M, Freeman GJ, Chisari FV. PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver. J Immunol. 2007 ;178(5):2714-20. doi: 10.4049/jimmunol.178.5.2714.

Errico A. Immunotherapy: PD-1-PD-L1 axis: efficient checkpoint blockade against cancer. Nat Rev Clin Oncol. 2015 ;12(2):63. doi: 10.1038/nrclinonc.2014.221.

Wu X, Zhang H, Xing Q, Cui J, Li J, Li Y, Tan Y, Wang S. PD-1(+) CD8(+) T cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients. Br J Cancer. 2014;111(7):1391-9. doi: 10.1016/j.isci.2020.101056.

Adams S, Gatti-Mays ME, Kalinsky K, Korde LA, Sharon E, Amiri-Kordestani L, et al. Current Landscape of Immunotherapy in Breast Cancer: A Review. JAMA Oncol. 2019;5(8):1205-1214. doi:10.1001/jamaoncol.2018.7147.


Suma Nayek
Sourav Sau
Kaushik Majumdar
Anupam Basu
Arghya Bandyopadhyay
drarghyabanerjee@yahoo.com (Primary Contact)
Nayek S, Sau S, Majumdar K, Basu A, Bandyopadhyay A. Histomorphology of immunomodulation and PD1 expression in breast cancer tumor draining lymph nodes: Determinants of Breast Cancer Screening. Arch Breast Cancer [Internet]. 2022 Mar. 24 [cited 2024 Jun. 16];9(2):213-20. Available from: https://www.archbreastcancer.com/index.php/abc/article/view/495

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