Stains & molecular markers
Programmed death-1 (PD-1)


Minor changes: 26 July 2021

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PubMed Search: Programmed death-1 [TI] review [PT]

Ashley Keller Volaric, M.D.
Oscar Silva, M.D. Ph.D.
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Cite this page: Volaric AK, Silva O. Programmed death-1 (PD-1). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainspd1.html. Accessed July 28th, 2021.
Definition / general
  • Programmed cell death-1 (PD-1)
  • Co-inhibitory checkpoint receptor
  • 1 of 5 receptors within the CD28 coreceptor family [CD28, inducible T cell costimulatory (ICOS), cytotoxic T lymphocyte associated antigen 4 (CTLA4), B and T lymphocyte associated (BTLA)] that regulate the balance between T cell activation and immune tolerance
  • Monomeric, not homodimeric like other CD28 coreceptors
  • Known ligands are PDL1 (B7H1; CD274) and PDL2 (B7DC; CD273)
Essential features
  • Co-inhibitory checkpoint receptor
  • Highly expressed in normal T follicular helper cells (TFH)
  • Expressed in neoplastic cells of angioimmunoblastic T cell lymphoma (AITL), nodal lymphomas of TFH origin and T lymphocytes of primary cutaneous CD4+ small / medium T cell lymphoproliferative disorder
  • Expressed on nonneoplastic T cells, which form rosettes around lymphocyte predominant (LP) cells of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and Hodgkin cells in classic Hodgkin lymphoma (CHL)
  • Targeted by monoclonal antibodies (nivolumab or pembrolizumab) to prevent inhibitory immune signaling and unleash the immune system to fight cancer (more commonly used and standardized for melanoma and non small cell lung cancer and less frequently used for hematologic malignancies such as Hodgkin lymphoma) (Int J Mol Sci 2021;22:6288)
Terminology
  • CD279
  • Programmed cell death protein 1 (encoded by PDCD1 at chromosome 2q37.3)
Pathophysiology
  • Expressed on T cells upon T cell receptor (TCR) engagement to decrease T cell activation through inhibitory signaling
  • Binding of PD-1 to PDL1 / PDL2 allows SHP1 / SHP2, intracellular phosphatases, to inhibit TCR / CD28 induced signaling (J Exp Med 2012;209:1201)
  • PD-1 usually binds PDL1 / PDL2 in trans (T cell with PD-1 and antigen presenting cell [APC] / cancer cell with PDL1 / PDL2); however, PD-1 can also bind PDL1 in cis on APCs (Cell Rep 2018;24:379)
  • Highly expressed by germinal center associated helper T cells / T follicular helper cells (TFH); inhibits T cell activation (Immunol Lett 2002;83:215, Am J Surg Pathol 2006;30:802)
  • Also expressed by CD8+ T cells and can be induced in CD4+ regulatory T cells (Tregs), B cells, NK cells, monocytes and myeloid derived dendritic cells leading to inhibitory signaling within these cell types (Nat Rev Immunol 2018;18:153)
Clinical features
  • High and sustained PD-1 expression and binding with PDL1 or PDL2 is associated with T cell exhaustion, secondary to chronic viral infection and cancer
  • Inhibition of PD-1 signaling is a major target in cancer immunotherapy to unleash the immune system to fight cancer (melanoma, carcinoma, classic Hodgkin lymphoma, etc.)
  • PD-1 / PDL1 inhibition can precipitate autoimmune endocrinopathies, confirming that PD-1 is important for maintaining self tolerance and preventing autoimmunity in humans (Diabetes Care 2015;38:e65)
  • PD-1 inhibition may lead to lymphoid proliferations that mimic lymphoma (J Cutan Pathol 2021;48:674)
  • PD-1 in T cell lymphomas may inhibit oncogenic T cell signaling and thus may be a tumor suppressor (Nature 2017;552:121)
Interpretation
  • Membranous stain
Uses by pathologists
  • PD-1 is a follicular helper T cell marker and helps identify neoplastic T cells in angioimmunoblastic T cell lymphoma and other T cell lymphomas with follicular helper phenotype (Am J Surg Pathol 2010;34:178)
  • Differentiates primary cutaneous CD4 small / medium sized pleomorphic T cell lymphoproliferative disorder and mycosis fungoides (subset with PD-1 positive) from other cutaneous T cell lymphomas (usually PD-1 negative) (Am J Surg Pathol 2009;33:81, Am J Dermatopathol 2015;37:115)
  • PD-1+ rosettes of nonneoplastic T cells around neoplastic B cells is relatively specific for nodular lymphocyte predominant Hodgkin lymphoma (Hum Pathol 2009;40:1715)
  • PD-1+ cells can be increased in reactive T cells of marginal zone lymphoma (Am J Surg Pathol 2020;44:657)
Prognostic factors
  • Anti-PD-1 / PDL1 therapy has led to strong response in refractory / relapsed classic Hodgkin lymphoma, which typically harbors increased PD-1+ tumor infiltrating T cells and PDL1 expression by Hodgkin Reed-Sternberg cells (Blood 2018;131:68, Curr Hematol Malig Rep 2020;15:372)
Microscopic (histologic) images

Contributed by Ashley Keller Volaric, M.D., Oscar Silva, M.D. Ph.D. and GenomeMe
Angioimmunoblastic T cell lymphoma Angioimmunoblastic T cell lymphoma

Angioimmunoblastic T cell lymphoma

T cell rosettes T cell rosettes

T cell rosettes

Tonsil (normal), clone IHC001

Tonsil (normal), clone IHC001

Positive staining - normal
  • Follicular helper T cells (germinal center associated)
  • Pro-B cells
Positive staining - disease
Negative staining
Molecular / cytogenetics description
  • Deletions of PD-1 have been identified in T cell lymphomas, with the highest proportion (36%, 13 out of 36) in a group of patients with advanced cutaneous T cell lymphoma (Nature 2017;552:121)
Sample pathology report
  • Lymph node, excision:
    • Nodular lymphocyte predominant Hodgkin lymphoma (see comment)
    • Comment: CD20 highlights large atypical B cells within small B cell rich nodules. CD3 is positive in background small T cells with occasional CD3 positive T cell rosettes around the large atypical B cells. A PD-1 stain shows T cell rosettes encircling the large atypical B cells in the nodular areas. CD30, CD15 and EBV in situ hybridization (EBER) are negative in the large B cells.
Board review style question #1

PD-1+ rosettes are a relatively specific diagnostic finding for which hematolymphoid malignancy?

  1. Angioimmunoblastic T cell lymphoma
  2. Classic Hodgkin lymphoma
  3. Nodular lymphocyte predominant Hodgkin lymphoma
  4. T / histiocyte rich large B cell lymphoma
Board review style answer #1
C. Nodular lymphocyte predominant Hodgkin lymphoma. PD-1 highlights a single layer of follicular helper T cells, which surround neoplastic lymphocyte predominant (LP) cells of nodular lymphocyte predominant Hodgkin lymphoma, forming rosettes. PD-1 rosettes are indicative of the interaction between follicular helper T cells and neoplastic lymphoma cells and are not observed exclusively in nodular LP Hodgkin lymphoma, although this morphologic finding is relatively specific for this entity. PD-1 rosettes can be found occasionally in cases of T / histiocyte rich large B cell lymphoma that arise from nodular LP Hodgkin lymphoma as well as in classic Hodgkin lymphoma (lymphocyte rich), angioimmunoblastic T cell lymphoma and nodal based peripheral T cell lymphoma (see reference). Thus, the finding of PD-1 rosettes must be considered in the overall context of the whole case and clinical presentation and not used solely as a diagnostic criterion. (Am J Clin Pathol 2021;156:1)

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Reference: Programmed cell death-1 (PD-1)
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