Heart & vascular pathology

• Endomyocardial biopsy remains a critical diagnostic tool for AMR (Circulation 2015;131:1608)
• Histologic features of AMR include activated intravascular mononuclear cells / endothelial cells as well as macrophages (J Heart Lung Transplant 2013;32:1147)
  • Intravascular macrophages accumulate in capillaries and venules
  • Endothelial cells are prominent with large nucleoli
  • Severe AMR shows interstitial edema, myocyte necrosis, mixed inflammatory infiltrate and endothelial pyknosis or karyorrhexis
• Characteristic immunologic features of AMR are capillary deposition of immunoglobulins (IgG, IgM or IgA) and complement activation product (C3d, C4d or C1q) either by immunofluorescence (IF) or by immunohistochemistry (IHC) (J Heart Lung Transplant 2011;30:601)

• ICD-9: 996.83 - complications of transplanted heart
• ICD-10: T86.21 - heart transplant rejection
• ICD-11
  • QB63.1 - presence of transplanted heart
  • NE84 - failure or rejection of transplanted organs or tissues

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Contributed by Fabiola Reyes, M.D. and Knarik Arkun, M.D.


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• Classic histopathologic features of AMR on H&E stained sections include (J Heart Lung Transplant 2013;32:1147)
  • Interstitial capillary injury with swollen endothelial cells in myocardium
  • Intravascular macrophages in myocardium
  • Activated mononuclear cells refer to both the endothelial and macrophage components
  • Edema is typically found in association with activated mononuclear cells and rarely is a solitary finding; it is pale eosinophilic to dull basophilic proteinaceous strands between myocytes and around intramyocardial venules and arterioles producing separation of the myocytes, vessels and connective tissue elements
  • Severe AMR is characterized by hemorrhage and neutrophilic infiltrates in and around the microvasculature
  • Severe AMR also includes intravascular thrombi and myocyte necrosis, as well as karyorrhectic debris in the absence of cellular rejection
• See Diagrams / tables

Contributed by Fabiola Reyes, M.D., Atreyee Basu, M.D. and Knarik Arkun, M.D.

• Primary panel includes C4d, C3d and anti-HLA-DR
• Optional secondary panel includes fibrin and immunoglobulins
• Immunofluorescence staining on paraffin immunohistochemistry is limited
• Prognostic significance of C3d on frozen specimen is reported
• Intensity ranges from 0 - 3+
• Distributions of staining patterns are divided as < 10%, 10 - 50% and > 50%
• Reporting of the staining for immunofluorescence is described in Table 3
• Reference: J Heart Lung Transplant 2013;32:1147

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• C4d paraffin section, primary panel; only capillary staining counts; granular stain in C4d is possible but should consider negative / nonspecific
• CD68 paraffin section, primary panel
• CD163 paraffin section
• CD34 or CD31: endothelial markers, to assess microvascular integrity
• C3d: not commonly used; however, if done, interpretation criteria would be the same as C4d
• Reference: J Heart Lung Transplant 2013;32:1147

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• Molecular Microscope Diagnostic System (MMDx) is a novel tool used for the diagnosis of AMR in heart transplant biopsies
• MMDx utilizes microarray technology to measure gene expression profiles in endomyocardial biopsies
• Machine learning algorithms to interpret these profiles and compare them to a large reference set of biopsies allows for the classification of rejection states (Transplantation 2023;107:27)
• Molecularly, 3 types of AMR selective transcripts are reported: NK, interferon gamma (IFNG) inducible and endothelial
• NK cell transcripts such as granulysin (GNLY) and granzyme B (GZMB) are highly associated with AMR
• Reference: Transplantation 2023;107:27

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• Heart transplant, myocardium, biopsy:
  • There is no evidence of acute cellular rejection, 2004 ISHLT 0R (1990 ISHLT grade 0)
  • There is no evidence of AMR (pAMR0) (see comment)
  • Comment: There are 3 adequate fragments of myocardium for evaluation. Immunohistochemical stains for C4d and CD68 are negative for capillary staining and intravascular macrophages, respectively, supporting the diagnosis.
  
  
• Heart transplant, myocardium, biopsy:
  • There is no evidence of acute cellular rejection, 2004 ISHLT 0R (1990 ISHLT grade 0)
  • There is histologic evidence of AMR, pAMR1 (H+) (see comment)
  • Quilty lesion
  • Comment: There are 3 adequate fragments of myocardium for evaluation. On histology, prominent endothelial cells and patchy edema are seen in the myocardium (features of histologic AMR). However, immunohistochemical stain for C4d is negative for capillary staining and CD68 immunostain is predominantly negative for intravascular macrophages. The overall findings support the diagnosis and do not appear to meet the immunohistochemical criteria for AMR.

• Acute cellular rejection:
  • Interstitial or perivascular distribution of predominantly lymphocytes and macrophages and or myocyte injury; C4d- and C3d-
  • Negative for CD68 / CD163 for intravascular macrophages
• Peritransplant / operative ischemic injury:
  • Inflammatory infiltrate composed of mixed neutrophils, eosinophils, lymphocytes and macrophages
  • Coagulative type myocyte necrosis, fat necrosis, contraction band necrosis and myocyte vacuolization frequently extend to the endocardial surface
• Infection (e.g., cytomegalovirus, myocarditis, toxoplasmosis, disseminated aspergillosis):
  • Serology positive
  • Demonstration of infectious entity on endomyocardial biopsy

• UpToDate: Heart Transplantation in Adults - Diagnosis of Allograft Rejection [Accessed 7 February 2025], UpToDate: Heart Transplantation in Adults - Treatment of Rejection [Accessed 7 February 2025]

A 55 year old woman with a history of dilated cardiomyopathy undergoes orthotopic heart transplantation. 1 month posttransplant, she presents with worsening dyspnea and elevated cardiac enzymes. Endomyocardial biopsy reveals the histology shown above with the diffuse presence of C4d deposition in the capillaries (> 50%). Which of the following is the most likely mechanism underlying her condition?

1. Cellular infiltration by T lymphocytes
2. Direct cytotoxicity by donor specific antibodies (DSAs)
3. Graft versus host disease
4. Inflammation mediated by infectious organism
5. Quilty lesion

B. Direct cytotoxicity by donor specific antibodies (DSAs). The presence of C4d deposition in the capillaries signifies the activation of the complement system due to DSAs. The mechanism of AMR involves DSAs binding to endothelial cell antigens, triggering cytotoxic effects, complement activation and subsequent inflammatory responses, all of which contribute to graft dysfunction. Answer A is incorrect because cellular infiltration by T lymphocytes typically does not activate the complement system. As a result, C4d deposition would be negative in cases of cellular rejection. Answer C is incorrect because graft versus host disease is a rare complication in solid organ transplants, primarily involving a T lymphocyte response. Answer D is incorrect because inflammation caused by infectious organisms typically presents with diffuse lymphocytic eosinophils or histiocytic infiltration of the myocardium and an identifiable microorganism is sometimes present. Answer E is incorrect because Quilty lesion consists of a cellular infiltrate made up of T and B lymphocytes, macrophages and occasional plasma cells, often found on the endocardial surface. The pathogenesis of Quilty lesions is largely unknown; however, it is hypothesized to have an association with cyclosporin based immunosuppressive regimens.

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Reference: Antibody mediated rejection

A 62 year old man underwent a heart transplant due to ischemic heart disease. He is treated with a combination of immunosuppressive medications. 5 weeks after surgery, he developed acute rejection characterized by high fever, malaise and chest discomfort. Laboratory studies showed elevated titers of antidonor antibodies and a biopsy revealed evidence of antibody mediated rejection. Which of the following findings is indicative of antibody mediated rejection?

1. C4d deposition in capillaries (multifocal staining)
2. Lymphocytic infiltrate in interstitial or perivascular distribution of myocardium
3. Mixed inflammation with myocyte necrosis
4. Subendocardial lymphocytic aggregate with prominent blood vessels
5. Transmural inflammation with eosinophils and myocyte injury

A. C4d deposition in capillaries (multifocal staining). C4d deposition in the capillaries serves as a marker for antibody mediated rejection, indicating complement activation triggered by antibodies binding to the vascular endothelium, which leads to tissue injury. Answers B, C and D are incorrect because in a clinical context, the presence of high titers of antidonor antibodies alongside C4d positivity confirms acute antibody mediated rejection, distinguishing it from acute cellular rejection (answer B), peritransplant injury (answer C) and Quilty lesion (answer D). Answer E is incorrect because transmural inflammation with eosinophil and myocyte injury is seen in eosinophilic myocarditis. C4d deposition in the capillaries would not be present in this condition.

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Reference: Antibody mediated rejection