A 50-year-old man undergoes resection of a neuroendocrine tumor (NET). Three years later, he develops exertional dyspnea and lower extremity edema. An echocardiogram reveals severe tricuspid and pulmonary valve regurgitation, as well as an enlarged right ventricle.
The correct answer is ...
Recurrent NET of the left testicle.
This case is that of a patient with carcinoid syndrome resulting in valvular dysfunction. Carcinoid tumors are neuroendocrine tumors that commonly arise in the lungs and gastrointestinal tract, but have been known to arise in other less common primary sites. They may secrete substances such as serotonin, histamine, tachykinins, and prostaglandins, resulting in various clinical manifestations. Carcinoid heart disease (CHD), or Hedinger syndrome, occurs when serotonin, through the activation of TGF-beta, acts on heart valves by inducing myofibroblastic metaplasia. Histologically, this results in plaques with a “stuck on” appearance composed of fibroblasts, smooth muscle cells, and extracellular matrix components such as collagen and myxoid ground substance. Grossly, the valves and chordae are thickened with a pearly appearance.
The pathogenicity of serotonin with regards to valvular heart disease is highly dependent on the location of the primary tumor as well as any possible metastases. Tumors with venous drainage into the portal circulation are subjected to the hepatic metabolism of serotonin. However, a tumor location with drainage to the systemic circulation bypasses this inactivation. Likewise, serotonin can be deactivated in the lungs.
As such, the correct answer for this question is “recurrent NET of the left testicle,” as the venous drainage of the testes occurs via the gonadal veins to the inferior vena cava and the systemic circulation. This allows unmetabolized serotonin to reach the right side of the heart, affecting the tricuspid and pulmonary valves, as seen in this case example. Two of the answer choices (“residual NET of the stomach” and “recurrent NET of the small intestine”) both describe scenarios whereby tumors would drain into the portal circulation. Of note, in either of those choices, metastatic disease or cirrhosis could also allow for the bypassing of hepatic serotonin metabolism.
Though this question describes right-sided carcinoid heart disease, there are other situations in which the left-sided valves can be affected. One of the answer choices (“primary NET of the right lung”) describes a scenario in which serotonin could be secreted into the pulmonary venous drainage and subsequently exposed to the mitral and aortic valves. Another possibility would be a patient with a patent foramen ovale or other septal defect. Under the proper hemodynamic conditions, a right-to-left shunt would allow for secreted serotonin to bypass the lungs (where it would otherwise be metabolized) and affect the left-sided valves.
Of note, there are also a few medications that can produce similar valvular findings to those seen in patients with carcinoid heart disease, including fenfluramine and ergot alkaloids.
Philip Hurst, M.D.
Fellow, Cardiovascular Pathology
Andrew Layman, M.D.
Senior Associate Consultant, Anatomic Pathology