Pathophysiological features of neuroendocrine tumors in cyanotic congenital heart disease: a systematic review
Authors: Miranda Barrio B , Rodrigo Toledo R T , Anna Casteras A C , Carlota Arenillas C A , Antonia Pijuan A P , Blanca Gordon B G , Manel Maymi M M , Victor Gonzalez V G , Ignacio Ferreira I F , Laura Dos L D 
Published: November 2023

Abstract

Background
Patients with cyanotic congenital heart disease (CCHD) have an increased risk to develop pheochromocytomas or paragangliomas (PPGL), which are rare neuroendocrine tumours molecularly driven by the activation of the hypoxia-inducible factor 2-alpha (HIF-2α ).

Purpose
To define the clinical characteristics of CCHD-PPGL patients.

Methods
An international multicentre CCHD-PPGL consortium from 8 countries was stablished. The group performed a systematic review of clinic-pathological features of 149 CCHD-PPGL cases and compared to 1559 CCHD non-PPGL patients.

Results
CCHD-PPGL were predominantly women (56.4%) with univentricular heart (UVH) (55.0%), followed by tetralogy of Fallot (23.5%). Most patients remained unoperated (28.6%) or had only undergone a palliative procedure (25.8%), and the mean saturation at diagnosis was 84.0%.
The median age at PPGL diagnosis was 27.0 yo [20-38]. Pheochromocytoma (PCC) occurred in 36.9% of patients, abdominal or thoracic paraganglioma (TA-PGL) in 40.3%, carotid body paraganglioma (CB-PGL) in 14.7% and a combination in 8.0%. Most CB-PGLs were non-secreting, non-symptomatic tumors while PCC and TA-PGL were mostly noradrenalin-secreting and symptomatic tumors. Metastatic disease was documented in 10.3% of non-CB and none in CB-PGL .
Comparing to patients with PCC or TA-PGL, CB-PGL patients were predominantly female (81.8% vs 52.0%), older at time of diagnosis (43 yo [36.0 – 52.0] vs 25.0 yo [19.0-35.0], p&lt;0.01) and with a longer period of cyanosis at diagnosis (37.0 [23-47] vs 23.0 [13-46], p&lt;0.01).
Patients with Fontan procedure were mostly men (63.3%) who developed a noradrenalin-secreting PCC or a TA-PGL (42.0% and 58.0% respectively) at an earlier age than non-Fontan patients (22.0yo [18.0-27.0] vs 29.0yo [21.0-41.0], p&lt;0.01). Patients with Eisenmenger physiology were female patients (100%) who developed mostly CB-PGL, non-secreting tumors (54.5%) and were older at diagnosis (48.0 yo [42-58]).
Compared to a cohort of 1599 CCHD non- PPGL patients, CCHD-PPGL were predominantly women (57.7% vs 44.8%, p&lt;0.01), with forms of UVH (53.7% in CCHD-PPGL vs 14.1% in CCHD, p &lt;0.01 ) and were mainly unoperated and palliated patients (27.1% and 26.4% respectively vs 10.0% and 5.3% in CCHD, p &lt;0.01). CCHD-PPGL patients showed lower levels of oxygen saturation (80.0% [76.0-85.0] vs 84.0% [80.0-88.0], p&lt;0.01) and higher haematocrit levels (60.0% [52.0-66.5] vs 53.3% [46.3-62.0], p&lt;0.01) than CCHD without PPGL.

Conclusions
Patients with CCHD and lifelong cyanosis, and especially those with Eisenmenger physiology, probably develop CB-PGL as an adaptive response to chronic systemic hypoxemia, present a good clinical course, and usually do not require an initial surgical approach. In patients with Fontan circulation, the risk of developing a sympathetic thoracic-abdominal PPGL persists, despite correction of hypoxemia, possibly due to the initial hypoxemia during adrenal medulla post-natal development.