Writer｜Asteria Xu
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Pheochromocytomas
/tumors found in the adrenal glands/
Pheochromocytomas are tumors found in the adrenal glands and are composed of chromaffin cells. Chromaffin cells produce catecholamine, hormones typically released when someone is under physical or emotional stress. The overproduction of catecholamine in pheochromocytoma can cause numerous symptoms, and the most commonly seen ones are high blood pressure, headache, heavy sweating, strong and irregular heartbeat and fatigue.
/Clusters/
Pheochromocytomas are categorized into three clusters based on their germline or somatic mutations, and these three clusters are pseudohypoxic signaling, kinase signaling and Wnt signaling.
Cluster 1: Pseudohypoxic Cluster
When the oxygen levels are low, cells will trigger a series of reactions called hypoxia response. Cells that activate hypoxia responses under normal oxygen levels are said to exhibit a pseudohypoxic response. Pseudohypoxic responses are commonly seen in tumors, leading to heightened glycolytic metabolism and angiogenesis, the formation of new capillaries.
Cluster 1 is divided into two subclusters: cluster 1A, which involves the Krebs Cycle and cluster 1B, which pertains hypoxia signaling. Mutations in the Krebs cycle result in the accumulation of oncometabolites, which are metabolites that are significantly elevated in tumor cells compared to normal cells. The accumulation of oncometabolite, together with mutations in the hypoxia signaling, lead to the stabilization of Hypoxia Induced Factor 1α (HIF-1α).
Hypoxia Induced Factor 1 (HIF-1)is a heterodimeric transcription factor, which means that it consists of two subunits, HIF-1α and HIF-1β. Under normal circumstances, HIF-1α undergoes continuous degradation. However, when the concentration of oxygen decreases, the degradation of HIF-α is retarded, leading to its increased expression under hypoxic conditions. In cancer, HIF-1α activates the transcription of genes that promotes angiogenesis, metastasis and other cellular processes.
Cluster 2: Tyrosine Kinase-Linked Signaling Pathway
Activated mutations in genes such as RET, NF1, HRAS, TMEM127, MAX, FGFR1, Met, MERTK, BRAF and NGFR lead to overactivation of PI3K/AKT, RAS/RAF/ERK, and mTORC1/p70S6 pathways. Similar to cluster 1, these pathways eventually result in the synthesis of HIF-α, leading to cell proliferation and angiogenesis.
Cluster 2 tumors show the adrenergic phenotype, which means that the quantity of epinephrine is greater than 5% of the total amount of catecholamines present. Cluster 2 tumors are generally less aggressive than cluster 1 and cluster 3 tumors.
Cluster 3: Wnt signaling
Compared to cluster 1 and cluster 2, cluster 3 remains relatively unexplored. Two mutations hold significance within the Wnt cluster. First, the mutation of MAML3 results in the overactivation of Wnt/Hedgehog signaling. Second, the mutation of CSDE1 leads to the overactivation of ß-catenin, a target of Wnt signaling. Consequently, these two mutations result in angiogenesis and cell proliferation.
Treatment
For locoregional diseases, the primary option for patients is the surgical removal of tumors. In the case of metastatic disease, alleviating symptoms by reducing catecholamine production can also result from removing primary tumors.
Preoperative treatments
Before surgery, patients’ blood pressure and heart rate must be brought under control to prevent the occurrence of cardiovascular emergencies and other catecholamine-associated side effects. Alpha-adrenoceptor blockers are usually employed to control high blood pressure. They prevent norepinephrine, a type of catecholamine, from tightening the walls of blood vessels. Phenoxybenzamine, a type of alpha-adrenoceptor blocker, is the most frequently used.
Surgery
Typically, doctors perform a procedure called adrenalectomy to remove the primary tumor, thereby reducing catecholamine levels by excising the adrenal glands. There are various approaches to adrenalectomy.
One approach is open adrenalectomy involving a large abdominal incision. Although once the standard for tumor removal, open adrenalectomy is being supplanted by a newer technique, laparoscopic adrenalectomy.
Laparoscopic adrenalectomy has become the golden standard of surgical treatment for benign tumors. In this approach, doctors make three or four small incisions and put laparoscopes, which are small cameras, through these incisions. The laparoscopes allow the surgeons to see the internal organs and guide them through the surgery. This approach is less invasive, resulting in reduced patient discomfort and faster recovery. After an overnight stay in the hospital, patients typically recover at home over a few weeks.
There are two distinct approaches to laparoscopic adrenalectomy. The first is lateral transperitoneal adrenalectomy (LTA) involving incisions on the side, and the adrenal glands are exposed by detaching adjacent organs. Another approach is the posterior retroperitoneal adrenalectomy (PRA), which is minimally invasive and is commonly used to remove benign tumors. In PRA, incisions are made on the back rather than the through the abdomen, offering advantages for patients with previous abdominal incisions (because it doesn’t enter the abdomen, so is preferred by patients who have had incisions on the abdomen before). This approach, however, is only effective for tumors that are smaller than 6cm.
Chemotherapy
Metastatic pheochromocytoma can be treated by chemotherapy. Chemotherapy targets rapidly dividing cells, which is a feature of cancer. Unfortunately, hair cells and cells in the stomach are also rapidly dividing, resulting in chemotherapy-related side effects such as hair loss and loss of appetite.
CVD (cyclophosphamide, vincristine, and dacarbazine） can also be used for the treatment of malignant pheochromocytomas. Studies have shown that a partial response to tumor volume can be seen in 37% of patients and a partial response to catecholamine excess can be seen in 40% of patients.
Conclusion
Although in recent years, many studies have been done on pheochromocytoma that provide valuable insights into the causes and treatments, many details regarding the mechanism of pheochromocytoma remain unclear. Further research is needed to enhance our understanding of the disease and to develop more efficient treatment methods for this form of cancer.
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