RELAPSE OF PHEOCHROMOCYTOMA WITH
HIPERTENSIVE HEART DISEASE
MILDLY REDUCED LEFT VENTRICLE
EJECTION FRACTION
Merylla Filianty Sipayung1, Yulianto
Kusnadi2, Alwi Shahab3,
Ratna Maila Dewi4, Imran Soleh5,
Fadil Pramudhya Hoesain6�
Universitas Sriwijaya, Sumatera Selatan, Indonesia
[email protected]
ABSTRACT
Pheochromocytoma is a tumor originating from the
medulla of the adrenal gland. This tumor is rare and is caused by excessive
production of catecholamines. There are three classic triads of
pheochromocytoma: diaphoresis, palpitations and headaches. Elevated
metanephrines and normetanephrine in plasma or urine confirm the diagnosis. At
the same time, radiological examination helps in the tumor's location and the
presence of local invasion or metastasis. Hypertension is a health problem that
is quite dangerous worldwide because it is a significant risk factor for
cardiovascular diseases such as heart attack, heart failure, stroke, and kidney
disease. Hypertension can cause Hypertensive Heart Disease, which is a
significant cause of morbidity and mortality due to cardiovascular disease.
This scientific report presents a case study of a 19-year-old woman diagnosed
with relapsed pheochromocytoma and hypertensive heart disease with mildly
reduced left ventricular ejection fraction. This patient was previously
diagnosed at the age of 13 with pheochromocytoma, where the patient experienced
symptoms of headache, sweating, especially in the forehead area, trembling
hands, and hypertension. Hence, the patient had to be treated. The patient
underwent further examination and found a right adrenal tumor, so an
adrenalectomy was performed on the patient. Similar complaints appeared again
in the patient, and further examination was carried out. Moreover, an increase
in plasma metanephrine and normetanephrine levels was found. A CT scan of the
abdomen revealed a right adrenal tumor, so this patient underwent another
adrenalectomy.
Keywords: relapsed
pheochromocytoma, hypertensive heart disease.
Corresponding Author: Merylla
Filianty Sipayung
Email: [email protected]
INTRODUCTION
Pheochromocytoma is a neuroendocrine tumor originating
from the chromaffin cells of the adrenal medulla gland. The incidence is 0.3% cases per million per year, and
one piece of literature states that 50% are diagnosed at autopsy. The first
histologically proven pheochromocytoma was diagnosed by Felix Fraenkel at the
University of Freiburg in Germany, finding classic signs and symptoms of
pheochromocytoma in a young woman with bilateral adrenal tumors. His colleague
professor of pathology, Max Schotellus, carried out a histological
investigation and was the first to notice that when the tumor was fixed with
Mueller's solution containing chromate, it was reddish-gray when fresh and
turned brown in Mueller's solution (Sănchez-Turcius
RA, 2015); (Farrugia et al., 2017).
�Manifestation
of signs and symptoms of pheochromocytoma includes hypertension, palpitations,
headaches, sweating, and paleness. Other symptoms that sometimes occur are
weakness, nausea, weight loss, constipation, and fever (Sănchez-Turcius
RA, 2015).
Pheochromocytoma is an endocrine hypertension that
should be suspected if there is a family history. Other causes of endocrine
hypertension are disorders of the pituitary, adrenal cortex, thyroid, and renal
tumors. The incidence of pheochromocytoma is approximately 0.1% to 0.2% in the
patient population suffering from hypertension. This condition can occur at any
age but is more common in the 3rd to fifth decades of life. The frequency of
occurrence in men is the same as in women �(Sănchez-Turcius
RA, 2015).
Pheochromocytoma is brown, and most tumors grow inside
the adrenal glands, only 10% outside the adrenal glands (paraganglioma).
Generally, it is benign, and only 10% metastasize to the bones, lungs, liver,
and lymph nodes. Tumors can secrete various hormones, especially epinephrine,
norepinephrine, and dopamine.
Pheochromocytoma is closely
associated with high morbidity and mortality, especially cardiovascular
complications (Lenders et al., 2014). Rapid and accurate diagnosis
of pheochromocytoma is essential in providing optimal treatment. The following
presents a relapsed pheochromocytoma with hypertensive heart disease and
mildly reduced left ventricular ejection fraction.
RESULTS AND DISCUSSION
Case Illustrations
A woman
named Ms VT, 19 years old. City address Lubuk Linggau, Palembang. The patient
came to the Endocrine Metabolic Diabetes Polyclinic at RSMH Palembang on
January 5, 2023, complaining of sweating all over the body, especially the
forehead and chest area, and additional complaints of headaches and back pain.
History of the disease in 2016. The patient complained of constant headaches,
which were reduced if the patient drank. paramek drug. The patient's vision is
sometimes blurry. The patient also complained of nausea, no vomiting, and
normal appetite. Patients also complain of sweating all over the body,
especially the forehead area. The patient also complained of palpitations and
shaking hands. The patient did not go to the hospital for treatment.
In 2017,
the patient again complained of headaches, body sweating, and shaking hands.
The patient went to Linggau Hospital for treatment and was suspected of
hyperthyroidism. The patient was referred to RSMH Palembang. The patient was
admitted to the pediatric ward and underwent a complete examination. While
being treated, the patient experienced high blood pressure, which, according to
the patient, was 200/180 mmHg. The patient was treated in the HCU for
approximately one month. The patient underwent an ultrasound examination and CT
scan of the abdomen, and the doctor said there was a mass in the adrenal gland
of the right kidney. The patient underwent surgery in December 2017.
In 2018,
patients complained of sweating, shaking hands, palpitations, and sometimes
headaches. The patient's blood pressure began to stabilize. The patient
receives routine treatment at Linggau Hospital. At the beginning of 2019, the
patient complained of right hip pain. The patient still complains of headaches,
trembling hands, and sweating, especially in the forehead area. The patient
went to the hospital in Linggau and had another abdominal CT scan, and a mass
was found. The patient was referred to RSMH Palembang. Patients do not come to
RSMH; patients also do not seek treatment and control until 2021 because
patients are afraid to come to the hospital because of COVID-19.
In 2022,
the patient complained of frequent sweating, especially in the forehead area,
headaches, back pain, and palpitations. The patient went to the hospital in
Lubuk Linggau for treatment. In early December 2022, the patient was referred
to the Endocrine Polyclinic at RSMH Palembang. The patient's previous medical
history did not reveal a history of hyperthyroidism and similar illnesses or a
family history of the disease. Physical examination revealed sensorium compos
mentis. The general condition appeared moderately ill, with BP 150/95 mmHg,
pulse 100 times/minute, regular, sufficient tension, respiration 22x/minute,
temperature 36.5C, BW 53 kg, TB 158 cm. Body Mass Index (BMI) 22.06% kg/cm2.
The
physical examination results of the head and neck organs were average. On chest
examination, the cast and pulmo were regular. The abdominal region shows scars
from surgical sutures, the liver and spleen are not palpable, and the tympanum
and bowel sounds are normal. Normal superior and inferior extremities.
In laboratory supporting examinations,
plasma-free metanephrine was found to be 26 pg/ml, free normetanephrine 7411
pg/ml, total free metanephrine, and normetanephrine 7437 pg/ml. Urine VMA
examination ≤ 8 mg/hour. Left Ventricular Hypertrophy was found on
electrocardiographic examination, and chest and pulmonary X-rays showed no
abnormalities. Echocardiography examination showed the impression of
Hypertensive Heart Disease and Mildly Reduced Left Ventricle Ejection Fraction.
In this patient, a CT examination of the abdomen was carried out, and an
impression of a cystic, solid mass in the right suprarenal area was obtained,
measuring 46.92 mm x 40.24 mm. No intra-abdominal metastases were visible.
Figure 1 . Abdominal CT scan
In this patient, from the history, physical examination, laboratory
results, and other supporting factors, a diagnosis of relapsed
pheochromocytoma, Hypertensive Heart Disease with mildly reduced Left Ventricle
Ejection Fraction, was diagnosed. This patient was then consulted by the
urological surgery department and advised to undergo an open adrenalectomy due
to the presence of adhesions. On July 6, 2023, the patient underwent an open
right suprarenal adrenalectomy.
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Figure
2. Open adrenalectomy operation
After surgery, the tumor from the adrenal gland was sent to the
anatomical pathology department, and the histopathological examination results
on July 14, 2023, showed support for pheochromocytoma of the adrenal. In 2017,
this patient also underwent surgery on the right adrenal gland, and
histopathology and immunohistochemistry showed benign right suprarenal
pheochromocytoma.
Pheochromocytoma is a
rare case with clinical manifestations related to catecholamine overproduction
(headaches, sweating, palpitations), local pressure, or metastasis (Rachmat et al., 2016). In meta-analysis studies conducted by Pourian et al.
in 2016 and Soltani et al. in 2017, the most significant signs and symptoms of pheochromocytoma
were hypertension (80.7%), headache (60.4%), palpitations (59.3%), diaphoresis
(52 .4%). Other less common signs and symptoms are fatigue, nausea, vomiting,
weight loss, constipation, fever, and chest and abdominal pain. The classic
triad of diaphoresis, palpitations, and headache is reported to have a
sensitivity of 89% and a specificity of 67% for pheochromocytoma, and in the
presence of hypertension, a sensitivity of 91% and a specificity of 94%.
Endocrine
hypertension is often not diagnosed because the signs and symptoms are unclear,
and no abnormalities are found in routine laboratories. For this reason, there
are several clinical signs to suspect the presence of pheochromocytoma, namely (Sănchez-Turcius
RA, 2015) :
1.
Resistant
hypertension, refractory hypertension
2.
Hypertensive crisis
3.
Hyperadrenergic
(palpitations, diaphoresis, headache, tremor, pallor)
4.
Adrenal Incidentaloma
5.
Genetic history of
pheochromocytoma
6.
Hypertension at a
young age (< 20 years)
7.
Hypertension with
impaired glucose tolerance and diabetes mellitus
This
patient had a history of hypertension when he was 13 years old and had clinical
symptoms typical of pheochromocytoma, namely diaphoresis, headaches,
palpitations, and additional complaints of back pain. To confirm the diagnosis
of pheochromocytoma, other supporting examinations are needed.
This
patient was examined for plasma-free metanephrine and free normetanephrine,
which are metabolites of catecholamines, as well as urine VMA, where free
metanephrine levels were found to be 26 pg/ml (< 57 pg/ml) and free
normetanephrine 7411 pg/ml (< 148 pg/ml). So, there was an increase in free metanephrine
and normetanephrine levels 7437 (< 205 pg/ml). Results of urine VMA ≤
8 mg/24 hours (N = ≤ 8 mg/24 hours). Measurement of plasma metanephrines
is susceptible and is recommended for first-line examination, which has a
sensitivity of 96-100% and a specificity of 89%-98% (Lenders et
al., 2014) .
This patient then
underwent a CT scan of the abdomen and found a right adrenal tumor.
Pheochromocytoma should be evaluated with a CT scan or MRI anatomical imaging.
This imaging study is essential for localizing tumors and describing the extent
of the tumor as well as diagnosing several primary tumors and metastatic
lesions in patients with various genetic disorders. In the study of Mantero et
al., pheochromocytomas accounted for 11% of all adrenal incidentalomas. CT
scans can show tumor sizes > 1 cm with a sensitivity of 87% to 100% (Farrugia et al., 2017).
This patient was
referred to urological surgery for further treatment. The
primary treatment modality for pheochromocytoma is surgical resection.
Minimally invasive laparoscopic adrenalectomy is recommended in most cases of
pheochromocytoma. Open resection laparotomy is indicated for pheochromocytoma
with a large tumor size (> 9 cm) (Sănchez-Turcius
RA, 2015). The urology surgeon planned an open adrenalectomy because
adhesions had occurred, and the operation was carried out together with a
pediatric surgeon who knew the patient's previous surgical history.
Approximately
6.5-16.5% of pheochromocytoma patients experience relapse, and 10% experience
metastases. A retrospective study of 135 patients who had undergone
adrenalectomy and were followed for 14 years showed that tumors measuring >
5 cm were at high risk for recurrence. Another study with 192 patients showed
that age, family history, tumor location (right side, extra-adrenal), and tumor
size were also predictors of recurrence in pheochromocytoma patients. Genetic
mutations such as SDHB ( succinate dehydrogenase subunit B ) are also a
high risk of recurrence and malignancy in pheochromocytoma. For this reason,
long-term monitoring with biochemical examination and imaging modalities is
needed after the patient undergoes surgical resection (Venugopal et al.,
2020) (Amar et al., 2016).
Hypertensive heart
disease (HHD) is a collection of disorders that include left ventricular
hypertrophy (LVH) and systolic and diastolic dysfunction, with clinical
manifestations including arrhythmias and symptomatic heart failure. The classic
paradigm of hypertensive heart disease is that the left ventricular (LV) wall
thickens in response to increased blood pressure as a compensatory mechanism to
minimize heart wall stress. The presence of left ventricular hypertrophy (LVH)
is a compensation of the heart in the face of high blood pressure coupled with
neurohormonal factors, which are characterized by concentric thickening of the
heart muscle (concentric hypertrophy) (Yandriani & Karani, 2018). The diastolic function will be disrupted due to
impaired left ventricular relaxation, followed by left ventricular dilatation
(eccentric hypertrophy). Sympathetic stimulation and activation of the RAA
system triggers the Frank-Starling mechanism by increasing ventricular
diastolic volume to a particular stage and ultimately causing disruption of
myocardial contraction (decreased/impaired systolic function). Myocardial
ischemia (asymptomatic, angina pectoris, cardiac infarction, etc.) can occur
due to accelerated atherosclerotic processes with increased myocardial oxygen
demand resulting from LVH. The main factors of myocyte damage in hypertension
are LVH, myocardial ischemia, and impaired endothelial function (Raman, 2010).
Changes in heart
structure and function in HHD are caused by hypertension, which causes
concentric hypertrophy, followed by dilated heart failure. Patients with
hypertrophy have higher systolic blood pressure and peripheral resistance. In
addition, blood pressure after outpatient treatment correlates better with left
ventricular mass than blood pressure alone, and concentric hypertrophy,
compared with eccentric hypertrophy, has higher ambulatory blood pressure rates
(Raman, 2010); (Drazner, 2011).
This patient had
developed hypertension at the age of 13 years and had been diagnosed with
pheochromocytoma. The average age of pheochromocytoma in children is 11-13
years, with males being more likely to be 2:1. In hypertensive children, 1.7%
had catecholamine-secreting neoplasms. Ongoing hypertension is a common symptom
in 60-90% of children with pheochromocytoma. Other symptoms are headaches in up
to 67% and nausea, sweating, palpitations, and pallor in 47-57% of children (Farrugia et al., 2017).
The prognosis of
pheochromocytoma depends on resectability and genetic profile. If there are
metastases, the 5-year survival rate in pheochromocytoma patients is 34-60%.
Survival is <5 years if metastases occur in the liver or lungs and longer if
there are bone metastases. If complete excision is performed, local invasion
can provide long survival rates (Drazner, 2011).
CONCLUSION
Pheochromocytoma is a
rare form of endocrine tumor. However, it can significantly impact the
patient's health and quality of life. Although most pheochromocytomas can be
removed surgically, the tumor may return or relapse after removal. Relapse
rates vary depending on tumor size, location, and cell type. In relapse cases,
proper diagnosis and diagnosis must be made using various diagnostic methods
such as laboratory analysis, CT scan, or MRI imaging. This helps determine the
tumor's location, size, and characteristics, which may differ from previous
tumors.
Relapsed pheochromocytoma
may worsen the symptoms and prognosis of HHD. When pheochromocytoma recurs or
recurs, excessive release of the hormones epinephrine and norepinephrine can
significantly increase blood pressure and worsen damage to target organs,
including the heart. This may increase the risk of complications and worsen the
prognosis in patients with HHD. Patients with relapsed pheochromocytoma and HHD
require regular follow-up and monitoring to identify possible symptoms and
complications. Regular medical examinations, blood pressure monitoring, and
evaluation of the function of the heart and other target organs need to be
carried out to ensure reasonable control and prevent further complications.
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