Case Report
Malignant Pheochromocytoma Diagnosed by Fine Needle Aspiration: Report of a Case with Unusual Clinical Presentation and Review of the Literature
Nadine Shabti*, Andressa Balbi, Taylor Avakian, Phillip Pearson, and Mohamad Aziz
1Department of Pathology, American University of the Caribbean School of Medicine, USA
*Corresponding author: Nadine Shabti, Department of Pathology,
American University of the Caribbean School of Medicine, USA, Email:
nadineshabti@students.aucmed.edu
Submitted: 27 May, 2019; Accepted: 10 June, 2019; Published: 12 June, 2019
Cite this article: Kiang LE (2019) Malignant Pheochromocytoma Diagnosed by
Fine Needle Aspiration: Report of a Case with Unusual Clinical Presentation and Review of the Literature. JSMC Clin Case Rep 4: 4.
PCC: Pheochromocytoma; US-FNA: Ultrasound Fine Needle Aspiration
A distinct problem of diagnosing malignant pheochromocytoma
is the significant variation in clinical presentation that can arise
from distant metastasis and local infiltration in many systems
including the auditory canals. Classical guidelines state that 10%
of pheochromocytomas are malignant and 10% are extra-adrenal
as these tumors can present anywhere along the sympathetic
chain [1]. PCC is mostly sporadic, but may also be associated
with familial disorders such as Neurofibromatosis I, Von Hippel
Lindau disease, and multiple endocrine neoplasia type II [1].
Malignant pheochromocytoma is defined clinically by metastasis
of chromaffin tissue to at least one non-chromaffin site with the
most commonly involved areas including liver, lymph nodes and
bone. Malignant pheochromocytoma is an uncommon tumor.
There are few reports of its clinical course in the literature
and thus, increased awareness of this possible diagnosis by
pathologists and clinicians makes it important to include in the
initial differential diagnosis.
A 53-year-old African American man presented with one
month of diffuse abdominal pain associated with nausea, emesis
and anorexia. He also reported 15 pounds of recent unintentional
weight loss and fatigue. He denied any past medical history
beyond an episode of Bell’s palsy of the left side several years
prior to his current presentation, and a smoking history of 35
pack-years. Vital signs were stable upon admission and physical
examination revealed norm active bowel sounds, abdominal
tenderness to palpation with guarding. No masses were
appreciated due to pain on minimal palpation. Initial laboratory
studies included normal complete blood count, renal and liver
function tests, amylase, lipase, lactate, uric acid, and coagulation
panel. However lactic dehydrogenase (LDH) levels were found
to be elevated at 1222 U/L; although high LDH is a nonspecific
indicator of neoplasia it is also viewed as a useful clue in the
diagnosis of pheochromocytoma [2].
Evidence of malignancy and metastasis of suspected
pheochromocytoma was apparent via imaging studies. Computed
tomography imaging of the abdomen/pelvis revealed a centrally
necrotic cystic right adrenal mass (14 x 19 cm) with marked mural
modularity, and no significant calcification. In addition, multiple
necrotic mesenteric lymph nodes, a 4.3 cm retroperitoneal
necrotic mass inferior to the cecum, two cavitated masses in the
right upper lung lobes, and scattered nodules in the left upper
lobes were also noted.
Enhancing lytic lesions consistent with diffuse bony
metastases were identified involving the left scapula, transverse
process of C7, L3 spinous process, iliac bone, 9th and 6th ribs,
and T10-11 vertebral bodies. The impression was a right adrenal
mass, most likely a primary adrenal carcinoma with widespread
pulmonary and osseous metastases.
Ultrasound guided fine needle aspiration biopsy (US-FNA) of
the 9th rib was performed. As cytopathology results were pending
the patient developed precipitous sensor neural hearing loss. A slight left ear hearing difficulty he endorsed on presentation
worsened to complete bilateral hearing loss over the course
of one week. Magnetic resonance imaging (MRI) of the brain
showed leptomeningeal disease with bilateral metastases to
the internal auditory canals (Figure 1). US-FNA biopsy results
revealed malignant cytomorphologic features (Figure 2A & B).
Immunocytochemical studies performed on cellblock prepared
from the cytology specimen were positive for chromogranin
(Figure 2C) and Synaptophysin (Figure 2D). These findings were
diagnostic of metastatic pheochromocytoma, and consistent
with initial laboratory studies showing urine Metanephrines
541mcg/24h and Chromogranin A 261 ng/ml.
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Figure 1: T1 weight post-contrast administration image.
Enhancement within the ependymal surface of the lateral ventricles
most pronounced in the periatrial regions, fourth ventricle as well as
superior cerebellar sulci, and within the bilateral internal auditory canals. View Figure
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Figure 2: Pheochromocytoma cells arranged as loose clusters and single cells in a necrotic background. Papanicolaou, ×100(A). Pleomorphic large
binucleated malignant Pheochromocytoma cell with prominent macronucleoli and stippled chromatin. Papanicolaou stain, ×200(B). Tumor cells are
strongly positive for Synaptophysin (C). Tumor cells are strongly positive for Chromogranin (D). View Figure
Extirpative surgery was performed with removal of the
pelvic/abdominal mass as well as the lung nodules and surgery
was uneventful as planned. Due to extensive disease, the
patient also received high-dose combined chemotherapy using
cyclophosphamide, vincristine and dacarbazine (CVD) as well as
internal radiation. Patient was in a relatively stable condition and
was determined not to be too ill to benefit from such aggressive
therapy.
Our patient was alive with disease for two years after which
recurrence was identified in both lungs. Patient refused any
additional treatment and expired one year later due to massive
metastatic disease and multiple organ failure.
Pheochromocytoma is an uncommon cause of hypertension
in the general population, accounting for less than 1% of
cases in hypertensive individuals [3]. In addition, of all
pheochromocytomas, only 10% exhibit malignant behavior [4]. The most significant criteria that can definitively establish
malignancy in a pheochromocytoma is recurrence of the tumor
in sites devoid of chromaffin tissue [5]. Other considerations
such as large size, extra-adrenal location, dopamine secretion,
and a high ki-67 index are indicators for potential malignancy
[5]. In our patient, malignant pheochromocytoma primarily
produced a clinical syndrome of abdominal pain and nausea,
dissimilar to the classic triad of hypertension, palpitations, and
headache of PCC. The absence of these typical symptoms of PCC
in the chief complaint drives the diagnosis away from benign
and more towards malignancy [6]. A new mechanism to explain
normotensive hypertension associated with PCC suggests a
deficiency in dopamine-β-hydroxylase resulting in a decrease in
norepinephrine [7]. However, the progressive hearing loss has
not been described in the literature and may indicate malignant
character as well as involvement of the auditory canals, an
unusual site of distant metastasis.
Urinary Metanephrines have been determined to be the most
sensitive diagnostic aids in identifying pheochromocytoma with
accuracy rates of 95% and their significantly elevated levels in
our patient supported this diagnosis [8]. Due to the importance
of differentiating typical signs and symptoms of malignant versus
benign pheochromocytoma several parameters were investigated
including computed tomography. Computed tomography (CT)
has been found to represent a major step forward in the overall
management of PCC with 90% accuracy and was subsequently
performed on our patient who unveiled bilateral adrenal lesions
and necrotic areas of metastasis suggesting malignancy and
distant spread [8]. The pathological differentiation amid clinically
benign and malignant pheochromocytoma can be arduous to
make [9]. However, in a study of several sympatho-adrenal
paragangliomas only four factors were found to meaningfully
correlate with malignancy including (1) extra adrenal location,
(2) coarse nodularity of the primary tumor, (3) confluent tumor
necrosis, and (4) absence of hyaline globules [10]. In our patient,
malignancy was further supported by ultrasound guided fine
needle aspiration lymph node biopsy which revealed clusters of
pleomorphic, hyperchromatic pheochromocytoma cells amidst
a necrotic background positive for markers of neuroendocrine
tumor origin [4].
An important consideration in the list of differential
diagnoses for pheochromocytoma is paraganglioma, an entity
composed of chromaffin-cell tumors located at extra-adrenal
sites along the sympathetic and/or parasympathetic chain
[11,16]. Paragangliomas commonly occur from the head and neck
to the pelvis and thus depending on the site of tumors, acoustic
symptoms can develop [12,13]. Jugulotympanic paragangliomas
(JTP) is a paraganglioma that arises in the middle ear and mastoid.
This neoplasm is thought to originate from the minute paraganglia
at the middle ear and base of the skull. It usually develops in the
5th and 6th decade of life at either side with equal frequency. It
grows along the course of Jacobson’s nerve in the middle ear
cavity and can be associated with tinnitus, aural pulsations and
conduction type hearing loss as it encroaches on the middle ear
ossicles [14]. JTP can grow large enough to fill the middle ear
cavity and bulge through the tympanic membrane, Eustachian tube or aditus ad antrum, with associated bony erosions. Given
the similar syndrome of hearing loss that was seen in our patient,
this neoplasm is an important entity to consider in the differential
diagnosis of metastatic pheochromocytoma. One key difference
is that these tumors are known to be mostly locally aggressive.
In a study of JTP, regional and distant metastases were rare,
with estimates by Alford and Guilford showing that less than
2% were metastatic and 3% were clinically malignant [14]. In
our patient, the nature of the hearing loss was sensorineural.
Given the presence of the bulk of the tumor within the abdomen,
with multiple sites of distant metastasis and bilateral middle
ear involvement, the overall clinical presentation supported the
diagnosis of malignant pheochromocytoma.
Since there is no definitive curative treatment for malignant
pheochromocytoma and due to its poor prognosis, treatment
initiatives are a prevalent topic of research. In a study conducted
by Remine et al., reviewing 138 cases of pheochromocytoma
encountered at the Mayo Clinic spanning the period of fortyfour-
year, the five-year survival rate subsequent to treatment
for benign tumors was found to be 96% and for malignant
tumors, 44% [17]. Currently a preoperative treatment regimen
consisting of alpha and beta blockers followed by laparoscopic
surgery to remove the tumor remains the gold-standard [3,16].
In a literature review conducted by Hartgrink et. al., concerning
the rare local invasion of the right atrium by a case of malignant
pheochromocytoma, an aggressive surgical approach was always
warranted as it provided relief of symptoms as well as prolonged
survival [18].
To this day, there is much controversy over the parameters
delineating malignant pheochromocytoma, with the general
consensus identifying it based on metastasis to distant nonchromaffin
sites. Consequently our case report serves to provide
insight on a rare condition that strays from the classical textbook
case. In addition, it is important to consider the differential
diagnosis of a sympathetic/parasympathetic paraganglioma
when investigating the potential for a malignant PCC as a similar
clinical course can arise depending on the site of the tumor. While
the populations involved in this etiology are a small subset of
pheochromocytomas, no less attention should be given to this
critical potential diagnosis. Exact survival has not been clearly
reported, nor has an analysis of the efficacy of chemotherapy on
survival time. Kaoru Nomura et al., analyzed the survival curves
and survival times of patients with malignant pheochromocytoma
and determined the efficacy of chemotherapy on prolongation of
life. They reported an unexpected long survival time. They also
noted that cyclophosphamide, vincristine, and dacarbazine (CVD)
chemotherapy was not shown to extend survival, especially for
women and patients with adrenal gland-derived primary tumors.
They also reported that patients who already had metastases at
the time of Pheochromocytoma diagnosis had better survival
than those whose metastases were found later [19].
Our case shows that definitive diagnosis of malignant
pheochromocytoma can be based only on cytological specimens,
especially when there is sufficient material to prepare a cellblock
which can be utilized for immunohistochemistry studies as the
case in our patient, and even molecular studies as needed. We
also report this case with the unusual clinical presentation of seeding of the internal auditory canals and precipitous hearing
loss, which may indicate additional feature of possible malignant disease.
It is our hope that this report raises awareness of what
remain an unmet need in management of malignant metastatic
pheochromocytoma and that continued investigation drives
further development of efficacious and safe treatments for
improving patient outcomes.