Keywords
paraganglioma - radiation - vagus nerve - malignant peripheral nerve sheath tumor
- radiation-induced sarcoma - glomus vagale
Case Report
A 28-year-old woman with a known history of multiple paraganglioma syndrome presented
with enlarging mass in the right neck, dysphonia, cough, dysphagia, and severe neck
pain. Weight loss was attributed to poor oral intake secondary to dysphagia and nausea.
Four years previously, the patient was diagnosed with bilateral carotid body tumors.
She completed a course of 6 weeks of external beam radiation therapy (EBRT) at that
time for the right-sided tumor which was felt to be inoperable due to rostral extension
to the skull base. The prescription dose was 5,400 cGy delivered in 180 cGy fractions.
She subsequently had a left-sided carotid body tumor removed approximately 1 year
later with no adverse sequelae. Both procedures were performed at an outside hospital.
After radiation treatment, the patient had a partial imaging response and reported
improvement in local symptoms until 4 years later, when she noticed progressive dysphonia,
dysphagia, and pain. The patient was not evaluated for succinate dehydrogenase (SDH)
mutation or other germline genetic analysis.
On physical examination, a firm mass was palpable in the upper neck. The patient had
deviation of the soft palate/uvula to the left consistent with right-sided glossopharyngeal
nerve deficit. On direct laryngoscopy, she was found to have an immobile right vocal
cord consistent with vagus nerve palsy. The remainder of the patient's neurologic
examination was unremarkable. In addition, the patient did not have café-au-lait macules,
freckling of the axilla or groin, cutaneous or subcutaneous tumors, or other clinical
stigmata of neurofibromatosis.
Magnetic resonance imaging (MRI) of the neck demonstrated a homogeneously enhancing
mass in the posterior parapharyngeal space of the neck on the right side with anterior
displacement of the carotid artery and internal jugular vein, extending from the carotid
bifurcation inferiorly to the jugular foramen rostrally ([Fig. 1]). Based on this imaging and the patient's clinical history of multiple paraganglioma
syndrome, the presumptive diagnosis was that of a glomus vagale, carotid body tumor,
or possibly a “collision tumor” of both. Given that the patient was symptomatic with
enlarging neck mass, new neurologic deficits (i.e., glossopharyngeal and vagus neuropathies),
and prior failed radiation treatment, surgery was recommended.
Fig. 1 Preoperative T2-weighted axial (a) and coronal (b) magnetic resonance imaging of the brain and neck showing a large mass in the carotid
sheath with “popcorn”-type appearance of flow voids suggestive of paraganglioma; T1-weighted
axial and coronal images following administration of gadolinium demonstrate avid contrast
enhancement and splaying of the internal and external carotid arteries (c and d, respectively).
Surgery Details
Preoperative angiography with embolization was performed 1 week prior to surgery.
The angiogram demonstrated a vascular blush typical of paraganglioma, but limited
to only part of the tumor mass that enhanced on MRI ([Fig. 2]). This was attributed to a partial response to radiation. A balloon test occlusion
was performed, which the patient tolerated without evidence of ischemia. A gastrostomy
tube was placed prior to surgery to assist with nutrition both before surgery and
in anticipation of persistent postoperative dysphagia. The patient underwent a transjugular
approach to the infratemporal fossa and cervical carotid artery, including blind sac
closure of the external auditory canal, anterior transposition of the facial nerve,
ligation of the internal jugular vein and sigmoid sinus, exenteration of the jugular
foramen contents, and carotid artery sacrifice. A gross total resection of tumor was
felt to have been obtained; however, surgical margins were not evaluated at the time
of surgery. Four regional lymph nodes were excised for pathological evaluation of
possible metastases.
Fig. 2 Preoperative anteroposterior (a) and lateral (b) angiograms show two distinct patterns of vascularity: a prominent blush typical
of paraganglioma and an avascular component with pronounced mass effect on the distal
carotid artery.
Pathology
Pathology revealed two separate and distinct histologic components, including one
comprised weakly eosinophilic large cuboidal and polygonal cells arranged in clusters,
or “zellballen” with supporting sustentacular cells, and an infiltrating spindle cell
lesion composed of large ovoid spindle-shaped cells with prominent nucleoli and amphophilic
cytoplasm ([Fig. 3]). No necrosis was seen. Additional immunohistochemistry was performed that demonstrated
S100 positivity in the high-grade, spindle-cell component of the tumor and chromogranin
A, and synaptophysin staining in the sustentacular cells of the paraganglioma component.
Ki-67 staining was present in 2% of the paraganglioma and 70% of the spindle cell lesion.
The overall pathology impression was that of two separate contiguous tumors: a paraganglioma
and also a spindle cell neoplasm consistent with high-grade malignant peripheral nerve
sheath tumor (MPNST). There was no evidence of underlying plexiform neurofibroma on
histopathology. Regional lymph nodes were negative for tumor.
Fig. 3 Hematoxylin and eosin staining shows two distinct tumors: paraganglioma (a) characterized by “zellballen” and a spindle cell neoplasm (b). This latter tumor had a high mitotic rate and demonstrated a high Ki-67 staining rate (70%) (not shown).
Postoperative Course
Postoperatively, the patient developed new facial nerve weakness (House–Brackmann
grade 6/6, which improved to grade 4/6 at last follow-up) but was otherwise neurologically
intact. Her pain was improved, but she complained of persistent nausea and vomiting.
She was discharged home and referred to speech and language pathology. Given the diagnosis
of MPNST, staging computed tomography (CT) was obtained and multiple pulmonary nodules
were identified. A CT-guided biopsy confirmed metastatic MPNST to the lung. The patient
was referred to oncology and completed an initial regimen of vincristine, doxorubicin,
and cyclophosphamide. Additional metastatic lesions were subsequently identified in
the left ilium and at L2. A second round of chemotherapy with doxorubicin and ifosfamide
was completed with partial response of systemic metastatic disease but with progression
of locally recurrent disease in the jugular foramen and cerebellopontine angle. The
patient had multiple chemotherapy-related complications, including neutropenia with
opportunistic fungal infection and fungemia, and thrombocytopenia. Given the rapid
local progression of disease and poor performance status, the patient was transitioned
to palliative care. She expired 2 months thereafter (6 months after surgery).
Discussion
Radiation therapy is an established treatment option for patients with skull base
paragangliomas.[1]
[2] Tumor control (defined as cessation of tumor growth, including both stable and shrinking
tumors) is achieved in 88 to 100% of patients following radiation therapy, with fewer
cranial nerve complications compared with surgery.[3]
[4]
[5] Radiation treatment options for patients undergoing radiation therapy include both
conventional EBRT and stereotactic radiosurgery (SRS), sometimes called stereotactic
body radiation therapy (SBRT). EBRT for paraganglioma has decades of proven efficacy
at achieving tumor control.[6]
[7]
[8]
[9] Although most complications associated with conventional radiation therapy are not
life threatening, induction of malignancy following EBRT for paraganglioma may also
occur.[1]
[2]
[10]
[11]
Radiation-Induced Malignant Peripheral Nerve Sheath Tumor
The association between radiation therapy and subsequent development of sarcoma has
been appreciated since Cahan et al's original report in 1948 of 11 sarcomas of bone
following irradiation.[12] Approximately 6% of all head and neck sarcomas occur in patients with a history
of prior irradiation,[13] with leiomyosarcoma and other subtypes of sarcoma more commonly seen with a history
of prior irradiation.[14] Conversely, although MPNSTs are rare, roughly 10% of all MPNST occur in patients
with a history of prior irradiation and are associated with high local recurrence
and poorer overall prognosis.[15]
Our case satisfies Cahan et al's criteria for radiation-induced sarcoma: (1) the malignancy
arose from the irradiated field; (2) the malignancy was of a different histology than
the neoplasm treated with irradiation; (3) sufficient delay exists between the radiation
exposure and development of secondary malignancy; and (4) the secondary malignancy
arose from normal in-field tissue. Latency in our case between radiation exposure
and sarcoma development is just over 4 years, consistent with Cahan et al's original
criteria but less than the median reported by others.[13]
[14]
[16]
[17]
[18]
[19] This may be attributable to the patient's relative young age and the possible presence
of a genetic tumor predisposition syndrome. The final Cahan et al's criteria, that
the induced neoplasm arises from tissue “normal” prior to treatment, are in this case
speculative. Importantly, we do not have the patient's initial presenting imaging
(i.e., prior to radiation therapy), and hence cannot unequivocally rule out the presence
of a coexisting neurofibroma of the vagus nerve. At surgery, the tumor specimen consisted
of both paraganglioma and MPNST both involving the vagus nerve. It is possible that
the patient previously had both a carotid body tumor and glomus vagale on that side,
although this may not have been appreciated at the time of initial treatment. In any
event, the vagus nerve would be in contact with the paraganglioma from the skull base
to carotid bifurcation. Although biopsy was not obtained prior to radiation treatment
on the patient's right side, she had a history of prior surgery for carotid body tumor
on the contralateral side, confirming the diagnosis of multiple paraganglioma syndrome.
Furthermore, at the time of radiation treatment, the patient displayed no signs or
symptoms of MPNST, only later developing (e.g., severe pain). Nevertheless, without
preoperative imaging and genetic analysis (see later), it remains theoretically possible
that the patient had either coexisting neurofibromatosis type 1 (NF1) and multiple
paraganglioma syndrome or had a pathological mutation contributing to a mixed phenotype.
If so, the induction of a secondary malignancy may not fully fulfill Cahan et al's
criteria for malignant transformation of “normal” in field tissue.
Role of Radiation Therapy Technique in Induction of Malignancy
A dose–response relationship between radiation exposure and induction of malignancy
has been well established in both experimental models and clinically, such as in survivors
of atomic bomb exposure.[17]
[20] Whether there is a threshold of exposure for cancer induction, and the shape of
the dose–response curve for higher radiation exposures, however, is not well established.
It has been postulated that for hematological malignancies, reduced cell survival
seen with higher doses of therapeutic radiation leads to a decrease in malignancy
induction with high doses, that is, that the dose–response relationship is “bell shaped.”[17]
[19] In contrast, sarcoma induction is more commonly seen after high radiation doses,
with evidence of an increased risk of secondary malignancy with doses up to 60 Gy.[13]
[16]
[21] This dose dependence may be clinically relevant when comparing SRS with EBRT: In
a large study of sarcoma risk following breast irradiation, Rubino et al found the
risk of sarcoma 30.6 times higher for doses more than 44 Gy compared with 15 Gy.[22] SRS allows for highly conformal treatment plans resulting in minimal dose to surrounding
tissues and achieves rates of tumor control comparable to conventional (Guss et al,
2011).[3]
[23]
[24]
[25]
[26]
[27] Importantly, the mean prescription dose for patients treated with SRS (median marginal
doses between 1,400 and 1,730 cGy)[14] is significantly less than with traditional EBRT regimens such as were employed
with our patient (5,400 cGy in 180 cGy fractions). As SRS achieves tumor control comparable
to that obtained with EBRT with a significantly lower prescription dose, SRS might
have a lower risk of induction of malignancy when treating head and neck paragangliomas.
However, given the rarity of head and neck paraganglioma and the infrequency with
which SRS has historically been used for these tumors, there is insufficient data
in the literature to make any firm conclusions regarding the relative safety of SRS
versus EBRT.
Role of Mutational Analysis of Paraganglioma Syndrome
Our patient did not have genetic testing performed prior to treatment. Multiple genes/genetic
pathways have been shown to contribute to head and neck paraganglioma formation, including
SDH, Von Hippel–Lindau, and RAS signaling pathway genes such as NF1.[28] Some SDH mutations (i.e., SDHB) are associated with a significantly increased risk
of malignant paraganglioma,[29] whereas NF1 mutations may predispose to MPNST, as seen in our patient. Whether a
patient's specific genetic landscape poses a predictable risk factor with regard to
the underlying radiation dose–response relationship of new tumor induction is however
unknown. Specifically, whether patients' susceptibility to either malignant transformation
or sarcoma induction is impacted by a given specific causative mutation (e.g., SDHB,
NF1, etc.) is not established. Nevertheless, we believe that characterization of the
causative genetic mutation(s) could have helped inform the patient's initial decision
to proceed with radiation treatment (e.g., if an underlying NF1 mutation had been
identified).
Summary
Clinical suspicion for malignancy in head and neck paragangliomas previously treated
with radiation is warranted. Pain is an unusual symptom with paraganglioma, and as
is the case with peripheral nerve tumors should raise suspicion of malignant transformation.
Radiation strategies aimed at lowering overall dose such as SRS/SBRT may be preferable
to conventional EBRT for patients undergoing radiation of head and neck paraganglioma.
Genetic analysis should be obtained prior to initiation of treatment in the management
of head and neck paraganglioma.
