Metastatic Paraganglioma: An Uncommon Manifestation of an Uncommon Disease

In this edition of Clinical Quandaries, Trombetta et al present a 64-year-old man who seeks care because of a new, asymptomatic right midneck mass. Because the mass is not warm or tender and the patient does not have an elevated temperature, an infectious etiology is unlikely. We are not told if he is a smoker or drinker and we assume he does not have any other signs or symptoms (such as recent-onset hoarseness) that would point us to a head and neck cancer as a primary source.

Nevertheless, after reading only the beginning of the report, a squamous cell carcinoma of the head and neck (perhaps an asymptomatic hypopharyngeal primary) is high on my differential diagnosis list. If we were told that the mass was not rock hard, I'd consider lymphoma a reasonably likely possibility too. Instead, we learn that a computed tomography scan demonstrated a "vascular tumor near the carotid body," and surgery produced a specimen that was interpreted as a gross totally resected glomus jugulare paraganglioma of the right carotid bifurcation.

Rare Benign Tumors

The recently published fifth edition of Perez and Brady's Principles and Practice of Radiation Oncology[1] describes paragangliomas (also known as nonchromaffin paragangliomas, chemodectomas, or glomus tumors) as rare benign tumors that are most commonly located near the base of the skull in the jugular fossa, which are diagnosed at a peak age of 45 years and have no gender preference. Organizationally, they are described in the chapter titled "Radiotherapy of Nonmalignant Diseases."

A standard reference text of pathology[2] describes the histology of paragangliomas as having a deceptively bland, well differentiated morphology, resembling the normal paraganglia. The cells are arranged in nests or lobules that are surrounded by an inconspicuous layer of single cells. The nests of cells have uniform, round-to-oval nuclei with fine chromatin and without visible nucleoli. Nuclear pleomorphism, if present, is usually mild. In short, the appearance suggests benign behavior.

Do Resected Benign Tumors Recur?

Thus far in the patient's history the treating physicians are dealing with a rare tumor, but have good reason to believe that the lesion has been adequately treated and should not recur. However, 1 year later, the patient has right vocal cord paralysis and pharyngeal incompetence, and a magnetic resonance imaging (MRI) scan reveals a carotid body lesion. We are not told the characteristics of the lesion and we don't know if surgery was then done (1) to establish the diagnosis, (2) to try to extirpate the lesion, or (3) both. We do know that only a subtotal resection could be done and that specimen was interpreted as a recurrent paraganglioma. If surgery was done only to establish the diagnosis, it was successful, but if other objectives were desired, surgery failed.

The patient then received radiation therapy-54.0 Gy at 1.8 Gy per fraction-and appeared to be doing well for just under 2 years. He then developed pain in his lower thoracic spine. An MRI scan at this time demonstrated a metastatic-appearing lesion in the 11th thoracic vertebral body without evidence of spinal cord compression.

The Quandary Defined

The treating physicians now have a clinical quandary: Are they dealing with a common manifestation of a disease process that their patient is not known to have or a rare manifestation of a disease process that their patient is known to have? Paragangliomas are rare in any variety, and metastases from paragangliomas are extremely rare. Other lesions in bone (neoplastic and non-neoplastic) are much more common. Common tumors, such as those arising in the lung, breast, and prostate, frequently spread to bony sites and far more bone metastases occur from such tumors than from paragangliomas.

However, lung cancers are less common in nonsmokers, breast cancer is only 1/100th as common in men as in women, and metastases from prostate cancer usually are blastic, not lytic. That said, I'd look at these potential primary sites (as well as some less common ones such as the kidney and skin [ie, melanoma]) to see if I could explain the vertebral lesion in the context of another disease. If that attempt did not uncover a primary source, I'd remember Ockham's razor ("entities should not be multiplied beyond necessity"-ie, all things being equal, the simplest solution is the best) and contemplate the possibility that the vertebral lesion is related to the known paragangliomas.

The treating physicians appear to have been unable to resolve this quandary to their satisfaction without tissue. The authors do not tell us if a CT-directed needle biopsy was considered for tissue diagnosis, and it may be fair to assume that they were concerned about the possibility of bleeding from the lesion if it proved to be a hypervascular paraganglioma. We do know that the patient underwent posterior thoracic laminectomy with T11 corpectomy, and the specimen was interpreted as an incompletely excised metastatic paraganglioma. Again we can ask: Was surgery done (1) to establish the diagnosis and/or stabilize the spine, (2) to try to extirpate the lesion, or (3) both? Again, if surgery was done to establish the diagnosis and/or stabilize the spine it was successful, but if other objectives were intended, surgery failed.

Another Quandary

The patient again received radiation therapy, but this time clearly as "salvage" therapy with a more accelerated palliative-intent approach consisting of 39 Gy in 13 fractions. The decreased total dose and increased dose-per-fraction suggest that the treating physicians believed that more metastases were likely to appear in a reasonably short time.

However, the tumor failed to behave as expected, and the patient appeared to be free of progressive disease for approximately 8 years. At that point, he began to experience progressive headaches and an MRI demonstrated a hypervascular mass involving the right cavernous sinus, adjacent pituitary fossa, and medial right petrous bone. The physicians again faced a clinical quandary: What is the nature of this lesion? If it is a metastatic paraganglioma, why did it take 8 years to become evident when the first metastasis took only 3 years and metastases tend to become evident with progressively shorter intervals over time? If it is not related-for example, if it is a pituitary adenoma or meningioma-what is the appropriate therapy when the lesion is not amenable to surgical resection and even tissue diagnosis is believed to carry a high risk of potentially fatal hemorrhage?

What we do know is that contrast-enhanced MRIs done the year before showed no evidence of disease despite new-onset superior visual field cuts, suggesting a relatively rapidly growing process (ie, making the diagnosis of meningioma less likely). Interestingly, the authors never overtly state that they are treating yet another metastatic paraganglioma, but my interpretation of their language is that they would like us, the readers, to believe they think they are, particularly when the patient develops new midback pain and an MRI reveals a hypervascular lesion in the T6 vertebral body that most likely is yet another paraganglioma.

I cannot help but wonder if they are not concerned that the cerebral lesion really may be something else; if not, why did they prescribe a more protracted higher dose of radiation for this lesion than proved successful at controlling the T11 lesion for 8 years? Similarly, if the cerebral lesion is of the same histology as the T6 lesion, why treat the T6 lesion with a more accelerated lower total dose? Without tissue diagnosis, I think the physicians are hedging their bets (perhaps subconsciously) and treating with doses that would cover a broader spectrum than they lead us to believe.

Conclusions

So what do I conclude from this unusual case? First, rare tumors (eg, metastasizing paragangliomas) rarely do arise, and the unfortunate affected patient has it 100%. Second, in this era of reliance on evidence-based medicine, evidence does not exist to cover all situations. Third, when in doubt, cover as many bets as possible. And fourth, while the uncommon manifestation of a common disease is usually the right answer to a clinical quandary, a common manifestation of an uncommon disease always should be considered as well-and it never hurts to keep in mind that uncommon manifestations of uncommon diseases also occur.

-Jay S. Cooper, MD

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References
1. Seegenschmiedt MH: Radiotherapy of nonmalignant diseases, in Perez CA, Brady LW (eds): Principles and Practice of Radiation Oncology, 5th ed, p 1940. Philadelphia, Lippincott Williams & Wilkins, 2008.
2. Kleihues P, Cavenee WK (eds): WHO Classification of Tumors: Pathology and Genetics of Tumours of the Nervous System, p 113. Lyon, France, IARC Press, 2000.