Perineural Spread of Tumour- Beware That Trigeminal Neuralgia

Perineural spread of tumours is a phenomenon that is often subtle, unobtrusive until very late and below the radar for most physicians, including oncologists. Perineurium is the second of the three nerve covers, and under the perineurium lies a potential space, where tumors can spread freely, unimpeded by immune calls, often spreading centripetally towards the brainstem, and less commonly towards the periphery. One should perhaps start by explaining the difference between perineural spread (PNS) and perineural invasion (PNI).

PNI is of two types- one that is only picked up on miscroscopic examination of the resected tumour specimen, and one that is obvious clinically or radiologicaly (usually on MRI). The former is called microscopic PNI, while the latter is called clinical PNI, named nerve PNI, or PNS.

Therefore PNS can be a clinically manifest phenomenon, presenting with numbness or paralysis, or silent, but radiologically obvious on MRI. PNS, by definition, affects large nerves.

Where does PNS crop up most often? In the head and neck, typically in territories supplies by the cranial nerves V & VII, which tend to be the most commonly affected by PNS.

Cutaneous squamous cell cancer (SCC) is the most common malignancy that leads to PNS. The second most common, in terms of ratio, is adenoid cystic carcinoma of the salivary gland. Other predisposing tumours, albeit less common, include basal cell carcimoma, salivary ductal carcinoma, ex-pleomorphic adenoma, and rarely melanoma. Mucosal (head and neck) SCC is a distinctly uncommon source of PNS.

In most cases, the tumour, usually a SCC, has been removed in the remote past, ranging from a few months to few years ago. There are no signs of metastases anywhere else in a third of cases, just in the perineural space.

One must suspect PNS when a subject with a remote history of treated SCC presents with numbness, or paresthesiae in one or more divisions of the trigeminal nerve. The most commonly affected is the maxillary branch. Symptoms are often attributed to trigeminal neuralgia. Men are affected 5 times more commonly as women. Similarly, the facial nerve may be involved, often partially. Upon exiting the stylomastoid foramen, the VII nerve splits into two divisions which then give rise to 5 branches. Usually one or more such branches are involved, for example giving rise to weakness of muscles of mastication. When the entire VII nerve is involved, an erroneous diagnosis of Bells palsy is often made. However, it is worth remembering that Bells palsy occurs acutely while VII nerve involvement in PNS occurs gradually over months.

The median interval between removal of the primary tumour and manifestation of PNS is 16 months, but can be years. Six out of 7 patients have a previous history of cancer, while around 7.5% have no previous history. In a third of cases there is no evidence of PNI in the excised original tumour. The original tumour may have been unclassifiable, treated early with radiotherapy or cryotherapy or not biopsied at all, and thus a definite history of a preceding primary may be difficult to establish, with the only evidence of the same being sun damaged skin.

MRI with neural imaging is better at diagnosis than CT, and should be used when available. Normal nerves appear isointense to the surrounding tissue on T1- and T2-weighted MRIs, but upon injury the nerves become hyperintense and thus visible on T2-weighted MRI. Survival at 5 years is 50-64%. Most patients are treated with a combination of surgery and radiotherapy.

Read the following article for a more comprehensive review.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846401/

Phaeochromocytoma/Paragangliomas Arise Against a Background of Chonic Hypoxia

Phaeochromocytomas/paragangliomas (Pheo/PGL) are tumours of the neuroendocrine system. Roughly a third of these tumours are inherited, driven by genes such as VHL, EPAS-1, EGLN-1, SDH A, SDH B, SDH C, SDH D, SDH AF, RET, and a couple of others. Several of these genes, epitomised by Hypoxia Inducing Factor (HIF), are activated in response to hypoxia. HIF-beta is constitutive, while HIF-alpha is inducible. Several of the SDH genes are also "turned on" by hypoxia. When these genes are constitutively activated in the absence of hypoxia, say due to a mutation, they are said to mimic "pseudohypoxia".

In the 1960s, it became apparent that pheo/PGL was more common in subjects with chronic hypoxia, specifically in two subgroups- in subjects with congenital cyanotic heart disease (CCHD) and in subjects living at high altitudes. Subjects with CCHD in particular, have a much higher incidence of pheo/PGL than the general population. The incidence of pheo/PGL in subjects with non-cyanotic congenital heart disease such as VSD, PDA, ASD and bicuspid aortic valve is no different than the general population.

Similarly subjects living at high altitudes have a higher risk of paragangliomas.

In the latest issue of New England Journal of Medicine, Vaidya and colleagues found that activating somatic mutations in EPAS-1, which codes for HIF-2 alpha, were present in 4 out of 5 subjects with CCHD presenting with pheo/PGL. To put this in perspective, the incidence of EPAS-1 activating mutations in subjects with pheo/PGL who do not have CCHD is only 5-6%.

In developed countries, most subjects with CCHD would have had surgical corrections such as Fontan's procedure in childhood. While the duration of uncorrected CCHD correlates positively with the risk of pheo/PGL, corrective procedures do not ameliorate risk. These tumors can arise many decades later.

Most of these subjects have striking polycythaemia. The latter is of course seen in tumours other than pheo/PGL. For example germ line mutations in VHL lead to the Von Hippel Lindau syndrome, with a higher risk of haemangioblastomas and renal cancer. Somatic mutation in VHL leads to a higher risk of renal cell cancer, and can again be associated with polycythaemia.

It is tempting to hypothesise that the hypoxia inducible genes, when chronically activated by hypoxia itself, through the agency of EPAS-1, as in CCHD, or constitutively (and inappropriately) activated by germline and somatic mutations in genes such as VHL, lead to increased risk of tumours- pheo/PGL in the case of CCHD, pheo/PGL & renal cell cancer with germline VHL mutations, and renal cell cancer in somatic VHL mutations.

It is worth clarifying here that VHL is an inbuilt inhibitor of HIF-alpha. When VHL is mutated (with inactivation), HIF-alpha becomes disinhibited and is free to act as a growth promoting gene (new blood vessels, pheo/PGL, renal cell cancer).

There is no suggestion that acquired causes of hypoxia in adulthood such as heavy smoking or chronic lung disease lead to a higher risk of pheo/PGL. It appears that the drive from hypoxia must start very early in life, such as with CCHD, in order to lead to activating mutations such as in EPAS-1, that would in turn increase the risk of pheo/PGLs.

Since many of the symptoms of CCHD mimic pheo/PGL (tachycardia, palpitation, headache, fatigue), physicians dealing with such patients should have a high index of suspicion for pheo/PGL.

Interestingly the profile of secreted catecholamines in pheo/PGL arising in CCHD is very similar to those where pheo/PGLs arise as part of an inherited syndrome due to "pseudohypoxia" mimicking mutations (VHL, SDH-x). Such subjects have high levels of noradrenaline and normetanephrines and almost normal levels of adrenaline and metanephrines.