A.Griguolo neurofibroma

Generality

The neurofibroma is a benign tumor of the nerves of the peripheral nervous system, visible from the outside as responsible for a protuberance or in any case an alteration of the physical aspect.

Existing in two different types (dermal and plexiform), the neurofibroma appears following a particular mutation of the NF1 gene; this mutation can occur without apparent reason or due to a condition known as neurofibromatosis type 1.

Neurofibroma with unknown causes is usually a single presence, while neurofibroma related to type 1 neurofibromatosis is usually a multiple presence (ie the patient develops more neurofibromas).

The neurofibroma is a tumor that has undergone treatment, when the symptoms associated with it are severe or when there is a real risk of complications.

What is Neurofibroma?

Neurofibroma is a benign tumor that affects the nerves and tissues of the peripheral nervous system . In other words, the neurofibroma is a mass of benign tumor cells, which originates from one of the cells constituting the nerves or tissues of the peripheral nervous system.

General characteristics

The neurofibroma is an abnormal formation, which includes, in addition to the cellular nerve component from which it also originates: inflammatory cells ( mast cells ), blood cells and connective tissue cells .

As a single or multiple lesion, the neurofibroma is widely visible on the outside of the human body, because, on its carrier, it determines a cutaneous or subcutaneous protuberance, of variable size and, in some cases, disfiguring.

The neurofibroma according to the WHO

According to the WHO system (World Health Organization) for the classification of tumors of the nervous system, the neurofibroma is a grade I tumor, that is a well differentiated tumor, slow growing, non-malignant and associated with long survival (by the patient).

Types

Doctors and pathologists recognize the existence of two types of neurofibroma: dermal neurofibroma (or cutaneous neurofibroma ) and plexiform neurofibroma .

Reserving the details in the next sections of this chapter, all the neurofibromas associated to a single superficial peripheral nerve belong to the dermal typology, while all the neurofibromas associated to a complex of superficial peripheral nerves and all the neurofibromas associated to a complex of belong to the plexiform type. deep peripheral nerves .

Dermal neurofibroma

There are two subtypes of dermal neurofibroma: the discrete cutaneous subtype (or discrete cutaneous neurofibroma) and the discrete subcutaneous subtype (or discrete subcutaneous neurofibroma).

• Characteristics of the discrete cutaneous neurofibroma: it is a cutaneous protuberance (it resides on the surface of the skin); it can be pedunculated or not pedunculated; it is meaty; it does not have a tender consistency; it is variable in size.
• Characteristics of discrete subcutaneous neurofibroma: on the skin, it appears as a subcutaneous protuberance (it resides in the first layers of the skin); it can have a tender texture to the touch.

Plexiform neurofibroma

Plexiform neurofibroma is a large tumor mass; this is why it involves more superficial or deep peripheral nerves.

When it grows close to a complex of deep peripheral nerves, the plexiform neurofibroma resides below the dermis and can become the protagonist of a compression process not only of the affected nervous structures, but also of the organs adjacent to these nervous structures.

As in the previous case, there are two subtypes of plexiform neurofibroma: the diffuse subtype (or diffuse plexiform neurofibroma) and the nodular subtype (or nodular plexiform neurofibroma).

• Characteristics of the diffuse plexiform neurofibroma: it appears as a subcutaneous swelling of soft consistency; the margins are poorly defined.
• Characteristics of nodular plexiform neurofibroma: it is located below the dermis, but despite this it determines a protuberance visible from the outside; it can be ovoid or spherical in shape; the consistency is hard; it is well circumscribed.

Plexiform neurofibromas are never an evolution of dermal neurofibromas, but they are formations that are born as such.

Causes

The neurofibroma is the result of a specific mutation of the NF1 gene, a gene that is located on chromosome 17 .

The aforementioned mutation can be idiopathic - that is, that "occurs spontaneously, without apparent and recognizable causes" - or it can be part of a medical condition called type 1 neurofibromatosis .

Idiopathic neurofibroma

Idiopathic neurofibroma is usually a single lesion, the result of a spontaneous mutation acquired during life, which affects, for completely unknown reasons, a certain cellular element of the peripheral nervous system.

Neurofibroma as a result of neurofibromatosis type 1

Neurofibromatosis type 1 is a genetic, hereditary or acquired during embryonic development, which in its carriers induces the formation, a little on the whole body, of numerous neurofibromas. In other words, therefore, when it is related to neurofibromatosis type 1, the neurofibroma appears as a multiple lesion.

Type 1 neurofibromatosis is an example of an autosomal dominant disease .

Other signs and symptoms of neurofibromatosis type 1

Type 1 neurofibromatosis is responsible for a rich symptomatology; in fact, in addition to neurofibroma, it causes coffee-colored skin spots, benign skin tumors, benign iris tumors, benign brain tumors, physical-skeletal abnormalities, vision problems and hypertension.

What are the functions of non-mutated NF1? What happens when it has changed?

Premise: the genes present on human chromosomes are DNA sequences that have the task of producing fundamental proteins in biologic processes indispensable to life, including cell growth and replication.

When it is healthy (that is, free of mutations), the NF1 gene produces a protein called neurofibromine, which is responsible for regulating the growth process of nerve cells.

When instead it carries the mutation responsible for neurofibromas, NF1 loses the ability to generate the neurofibromy and this leads to the development and completely anomalous growth of nerve cells.

Did you know that ...

The NF1 gene is one of the genes of the human genome most subject to mutations; these, however, are often devoid of consequences, because the gene in question is very large and includes numerous portions of DNA that do not have a particular relevance in the final formation of the neurofibromine protein.

Which cells of the peripheral nervous system affects?

Within the peripheral nervous system, the neurofibroma affects the non-myelinated Schwann cells, which is the myelin-free version of the most well-known myelinated Schwann cells .

For neurofibromas, non-myelinated Schwann cells are highly specific targets; in fact, although they belong to the same cell type as myelinated Schwann cells, only they are affected by the NF1 mutation responsible for the neurofibroma formation process.

The reason why the neurofibroma, with the same NF1 mutation, originates only from non-myelinated Schwann cells is completely unknown and represents one of the most studied topics by geneticists and molecular biology experts.

Epidemiology

According to statistics, neurofibromas are, in 90% of cases, idiopathic, and, only in the remaining 10% of the circumstances, due to the presence of type 1 neurofibromatosis; nevertheless, they owe most of their fame to the latter.

EPIDEMIOLOGY OF TYPE 1 NEUROPHIBROMATOSIS

Statistics show that he is a carrier of type 1 neurofibromatosis, a new born every 3, 000 ; the same testify, moreover, that the genetic disease in question is hereditary, in 50% of the cases, and acquired during the embryonic development, in the remaining 50% of the cases (therefore, there is equivalence between the number of hereditary cases and the number of non-hereditary cases).

Symptoms and Complications

When it is dermal, the neurofibroma is responsible, where it has formation, for pain, burning and itching . When instead it is plexiform, the neurofibroma causes, on the overlying skin, signs of hypertrophy, hyperpigmentation and hypertrichosis ; moreover, if it grows strictly close to deep peripheral nerves, it can cause neurological compression problems .

Dermal neurofibroma and type 1 neurofibromatosis

In people with type 1 neurofibromatosis, dermal neurofibroma generally appears in the form of multiple lesions, beginning in adolescence (the arrival of puberty is often a critical moment, because it establishes the onset of the first neurofibromas); with the passing of the years, therefore, the number and size of these lesions increases progressively (NB there is a limit to the size, in the sense that beyond a certain size they do not grow further), reaching to cover most of the patient's body.

Plexiform neurofibroma and type 1 neurofibromatosis

In subjects with type 1 neurofibromatosis, the plexiform neurofibroma makes its appearance, also in the form of multiple lesions, at a very young age (therefore before dermal neurofibromas); in the circumstances in question, the most affected anatomical sites are the eyeball, the face, the arms, the legs and the trunk.

Complications of dermal neurofibroma

Dermal neurofibroma causes complications when presented as multiple lesions in a context of type 1 neurofibromatosis; in these circumstances, in fact, it can disfigure the patient's appearance in a very profound way.

CAN IT EVOLVE IN A MALICNO CANCER?

To date, no member of the medical-scientific community has ever recorded cases of dermal neurofibroma evolving into malignant tumors. This suggests that it is impossible for a malign neoplasm to derive from the dermal neurofibroma.

Complications of plexiform neurofibroma

Plexiform neurofibroma is definitely more dangerous than dermal neurofibroma; in fact, from its presence different complications may depend, some even very serious.

Possible complications in question include:

• The possibility of disfiguring the patient's appearance, even when the presentation mode is single;
• The possibility of causing, due to the compression of the affected nerves, severe neurological deficits;
• The possibility of evolving into a malignant tumor.

MALIGUOUS EVOLUTION OF A PLESSIFORM NEUROFIBROMA: THE DETAILS

Plexiform neurofibroma can develop into a malignant tumor known as malignant tumor of peripheral nerve sheaths ( MPNST ).

According to statistical studies, the process of malignant evolution of which the plexiform neurofibroma can become the protagonist would affect about 9-10% of clinical cases.

Diagnosis

The course of investigations that leads to the diagnosis of a neurofibroma always starts from the physical examination and from the anamnesis ; therefore, based on what emerges from the checks just mentioned, it can continue with:

• A CT scan or nuclear magnetic resonance of the anatomic site where the tumor (s) resides, to study the location and extent of tumors;
• A tumor biopsy, for the diagnostic confirmation of neurofibroma;
• A genetic test to determine if the patient suffers from type 1 neurofibromatosis.

Therapy

The treatment of the neurofibroma varies in relation to several factors, which are:

• The type of neurofibroma;
• The presentation in single or multiple mode;
• Size and symptomatology;
• The triggering cause.

Treatment of dermal neurofibroma

Whether single or multiple, dermal neurofibroma generally does not require any treatment, as in both circumstances it is not dangerous for the patient's health.

The only dermal neurofibromas subjected to therapy - to be precise a surgical therapy - are those that are very painful and positioned in anatomical sites that profoundly disfigure the subject's appearance.

From the point of view of its complexity, the surgical treatment of dermal neurofibroma is not particularly difficult.

In the presence of type 1 neurofibromatosis, the use of surgery to eliminate neurofibromas is infrequent not only because these tumors lack danger, but also because they are many (and the removal operation would be very prolonged).

Treatment of plexiform neurofibroma

The plexiform neurofibroma is a tumor formation that would always be subjected to surgical treatment, except that the aforementioned treatment is:

• Difficult to perform . Plexiform neurofibromas reside in depth and close to more nerves; these characteristics complicate, and not a little, the feasibility of a removal operation;
• Very invasive . The operation of removal of a plexiform neurofibroma imposes, in fact, the complete removal of the sections of the nerves concerned (nervous resection intervention).

In light of this, doctors believe it is essential to perform surgical removal of plexiform neurofibromas, only when the latter are responsible for severe symptoms or are at high risk of malignant transformation . In the absence of the aforementioned assumptions (therefore limited symptoms and low risk of malignant transformation), the only viable way is the periodic monitoring of the tumor formation (s).

Curiosity

Radiation therapy is not among the treatments for the treatment of plexiform neurofibroma, as it is a factor favoring the transformation processes in the malignant tumor of peripheral nerve sheaths.

The treatment of a plexiform neurofibroma has become a malignant tumor

The malignant evolution of a plexiform neurofibroma always requires the use of a treatment for the removal of the tumor mass.

Possible treatments for a malignant tumor of peripheral nerve sheaths include surgery, radiotherapy and chemotherapy .

Post-operative removal of the plexiform neurofibroma

After surgery to remove the plexiform neurofibromas or their malignant versions, the patient must undergo a series of physiotherapy-type rehabilitation treatments in order to recover from certain neurological deficits induced by nervous resection.

The possible treatments of the future

Recently, experts engaged in the search for new treatments against the neurofibroma have noticed that the latter seems to undergo a slowdown in development, when exposed to ACE inhibitor drugs; ACE inhibitors, as is perhaps already known to many readers, are medicines indicated for the treatment of hypertension and other cardiovascular diseases.

Prognosis

The prognosis in the presence of a neurofibroma varies depending on whether the tumor is dermal or plexiform and depending on whether the mode of presentation is single or multiple (NB: when speaking of multiple modality, reference is obviously made to neurofibromatosis type 1).

Dermal neurofibroma

Considering only the absence of consequences on patients' life expectancy, both single and multiple dermal neurofibroma have a benign prognosis.

However, if the effects on the physical aspect are also taken into account, what has just been stated is no longer valid; in fact, while the single dermal neurofibroma continues to have a benign prognosis, the multiple dermal neurofibroma assumes the connotations of a very unpleasant condition, as it can deeply disfigure the face, the trunk, the arms etc.

Plexiform neurofibroma

Plexiform neurofibroma is a tumor formation with a potentially poor prognosis; its possible malignant evolution, in fact, can have lethal consequences (the malignant tumor of peripheral nerve sheaths is a sarcoma, from which metastases may depend).

In such a context, the mode of presentation has a relative importance, in the sense that the dangers associated with plexiform neurofibroma exist both when the latter is presented in single form and when it occurs in multiple form.

Prevention

Currently, there is no way to prevent the formation of a neurofibroma, neither the idiopathic form nor the form associated with type 1 neurofibromatosis.