Table 5.1. Diagnostic Criteria for NF1

National Institutes of Health Diagnostic Criteria for NF1 [37]

Two or more of the following features signify the presence of

5NF1 in a patient:

Six or more café-au-lait macules (>0.5 cm at largest diameter in prepubertal individuals or >1.5 cm in individuals past puberty)

Axillary freckling or freckling in inguinal regions

Two or more neurofibromas of any type or ≥1 plexiform neurofibroma

Two or more Lisch nodules (iris hamartomas) A distinctive osseous abnormality

A first-degree relative with NF1 diagnosed using these criteria

National Institutes of Health Diagnostic Criteria for NF1 [37]

Other manifestations include café-au-lait macules; axillary and inguinal freckling; malignant peripheral nerve sheath tumors; Lisch iris nodules; skeletal dysplasia, including the absence of the greater sphenoid wing; neurocognitive defects; and cardiovascular abnormalities. Ocular findings can manifest as proptosis, glaucoma, buphthalmos, and vision loss. Lee et al. described additional periorbital sequelae of brow ptosis, lateral canthal disinsertion, conjunctival and lacrimal gland infiltration, as well as lower and upper eyelid infiltration with ptosis [28]. The National Institute of Health diagnostic criteria for NF1 are listed in Table 5.1 [36].

5.4Orbitofacial Tumors in NF1

5.4.1Neurofibromas

The NF1 tumors affecting the orbit include neurofibromas and OPGs. Neurofibromas are benign tumors that arise from peripheral nerve sheaths and are composed of Schwann cells, endoneural fibroblasts, and perineural cells [29]. The multicellular histology of the neurofibroma distinguishes it from the schwannoma, which is a pure proliferation of Schwann cells. Neurofibromas can be subdivided into localized, plexiform, or diffuse.

Localized neurofibromas are associated with NF1 in approximately 10% of cases [25]. They can present in the orbit, causing proptosis in adults, usually young to middle aged. These lesions often behave like isolated schwannomas, although they can present as multiple lesions within the orbit and can cause pain if involving a sensory nerve. The tumors are not encapsulated but can often be removed intact because they are well circumscribed [29].

Plexiform neurofibromas typically are congenital, with 50% of the tumors occurring in the head and neck [36]. They exhibit an earlier growth phase than the localized form, with the most rapid growth occurring before the onset of puberty. A study identified the presence of growth hormone receptors on plexiform neurofibromas, which suggests that their propensity to grow may be further induced by hormonal signals [8]. Plexiform neurofibromas grow along the length of a nerve and may arise from multiple nerve fascicles. External plexiform neurofibromas (i.e., not within the cranium) occur in approximately 30% of patients with NF1 [33]. These tumors can cause pain, localized pruritis, and neurologic deficits in addition to severe disfigurement and amblyopia [38]. Plexiform neurofibromas carry a 4–5% rate of malignant transformation [11]. In contrast to the localized neurofibroma, the plexiform type is not well circumscribed and usually infiltrates local tissues. This makes complete resection of this tumor very challenging and often impossible. Tarsal thickening, an S-shape lid deformity and overgrowth of the eyelid are induced by this tumor (Fig. 5.1).

The diffuse form of neurofibromas is not ensheathed in repeating perineura as is found in plexiform neurofibromas [29]. Diffuse neurofibromas also appear early in young patients as with the plexiform neurofibromas. One distinguishing characteristic from the plexiform type is the inability to palpate discrete tumors. Diffuse neurofibromas often present as a thickening of tissues, such as the tarsus and levator muscle often seen in NF1 lid deformities. These tumors are highly infiltrative, bleed heavily, and are virtually impossible to completely remove (Fig. 5.2).

Fig. 5.1 A 4-year-old boy with NF1 and right upper eyelid S-shape deformity from plexiform neurofibroma in the upper eyelid

5.4.2Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors are aggressive spindle cell tumors that are also called malignant schwannomas or neurofibrosarcomas. These tumors present in the orbit and eyelids and usually arise from branches of the trigeminal nerve [29]. They typically arise from plexiform neurofibromas; however, a large study of 1,475 NF1 patients found that 36% of the 30 cases of malignant peripheral nerve sheath tumors occurred in patients with no known history of neurofibromas [24]. The lifetime risk of developing this tumor is 10% in NF1 patients [13]. Although fluorodeoxyglucose positron emission tomographic (PET) scans have generally been of little value in evaluating optic nerve gliomas in the orbit, they may be of

value for differentiating benign plexiform neurofibromas from malignant peripheral nerve sheath tumors [14].

5.4.3Optic Pathway Gliomas

Optic pathway gliomas can extend from the orbit to the chiasm and optic tract (Fig. 5.3). OPGs are low-grade pilocytic astrocytomas that occur in approximately 15–20% of patients with NF1 [30, 31]. Other central nervous system gliomas associated with NF1 can also occur in the cerebellum, diencephalon, and brain stem at a rate of 3.5% [15]. OPGs in NF1 typically occur before the age of 10 and are usually located along the optic nerve. In contrast, sporadic gliomas not associated with NF1 are typically chiasmal or prechiasmal [31]. This common

belief has been challenged by Singhal et al., who found a significant involvement of the chiasm in NF1-associated OPG as compared to sporadic cases (10 of 17 cases with NF1 and 6 of 17 sporadic OPGs) [44]. Symptoms can

5include proptosis, vision loss, and hypothalamic involvement, resulting in precocious puberty. There are reports of progression of OPGs, although the common belief is that this occurs more frequently in sporadic cases [50].

When considering outcomes, the term progression, from an orbital surgeon’s perspective, needs clarification. In this regard, it is useful to review the neurooncology perspective, particularly as it applies to NF1. There are several categories that can be used to describe the clinical status of OPGs from initial diagnosis to remission or cure. Remission is most commonly used to describe a positive response to medical therapy. While spontaneous remissions can occur in NF1 OPGs, this is rarely, if ever, observed in sporadic OPGs [41]. Recurrence of tumor describes evidence of tumor after an apparent tumor-free period. Progression of tumor describes growth of an existing mass. This can be observed either clinically (i.e., increasing proptosis), for example, or by serial imaging studies demonstrating an increase in volume or expansion of the lesion. For the orbital surgeon, the major concern has related to the possibility of “retrograde progression,” particularly regarding optic nerve gliomas growing posteriorly from the orbital apex through the bony optic canal toward the chiasm [2, 22].

Management paradigms for treating NF1 orbital tumors and particularly optic nerve glioma have been somewhat controversial. A common assumption has been that these lesions represent hamartomas with early and then static growth. The traditional concepts have been that (1) NF1-related gliomas act more benignly, (2) optic nerve gliomas without chiasmatic involvement do not later spread into the chiasm, and (3) surgical removal to prevent spread is unnecessary. Studies, however, indicated that there may be some cases when retrograde progression can occur. Singhal et al. reported one case of an NF1-associated glioma that had affected the left optic nerve and was excised. Nine years later, the optic glioma recurred in the chiasm [44].

A report by Walrath et al. demonstrated retrograde growth in a non-NF1 patient [47]. Progression from prechiasmal to chiasmal to postchiasmal disease was demonstrated on serial magnetic resonance imaging (MRI) scans. Of significance, clinically, with treatment using confocal radiation and intravenous steroids, vision was regained from no light perception (NLP) to 20/20. Because of disfiguring proptosis, however, an excisional biopsy was done. The histopathology confirmed that the tumor was a benign pilocytic astrocytoma. Of major

interest, however, were the results of histochemical studies, which revealed evidence of a mindbomb homolog (MIB-1 LI) [6]. This homolog is an antibody that recognizes Ki 67, a protein active during all phases of the cell cycle. Increased levels of Ki 67 have been found to be consistent with aggressive tumor behavior in OPGs [7, 47]. The normal value for Ki 67 in benign pilocytic astrocytomas is less than 1%. In this patient, however, the specimen revealed an average of 2.8%, with some areas as high as 7%. The importance of this case is not only that active growth in the tumor was observed both clinically and histologically but also that the tumor responded to therapy with a dramatic improvement in vision. These findings do not conform with the concept of a hamartoma. An accompanying editorial by Miller in the same journal emphasized that it is “inaccurate to consider such lesions to be hamartomas and equally inappropriate to recommend no treatment for lesions that show evidence of clinical or imaging progression” [34]. Walrath and his coauthors further suggested that early biopsy with histochemical studies may possibly provide prognostic information regarding timing and extent of surgical resection [47].

This assertion is supported by the histologic findings by Burstine et al. [6], who performed quantitative analysis of proliferative activity of 14 optic nerve gliomas using the silver nucleolar organizing region technique and found 6 of 14 gliomas positive. A similar finding was observed in other malignant tumors. In addition, the analysis was equivocal regardless of location or NF1 association.

First-line therapy for OPGs includes appropriate imaging and chemotherapy [39]. Although chemotherapy regimens vary depending on the institution, a new protocol (Children’s Oncology Group Chemotherapy Protocol CCG-A9952) has completed a phase III randomized study of carboplatin and vincristine compared to thioguanine, procarbazine, lomustine, and vincristine in children with progressive low-grade astrocytoma [4]. Although the results of this study have not yet been published, it does appear from other reports that the effectiveness of chemotherapy for chiasmal gliomas has been greatly improved, with 5-year survival rates of over 70% [44]. Radiation for chiasmal lesions has not been recommended for children under 5 years of age because of damage to the brain and hypothalamus. Because of the success rates with chemotherapy, however, the use of radiation even in older patients is no longer recommended [26]. Surgical intervention is usually reserved for gliomas that either respond poorly to chemotherapy or radiation or are associated with severe proptosis causing vision loss or a marked cosmetic deformity. This is discussed more fully in other sections of this chapter.