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A 10-year-old girl with multiple eyelid neuroproliferative tumors
Digital Journal of Ophthalmology 2021
Volume 27, Number 3
July 12, 2021
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Kristin Torroella | George Washington School of Medicine and Health Sciences, Washington, DCGeorge Washington School of Medicine and Health Sciences, Washington, DC Jana Bregman, MD | Department of Ophthalmology, Childrens National Hospital, Washington, DC Maria Isabel Almira-Suarez, MD, FASCP | Neuropathology Service, Division of Anatomic Pathology, Childrens National Hospital, Washington, DC Marijean Miller, MD | Department of Ophthalmology, Childrens National Hospital, Washington, DC
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| Diagnosis and Discussion | Multiple endocrine neoplasia type 2B (MEN2B) describes a spectrum of disorders that presents with tumors in two or more endocrine glands, most commonly MTC, pheochromocytoma, and mucosal neuroproliferative tumors.(6-10) This condition can also present with nonendocrine features, such as marfanoid body habitus, gastrointestinal ganglioneuromas, thickened lips, tongue nodules, café-au-lait spots, and ocular abnormalities.(6,7,9,11) MEN2B is caused by a RET proto-oncogene mutation, which is heritable in approximately half of cases, located on chromosome 10, and confers 100% penetrance but variable expressivity.(9-11) MTC occurs in nearly 100% of patients with MEN2B. Late diagnosis can be fatal, with a 5-year survival rate of 35% for patients with MTC in MEN2B.(9,11) Diagnosing patients before the development of MTC can be lifesaving.
With genetic testing becoming more available, it is now common to screen newborns with a family history of MEN2B, allowing for earlier molecular diagnosis and thus improved outcomes.(10) However, 50% of MEN2B cases stem from de novo mutations, resulting in delayed diagnosis and poorer prognosis.(10) In nonfamilial MEN2B, patients are most often diagnosed at an advanced stage, triggered by systemic symptoms related to elevated catecholamines due to pheochromocytoma or elevated calcitonin due to MTC.(6) By this point in time, MTC has often progressed to an advanced stage, marked by metastatic cancer most commonly seen in the liver and lungs.(8)
Early MEN2B diagnosis allows for prompt MTC surveillance, surgical resection of the tumor or even prophylactic thyroidectomy if needed, which can be life-saving.(11) Early diagnosis of asymptomatic patients with de novo mutations is challenging and relies on clinical findings, including ocular abnormalities.(12) Ocular changes may be the first manifestations of MEN2B, presenting before systemic signs and symptoms of pheochromocytoma and/or MTC.(6,11) In addition, ocular findings can be detected with a noninvasive examination, whereas identifying other systemic findings in MEN2B may require imaging, lab work, and even diagnostic biopsies. Although the ophthalmic signs are not visually significant, they can play a critical role in early detection.(11) The exact incidence of ocular findings is unknown since MEN2B itself is rare.(11) However, of 33 reported ocular cases, 100% of patients were found to have prominent corneal nerves. Additional findings included eyelid neural tumors or thickening (88%), subconjunctival neuromas (79%), decreased tear production (48%), rostral displacement of the cilia (12%), and poor pupillary dilation (12%).(11)
Our patient was found to have prominent corneal nerves, thickened eyelids, and multiple eyelid conjunctival plexiform schwannomas. Histologic studies have demonstrated that the appearance of prominent corneal nerves is due to nonmyelinated axons associated with Schwann cells.(13) Although prominent corneal nerves have been reported in 100% of MEN2B cases, they can also be seen in a number of other diseases such as MEN2A, Refsum disease, pheochromocytoma, primary amyloidosis, ectodermal dysplasia, leprosy and herpes zoster keratopathy.(6,9) Therefore, it is important to be aware of additional distinctive ocular features of MEN2B, such as eyelid thickening, ptosis, impaired pupillary dilation, and eyelid, conjunctival, and subconjunctival neuroproliferative tumors.(11)
Plexiform schwannomas—also referred to as neurilemomas, neurolemomas, or neuromas—are benign tumor proliferations of nerve tissue. In MEN2B, they are seen as multiple unencapsulated lesions in the palpebral conjunctiva or subconjunctiva.(14) A diagnostic biopsy can help confirm the suspected diagnosis of MEN2B associated neural lesion, which reacts positively with the immunohistochemical S100 and demonstrates a disorganized conglomeration of nerve twigs.(10,11) The formation of nodules is attributed to prominent nerves forming plexiform bundles aligned parallel to the epidermis.(6,7,14) These lesions often increase in size over time, which in many patients, as in ours, prompt further ophthalmologic evaluation.(10)
Such tumors can be surgically removed under local anesthesia with a shave biopsy or full-thickness wedge resection under monitored sedation.(15) However, with the former, there is a risk of residual tumor being left behind, possibly leading to reocurrence.(14,15) In order to prevent eyelid notching during direct closure of the lid defect following wedge resection, the tarsus and eyelid margin are meticulously reapproximated.(15) If the lesion is large (greater than 30% of the eyelid width), a more complex eyelid reconstruction is necessary, requiring tarsoconjunctival and skin grafts from adjacent tissues to reconstruct the anterior and posterior lamellae of the eyelid.
This pediatric case of MEN2B highlights important ocular findings in MEN2B, some of which can be detected by the naked eye, with no need for a slit-lamp examination or invasive testing. Ophthalmologists aware of its ocular manifestations can play a vital role in detecting MEN2B at an early precancerous stage, establishing care with other subspecialists as needed (ie, endocrinology), and helping to screen immediate family members who may also be affected. | |
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