Marc R. Safran, MD

• Professor, Orthopedic Surgery, Stanford University
• Associate
• Director, Sports Medicine, Stanford University Hospital and
• Clinics, Redwood City, California

This laissez-faire approach can lead to satisfactory cosmetic and functional results in 90% of cases (22) womens health skinny pill cheap 100 mg serophene mastercard. After confirmation of the diagnosis menstruation 60 year old purchase 50 mg serophene visa, wide excision and frozen section control or Mohs chemosurgery offer the best control rates (21) pregnancy 7dpo best purchase serophene. Radiotherapy is generally reserved as palliative treatment for aggressive recurrent lesions or for patients who are physically unable to undergo surgery women's health birth control methods purchase serophene 50 mg with visa. Metastatic basal cell carcinoma: report of five cases and review of 170 cases in the literature menopause 19 year old buy serophene with mastercard. The association between cigarette smoking and basal cell carcinoma of the eyelids in women. Surgery for primary basal cell carcinoma including the eyelid margins with intraoperative frozen section control: comparative interventional study with a minimum clinical follow up of 5 years. Management of peri-ocular skin tumours by laissez-faire technique: analysis of functional and cosmetic results. However, incomplete removal can be associated with aggressive recurrence, leading to a poorer cure rate. Neglected or incomplete initial excision can result in orbital invasion and rarely death can ensue due to intracranial invasion via emissaries in the orbital bone. Nevoid Basal Cell Carcinoma Syndrome the basal cell nevus syndrome, also known as the Gorlin-Goltz syndrome, or Goltz syndrome, deserves special mention. It is a multisystem, autosomal-dominant syndrome involving both ectoderm and mesoderm tissues (6,7). Other less common ocular abnormalities include congenital cataracts, uveal and optic nerve coloboma, strabismus, nystagmus, and microphthalmos. Imiquimod treatment of superficial and nodular basal cell carcinoma: 12-week open-label trial. The basophilia of the basal cell nuclei give the cellular areas a typical blue color on light microscopy. Curiously, the patient had a simultaneous conjunctival malignant melanoma on the opposite eye. Diffusely infiltrating tumor extending over half of face and destroying the globe. Facial appearance of same patient wearing glasses after exenteration and fitting of the prosthesis. Facial appearance of woman at about age 40 years, showing multiple facial basal cell neoplasms. Facial appearance of same woman at age 86 years, showing extensive involvement and blepharoptosis. X-ray of teeth showing odontogenic keratocyst (clear black area above in area of absence of teeth). Pathology of odontogenic keratocyst, showing keratinizing epithelium and keratin debris in the lumen. Examples of full-thickness eyelid resection and topical imiquimod are illustrated here. The surgical method is shown briefly below and is illustrated in more detail in Chapter 15. Patients who are very old and poor surgical candidates are treated today with topical imiquimod, an agent that boosts the immune system. Appearance several months after treatment showing complete resolution of the lesion. It was excised with frozen section control and closed by primary closure assisted by a temporal semicircular (Tenzel) flap. After circular excision with frozen section control, the large defect and the tight skin made primary closure difficult, so the lesion was allowed to heal by granulation without sutures. The lesion was removed with frozen section control and a free skin graft from upper eyelid of opposite eye was used to close the defect. It can occur at a younger age in patients who are immunosuppressed or who have excess sensitivity to sunlight, particularly albinos. The squamous cells have eosinophilic cytoplasm, intercellular bridges, and can have keratin pearls. Although the tumor foci appear to be discrete microscopically, they actually represent fingerlike extensions passing down from the epidermis. A more poorly differentiated tumor may require immunohistochemistry or electron microscopy to identify the squamous cell origin of the lesion and to rule out other malignant neoplasms. It begins as a sessile or papular lesion that is similar to early basal cell carcinoma. It frequently ulcerates centrally, producing the rodent ulcer appearance; it can be irritating and bleed. This can lead to numbness, pain, blepharoptosis, diplopia, and displacement of the globe. More sizable lesions in which extensive eyelid reconstruction is anticipated should be diagnosed by a shaving or punch biopsy to establish the diagnosis before embarking on definitive surgical management (16). The lesion should then be surgically excised using Mohs microsurgery or frozen section control. Eyelid reconstruction should be undertaken when the margins are confirmed to be negative for tumor. The indications and techniques of these methods are discussed in more detail elsewhere. It can resemble basal cell carcinoma, sebaceous carcinoma, Merkel cell carcinoma, and benign lesions like actinic keratosis, seborrheic keratosis, inverted follicular keratosis, pseudoepitheliomatous hyperplasia, and keratoacanthoma. It also has a greater tendency toward neurotropism and can extend to the orbit and brain along nerves (13­15). Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update. The management of perineural spread of squamous cell carcinoma to the ocular adnexae. Efficacy of incisional vs punch biopsy in the histological diagnosis of periocular skin tumours. Patterns of regional and distant metastasis in patients with eyelid and periocular squamous cell carcinoma. Brachytherapy with 192Ir as treatment of carcinoma of the tarsal structure of the eyelid. Imiquimod: an effective alternative for the treatment of invasive cutaneous squamous cell carcinoma. Squamous cell carcinoma of upper eyelid in an 87-year-old light-skinned man who had chronic sunlight exposure years earlier as a lifeguard. Appearance of face 6 months after full-thickness eyelid resection and frozen section control showing satisfactory appearance. The tarsus and palpebral conjunctiva (below) are encroached upon, but still unaffected by the tumor. Higher magnification photomicrograph showing invasive squamous cells with dyskeratosis and a marked chronic inflammatory cell infiltration. The tumor can be highly aggressive and can invade the orbit, requiring orbital exenteration. Such individuals have a marked predisposition to develop various skin cancers at a young age. Close view of lesion, showing erythematous elevated lesion above left upper eyelid. Histopathology showing invasive squamous cell carcinoma, showing infiltrating malignant squamous cells. Each can give rise to hyperplasia, adenoma, or adenocarcinoma (sebaceous carcinoma) (1­14). Sebaceous gland adenoma of the tarsal conjunctiva in a patient with Muir-Torre syndrome. A patient with one or more cutaneous sebaceous adenomas has a greatly increased chance of developing internal malignancies. The internal cancer can become clinically apparent long after the detection of the sebaceous tumor or it can precede it. It occurs as one or more focal tanyellow papules or as a diffuse thickening of the eyelids (3). Pathology Sebaceous hyperplasia is composed of well-demarcated lobules of mature sebaceous glands usually located around a dilated sebaceous duct. In contrast, sebaceous gland adenoma is composed of two types of cells: Mature sebaceous cells and poorly differentiated basal cells (2). In some cases, there may be histopathologic overlap between sebaceous hyperplasia and adenoma, making histopathologic classification difficult. In patients with multiple small lesions, electrodessication or cautery and trichloroacetic acid are effective (14). Chapter 3 Eyelid Sebaceous Gland Tumors 51 Eyelid Sebaceous Carcinoma General Considerations Sebaceous carcinoma is an important neoplasm that occurs most frequently in the periorbital area, usually the eyelid. It can exhibit aggressive local behavior and metastasize to regional lymph nodes and distant organs. Historically, this neoplasm has been notorious for masquerading as other benign and malignant lesions, resulting in delays in diagnosis and higher morbidity and mortality. Hence, it is important for the ophthalmologist to be cognizant of the clinical features of and current therapy for periorbital sebaceous carcinoma. Recently, greater awareness of this neoplasm has resulted in earlier diagnosis and provided the opportunity for less aggressive therapy (12,13,31,32). Although ophthalmologists have become more familiar with the clinical variations of periorbital sebaceous carcinoma, there remain delays in diagnosis and misdirected therapy (12). In China and India, where basal cell carcinoma is less common, sebaceous carcinoma accounts for approximately half of all malignant eyelid tumors (4). This aggressive neoplasm can exhibit local recurrence and regional and distant metastases. It generally affects elderly patients, although it has been seen in children and young adults who have undergone irradiation for retinoblastoma or acne (21­23). In the periorbital area, it usually arises from the meibomian glands of the upper tarsus, but can originate from the sebaceous glands of the cilia (Zeis glands), caruncle, or eyebrow (2,12,13,15). Like sebaceous adenoma, sebaceous carcinoma can also be associated with the MuirTorre Syndrome (38,39,41). We have also seen it present as a pedunculated mass and as a yellow enlargement of the caruncle. Differential Diagnosis Clinically, sebaceous carcinoma of the eyelid area has no pathognomonic features that differentiate it from the other epidermal lesions described in this section. It should be differentiated from other malignant neoplasms like basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, and from inflammatory lesions like chalazion and blepharoconjunctivitis. Pathology Sebaceous carcinoma is composed of a malignant proliferation of sebaceous cells with vacuolated cytoplasm owing to the presence of lipid, which is better shown with special fat stains, such as oil red-O stain. In some cases, the exact gland of origin is difficult to identify because of diffuse or multicentric tumor origin. Although there are several methods of classifying sebaceous carcinoma, most authorities recognize four histopathologic patterns: lobular, comedocarcinoma, papillary, and mixed (3,10,18,33). Histopathologically, sebaceous carcinoma can be further grouped into well-, moderately, and poorly differentiated varieties (33). The more common lobular pattern mimics normal sebaceous gland architecture with less differentiated cells situated peripherally, and better differentiated, lipid-producing cells located centrally. In the comedocarcinoma pattern, the lobules show a large necrotic central core surrounded by viable tumor cells. The papillary pattern shows papillary projections and areas of sebaceous differentiation. When the tumor arises from, and is confined to , the Zeis glands, it appears microscopically to affect the glands near the eyelid margin but spares the tarsus. A well-known and highly quoted aspect of sebaceous carcinoma is its ability to exhibit intraepithelial (pagetoid) spread into the eyelid epidermis and conjunctival epithelium. In a review of 52 cases of orbital exenteration for more advanced sebaceous carcinoma, Jakobiec and To found that some degree of conjunctival epithelial involvement could be identified in 100% (13). Clinical Features the two most common clinical presentations of sebaceous carcinoma are a solitary eyelid nodule and diffuse eyelid thickening. The solitary lesion begins as a firm nodule arising from the tarsus, deep to the epidermis. If the eyelid is everted, the lesion may be more visible through the tarsal conjunctiva. The solitary nodular growth pattern is often misdiagnosed in the early stages as a chalazion. The diffuse growth pattern of sebaceous carcinoma is responsible for its masquerading as chronic blepharoconjunctivitis. Diffuse intraepithelial involvement can extend in a pagetoid pattern across the tarsal conjunctiva, bulbar conjunctiva, and even the cornea and caruncle (12,13). In contrast to most cases of blepharitis, it is unilateral and causes more thickening and induration of the eyelid. When it originates in a Zeis gland, it is located at the eyelid margin rather than deep in the tarsus (15). It can sometimes present as a lacrimal gland mass secondary to deeper invasion of a subtle or subclinical eyelid lesion and can simulate a pri- Management the best management is wide surgical excision with frozen section or chemosurgery control. If the suspected lesion is large and extensive closure is anticipated, a shaving or punch biopsy can be performed first. For diffuse lesions that affect the bulbar and palpebral conjunctiva, small map biopsies can be done and final surgical planning is based on the extent of the tumors found histopathologically. In advanced diffuse cases with mainly superficial pagetoid involvement of the epithelium, we have used a posterior lamellar resection of the upper eyelid and conjunctiva combined with a buccal mucosal graft. It can also be used for diffuse tumors when map biopsies suggest that the tumor is confined to epithelium.

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Patients may present with decompensated chronic liver disease with hepatosplenomegaly women's health clinic santa rosa discount serophene 100 mg buy on-line, ascites women health issues discount serophene 50 mg amex, a low serum albumin level womens health 3 day cleanse order generic serophene on-line, and persistently abnormal coagulation test results pregnancy x-rays purchase discount serophene on line. Many of these findings relate to portal hypertension as a consequence of Wilson disease rather than to the metabolic disorder itself pregnancy kidney stones buy serophene 100 mg overnight delivery. Wilson disease may present in children and young adults with clinical liver disease indistinguishable from autoimmune hepatitis (see Chapter 90). Wilson disease must be specifically ruled out because the treatment of the 2 diseases is entirely different. With appropriate treatment, the long-term outlook for patients with Wilson disease that manifests as autoimmune hepatitis appears to be favorable, even if cirrhosis is present. In some patients, encephalopathy is not initially present but develops within a few days of clinical presentation. In this "classic Wilsonian acute liver failure," acute Coombs-negative intravascular hemolysis is present, and renal failure may develop. Children with unexplained cholelithiasis, particularly bilirubinate stones, should be tested for Wilson disease. Mood disturbance (mainly depression, but sometimes impulsive or neurotic behavior), deterioration in school performance or handwriting, and clumsiness may be identified by careful direct questioning. A soft whispery voice (hypophonia) is another early feature of neurologic involvement. Most patients with a neurologic presentation have hepatic involvement, albeit often asymptomatic. Neurologic involvement follows 1 of 2 main patterns: a movement disorder or rigid dystonia. A movement disorder tends to occur earlier and includes tremors, poor coordination, and loss of fine motor control. Spastic dystonic disorders generally develop later, with mask-like facies, rigidity, gait disturbance, and pseudobulbar involvement such as dysarthria, drooling, and swallowing difficulty. Imaging of the brain is important for assessing neurologic Wilson disease, and results may be abnormal in the absence of overt neurologic symptoms. Phobias and compulsive behaviors have been reported; aggressive or antisocial behavior may also be found. Copper is actually distributed throughout the cornea, but fluid streaming favors accumulation near the limbus, especially at the superior and inferior poles, and eventually circumferentially around the iris. Copper deposition in the lens (sunflower cataract), which does not interfere with vision, may be seen on slit-lamp examination and, like Kayser-Fleischer rings, disappears with chelation therapy. Kayser-Fleischer rings may be absent in 40% to 60% of patients with exclusively hepatic involvement and in asymptomatic patients. Most patients with a neurologic or psychiatric presentation of Wilson disease have Kayser-Fleischer rings; only 5% do not. In rare persons with Kayser-Fleischer rings found incidentally, Wilson disease should be excluded. Involvement of Other Systems Wilson disease can be accompanied by various extrahepatic disorders apart from neurologic disease. Self-limited episodes of hemolytic anemia can result from the sudden release of copper into the blood. Findings include microscopic hematuria, aminoaciduria, phosphaturia, and defective acidification of the urine. Arthritis, mainly affecting the large joints, may occur as a result of synovial copper accumulation. Other musculoskeletal problems include osteoporosis and osteochondritis dissecans. Sudden death in Wilson disease has been attributed to cardiac involvement but is rare. Amenorrhea and testicular problems appear to result from Wilson disease itself, not from cirrhosis. Pancreatitis, possibly resulting from copper deposition in the pancreas, may also occur. A diagnostic scoring system (the Leipzig scoring system)38 has had limited evaluation39,40; however, it provides some guidance as to diagnostic strategy. Suggestive clinical symptoms are often the main prerequisite for diagnosing Wilson disease, and laboratory investigations may provide confirmation. Kayser-Fleischer rings should be sought through a careful slit-lamp examination, repeated if necessary. Tests A summary of biochemical features in Wilson disease in comparison with normal persons is shown in Table 76. The classic feature of a low ceruloplasmin concentration has proved less typical than previously thought, partly because hepatic inflammation may be sufficient to elevate serum ceruloplasmin levels. Also, the normal range for serum ceruloplasmin is increased in very young children. The method of measuring ceruloplasmin is likely the most important reason for finding normal ceruloplasmin levels in patients with Wilson disease. Immunologic methods, which are used in most laboratories, measure both apoceruloplasmin and holo-ceruloplasmin and typically overestimate the true amount of functional ceruloplasmin in plasma. The oxidase assay, although technically less convenient for laboratories that perform automated testing, provides a more reliable measure of ceruloplasmin for diagnosis because the assay measures enzymatically active, copper-containing ceruloplasmin. This method permits an accurate estimate of non-ceruloplasmin-bound copper41 and can also indicate possible early copper deficiency in treated patients. A low serum level of ceruloplasmin is not unique to Wilson disease; synthesis of ceruloplasmin may be reduced in other types of chronic liver disease, intestinal malabsorption, nephrotic syndrome, and malnutrition. Furthermore, a subnormal ceruloplasmin concentration is found in at least 10% of heterozygotes for Wilson disease. Nevertheless, an impressively low ceruloplasmin concentration (<10 mg/ dL) strongly suggests Wilson disease. Complete absence of ceruloplasmin is found in hereditary aceruloplasminemia, a rare autosomal recessive condition that is associated with neurologic, retinal, and pancreatic degeneration caused by iron accumulation in the brain, retina, and pancreas, respectively. Aceruloplasminemia has confirmed the important function of ceruloplasmin as a ferroxidase that oxidizes iron for transport from ferritin to transferrin. Targeted disruption of the ceruloplasmin gene in a mouse model has confirmed the critical role of ceruloplasmin in transporting iron out of cells. The non-ceruloplasmin-bound copper concentration, which can be estimated by subtracting the amount of copper associated with ceruloplasmin from the total serum copper, is elevated. The amount of ceruloplasmin-bound copper (in g/dL) is estimated by multiplying the serum ceruloplasmin (in mg/dL) by 3. In normal persons the non-ceruloplasmin-bound copper concentration is less than 15 g/dL. The usefulness of this calculation, which is highly dependent on the accuracy of the copper and ceruloplasmin measurements, is limited; it cannot serve as a diagnostic criterion. Conceptually, the point is that this copper is bioavailable, and calling it "exchangeable" copper has merits. Serum uric acid and phosphate concentrations may be low in patients with untreated Wilson disease, reflecting renal tubular dysfunction. Urinalysis may show microscopic hematuria; if possible, aminoaciduria, phosphaturia, and proteinuria should be quantified. Studies of basal urinary copper excretion, preferably with 3 separate 24-hour collections, have proved useful for diagnosis. Urinary copper excretion reflects the non-ceruloplasmin-bound copper concentration in plasma. The collection must be complete, and the volume and total creatinine excretion should be measured; precautions against contamination with copper in the collection process are essential. The basal 24-hour urinary copper excretion is elevated at least 2 to 3 times normal in the vast majority of patients; however, the conventional diagnostic criterion of greater than 100 g/day (>1. A patient with a basal 24-hour urinary copper excretion of greater than 40 g/day (>0. In the standard provocative test with administration of d-penicillamine, urinary copper excretion of 25 mol (1600 g) or more per 24 hours is diagnostic of Wilson disease; however, the test lacks sensitivity for diagnosing Wilson disease and for identifying asymptomatic affected siblings. A hepatic copper content greater than 250 g/g dry weight of liver is considered diagnostic of Wilson disease. On the basis of a large series of genetically diagnosed patients, a value of greater than 70 g/g dry weight has been proposed as a better diagnostic threshold, although some specificity is lost. Liver biopsy samples must be collected without extraneous copper contamination, but in general, ordinary disposable liver biopsy needles can be used. In the early stages of Wilson disease, when copper is distributed diffusely in the liver cell cytoplasm, this measurement may clearly indicate hepatic copper overload. In later stages of hepatic Wilson disease, the measurement of hepatic copper is less reliable because copper is distributed unequally in the liver (see earlier). Moreover, liver biopsy may not be safe in such patients because of coagulopathy or ascites; a transjugular biopsy may be performed, or hepatic copper measurement may be omitted. An elevated hepatic copper concentration is not specific for Wilson disease; patients with chronic cholestasis or Indian childhood cirrhosis may also have elevated hepatic copper levels. In the presence of chronic liver disease (indicated by hepatomegaly or biochemical abnormalities) or typical neurologic symptoms, the combination of a low serum ceruloplasmin level (<140 mg/L)59 and elevated basal 24-hour urinary copper excretion (>40 g/day) is highly suggestive of Wilson disease. A percutaneous liver biopsy is useful for assessing the severity of liver damage and measuring parenchymal copper concentration, which is regarded by some to be the sine qua non for the diagnosis of Wilson disease. This procedure, however, may have to be delayed in patients with severe liver dysfunction. Other clinical entities in the differential diagnosis must be appropriately excluded. Ultimately, molecular genetic analysis is the only convincing and reliable diagnostic procedure. Many of these mutations are recorded in the Wilson Disease Mutation Database Although identification of a mutation is technically straightforward, care must be taken that the change detected causes disease and is not a rare normal variant, particularly for single amino acid missense mutations. Because of the similarity between yeast and mammalian copper transport systems, yeast and cell assay systems have been developed for the functional assessment of variants. The identification of one mutation may be adequate to confirm the diagnosis, if characteristic clinical symptoms and biochemical features are present and if the one mutation detected is clearly established as a disease-causing mutation. With current analytical techniques, 2 mutations can be found in more than 95% of affected patients. Small deletions, insertions, nonsense, and splice-site mutations occur throughout the gene. The histidine1069glutamine (H1069Q) mutation is present, at least in the heterozygous state, in 35% to 75% of Europeans with Wilson disease. Mutation detection is more challenging in Japanese and Mediterranean populations, in whom no mutation is present in high frequency. In populations with ethnic homogeneity or in which a limited spectrum of mutations is established, testing strategies Approach In view of the numerous available diagnostic tests, a methodical approach is required. A prominent example is Sardinia, where the disease frequency is 1 in 7000 live births67 and a mutation in the 5-untranslated region predominates. In populations with a limited number of mutations, use of a customized "Wilson disease chip"68 may be cost effective. Someone who is clinically normal, has only mild signs of the disease, or has a late age of onset could be a heterozygote carrying only one mutated allele. Heterozygotes have not been known to develop clinical disease or require treatment. Efforts to identify clear patterns of correlation between genotype and phenotype have been largely disappointing in Wilson disease. With the opportunity of confirming a diagnosis of Wilson disease by direct identification of mutations, the spectrum of manifestations of Wilson disease has been found to be even wider than previously recognized. Mutation analysis should also be carried out to distinguish asymptomatic patients from heterozygotes. Three markers are usually adequate for an unambiguous result: D13S314, D13S301, and D13S316. The proband (arrow) and asymptomatic sibling confirmed as affected are shown as filled circles. Diagnosis of First-Degree Relatives If mutations have been identified in a patient, mutational analysis is easily carried out in first-degree relatives (siblings, parents, and offspring) by direct testing for the mutations found in the patient. If mutations have not been identified, accurate diagnosis can be achieved using markers flanking the gene. The most useful genetic markers are stretches of dinucleotides or trinucleotides that show extensive variability in the normal population, so that parents within any one family will carry different alleles of these markers. This variability allows the tracking of the disease gene as it segregates within families, as shown in. It is important that informative markers flank the gene, because an erroneous diagnosis could result if markers on only one side of the gene are informative and a recombinant event has occurred close to the gene. The combination of markers, or haplotype, reliably indicates the genetic status within the family. According to marker studies or genetic diagnosis, an occasional person considered as a result of biochemical testing to have a high probability of being an asymptomatic patient has been shown to be a heterozygote. Therefore, confirmation of the genotype is highly recommended before treatment is initiated. Conversely, if the clinical diagnosis of a heterozygote is uncertain, genetic diagnosis can be highly informative. In the absence of genetic analysis, screening should include physical examination, liver biochemical tests, serum copper and ceruloplasmin measurements, a basal 24-hour urinary copper determination, and a careful slit-lamp examination. Children 6 years of age or younger who appear to be unaffected should be rechecked at yearly intervals over the next 5 to 10 years. Accumulating data indicate that the incidence of Wilson disease in children of patients with Wilson disease is higher than predicted. Therefore, screening of all first-degree relatives, not just siblings, is mandatory.

Natural course and histopathologic findings of lacrimal gland choristoma of the iris and ciliary body menstrual neck pain buy serophene uk. Lacrimal gland choristoma of the conjunctiva simulating a squamous cell carcinoma women's health clinic kearney ne 50 mg serophene order visa. Hyperkeratotic lacrimal gland choristoma posterior to the limbus in a 13-year-old boy menstruation 4 days serophene 50 mg with visa. Choristomatous respiratory cyst involving inferior portion of cornea and conjunctiva in a 3-month-old infant who was noted to have sclerocorneal ectasia at birth menstrual cramps 5 weeks pregnant serophene 25 mg buy otc. As mentioned menopause urinary frequency generic 50 mg serophene, it may overlap with a simple choristoma, which can occasionally contain a small amount of a second tissue element. In the conjunctiva, the most frequent heterotopic tissues include skin, lipid, lacrimal gland, and cartilage. Complex choristoma has an association with an oculoneurocutaneous condition, most recently called the "organoid nevus syndrome" (1,2). The most common cutaneous feature of the organoid nevus syndrome is the sebaceous nevus of Jadassohn, which frequently affects the skin of the face, retroauricular area, and scalp. This congenital cutaneous lesion can give rise later in life to basal cell carcinoma and other benign and malignant cutaneous tumors. The neurologic aspects of the organoid nevus syndrome include seizures and mental retardation, which occur secondary to arachnoid cysts and cerebral atrophy. The epibulbar lesions can show considerable variation, ranging from a small, minimally symptomatic lesion to a large mass that involves the conjunctiva and covers a portion of the cornea (1­9). It can be obvious in the interpalpebral area or it can be hidden beneath the upper eyelid. Pathology Histopathologically, complex choristoma has highly variable elements, but the most characteristic features are a dermolipoma, often associated with ectopic lacrimal gland and mature hyaline cartilage. Large lesions that cover the cornea may require extensive surgery and reconstruction. Epidermal nevus syndrome associated with a complex choristoma and a bilateral choroidal osteoma. Epibulbar complex choristoma covering temporal conjunctiva and most of the cornea in a young African-American boy. Note the characteristic alopecia in the scalp, corresponding to the sebaceous nevus. The child was believed to have idiopathic congenital blepharoptosis for several years before the forniceal lesion was discovered. Linear nevus sebaceous in an infant involving the chin and extending into the neck. Close up view of lateral canthus of left eye, showing congenital cutaneous nodule and maldevelopment of the lateral canthus. There is involvement of the forniceal conjunctiva superiorly and bulbar conjunctiva and cornea temporally. Based on histopathology of a similar case, we believe that the lesion is most likely intrascleral cartilage. We prefer to use the term "childhood papilloma" to distinguish it from the adult form that usually occurs in the elderly and generally has somewhat different clinical characteristics. Other reported methods include laser treatment (19,20), dinitrochlorobenzene immunotherapy (21), -interferon (22), and topical mitomycin chemotherapy 0. We have observed dramatic response to recurrent papilloma to oral cimetidine (Tagamet) (25). Clinical Features Childhood conjunctival papilloma can be solitary or multiple and may assume a sessile or pedunculated configuration. In extreme cases, several lesions may become confluent, producing massive papillomatosis. Childhood conjunctival papilloma has a fleshy red appearance owing to the numerous fine vascular channels that ramify through the stroma beneath the epithelial surface of the lesion (1­9). It most often occurs in the inferior fornix or on the bulbar conjunctiva and rarely encroaches on the cornea (1­26). Occasionally, conjunctival papilloma can be pigmented and simulate a melanoma (7). This is more likely to occur in the adult form, which will be discussed in the next section. Pathology and Pathogenesis Histopathologically, childhood conjunctival papilloma shows numerous vascularized papillary fronds lined by acanthotic epithelium, with minimal or no keratinization. The features of the conjunctival papilloma of adulthood are considered in the next section. Management the management of childhood conjunctival papilloma has been the subject of considerable interest (17­25). Incompletely excised lesions can recur with aggressive behavior owing to surgically induced liberation of virus particles into the surrounding tissues. Double freeze-thaw cryotherapy can be an effective adjunct in eradicating childhood papilloma (18). For fairly circumscribed pedunculated lesions, we have employed cryotherapy to the lesion, lifting and freezing the entire lesion, and immediately cutting the normal conjunctival tissue at its base, followed by closure with absorbable sutures. Larger lesions may require surgical excision with complete removal of the mass and primary closure. A meticulous "no-touch" technique should be attempted, handling only the adjacent, clinically normal tissues. In the rare case where the conjunctival defect cannot be closed primarily, a mucous membrane or amniotic membrane graft may be necessary. Human papilloma virus in neoplastic and non neoplastic conditions of the external eye. Treatment of recurrent squamous papillomata of the conjunctiva by carbon dioxide laser vaporization. Dinitrochlorobenzene immunotherapy of recurrent squamous papilloma of the conjunctiva. The use of postoperative topical mitomycin C in the treatment of recurrent conjunctival papilloma. Two contiguous sessile papillomas in bulbar and forniceal conjunctiva in a 5-year-old child. Multiple conjunctival papillomas arising from the palpebral conjunctiva and eyelid margin in a 4-year-old child. Chapter 17 Conjunctival Benign Epithelial Tumors 271 Conjunctival Papilloma of Childhood: Management With Oral Cimetidine Cimetidine is a histamine 2 receptor antagonist used to treat peptic ulcers. It also enhances the immune system by inhibiting suppressor T-cell function and augments delayed hypersensitivity. We have found it to be useful for selected recalcitrant or recurrent conjunctival papillomatosis. Histopathology after excision elsewhere, showing papillomatous lesion with acanthosis. Higher magnification photomicrograph showing fibrovascular cores within acanthotic epithelium. This technique is often effective in controlling selected small conjunctival papillomas. Appearance 10 months later showing marked resolution of the papilloma after treatment with cimetidine. Although the two types are similar, they also have some different characteristics (1­9). Clinical Features In contrast with the childhood type, adult papilloma usually occurs in young to elderly adults and may resemble squamous cell carcinoma or amelanotic melanoma clinically. Unlike the infectious papilloma of young children, it is more likely to be unilateral and solitary and is rarely multifocal. It most often begins near the limbus or bulbar conjunctiva and can encroach on the cornea and even completely cover the cornea in some cases. In some individuals, particularly those with dark skin, a conjunctival papilloma may appear clinically pigmented owing to excessive melanocytes in the acanthotic epithelium. Conjunctival papilloma of adulthood may have a low malignant potential to evolve into squamous cell carcinoma. However, occasionally a conjunctival papilloma can assume an inverted growth pattern similar to that seen in the nasal cavity and lacrimal sac. This variant has a greater tendency toward malignant transformation into transitional cell carcinoma, squamous cell carcinoma, or mucoepidermoid carcinoma (8,9). Pathology Histopathologically, the adult conjunctival papilloma is similar to the childhood variant and shows numerous vascularized papillary fronds lined by acanthotic epithelium. As mentioned, some papillomas have numerous melanocytes that impart a darker color to the lesion clinically (4). Using an immunoperoxidase technique, papillomavirus capsid antigen was found in nuclei of 23 conjunctival papillomas and 5 dysplasias and carcinomas these results suggest that papillomavirus may play a role in the etiology of conjunctival papilloma, as well as dysplasia, and carcinoma. Management Surgical excision and supplemental cryotherapy seems to be the best treatment for adult conjunctival papilloma. The surgeon should not overestimate the extent of the lesion because it appears to cover the cornea. In most such cases, the lesion usually arises from a small base near the limbus and overlies the cornea, but does not invade the cornea. Hence, it can be lifted off the cornea and removed by severing the stalk near the limbus. Note the three separate papillomas, pedunculated ones on the caruncle and forniceal conjunctiva and a small sessile lesion one on the tarsal conjunctiva near the eyelid margin. Bilobed squamous papilloma with a multinodular papillary configuration, located in the medial canthal region. Squamous papilloma with a smooth surface and highly vascular appearance located in region of nasal conjunctiva and semilunar fold, simulating a pyogenic granuloma. Note the straight radiating pattern of the blood vessels that characterize some papillomas. Subtle pigmented papilloma simulating a nevus on palpebral conjunctiva near the lacrimal punctum. Pigmented papilloma near the limbus and overriding the limbus, simulating a melanoma in an African-American patient. Large multinodular squamous papilloma in forniceal conjunctiva in an African American causing ectropion of lower eyelid. This patient underwent orbital exenteration elsewhere because of histopathologic misdiagnosis of squamous cell carcinoma. Sessile conjunctival papilloma in an immunosuppressed patient with acquired immunodeficiency syndrome. As mentioned, squamous cell carcinoma can have a papillomatous configuration and be very similar. Although generally considered to be a benign condition, there is a belief that it may represent a variant of squamous cell carcinoma (see Chapter 1). It is important that this benign lesion be differentiated from squamous cell malignancy of the conjunctiva. It generally has more of an inflammatory reaction than a lowgrade squamous cell carcinoma. Management Because squamous cell carcinoma cannot be ruled out clinically in most cases, treatment is generally complete excision and cryotherapy, similar to the technique used for squamous cell malignancies. Chapter 17 Conjunctival Benign Epithelial Tumors 277 Conjunctival Pseudoepitheliomatous Hyperplasia and Keratoacanthoma 1. Pseudoepitheliomatous hyperplasia of the conjunctiva at the limbus inferotemporally. Unlike squamous cell carcinoma, which evolves more slowly, this lesion grew rapidly. The intense white color is indicative of extensive keratinization on the surface of the lesion. This kindred, known as the Haliwa Indians, derive their name from their location in the counties of Halifax and Washington in North Carolina where the group originally resided (3). Hereditary benign intraepithelial dyskeratosis has subsequently been detected in several other parts of the United States and in patients who are not of Haliwa ancestry (1­9). Hereditary benign intraepithelial dyskeratosis: Report of two cases with prominent oral lesions. Clinical Features Hereditary benign intraepithelial dyskeratosis develops in the first decade of life and is characterized by bilateral elevated fleshy plaques on the nasal or temporal perilimbal conjunctiva, often in a V-shape. It can remain relatively asymptomatic or it can cause severe redness and foreign body sensation. Pathology Histopathologically, hereditary benign intraepithelial dyskeratosis is characterized by foci of markedly acanthotic and hyperkeratotic conjunctival epithelium with prominent dyskeratosis. Management Hereditary benign intraepithelial dyskeratosis has no known malignant potential. Smaller, less symptomatic lesions can be treated with ocular lubricants and judicious use of topical corticosteroids. Larger, symptomatic lesions can be managed by local resection with mucous membrane or amniotic membrane grafting if necessary. Chapter 17 Conjunctival Benign Epithelial Tumors 279 Conjunctival Hereditary Benign Intraepithelial Dyskeratosis Hereditary benign intraepithelial dyskeratosis is an epithelial lesion of conjunctiva and other mucous membranes. Hereditary benign intraepithelial dyskeratosis in a 37year-old woman who had bilateral interpalpebral lesions present since age 3 years. She was a descendent of a Haliwa Indian tribe and traced her ancestry to North Carolina.

Diseases

• Trigeminal neuralgia
• Hyperkalemia
• Fibrodysplasia ossificans progressiva
• GTP cyclohydrolase deficiency
• Acute respiratory distress syndrome
• Arthrogryposis ectodermal dysplasia other anomalies

In contrast with neurofibroma menopause questions and answers purchase serophene 50 mg, solitary orbital schwannoma is not usually associated with neurofibromatosis women's health clinic brighton buy generic serophene 50 mg on line. Diagnostic Approaches Imaging studies disclose a solid ovoid to elongated mass usually outside the muscle cone along the course of the supraorbital or supratrochlear nerve and occasionally along the infraorbital nerve menstrual weight gain generic serophene 100 mg buy. It shows very low signal on T1weighted images and homogeneous postcontrast enhancement (10) women's community health bendigo serophene 50 mg purchase with amex. Pathology Histopathologically menstrual interval buy genuine serophene online, schwannoma is a benign proliferation of Schwann cells that can show several variations in one tumor. Some areas are characterized by ribbons or fascicles of spindle cells (Antoni A pattern) and other areas have ovoid clear cells (Antoni B pattern). Large cystoid spaces are sometimes present and can even occupy most of the tumor, suggesting a cystic, rather than a solid lesion. Ancient schwannoma is a variant of schwannoma that can be confused with a malignant mesenchymal tumor because of increased cellular, nuclear pleomorphism, and hyperchromatism. The variant often shows cyst formation, calcification, hemorrhage, and hyalinization (5). Although there are no immunohistochemical stains that are specific for Schwann cells, immunohistochemistry can be used to exclude the diagnosis of other spindle cell tumors, like melanoma, leiomyoma, and rhabdomyosarcoma, thus lending support to the diagnosis of schwannoma. Electron microscopy can be used to demonstrate the cytoplasmic wide-spacing collagen that characterizes Schwann cells (1,5). Most can be successfully removed by a soft tissue approach; osteotomy is only occasionally necessary. Coronal magnetic resonance imaging in T1-weighted image showing circumscribed superior orbital mass. Sagittal magnetic resonance imaging in T1-weighted image showing ovoid shape of the superior orbital mass. Histopathology showing an area of Antoni A pattern with fascicles of nuclei with a ribbon arrangement. Once the tumor is removed, the optic disc swelling can resolve and the visual acuity can return to normal. Fundus photograph showing edema of left optic nerve, tortuous retinal blood vessels, and choroidal folds. Gross appearance of the circumscribed tumor immediately after removal through a superolateral orbitotomy. Fundus photograph taken 6 months later showing disappearance of the optic disc edema and reversal of the retinal vascular tortuosity. Fluorescein angiogram in the arterial phase 6 months after surgery showing transmission hyperfluorescence corresponding to the persistent choroidal folds. Illustrated is a clinicopathologic correlation of a large schwannoma in a 33-year-old man who declined a recommended neurosurgical approach and sought another opinion to see if it could be removed without a craniotomy. It was removed intact by way of a superolateral orbitotomy despite the fact that it protruded posteriorly through the superior orbital fissure. Appearance of mass immediately after removal by superotemporal orbitotomy with extraperiosteal approach and osteotomy. The nodular protrusion corresponds to where the tumor protruded posteriorly through the superior orbital fissure. Electron photomicrograph of tumor showing wide-spacing collagen in the cytoplasm (Luse body). She had an orbital mass that was found histopathologically after surgical excision to be a schwannoma. On lifting the eyelid, it was found that the left eye had complete absence of ocular motility ("frozen globe"). Magnetic resonance imaging in T1-weighted image, showing elongated mass extending through the optic foramen. Axial magnetic resonance imaging in T2-weighted image, further delineating the well-circumscribed mass. Coronal magnetic resonance imaging showing the location of the mass in the region of the optic foramen. The lesion was removed by a neurosurgical approach and there was no recurrence after 4 years of follow-up. The localized type is clinically and radiographically similar to schwannoma and is associated with neurofibromatosis type 1 in about 10% of cases (25). The diffuse type has a variable association with neurofibromatosis and the plexiform type is almost always seen in association with neurofibromatosis. The histopathologic findings of neurofibroma are discussed in more detail elsewhere (5). Management A patient with suspected localized orbital neurofibroma should be evaluated and managed as described for other localized orbital tumors. Clinical findings and imaging studies should be done and complete surgical excision should be considered for symptomatic lesions. However, surgical intervention is often necessary because of bothersome symptoms, threatened vision, or an unacceptable cosmetic appearance. In such instances, debulking surgery is often done, because complete surgical removal may not be possible. Depending on the extent of the disease, a combined approach with neurosurgeons and otolaryngologists may be prudent (19,24). Clinical Features Localized neurofibroma produces clinical symptoms and signs similar to schwannoma and other circumscribed orbital tumors and can manifest as proptosis, globe displacement, diplopia, and optic nerve compression. It is usually diagnosed in middle-aged or adult patients and, as mentioned, does not occur in patients with neurofibromatosis type 1. Localized neurofibroma can sometimes occur as multiple orbital tumors in patients without clear evidence of neurofibromatosis. Diffuse and plexiform neurofibromas are very similar clinically and radiographically, but are classified separately because of subtle histopathologic differences (5). They generally become clinically apparent in the first decade of life and show gradual progression, often with involvement of other periocular and ocular tissues, including the uveal tract. The diffuse, poorly defined mass can cause the classic S-shaped curve to the upper eyelid owing to subcutaneous involvement by the tumor. The plexiform form can be very extensive with massive involvement of the orbit, eyelids, and intraocular structures. In addition, patients with neurofibromatosis can have congenital defects in the sphenoid bone that can produce a characteristic pulsating proptosis similar to that seen with encephalocele. Diagnostic Approaches With orbital computed tomography and magnetic resonance imaging, localized neurofibroma appears as a circumscribed mass that is indistinguishable from schwannoma, described previously (6). Plexiform and diffuse neurofibromas show an irregular, ill-defined mass, often with extensive periorbital involvement, as mentioned. Pathology Localized orbital neurofibroma is circumscribed but lacks a true capsule. The classical case shows interlacing bundles of elongated spindle cells with variable quantities of mucoid material. Diffuse and plexiform neurofibromas are composed of a complex intertwining of bundles of enlarged nerves with proliferation of Schwann cells and endoneural fibroblasts in a mucoid Chapter 29 Orbital Peripheral Nerve Tumors 563 Selected References 1. Use of the carbon dioxide laser in the management of orbital plexiform neurofibromas. Another orbital manifestation is pulsating proptosis secondary to absence of the greater wing of the sphenoid bone but without an obvious tumor. Blepharoptosis and proptosis of the right eye in a 6-yearold boy with plexiform neurofibroma of the orbit. Note the advanced diffuse orbital tumor and the long section of grossly normal optic nerve. Note the absence of the sphenoid bone that allowed brain pulsations to be transmitted to the orbit. Chapter 29 Orbital Peripheral Nerve Tumors 565 Orbital Neurofibroma: Progression of Eyelid, Orbital, and Intraocular Neurofibromatosis In some instances, neurofibromatosis can involve almost every ocular structure and can demonstrate progressive growth and attain large proportions. One-month-old girl with type 1 neurofibromatosis involving the eyelid, orbit, and globe. Same child at age 4 months showing progression of proptosis and development of a cataract. Same child at 18 months showing progression of eyelid mass, proptosis, and subcutaneous involvement of right side of face. After much counseling, the parents requested attempted tumor debulking of the tumor and enucleation of the blind right eye, partly for cosmetic reasons. There is surgical anophthalmos but massive subcutaneous and orbital involvement continues to progress. Pathology of plexiform neurofibroma of orbit from same child showing enlarged nerve bundles typical of plexiform neurofibroma. A clinicopathologic correlation with computed tomography and magnetic resonance imaging in a 35-year-old woman is illustrated. Coronal computed tomography showing superior orbital mass with cystlike central portion. Coronal magnetic resonance imaging in T1-weighted image showing the superior orbital mass with low signal component. In the 58-year-old man illustrated here, there was no clinical evidence of neurofibromatosis except for three separate neurofibromas in the right orbit. It is possible that it could represent a forme fruste of von Recklinghausen neurofibromatosis. Proptosis of the right eye, which had been slowly progressive and painful for several years. Axial computed tomography showing retrobulbar mass and a separate mass in the temporal fossa. Coronal computed tomography showing the retrobulbar mass and a third mass in the inferior aspect of the orbit with displacement of the bony floor of the orbit. Appearance of the retrobulbar mass immediately after surgical removal of all three tumors. Multiple locations are involved in 10% to 20% of cases, especially if there is a familial predisposition (2). Prognosis the visual and systemic prognosis is generally good for patients with orbital paraganglioma. Paraganglioma of the orbit with extension to the middle cranial fossa: case report. Clinical Features Orbital paraganglioma can become apparent at any age with reported cases having their onset between 4 and 55 years (7). It has been reported to extend from the orbit into the middle cranial fossa (10) and to secondarily invade the orbit from an intracranial primary location (5). Diagnostic Approaches With imaging studies, orbital paraganglioma is usually a wellcircumscribed tumor that enhances with contrast agents and is often attached to a rectus muscle. Pathology and Pathogenesis Paraganglioma is an encapsulated tumor composed of clusters and nests of cells, called "zellballen" that are separated from one another by delicate vascularized septae, and that give the tumor a distinctive pseudoalveolar arrangement. Ultrastructurally, paraganglioma has small, dense core granules measuring 1,000 to 2,000 angstroms in diameter. The pathogenesis of paraganglioma is unknown, but some cases are familial and multifocal, suggesting a genetic mutation that is still undetermined. Management Orbital paraganglioma is almost never diagnosed clinically because it is rare and has no specific features. Axial magnetic resonance imaging in T1-weighted image in a 53-year-old man who presented with proptosis of left eye showing gadolinium enhancement of circumscribed, elongated mass filling most of the orbit. When it occurs in the head region, it usually involves the tongue or orbit (1­14). It is a rare tumor, with only 1 case among 1,264 patients with orbital lesions seen by the authors (2­4). Among the 17 patients, the mean age at diagnosis was 23 years and median age 18 years, with a range of 11 months to 69 years. If not treated early and effectively, it can become alarmingly aggressive and can fill the orbit and destroy the globe. The loosely cohesive cells sometimes float freely in the alveolar spaces, resembling the alveolar variant of rhabdomyosarcoma. A characteristic feature is the presence of typical periodic acidSchiff-positive, diastase-resistant intracytoplasmic crystalline structures that can be better demonstrated with electron microscopy (5,6,8). A leading possibility is that it represents a tumor of neural origin, perhaps a malignant variant of a paraganglioma (chemodectoma) or granula cell tumor (1,2). Alveolar soft-part sarcoma of the orbit: a clinicopathologic analysis of seventeen cases and a review of the literature. The ultrasonographic and radiologic features of a histologically proven case of alveolar soft-part sarcoma of the orbit. Histopathology of orbital alveolar soft-part sarcoma demonstrating the alveolar arrangement of the cells and periodic acidSchiff-positive crystals in cytoplasm. The child was treated elsewhere with corticosteroids with a diagnosis of orbital inflammatory pseudotumor, but the lesion continued to progress and biopsy revealed alveolar soft part sarcoma. Appearance of the patient 3 months later showing marked progression of the lesion. Histopathology showing periodic acid-Schiff-positive, diastase-resistant intracytoplasmic structures in the tumor cells. In the ocular region, it has been known to appear in the conjunctiva, caruncle, lacrimal sac, eyebrows, eyelids, and, rarely, the iris (11). Approximately 10% to 15% of reported cases from extraocular areas have been multifocal (2), but the orbital cases have all been solitary.

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