Malignant Tumors of Muscle Tissue Origin
Leiomyosarcoma
The leiomyosarcoma is a malignant tumor of smooth muscle origin. It is very rare in the oral cavity and whether it develops through malignant transformation of a leiomyoma or de novo is not known. It probably arises at these sites from smooth muscle cells, especially those found in blood vessel walls, and from undifferentiated mesenchymal cells.
Clinical Features
Leiomyosarcoma typically presents as painful, lobulated, fixed mass of the submucosal tissues in a middle-aged or older individual. It is exceedingly rare in children. Lesions are usually less than 2 cm in diameter at diagnosis and are slow-growing, but secondary ulceration of the mucosal surface has been reported. The cheek and floor of mouth were the most common sites. No gender predilection was apparent in these cases.
Histologic Features
Leiomyosarcoma is composed of fascicles of interlacing spindle-shaped cells with abundant eosinophilic cytoplasm and moderately large, centrally located, cigar-shaped or blunt-ended nuclei, often with mild atypia. Cellularity and cellular differentiation can vary considerably between tumors and between different areas of the same tumor. The well-differentiated lesion shows the spindled cells streaming or interweaving in fascicles in a fashion similar to that seen in leiomyoma. Nuclear palisading may be seen in several areas of the tumor, ischemic areas show stromal fibrosis and hyalinization (Fig. 2-97).
Figure 2-97 Leiomyosarcoma of oral cavity. Note the prominent cytoplasmic vacuoles indenting to the nuclear poles (Courtesy of Dr Juan Rosai).
The epithelioid variant, called malignant leiomyoblastoma or epithelioid leiomyosarcoma, is most prevalent in the gastrointestinal and genitourinary tracts and has rarely been reported in oral or pharyngeal locations.
Rhabdomyosarcoma
The rhabdomyosarcoma, the malignant tumor of striated muscle, is a relatively uncommon tumor in the oral cavity. According to Rubin, it is derived from primitive mesenchyme that retained capacity for skeletal muscle differentiation. The first published example of rhabdomyosarcoma was probably a tongue lesion reported in 1854.
There are four separate types of rhabdomyosarcoma based on histologic appearance, and many of the clinical features are quite characteristic of certain of these. The four forms of rhabdomyosarcoma are:
The embryonal form of rhabdomyosarcoma is recognized as having a marked predilection for occurrence in the head and neck area.
Clinical Features
This is the most common subtype observed in children, accounting for 60–70% of all rhabdomyosarcoma cases in this age group. These tumors can occur at any site, but they are most commonly observed either in the genitourinary region or the head and neck region. They occur more commonly in the head and neck area than any of the other forms. Stobbe and Dargeon have pointed out that this neoplasm arises chiefly from the orbital, facial, and cervical musculature. Of 15 cases reported by Stobbe and Dargeon, the sites of occurrence included the orbit and inner canthus, the tonsil, soft palate, mastoid, internal ear and parotid, zygoma, and temporal and cervical regions. The average age of this group of patients was six years, ranging from 16 months to 16 years, with no gender predilection. In another review of 37 cases of this tumor by Moore and Grossi, the cheek, mandible and gingiva were found to be additional sites of occurrence. The youngest patient in this series was seven weeks, although there is one case on record of an infant born with an embryonal rhabdomyosarcoma of the floor of the mouth. In a series of 48 patients with embryonal rhabdomyosarcoma reported by Lawrence and his associates, the ages at diagnosis ranged from 16 days to 14 years, with a mean of five years. Finally, a series of 11 cases of embryonal rhabdomyosarcoma of the oral soft tissues have been reported by O’Day and his associates. The age of these patients ranged between 2 and 41 years of age, with a mean of 16 years. Of these oral tumors, four were in the soft palate, three in the cheek and one each in the upper and lower labial folds, lower buccal fold and lateral aspect of the tongue (Fig. 2-98).
Figure 2-98 Embryonal rhabdomyosarcoma. The rapidity of growth of this type of neoplasm can be judged by the fact that the two illustrations of this lesion, originating in the buccal mucosa, were taken only 14 days apart.
Botryoid rhabdomyosarcoma (sarcoma botryoides) has been long recognized as a malignant tumor of the vagina, prostate, and base of the bladder in young children. Today, it is generally accepted as a variant of embryonal rhabdomyosarcoma and has been reported also involving the maxillary sinus, nasopharynx, common bile duct and middle ear. This tumor accounts for 10% of all rhabdomyosarcoma cases. It was formerly separated out as an entity because of its unusual clinical growth pattern.
This subtype making up about 20% of all rhabdomyosarcomas in an analysis of 110 cases by Enzinger and Shiraki, is reported to occur much earlier in life, generally between 10 and 20 years of age with a median of 15 years. However, the range in this group was five months to 58 years. While the majority of cases of this type also occurred in the extremities, approximately 18% were found in the head and neck region.
Pleomorphic rhabdomyosarcoma (least common of all rhabdomyosarcoma) is a form of the tumor which, according to Patton and Horn, occurs more frequently in the extremities than in other sites and is generally seen in older individuals. In a series of 19 cases reported by these authors, the average age was 53 years.
The chief presenting complaint of the patient with rhabdomyosarcoma, generally irrespective of the histologic type, is usually swelling, but pain may be present if there is nerve involvement. Depending upon the site of the lesion, the following phenomena may be recognized: divergence of an eye, abnormal phonation, dysphagia, cough, aural discharge or deviation of the jaw. The lesions are occasionally ulcerated and may invade underlying bone and develop distant metastases. The most common site of presentation is head and neck region (35 %).
Histologic Features
Embryonal rhabdomyosarcoma has been described by O’Day and his coworkers as exhibiting a mixture of four cell types:
• Eosinophilic spindle cells, usually arranged in interlacing fascicles.
• Round eosinophilic cells, large and intermediate in size, with a small nucleus and a granular eosinophilic cytoplasm, generally interspersed among other cell types.
• Broad elongated eosinophilic cells, occasionally with cross-striations.
• Small round and spindle cells with dark-staining nuclei and little cytoplasm (Fig. 2-99 C).
The more well-differentiated tumors demonstrate elongated, strap-shaped or tadpole-shaped rhabdomyoblasts. The background stroma consists of moderately loose to dense fibrous tissue and may be quite scant, myxoid zones are commonly seen in the stroma.
Pleomorphic rhabdomyosarcoma is composed chiefly of spindle cells in a haphazard arrangement. These cells are generally large and show considerable variation in appearance. The nuclei are ovoid or elongated with packed chromatin. A characteristic feature of this form of tumor is the large bizarre cells, the nuclei situated often in an expanded end of the cell, the ‘racquet’ cell. ‘Strap’ and ‘ribbon’ cells typically show processes of long streaming cytoplasm. Mitoses, particularly atypical, are common. The cytoplasm is eosinophilic, and intracytoplasmic longitudinal fibrils as well as transverse cross-striations may be seen. Cytoplasmic vacuoles are also present as a result of large amounts of glycogen in the cell (Fig. 2-99 A). This tumor is often so undifferentiated that the identification of the cell of origin is difficult or impossible. Positive immunostains for desmin and myoglobin are very helpful in such cases.
Alveolar rhabdomyosarcoma is comprised of relatively small, poorly differentiated round and oval cells aggregated into irregular clusters or nests separated by fibrous septa. Degenerated cells in the center of the clusters show lack of cohesiveness, while the peripheral cells adhere in a single layer to the septal walls. Multinucleated giant cells may be seen and mitotic figures are common and sometimes bizarre. It is differentiated from the alveolar soft part sarcoma by its less regular tissue pattern and more pleomorphic cells.
An occasional variant, referred to as the botryoid type, demonstrates a diffuse myxoid or mucoid matrix with sparsely scattered primitive mesenchymal cells. The characteristic feature of this type is a peripheral zone of increased cellularity, sometimes known as the ‘cambium layer’.
Regardless of the histologic subtype, special stains are often quite useful for differentiating rhabdomyosarcoma from other neoplasms. The trichrome stain colors rhabdomyoblasts bright red while myofilaments and cross-striations are stained by PTAH (deep purple color). Myxoid stroma may be positive for hyaluronidase with acid mucopolysaccharide staining, although many other tumors also have positive stroma with these stains.
Alveolar Soft-Part Sarcoma (Malignant granular cell myoblastoma)
The alveolar soft-part sarcoma is a tumor of uncertain histogenesis originally described under this name by Chris-topherson and his coworkers in 1952. It is a rare tumor, thought by some investigators to be of striated muscle origin, although it differs in some respects from the alveolar type of rhabdomyosarcoma. Other workers believe that it may be of neural origin and a variant of malignant granular cell tumor or a malignant nonchromaffin paraganglioma. Studies showed alveolar soft-part sarcomas are myogenic by immunophenotyping in a number of cases. In recent years, pathologists have shown this tumor to be a variant of a rhabdomyosarcoma, a sarcoma of skeletal muscle. Chromosome rearrangement at 17q25 and Xp11.2 in alveolar soft-part sarcoma was demonstrated.
Clinical Features
The initial report of Christopherson indicated that this is predominantly a tumor of females, occurring usually in the teens or early 20s. A study of 53 cases by Lieberman and his associates has confirmed these findings. Of the 53 patients, 34 were female and 19 were male. The average age of their male patients was 30 years but that of their female patients, only 20 years. Occasional cases in older adults are reported.
Approximately one in four lesions occur in the head and neck region, usually the oral cavity, pharynx and orbit. However, the greatest predilection is for the muscles of the extremities, although lesions in the tongue and floor of the mouth have been reported by Caldwell and his associates. Only one of the 53 cases reported by Lieberman and his associates was intraoral and this occurred in the tongue. Font and his associates have reported 17 cases involving the orbit. The lesions are usually slow-growing, well-circumscribed masses with no distinguishing gross features.
Histologic Features
This tumor is composed of large cells with a finely granular cytoplasm that is not as eosinophilic as the cell of the rhabdomyosarcoma. The lesional cell is large and polygonal with a distinct cell border, a vesicular nucleus, and dense, abundant granular, eosinophilic or vacuolated cytoplasm. There is minimal variation in size and shape between cells and mitotic activity is sparse. These cells have a uniform pseudoalveolar or organoid pattern, arranged in relation to numerous delicate endothelium-lined vascular channels and septa (Fig. 2-100). The pattern is reminiscent of that seen in the nonchromaffin paraganglioma.
Vascular invasion is a frequent finding. Reticulin stains will enhance the organoid arrangement of the tumor cells.
Marshall and Horn reported that the alveolar soft-part sarcoma consistently showed a strongly positive periodic acid-Schiff (PAS) reaction before and after treatment with diastase, similar to the benign granular cell myoblastoma, but in contrast to the alveolar rhabdomyosarcoma in which the PAS-positive material is removed by digestion with diastase. This PAS-positive material in the cytoplasm of the alveolar soft-part sarcoma, described by Font and his coworkers as a highly characteristic and virtually pathognomonic finding of this lesion, represents crystalline structures composed of a protein-carbohydrate complex. They appear to form by coalescence of peculiar membrane-bound granules that exhibit acid-phosphatase activity.
Treatment and Prognosis
Radical surgical excision is the accepted treatment for this lesion because of the high frequency of recurrence, metastases and death of patients. Marshall and Horn reported the recurrence or metastatic rate as 70%, five-year survival being uncommon. Lieberman and his coworkers stated that they knew of no lifetime cures.
Benign Tumors of Nerve Tissue Origin
Traumatic Neuroma (Amputation neuroma)
Traumatic (post-traumatic) or amputation neuroma is not a true neoplasm, but rather an exuberant attempt at repair of a damaged nerve trunk, i.e. a hyperplasia of nerve fibers and their supporting tissues. It most frequently follows accidental or purposeful sectioning of a nerve and may be incidental to difficult extraction. Cases also have occurred after an accident in which the lip or tongue was deeply lacerated by the teeth and nerve fibers were inadvertently severed.
Degeneration of the distal portion of the nerve after severance of the nerve fibers begins with swelling, fragmentation and disintegration of the axis cylinders and myelin sheaths. Macrophages serve to remove this tissue debris. The neuri-lemmal sheaths or tubes shrink until the distal degenerated fibers consist only of strands of connective tissue and the neurilemma. The nerve does not disappear completely.
Repair of a damaged nerve begins with proliferation of the axis cylinders, the cells of the neurilemmal sheaths and the endoneurium. Regeneration is facilitated by the persistence of the neurilemmal tubes, since new fibers proliferate through them and Schwann cells multiply around them.
Reinnervation usually occurs; unless the proliferating proximal end meets some obstruction, such as scar tissue or a malaligned bone, in which case the nerve continues to proliferate into an unorganized bulbous or nodular mass of nerve fibers and Schwann cells in varying proportions. This constitutes a traumatic neuroma. The pathogenesis of this lesion has been reviewed by Swanson.
Clinical Features
The oral traumatic neuroma usually appears as a small nodule or swelling of the mucosa, typically near the mental foramen, on the alveolar ridge in edentulous areas or on the lips or tongue (Fig. 2-101). A central lesion within the substance of the bone associated with a nerve trunk may also occur. This is a slowly growing lesion and seldom reaches a size greater than a centimeter in diameter (Fig. 2-101 A, B).
Figure 2-101 Traumatic neuroma. (A) The patient presented with several pedulous tumour masses of the facial skin. The patient had sustained a fracture of the mandible many years previously that had resulted in the abnormal course of the mandibular nerve seen in the lateral jaw radiograph (B). This nerve was subsequently sectioned for ‘relief of pain’. The photomicrographs (C, D) reveal the hyperplasia of nerve fibers in a fibrous stroma. (A, Courtesy of Dr K Murugesan, Maxillofacial Surgeon, Chennai)
Digital pressure may cause considerable pain locally, and in some instances along the course of the nerve involved. Reflex neuralgia with distant pain associated with the face, eyes and head has been recorded. Traumatic neuroma has been discussed in detail by Robinson and Slavkin and by Sist and Greene, who also reported 31 cases.
The palisaded, encapsulated neuroma is not a form of traumatic neuroma but may represent a primary hyperplasia of nerve fibers, the axons and their sheath cells. An alternative theory is that it represents a benign neoplasm. The lesion was first described by Reed and his coworkers as a clinically distinctive, solitary, benign cutaenous tumor occurring with equal frequency in both sexes and limited in its anatomic distribution (with rare exceptions) to areas bordering mucocutaneous junctions predominantly on the face. A case on the lower lip has been reported by Tomich and Moll.
Histologic Features
The histologic appearance of the neuroma is characteristic and shows a mass of irregular and often interlacing neurofibrils and Schwann cells situated in a connective tissue stroma scant or predominant. Much of this connective tissue is probably derived from the perineurium. The proliferating nerve fibers themselves may occur either in small discrete bundles or spread diffusely throughout the tissue (Fig. 2-101 C, D). Care must be taken to differentiate this lesion from both the neurofibroma and neurilemmoma. The histologic, histochemical and ultrastructural aspects of walle-rian degeneration of nerves have been described by Fisher and Turano and by Sist and Greene.
Treatment and Prognosis
Because of the progressive nature of this lesion and the associated pain, it is best treated by surgical excision along with a small proximal portion of the involved nerve. Recurrence is not common even though the sectioning of the nerve during treatment is similar to the injury that preceded the development of the tumor.
Multiple Endocrine Neoplasia Syndrome (MEN syndrome [MEN III, MEN IIb])
The multiple endocrine neoplasia (MEN) syndromes are characterized by tumors of neuroendocrine origin. The type, MEN III syndrome, also called MEN IIb syndrome or multiple mucosal neuroma syndrome, was initially described by Wagenmann in 1922.
The disease is associated with adrenal pheoc hromocytoma, medullary thyroid carcinoma, diffuse alimentary tract ganglio-neuromatosis, and multiple small submucosal neuroma nodules of the upper aerodigestive tract. The disease is inherited as an autosomal dominant trait, although many cases appear to be spontaneous mutations.
The affected individual has a tall, lanky, marfanoid body type, with a narrow face and perhaps with muscle wasting. The adrenal and thyroid tumors typically do not present until after puberty while the oral mucosal neuromas usually develop during the first decade of life. Mucosal neuromas are extremely rare, perhaps unheard of, outside of the MEN III syndrome. MEN syndromes are caused by mutations of the RET protooncogene, an important regulator of neural crest development and the receptor of glial derived neurotrophic factor (GDNF).
Clinical Features
The oral mucosal neuroma of this disease presents as a 2–7 mm yellowish-white, sessile, painless nodule of the lips, anterior tongue and buccal commissures. Usually there are two to eight (or more) neuromas, with deeper lesions having normal coloration. There may be enough neuromas in the body of the lips to produce enlargement and a ‘bumpy lip’ appearance. Similar nodules may be seen on the eyelids, sometimes producing eversion of the lid, and on the sclera. Facial skin, especially around the nose, may also be involved.
Abnormal laboratory values are part of this syndrome. When a medullary thyroid carcinoma is present, serum and urinary calcitonin levels are elevated. When a pheochromocytoma is present, there often is an increase in the serum levels of vanillylmandelic acid (VMA) and altered epinephrine/ norepinephrine ratios.
Histologic Features
The mucosal neuroma is comprised of a partially encapsulated aggregation or proliferation of nerves, often with thickened perineurium, intertwined with one another in a plexiform pattern. This tortuous pattern of nerves is seen within a background of loose endoneurium-like fibrous stroma. Individual nerves flow in fascicles of two or three fibers and are histologically normal except for occasional hyperplasias and bulbous expansions.
Inflammatory cells are not seen in the stroma and dysplasia is not present in the neural tissues. There may be close microscopic similarity with traumatic neuroma, but the streaming fascicles of mucosal neuroma are usually more uniform and the intertwining nerves of the traumatic neuroma lack the thick perineurium of the mucosal neuroma.
Treatment and Prognosis
The mucosal neuromas of this syndrome are asymptomatic and self-limiting, and present no problem requiring treatment. They may, however, be surgically removed for esthetic purposes or if they are being constantly traumatized. It is strongly suggested that other family members may also be evaluated for MEN III.
Neurofibroma (Neurofibromatosis, von Recklinghausen’s disease of the skin, fibroma molluscum)
The neurofibroma is a benign tumor of nerve tissue origin, derived from the cells that constitute the nerve sheath. Neurofibroma is seen either as a solitary lesion or as part of the generalized syndrome of neurofibromatosis (von Recklinghausen disease of the skin). The solitary form does not differ from the disseminated form or the multiple form of the disease except that systemic and hereditary factors present in the disseminated form are absent in the solitary type.
The cell of origin for neurofibroma has not been definitively identified, but is generally believed to arise from the perineural fibroblasts which are neuroectodermal in origin. The cause of solitary neurofibroma is unknown. However, neurofibromatosis is inherited as an autosomal dominant trait with a high degree of penetrance but variable expressivity. As many as 50% of cases are reported to be the result of spontaneous mutation. Recently, two subsets have been defined: one is associated with the neurofibromatosis type 1 (NF1), gene mutations of the tumor suppressor genes coding for neurofibromin on chromosome 17q11.2, and the other is associated with the neurofibromatosis type 2 (NF2), gene mutations of the tumor suppressor genes coding for schwannomin on chromosome 22q12.1.
Clinical Features
Neurofibromatosis, though not an exceedingly common disease, is by no means a clinical rarity. It has been reported in all races and does not exhibit a significant consistent sex predilection for occurrence. The hereditary nature of the disease has been recognized for many years and it is now known that it is inherited as a simple autosomal domi nant trait with variable penetrance and a 50% mutation rate. It occurs with a frequency of one case in approximately 3,000 births in the general population. The birth incidence of NF1 lies between 1 in 2,500–3,300 and its prevalence in the population is 1 in 5,000. The birth incidence of NF2 lies between 1 in 33,000–40,000 with a prevalence within the population of 1 in 210,000.
The great clinical significance of neurofibromatosis, aside from the cosmetic problem, lies in the fact that in some patients malignant transformation subsequently occurs in one or more of their lesions. The incidence of sarcomatous transformation in neurofibromatosis has been placed at approximately 15% of all cases by Hosoi and by Preston and his coworkers. The type of sarcoma has been variously described as fibrosarcoma, spindle cell sarcoma and neurogenic sarcoma. However, solitary neurofibromas seldom undergo malignant transformation. Preston and his coinvestigators have reported other associated pathologic lesions, including osseous changes, mental disorders, congenital defects and ocular disease occurring in approximately 20% of their patients.
Oral Manifestations
Oral lesions occur in patients with von Recklinghausen’s disease of skin, but the percentage of patients presenting such manifestations is not definitely known. In the series reported by Preston and his associates, intraoral neurofibromas were present in 7% of the patients. In contrast, Cherrick and Eversole reported that 20% of a series of 19 cases of intraoral neurofibroma occurred in association with von Recklinghausen’s disease.
Discrete, nonulcerated nodules, which tend to be of the same color as the normal mucosa, may be noted, usually occurring on the buccal mucosa, palate, alveolar ridge, vestibule and tongue (Fig. 2-102 A, B). Other cases exhibit diffuse masses of tissue which may involve the palate, buccal tissues and alveolar ridges and are composed of the same type of tissue as that seen in the isolated lesions. In addition, macroglossia due to diffuse involvement of the tongue is well recognized and has been reviewed by Ayres and his associates. Chen and Miller have also reported a series of 55 cases of benign nerve tumors of the oral cavity and noted the preponderance of neurofibroma over the neurilemmoma.
Figure 2-102 Neurofibroma. (A) The patient presented several pendulous, pigmented tumor masses of the skin. (B) Neurofibroma of the palate in a patient without apparent neurofibromatosis. (C) Multiple neurofibromas of the face. (D) Neurofibromatosis showing spindled, wavy nuclei in fascicular form.
Occasional cases of neurofibroma located centrally within the jaw are seen. These are generally in the mandible, associated with the mandibular nerve, and radiographically show a fusiform enlargement of the mandibular canal. Involvement of the trigeminal nerve may cause facial pain or paresthesia. Ellis and his associates have also discussed central nerve sheath tumors of the jaws and found that very few of these reported were associated with multiple neurofibromatosis.
Histologic Features
The neurofibroma exhibits considerable variation in histologic structure but is generally composed of a proliferation of delicate spindle cells with thin, wavy nuclei intermingled with neurites in an irregular pattern as well as delicate, intertwining connective tissue fibrils. Cellular and myxoid pat-terns predominate; organoid features are not present. Melanocytes may sometimes be found in the tumor and mast cells are common. The lesions may or may not be well circumscribed.
In plexiform neurofibroma, the pattern may be that of distorted masses of myxomatous peripheral nerve tissue still within the perineural sheath are scattered within a collagenrich matrix (Fig. 2-103). This histologic picture is considered to be virtually diagnostic of neurofibromatosis, even in the absence of other manifestations. There are reports of the existence of solitary plexiform neurofibromas unassociated with any established syndromes, occurring in the oral cavity (tumors on the buccal mucosa and gingiva) (Alatli C et al, 1996).
Figure 2-103 Plexiform neurofibroma of the gingiva. Abundant nerve tissue in fascicles and collagenous ibrous stroma in ordered arrangement.
The lesional cells are uniformly positive for S100 protein, signifying that they originate from neural crest-derived tissue. Antibodies to epithelial membrane antigen, CD57, and collagen IV are of secondary value and are used only when histologic differentiation with other neural tumors is difficult.
Treatment
Solitary oral neurofibromas are usually treated by surgical excision, depending on the extent and the site. Surgical removal may result in recurrence, and multiple recurrences have been associated with malignant transformation (5–15%). However, for neurofibromas associated with neurofibromatosis, surgical removal is attempted only for functional or cosmetic reasons. Genetic counseling and evaluation of other family members should be performed for those suspected to be affected by a syndrome.
Neurolemmoma (Neurilemmoma, perineural fibroblastoma, schwannoma, neurinoma, lemmoma)
The neurolemmoma is a rather common tumor accepted by most investigators today to be derived from Schwann cells. Neurites are not a component of the tumor as in the neurofibroma but may be found on the surface of the tumor. Tissue culture studies by Murray and Stout, who cultivated this tumor in vitro, lend credence to the idea of the Schwann cells as the source of origin.
Clinical Features
Available clinical evidence indicates that the neurolemmoma is a slowly growing lesion and is usually of long duration at the time of presentation by the patient. An occasional tumor does exhibit a relatively rapid course, however, the lesion does occur with some frequency in patients with neurofibromatosis. It may arise at any age, cases having been reported even during the first year of life as well as in elderly patients. There is no gender predilection.
Despite the fact that these tumors originate from nerve tissue, they are usually painless unless they are causing pressure on adjacent nerves rather than on the nerve of origin. The presenting symptom of the majority of patients is only the presence of a tumor mass.
Oral Manifestations
The head and neck are rather common regions for the development of this neoplasm, as shown by the report of Ehrlich and Martin, and a variety of oral and paraoral locations have been the site of development of the neurolemmoma. Furthermore, in a series of 303 patients with benign solitary neurolemmomas reported by Das Gupta and his associates, 136 occurred in the head and neck. Reported cases of intraoral soft-tissue neurolemmomas have been reviewed by Hatziotis and Asprides with the following frequency of occurrence: tongue, 59 cases; palate, 11 cases; floor of mouth, 10 cases; buccal mucosa, 9 cases; gingiva, 6 cases; lip, 6 cases; and vestibule, 5 cases. Other cases have involved the maxillary sinus and salivary glands, as well as the retropharyngeal, nasopharyngeal and retrotonsillar areas.
In addition, the neurolemmoma has been reported as a central lesion within bone, chiefly the mandible, apparently arising from the mandibular nerve. Eighteen such cases have been reviewed by Eversole, which Ellis and his coworkers have added additional cases.
The soft-tissue lesion is usually a single, circumscribed nodule of varying size that presents no pathognomonic features (Fig. 2-104 A, B). It may resemble any of a number of benign oral soft-tissue lesions. The central lesions in bone may produce considerable destruction of bone with expansion of the cortical plates and thus resemble a more serious lesion (Fig. 2-104 C). Pain and paresthesia may accompany these central lesions of bone.
Histologic Features
The microscopic picture of the neurolemmoma is characteristic and can seldom be confused with that of other lesions. The tumor is classically described as being composed of two types of tissue, Antoni type A and Antoni type B. Antoni type A tissue is made up of cells with elongated or spindle-shaped nuclei which are aligned to form a characteristic palisading pattern, while the intercellular fibers are arranged in parallel fashion between rows of nuclei. These fibers in some planes will give the impression of occurring in whorls or swirls. Antoni type B tissue does not exhibit this characteristic palisading, but rather a disorderly arrangement of cells and fibers with areas of what appears to be edema fluid and with the formation of microcysts. Verocay bodies, small hyaline structures, are also characteristically present in this tumor (Fig. 2-104 D). Of great importance is the fact that in nearly all instances the tumor is encapsulated.
Treatment and Prognosis
The treatment of the neuro-lemmoma is surgical excision. Like other nerve tumors, this lesion is not responsive to X-ray radiation. Since it is an en-capsulated tumor, little difficulty is usually encountered in its complete removal, but it has been suggested that in instances in which complete removal cannot be accomplished, a portion of tumor may be left without risk of recurrence. Such a pro-cedure is of poor clinical practice, however, except possibly in cases in which complete removal of the tumor would neces-sitate extensive sacrifice of structures and results in deformity. Recurrence is uncommon.
The neurolemmoma does not undergo malignant transfor-mation, as may the neurofibroma after numerous episodes of surgical tampering.
Melanotic Neuroectodermal Tumor of Infancy (Pigmented ameloblastoma, melanoameloblastoma, retinal anlage tumor, melanotic progonoma, melanotic epithelial odontoma, pigmented teratoma, atypical melanoblastoma, melanotic adamantinoma, pigmented epulis, retinal choristoma, retinoblastic teratoma, congenital melanocarcinoma)
The melanotic neuroectodermal tumor of infancy (MNTI) is a relatively uncommon osteolytic-pigmented neoplasm that primarily affects the jaws of newborn infants. Initially it was reported by Krompecker in 1918 as a congenital melanocarcinoma. Various theories suggested its origin from the odontogenic apparatus, the pigmented anlage of the retina, or the sensory neuroectodermal tissues.
In 1966, Borello and Gorlin reported a case with high urinary excretion of vanillylmandelic acid (VMA), suggesting a neural crest origin, and they proposed the term melanotic neuroectodermal tumor of infancy. Since then, numerous histochemical, immunohistochemical, electron microscopic, and tissue culture studies have supported the neural crest origin and confirmed the preferred term of melanotic neuroectodermal tumor of infancy.
Clinical Features
More than 90% of cases present within the first year of life, usually from age one to six months. The mean age of patients with MNTI is 4.3 months. Although extremely rare, cases of MNTI have been reported in adults. The sexual predilection is nearly equal, with a male-to-female ratio of 6 : 7.
More than 90% of MNTI occur in the head and neck region, with most on the anterior part of the maxillary ridge. Other common sites include the skull, the mandible, the epididymis, and the brain. Rare lesions have been reported in the shoulder, the skin, the femur, the mediastinum, and the uterus.
The majority of reported cases have been rapidly growing, nonulcerated, darkly pigmented lesions which have given a radiographic appearance of an invasive malignant neoplasm. In its typical premaxillary position, the tumor can displace or destroy the developing deciduous and permanent dentition. It can present as unilocular, or rarely as multiloculated radiolucency.
All the hematologic and blood chemistry values are within the normal range. The only finding in some but not all patients with MNTI is an increase in the urinary level of VMA, but shows no correlation with its clinical behavior. Elevated VMA has been reported in other tumors of neural crest origin, such as pheochromocytoma, ganglioneuroblastoma, retinoblastoma, and neuroblastoma.
Histologic Features
The microscopic appearance of this tumor is characteristic due to its distinct biphasic pattern. It is usually a nonencapsulated, infiltrating tumor mass of cells arranged in a pattern of alveolus-like spaces lined by cuboidal or large polygonal cells, which have pale abundant cytoplasm and nuclei with finely dispersed chromatin, many of which contain melanin pigment. Fontana stain can be used to demonstrate the melanin pigment. The central portions of the alveolar spaces contain many small round neuroblast-like cells which show little cytoplasm and exhibit a round, deeply staining nucleus. A moderately vascular fibrous stroma supports the tumor cells (Figs. 2-105, 2-106).
Figure 2-105 Melanotic neuroectodermal tumor of infancy. There is a rapidly growing mass present on the anterior maxilla. (A) The radiograph shows diffuse destruction of bone, suggestive of a malignant neoplasm. (B) The photomicrographs demonstrate typical alveolus-like structures lined by an irregular layer of cuboidal cells containing melanin pigment, (C) and (D) (A, Courtesy of Dr Jan L Silagi).
Treatment and Prognosis
The treatment of choice for MNTI is surgical excision, and it is usually curative. This treatment can usually be accomplished with a partial maxillectomy. Many clinicians advocate a 5 mm margin of healthy tissue to be included with the surgical specimen.
Local recurrence has been documented in 10–60% of patients. Overall, the average recurrence rate is 15–20%. Approximately 1% of tumors are malignant, with only rare tumors producing metastases.
Malignant Tumors of Nerve Tissue Origin
Malignant Peripheral Nerve Sheath Tumor (Malignant schwannoma, malignant neurilemmoma, neurogenic sarcoma, neurofibrosarcoma)
Malignant peripheral nerve sheath tumor (MPNST) is now the preferred name for the spindle cell malignancy of peripheral nerve Schwann cells. It represents approximately 10% of all soft tissue sarcomas and its diagnosis has been called ‘one of the most difficult and elusive diagnoses in soft tissue diseases’. Up to half of all cases of MPNST are diagnosed in persons with neurofibromatosis I (4% of patients with neurofibromatosis I). About one in 10 cases are associated with irradiation. The preferred site is the lower extremities, but a small percentage of these lesions occur in the head and neck region, usually associated with the large cranial nerves, especially the trigeminal nerve.
Clinical Features
These tumors commonly occur in per-sons of 20–50 years of age, but children and elderly persons may also be affected. Lesions which develop in persons with neurofibromatosis I typically occur a decade or more earlier than those in nonsyndrome patients. There is a slight predi-lection toward males in sporadic cases, but within the sub-group of patients with neurofibromatosis I, 80% of lesions are found in males. The most common head and neck area of involvement is the neck, but its occurrence in oral cavity is extremely rare. When it occurs in the oral cavity it is usually seen arising from the tongue or soft palate. The lip, gingiva, palate and buccal muosa have been sites of involvement. In the central tumors, the mandible or mandibular nerve is more frequently affected than the maxilla.
In some instances there is no complaint other than the presence of a mass, although in other cases pain and/or paresthesia, muscle weakness are present. At surgery, attachment to a major nerve trunk is not unusual, and the surgeon may notice cystic degeneration or hemorrhage within the lesional stroma.
Radiographic Features
The radiograph may reveal a diffuse radiolucency characteristic of a malignant infiltrating neoplasm (Fig. 2-107). On the other hand, the appearance may be that of only a smooth radiolucency, such as dilatation of the mandibular canal when the tumor is originating from this nerve. When this appearance prevails, the lesion may be mistaken on the radiograph for a benign one.
Histologic Features
The MPNST resembles fibrosarcoma in its overall organization, but the spindled lesional cells demonstrate the wavy or comma-shaped outline and nuclear contour of Schwann cells. The cytoplasm of lesional cells is usually indistinct and slightly eosinophilic. Cellular and nuclear pleomorphism may be quite pronounced and mitotic activity is usually high. Spindle cells are arranged in sweeping fascicles interspersed with hypocellular and myxoid regions.
Histologically MPNST may be classified into three major categories with epithelioid, mesenchymal or glandular characteristics.
The epithelioid variant demonstrates plump, rounded or ovoid epithelioid cells scattered throughout the spindled lesional cells, usually in rather small numbers and in well defined clusters. These cells may have vesicular or hyperchromatic nuclei and may bear slight resemblance to the cells of the amelanotic melanoma.
Some MPNST lesions show rhabdomyoblastic differentiation leading to the common use of the diagnostic term Triton tumor. The spindle cells are interspersed with large, plump, rounded or strap cells with eosinophilic, fibrillar cytoplasm and with cross-striations in the cytoplasm. These cells may be clustered and must be distinguished from simple entrapment of striated muscles fibers.
The glandular MPNST contains areas with usually welldifferentiated ductal structures lined by simple, stratified, cuboidal or columnar epithelial cells with occasional goblet cells. The lumen may contain PAS-positive, diastase-resistant mucus.
Rare MPNST cases contain multiple sarcomatous tissue types, especially osteosarcoma, chondrosarcoma and angiosarcoma. These have sometimes been indistinguishable from the malignant mesenchymoma of soft tissue.
MPNSTs may resemble fibrosarcoma and may require immunohistochemistry and EM evaluation to discern useful diagnostic differences. The other sarcomas most closely resembling this tumor are leiomyosarcoma and monophasic synovial sarcoma. In the oral cavity, the synovial sarcoma is so rare as to be excluded from the differential diagnosis, while the spindle cell of the leiomyosarcoma has a more distinct eosinophilic cytoplasm and a quite blunted nucleus.
Distinguishing the MPNST from a benign nerve sheath tumor is usually not difficult, but some neurofibromas may be quite cellular and may contain occasional pleomorphic cells. In such cases, presence or absence of mitotic activity is usually the determining feature.
Treatment and Prognosis
The MPNST of the oral region is treated by wide surgical excision, but local recurrences are common and hematogenous metastasis occurs in at least half of treated cases. The tumor is resistant to radiotherapy and chemotherapy, and those occurring in neurofibromatosis I behave in a more aggressive fashion than those not associated with the syndrome. Overall, the five-year survival for MPNST is 40–75%.
Olfactory Neuroblastoma (Esthesioneuroblastoma, esthesioneuroepithelioma)
The olfactory neuroblastoma is a rare tumor apparently originating from the olfactory apparatus, and therefore, found most frequently in the nasal cavity and nasopharynx. Occasional cases have been reported either originating in or invading the maxillary sinus. Such examples have been described by Church and Uhler and by Mashberg and his associates.
Clinical Features
The lesion generally appears as a painful swelling in the area of the nasal fossa. It is an invasive, destructive tumor, but only rarely metastasizes, chiefly to cervical lymph nodes and lungs. In contrast to other types of neuroblastoma, this lesion usually occurs in adults rather than children.
Histologic Features
The appearance of the tumor char-acteristically is one of densely packed masses of small darkly staining cells each with a poorly defined eosinophilic cyto-plasm and a regular round vesicular nucleus, sometimes with stippled chromatin. Rosette formation is common. This is a pseudoglandular structure lined by a single layer of nonciliated columnar cells with a basal nucleus and a cuticular border at the apex of the cell. These resemble the sustentacular and olfactory cells of the olfactory mucosa. Eosinophilic neurofibrils extend into the lumen from the cell borders. Pseudorosettes also occur. Mitotic figures are often present, but not in large numbers. The stroma has a fibrillar neuroid pattern. The difficulty in microscopic diagnosis, however, has been emphasized by Oberman and Rice.
Metastatic Tumors of Jaws (Metastatic tumors to oral cavity, metastatic tumors to the oral mucosa)
Metastatic tumors to the oral region are uncommon and may occur in the oral soft tissues or jawbones. Because of their rarity, metastatic tumors to the oral region are challenging to diagnose. Therefore, they should be considered in the differential diagnosis of inflammatory and reactive lesions that are common to oral region.
Even though the oral region is not a preferred site for metastatic deposits, approximately 30% of oral metastases are the first sign of the disease. In such cases, tumor cells bypass the filtration of the lungs, probably through the valveless vertebral venous plexus.
The pathogenesis of the metastatic process in the jawbones is not clear. In the skeleton, bones with red marrow are the preferred sites for metastatic deposits. Jawbones have little active marrow, especially in elderly persons. Remnants of hematopoietic active marrow can be detected in the posterior areas of the mandible. Since the mode of spread is usually hematogenous, tumor cells tend to be deposited in this vascular medullary tissue.
In dentulous patients, 80% of the metastatic tumors to the oral soft mucosa are found in the attached gingiva, whereas in edentulous patients, metastatic lesions are equally distributed between the tongue and the alveolar mucosa, and with much less frequency, the remaining mucosa. The rich capillary network of chronically inflamed gingiva has been suggested as a mechanism that entraps malignant cells. The proliferating capillaries have a fragmented basement membrane through which tumor cells can more easily penetrate.
Clinical Features
Most metastatic tumors to the oral region occur in patients aged 40–70 years. On average, patients with metastases to the jawbones are younger (aged 45 years) than those with metastases to the oral soft tissues (aged 54 years).
Metastatic tumors to the oral region are uncommon and account for approximately 1% of all malignant oral tumors. However, autopsies of patients with carcinoma reveal a higher frequency of metastatic deposits in the jawbones, which are not manifested clinically. Metastatic tumors to the jawbones are more frequently reported than those in the oral mucosa (Fig. 2-108).
Figure 2-108 (A) Metastatic carcinoma of the lower alveolus. (B) Primary from prostate. (C) An osteolytic lesion of the mandible. (D) Photomicrograph of metastatic carcinoma of the alveolus.
The most common primary sources of metastatic tumors to the oral region are cancers in the breast, lung, kidney, bone, or colorectum. The breast is the most common primary site for tumors that metastasize to the jawbones, whereas the lung is the most common source for cancers that metastasize to the oral soft tissues (Tables 2-19, 2-20).
Table 2-19
Metastatic tumors to the oral region in men
| Metastatic site and origin | Percentage |
| Oral mucosa | |
| Lung | 35.0 |
| Kidney | 16.0 |
| Skin | 15.0 |
| Liver | 7.0 |
| Colorectum | 5.5 |
| Testis | 5.5 |
| Bone | 3.0 |
| Stomach | 3.0 |
| Rare tumors | 10.0 |
| Jawbones | |
| Lung | 22.0 |
| Prostate | 12.0 |
| Kidney | 10.0 |
| Bone | 9.0 |
| Adrenal gland* | 9.0 |
| Liver | 7.0 |
| Testis | 5.5 |
| Colorectum | 4.0 |
| Rare tumors | 21.5 |
Source: Adapted from: Abraham Hirshberg. eMedicine Speciaities. Diseases of the Oral Mucosa, 2002
*Cases of neuroblastoma, including cases from retroperitoneum and mediastinum.
Table 2-20
Metastatic tumors to the oral region in women
| Metastatic site and origin | Percentage |
| Oral mucosa | |
| Breast | 24.0 |
| Genital organs* | 17.0 |
| Lung | 12.0 |
| Kidney | 10.0 |
| Bone | 10.0 |
| Skin | 7.0 |
| Rare tumors | 20.0 |
| Jawbones | |
| Breast | 42.0 |
| Adrenal gland† | 8.5 |
| Colorectum | 8.0 |
| Kidney | 6.0 |
| Bone | 6.0 |
| Thyroid | 6.0 |
| Rare tumors | 23.5 |
*Uterus, ovaries, cervix, fallopian tubes.
†Cases of neuroblastoma, including cases from retroperitoneum and mediastinum.
In female patients, the most common primary cancers that metastasize to the oral region are those in the breasts, followed with much lower frequency by those in the female genital organs, colorectum, bone, and kidneys (Table 2-20).
In its early manifestation, gingival metastasis resembles hyperplastic or reactive lesions (e.g. pyogenic granuloma, peripheral giant cell granuloma, fibrous epulis) and in other oral soft tissue locations, especially in the tongue, the metastatic lesion manifests as a submucosal mass.
The metastatic lesions of the jaw may be completely asymptomatic. Usually, however, the patient is aware of slight discomfort or pain, followed in many cases by paresthesia or anesthesia of the lip or chin due to involvement of the mandibular nerve. The teeth in the affected area may become loose and extruded. Unfortunately, these teeth may be extracted simply because they are loose without an attempt by the dentist to learn the cause of this phenomenon. In such cases, the main symptom is a soft tissue mass extruding from a recent extraction wound and accompanied by pain. In some cases, pain described as a toothache has been the chief complaint of the patient. A definite swelling or expansion of the jaw is also an almost constant finding.
With the progression of the disease, oral metastatic lesions (especially those in soft tissues) cause progressive discomfort. Pain, bleeding, superinfection, dysphagia, interference with mastication, and disfigurement are some of the main patient complaints.
Radiographic Features
Metastatic lesions produce no pathognomonic radiographic appearance. Although most of such metastases produce osteolytic lesions and thus appear as a radiolucency on the radiograph, certain tumors produce osteoblastic lesions or lesions characterized by the production of bone. Such lesions are manifested as radiopaque or sclerotic areas and are most often associated with carcinoma of the prostate, and occasionally, of the breast and lung. The metastases in the radiograph may be relatively well demarcated and confined or they may exhibit diffuse, poorly outlined involvement of a considerable portion of bone. Because of the destruction of bone which may occur, pathologic fracture is occasionally seen. Lack of radiographic changes does not exclude the possible presence of a small metastatic deposit in the jawbone.
Histologic Features
The diagnosis is always based on histologic findings in the biopsy specimen. The clue to the diagnosis is the resemblance of the metastasis to the primary tumor. If history of a previous tumor exists, current histologic findings should compare with those of the preexisting primary malignant tumor. In some cases, histochemical staining, immunohistochemical tests, and electron microscopy should be performed to identify the primary source of the metastatic tumor.
Several primary intraoral malignancies (especially those originating from salivary glands) have histologic features similar to those of tumors in distant organs: for example, primary ductal carcinoma of a salivary gland origin versus metastatic breast carcinoma, primary intraoral clear cell carcinoma versus metastatic renal cell carcinoma, primary intraoral squamous cell carcinoma versus metastatic squamous cell carcinoma from the lung, or primary intraoral malignant melanoma versus metastatic malignant melanoma. Malignant soft tissue tumors may originate intraorally, but, because of their rarity, one should always consider a metastatic origin.
Treatment and Prognosis
Oral metastases usually indicate widespread disease. Treatment modalities are limited to palliation. In some cases, surgical treatment, sometimes combined with radiation therapy and/or chemotherapy, can improve the patient’s quality of life. Adequate surgical treatment can improve the prognosis in some cases in which the oral region is the only metastatic site.
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