Vascular, neural, adipocytic, muscle, and myofibroblastic tumors

Clinical findings

• The majority of cases (80%) occur below 40 years of age with the highest prevalence in the second decade.

• It appears as a purple-to-blue-to-red nodule, sessile or pedunculated, with 90% affecting the lips (especially the upper lip), and tongue equally; a history of bleeding may be elicited ( Fig. 6.1 A–D).

  

Etiopathogenesis and histopathologic features

Pyogenic granuloma which is a mass of granulation tissue had been considered a reactive lesion to local trauma and irritation and this is likely true for gingival lesions. However, this may not be true for lesions on the lip and tongue which are more akin to cutaneous lesions with typical lobular morphology. Pyogenic granulomas have been shown to be driven by FLT4 and the nitric oxide pathway. However, cutaneous pyogenic granulomas or lobular capillary hemangiomas were shown to harbor RAS mutation in 4% to 10% and BRAF mutation in 16% of sporadic cases. Those that develop within port white stain exhibit BRAF mutation in 80% of cases. Oral lobular capillary hemangioma, both gingival and nongingival, show activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway but no RAS or BRAF mutations.

• There is a proliferation of endothelial cells and dilated capillaries, almost always in a lobular pattern. There may be overlying ulcer, and acute and chronic inflammation; mitotic figures are not uncommon ( Figs. 6.2 and 6.3 ); capillaries are surrounded by smooth muscle actin positive (SMA+) pericytes.

  
  

• Some lesions may show significant reactive atypia with hyperchromatic and pleomorphic nuclei ( Fig. 6.4 ).

  

• Older lesions sclerose and become infiltrated by densely collagenous fibrous tissue and may evolve into fibromas ( Fig. 6.5 ).

  

• Endothelial cells are positive for CD31 and CD34, but negative for glucose transporter-1 (GLUT-1).

Differential diagnosis

• Edematous polypoid masses of granulation tissue on the tongue or buccal mucosa are seen in stem cell transplant recipients on calcineurin inhibitors such as cyclosporine and these are more appropriately diagnosed as reactive fibrovascular hyperplasia or fibrovascular polyps. Their histopathology resembles that of gingival pyogenic granuloma without lobular architecture ( Fig. 6.1 E).

• Infantile capillary hemangioma shows a cellular proliferation of endothelial cells and capillaries that are positive for GLUT-1 and regress over time (see Chapter 5 ).

Management and prognosis

• Excision is the treatment of choice with recurrence in 5% to 6% of cases.

Clinical findings

• Varix (venous lake): This occurs in middle-aged and older adults as a bluish bleb, from a few millimeters to 1 to 2 cm in size, located on the lips, tongue, or buccal mucosa; pressure causes blanching and this is demonstrated by pressing a glass slide onto the lesion so that the vessel empties (diascopy), although this can also be accomplished with a dental instrument; lesions may bleed ( Fig. 6.6 A–C).

  

• Bilateral lingual varicose veins of the ventral tongue are common in older adults and are generally considered to be a variation of normal in older patients ( Fig. 6.6 D).

• Venous/venular or arteriovenous malformation: These are larger bluish masses usually present in the pediatric population. In the oral cavity, they occur in older patients and are usually several centimeters in size, often involving the underlying muscle leading to enlargement and deformity ( Fig. 6.6 E–F); some cases are within the maxilla or mandible (see Chapter 17 ).

Etiopathogenesis and histopathologic features

A varix (venous lake) is a dilated venule that results from loss of elasticity of the muscle around venules (likely postcapillary venules) leading to dilatation of the lumen. Venous malformation is a low-flow lesion that is a developmental malformation of the veins that is caused by local defects of vascular morphogenesis and dysembryogenesis; such malformations are connected to the normal vasculature. Mutations in TEK and PIK3CA account for 62% and 20% of unifocal venous malformations, respectively. They may occur as arteriovenous malformations and are best diagnosed by a thorough clinical examination and ultrasonographic and/or angiographic studies.

• Varix: These are dilated, tortuous, thin-walled vessels with a variable but usually thin muscular coat; valve leaflets are often present ( Figs. 6.7 and 6.8 ); thrombi in various stages of organization are often noted, sometimes with hyalinization or even calcifications, and Masson tumor (intravascular papillary endothelial hyperplasia), a pattern of thrombosis, is sometimes seen; this is composed of small hyalinized globules surrounded by endothelium forming papillary structures ( Figs. 6.9–6.11 ).

  
  
  
  
  

• Venous/venular malformation: Many dilated venules of varying sizes are noted, often intramuscular in location without a proliferation of endothelial cells; many lesions are venular rather than venous and some are arteriolar-venular ( Figs. 6.12–6.13 ).

  
  

Differential diagnosis

• Arteriovenous malformations exhibit the presence of arterioles, arteries, veins, and venules; these lesions have high flow and distinct ultrasonographic findings.

• Telangiectasia characterized by dilated vessels in the superficial lamina propria of the lips and tongue are seen in limited cutaneous systemic sclerosis (also known as calcinosis-Raynaud phenomenon-esophageal dysmotility-sclerodactyly-telangiectasia [ CREST ] syndrome), an autoimmune condition characterized by anticentromere antibodies. It is also seen in hereditary hemorrhagic telangiectasia , an autosomal dominant vascular dysplasia with mutation in ENG leading to Type 1 disease, mutation in ACVRL1 leading to Type 2 disease, and mutation in MADH4 with concomitant juvenile polyposis.

Management and prognosis

• Excision, laser ablation, and sclerotherapy are useful treatments with success rates of 70% to 100%.

Clinical findings

• The mean age of occurrence is in the sixth decade with equal gender distribution; there is a bluish, sometimes nodular, often vermiform, pulsatile lesion of the lip, with the lower lip involved twice as frequently; clinically it is often mistaken for a mucocele.

Etiopathogenesis and histopathologic features

Caliber-persistent labial artery represents a branch of the labial artery that fails to reduce its caliber even in the superficial tissues.

• A normal artery with inner continuous elastic lamina and thick muscular wall, and faint outer elastic lamina, lies within the lamina propria, with an artery diameter-to-depth ratio of less than 1.6 ( Fig. 6.14 ).

  

Management and prognosis

• Trauma leads to pulsatile bleeding, and the biopsy is diagnostic. Ultrasonographic imaging mitigates the need for a biopsy, but this is rarely performed because the clinical impression is usually that of mucocele, which is normally excised.

Clinical findings

• This occurs in children, teenagers, and young adults with a mean age in the third decade and infrequently occur in older adults. Congenital lesions occur on the alveolar ridge in neonates (see Chapter 2 ).

• There are clusters of translucent vesicular structures resembling “frog spawn,” with at least 50% of cases occurring on the tongue and 17% on the buccal mucosa ( Fig. 6.15 ); there may be pain and bleeding and with larger lesions, difficulty with speech and swallowing. A staging system for the tongue has been suggested as follows:

  • Stage I: superficial microcystic lymphatic malformations of the tongue

  • Stage II: isolated lymphatic malformations of the tongue with muscle involvement

  • Stage III: microcystic lymphatic malformations of the tongue and the floor of mouth

  • Stage IV: extensive microcystic lymphatic malformations involving the tongue, floor of mouth, and further cervical structures

  

Etiopathogenesis and histopathologic features

Mutations in PIK3CA and other genes in the PI3K/AKT/mTOR pathway have been identified in sporadic extraoral lymphatic malformations and in syndromes associated with malformative/overgrowth disorders (e.g., Klippel-Trenaunay and CLOVES syndromes). However, it is unclear whether the localized lymphangiectasias of the oral cavity harbor the same mutations.

• Dilated vascular spaces are lined by a single layer of endothelial cells that are usually positive for D2-40 (podoplanin) and exhibit valve leaflets. They are filled with pale, wispy, or denser eosinophilic material. These typically abut the epithelium, which has a bosselated surface, and lymphatic channels may insinuate into the underlying muscle; sometimes dilated venous channels are also present ( Fig. 6.16 ).

  

• Microcystic lesions have lumina that are <1 cm while macrocystic lesions have lumina >1 cm.

Differential diagnosis

• Venous malformations have thin muscular walls and usually do not abut the epithelium and are negative for D2-40.

Management and prognosis

• Excision or laser ablation is curative for small intraoral lesions, although larger and deeper lesions that cannot be completely removed recur. Larger lesions especially those of the subcutaneous tissues are treated with sclerotherapy, radiofrequency ablation, and electrocoagulation.

• Treatment with mTOR inhibitors such as sirolimus has led to partial regression in 85% of large lymphatic malformations.

Clinical findings

• This occurs in the third to fifth decades and is twice as common in males. The head and neck area is the most common site for this entity followed by the distal extremities.

• It presents as a painless nodule with 90% occurring on the lips (the most common site), tongue, or buccal mucosa, sometimes with a history of trauma; bone and deep soft tissue may be affected.

Etiopathogenesis and histopathologic features

FOS rearrangement has been noted in 50% of the cellular subtype arising in areas outside of the head and neck, and FOSB rearrangement in 20% of all cases, and both may occur within bone. GATA6::FOXO1 fusion has been reported in a small number of cases.

• Classic lesions exhibit a circumscribed, multilobular proliferation of endothelial cells with larger peripheral vessels and a central compressed vessel, and surrounding fibromyxoid stroma. The endothelial cells are plump and epithelioid protruding into vessels with a tombstone appearance, and contain abundant eosinophilic cytoplasm, sometimes with an intracytoplasmic vacuole representing a rudimentary lumen; nuclei have dispersed chromatin and small nucleoli.

• ALHE subtype exhibits a moderate to marked lymphocytic infiltrate and variable number of eosinophils ( Fig. 6.17 ). There may be outward maturation with nests of epithelioid cells in the center, small-lumen vessels further out, and well-formed vessels at the periphery.

  

• Cellular type exhibits >50% sheet-like growth of tumor cells.

• Endothelial cells are positive for CD31, GLUT-1, and for ERG. FOSB is present in 100% of the ALHE subtype, and in 75% and only 10% of conventional and cellular epithelioid hemangioma, respectively.

Differential diagnosis

• Kimura disease affects Asian men in the third and fourth decades who present with peripheral blood eosinophilia, elevated IgE, and nodules within the subcutaneous tissues of the head and neck, enlarged lymph nodes, and/or enlarged parotid gland. There is a patchy lymphocytic infiltrate with many germinal centers with distinct mantle zones and eosinophils, but not a proliferation of epithelioid endothelial cells although there are many dilated postcapillary venules; eosinophilic folliculolysis, necrosis, and eosinophilic abscesses may be present ( Fig. 6.18 ).

  

• Pseudomyogenic hemangioendothelioma, a vascular tumor of indeterminate biologic potential, exhibits a proliferation of plump, spindled and epithelioid cells with abundant eosinophilic cytoplasm in loose fascicles, often with rhabdomyoblastic cytomorphology with almost 100% expression of FOSB from SERPINE1::FOSB and ACTB::FOSB fusions.

• Epithelioid hemangioendothelioma consists of strands and cords of epithelioid and slightly atypical endothelial cells with abundant eosinophilic cytoplasm, prominent cytoplasmic vacuoles, and myxochondroid or hyaline stroma; well-formed vascular channels are usually absent. These are positive for CAMTA1 (from WWTR1::CAMTA1 fusion) and sometimes TFE3 (from YAP1::TFE3 fusion), and generally negative for FOSB.

Management and prognosis

• Excision is curative.

Clinical findings

There are five epidemiologic patterns as presented in Table 6.2 :

• The most common sites are maxillary gingiva, palatal mucosa, or tongue, and infiltration of bone results in loosening of teeth ( Fig. 6.19 ).

  

• Lesions go through stages as follows: dusky red or purple macule of early patch stage, plaque stage, and then nodular/mass of tumor stage; oral lesions are generally plaque or tumor stage.

• Up to 60% of subjects who have Kaposi sarcoma excrete this virus in saliva while up to 30% of African patients who do not have the disease do so.

• Worsening of Kaposi sarcoma is one of the features of patients on antiretroviral therapy who develop immune reconstitution inflammatory syndrome (IRIS).

Etiopathogenesis and histopathologic features

HHV-8 is a DNA, γ-herpesvirus and the pathogenic agent for Kaposi sarcoma. However, in countries where HHV-8 infection is high, many HIV-negative individuals never develop this tumor indicating that host factors play an important role such as HIV-coinfection, immunosuppression, and immunosenescence. Infection of endothelial cells by HHV-8 induces a plethora of proangiogenic molecules especially those in the vascular endothelial growth factor family and angiogenin. There is upregulation of HHV-8 gene products such as latency-associated nuclear antigen-1 (LANA-1) or latent nuclear antigen-1 (LNA-1).

• Patch stage lesions exhibit ectatic vascular channels that dissect between connective tissue fibers.

• Most oral cavity cases are in the nodular stage and consist of a cellular proliferation of spindle cells in fascicles with slit-like vascular spaces, and abundant extravascular erythrocytes, hemosiderin and intra- and extracytoplasmic periodic acid–Schiff (PAS)-positive eosinophilic globules. Nuclei are spindled with slight variation in size, dispersed chromatin, and small nucleoli; mitotic figures are infrequent in patch and plaque lesions but readily identified in nodular/mass lesions, and there is no pleomorphism or necrosis except in the anaplastic variant. ( Figs. 6.20 and 6.21 ).

  

• Histologic variants have been identified such as anaplastic, lymphedematous, telangiectatic, glomeruloid, keloidal, ecchymotic, pigmented, hyperkeratotic/verrucous, intravascular, and with myoid nodules, although rarely in the mouth. These do not appear to have prognostic significance.

• Patients with HIV/AIDS may also show concomitant opportunistic infections with cryptococcus, mycobacteria, or molluscum.

• Nuclear positivity for LANA-1 is diagnostic and both sensitive and specific ( Fig. 6.21 B); spindle cells also exhibit cytoplasmic positivity for factor VIII–related antigen, CD31 (lower diagnostic sensitivity compared with CD34 in tumor stage) as well as for lymphatic endothelium markers such as D2-40, LYVE-1, PROX-1, and VEGFR3.

  

Differential diagnosis

• The differential diagnosis of Kaposi sarcoma includes many spindle cell tumors but in the head and neck region and oral cavity, it must be distinguished from sarcomatoid carcinoma and spindle cell melanoma. Epithelial markers such as keratin and p40, S100, and SOX10 distinguish them.

Management and prognosis

• Localized lesions such as those in the oral cavity are successfully treated with excision, laser ablation, intralesional vincristine therapy, and radiation.

• More extensive lesions are treated with systemic therapy that includes paclitaxel and pegylated liposomal doxorubicin or daunorubicin, as well as vinblastine, etoposide or bleomycin, and antiangiogenic agents such as bevacizumab and pomalidomide.

• Those with HIV/AIDS-related Kaposi sarcoma are treated with combination antiretroviral therapy while those with posttransplantation lesions are often treated by reducing immunosuppression and treating with mTOR inhibitors.

Clinical findings

• Neural tumors are most common in the third and fourth decades of life with a very slight 1.3:1 female predilection.

• They present as a solitary nodule, most frequently on the tongue (50%–55%), lips (12%), and palatal mucosa (12%), sites that have rich innervation ( Fig. 6.22 A–B). Infrequently, neurofibroma or other nerve sheath tumors may occur within the mandible involving the inferior alveolar nerve, leading to a “blunderbuss” appearance of the canal (see Fig. 6.22 C).

  

• Traumatic neuroma: These are often painful or cause paresthesia and are seen at sites of previous surgery or frequent trauma such as lower lip, tongue, in the vicinity of the mental foramen in the edentulous mandible from denture trauma, and in the vicinity of the lingual nerve after third molar surgery.

• Neurofibroma , either solitary or multiple, may be associated with neurofibromatosis type 1 (NF1), whereas schwannomas, especially vestibular schwannomas, are associated with NF2.

• Solitary, circumscribed neuroma are generally located on the hard palatal and lip mucosa (70% of cases).

• Perineurioma is uncommon and tends to occur in the fifth decade and presents in both bone and soft tissue.

• Mucosal neuromas present as multiple nodules on the lips and tongue and strongly suggest multiple endocrine neoplasia (MEN) type 2B.

Etiopathogenesis and histopathologic features

Traumatic partial or total severance of nerve fibers leads to Wallerian degeneration and subsequent axonal regeneration and remyelination resulting in a tangle of nerve fiber surrounded by scar tissue. These are not uncommonly encountered associated with the lingual nerve after third molar extraction and may be intraosseous.

• There are nerve fibers of varying sizes, with some showing mucinous change or thickened perineurium with intervening fibrosis and scarring ( Figs. 6.23 and 6.24 A).

  

• Schwann cells are positive for S100 protein and SOX10; neurofilament protein (NFP) highlights axons and the perineurium is positive for epithelial membrane antigen (EMA), GLUT-1, and claudin-1 ( Fig. 6.24 B).

  

Differential diagnosis

• Mucosal neuromas of MEN type 2B show hyperplasia of nerve fibers but an absence of fibrosis and scarring.

Management and prognosis

• Excision is curative.

Etiopathogenesis and histopathologic features

Neurofibroma arises within a nerve and represents a neoplastic proliferation of Schwann cells, fibroblasts, perineurial cells, and myelinated and unmyelinated axons within myxoid and collagenous stroma. Neurofibromas are usually solitary and sporadic; some (especially the plexiform type) are seen in patients with NF1, an autosomal dominant disorder associated with an inactivating mutation in NF1 on 17q. It is associated with other signs of neurofibromatosis such as

• multiple skin neurofibromas;

• café-au-lait macules;

• freckling of the axillae or groin (Crowe sign);

• Lisch nodules;

• osseous dysplasia of the sphenoid or long bones;

• optic glioma;

• first-degree relatives with the syndrome;

• jaw abnormalities such as overgrowth of the alveolus and increased size of the coronoid notch; and

• dental abnormalities.

Only one segment or dermatome is involved by pigmentation and cutaneous neurofibromas in mosaic NF1.

• Localized type: There is a discrete proliferation of spindle cells in a delicately or densely collagenous stroma with variably (sometimes extensively) myxoid background. Cells have wavy cytoplasmic processes, indistinct cell borders, and curvilinear, comma-shaped, or tadpole-shaped nuclei with inconspicuous nucleoli, and there may be slight nuclei atypia ( Fig. 6.25 ). Mast cells are readily identified, neurites are often present, and the perineurium may be present. Some cases contain ganglion cells. Hybrid tumors with localized schwannomatous areas exist and “bizarre” neurofibroma exhibits pleomorphic, hyperchromatic, and degenerative nuclear changes.

  

• Diffuse type: This neurofibroma infiltrates adjacent structures, although cells have the same morphology as conventional neurofibroma; Wagner-Meissner corpuscles are usually present (see Fig. 6.25 F).

• Plexiform type: This neurofibroma consists of tortuous nodules and cords of neural tissue that represent the unevenly enlarged and expanded nerves of neurofibromatosis ( Fig. 6.26 ).

  

• Schwann cells are positive for S100 protein and SOX10 and non-schwannian spindle cells exhibit positivity for CD34 (see Fig. 6.25 E).

• Dendritic cell neurofibroma is a variant that contains spindled type I cells with comma-shaped nuclei that surround large, polygonal type II cells with dendritic processes, abundant pale cytoplasm, and vesicular nuclei with pseudoinclusions; pseudorosettes are present. Both populations are S100+; the large cells are CD57+ and spindled cells show slight and variable positivity for glial fibrillary acidic protein (GFAP), microphthalmic transcription factor (MITF), and NFP ( Fig. 6.27 ).

  

• Transformation of neurofibroma, usually plexiform type in patients with neurofibromatosis to malignant peripheral nerve sheath tumor is characterized by high cellularity, mitotic figures, loss of S100 protein and SOX10 and CD34+ fibroblasts, increased Ki67 labeling, and loss of H3K27me.