Ameloblastoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Ameloblastoma is a rare, benign tumor of odontogenic epithelium much more commonly appearing in the mandible than the maxilla. While these tumors are rarely malignant or metastatic (that is, they rarely spread to other parts of the body), and progress slowly, the resulting lesions can cause severe abnormalities of the face and jaw. Odontogenic tumors comprise of a complex group of lesions of diverse histopathological types and clinical behavior. Of all swellings of the oral cavity, 9% are odontogenic tumors and within this group, ameloblastoma accounts for 1% of lesions. WHO defines it as a locally invasive polymorphic neoplasia that often has a follicular or plexiform pattern in a fibrous stroma. Its behavior has been described as being benign but locally aggressive. In 20% of all cases the tumor can be found in the `maxilla, predominantly in the canine or molar region. Within the mandible, 70% are located in the molar region or the ascending ramus, 20% in the premolar region and 10% in the anterior part. Ameloblastoma was first described in 1868 by Broca. Based on the location, ameloblastoma may be classified into either intra-osseous or extra-osseous. Based on the clinicoradiologic features, ameloblastoma may be classified into four groups: solid or multicystic, unicystic, peripheral, and malignant. On gross pathology, the characteristic findings of ameloblastoma may include solid and cystic, mulitcystic and intraosseous or extraosseous, or rarely unicystic. On microscopic histopathological analysis, stellate reticulum, giant cells, subepithelial hyalinization, and columnar basal cells in palisading arrangement with vacuolated cytoplasm are characteristic findings of ameloblastoma. The exact pathophysiology of ameloblastoma is not fully understood. It is thought that ameloblastoma is the result of either suppression of matrix metalloproteinase-2 that may inhibit the local invasiveness of ameloblastoma, or there is also some research suggesting that α5β1 integrin may participate in the local invasiveness of ameloblastomas. Genes involved in the pathogenesis of ameloblastoma include BRAF V600E. There are no established causes for ameloblastoma. It is thought that ameloblastoma is the result of either suppression of matrix metalloproteinase-2 that may inhibit the local invasiveness of ameloblastoma, or there is also some research suggesting that α5β1 integrin may participate in the local invasiveness of ameloblastomas. Genes involved in the pathogenesis of ameloblastoma include BRAF V600E. The incidence of ameloblastoma is approximately 1.96, 1.20, 0.18, and 0.44 per 100,000 for black males, black females, white males, and white females respectively worldwide. Ameloblastoma affects men and women equally. There is no racial predilection to the ameloblastoma. Ameloblastoma usually occur in middle age group i.e. 20-40 years: the median age at diagnosis is 39 years. The incidence of ameloblastoma is approximately 1.96, 1.20, 0.18, and 0.44 per 100,000 for black males, black females, white males, and white females respectively worldwide. Ameloblastoma affects men and women equally. There is no racial predilection to the ameloblastoma. Ameloblastoma usually occur in middle age group i.e. 20-40 years: the median age at diagnosis is 39 years. Symptoms of ameloblastoma include mouth sores, painless swelling, loose teeth, facial deformity, swelling and numbness of the jaw, pain surrounding the teeth or jaw, and pain associated with the tissue growth, if ameloblastoma spreads to the sinus cavities and floor of the nose. The mainstay of therapy for ameloblastoma is surgery. Adjunctive chemotherapy/radiation/chemoradiation may be required.

Ameloblastoma was first described by Broca. This type of odontogenic neoplasm was designated as an adamantinoma by the French physician Louis-Charles Malassez.

Ameloblastoma may be classified based on histopathology into six subtypes including follicular, plexiform, acanthomatous, basal cell, granular cell, and desmoplastic. Based on the location, ameloblastoma may be divided into either intra-osseous or extra-osseous. Based on the radiologic features, ameloblastoma may be classified into four groups including solid or multicystic, unicystic, peripheral, and malignant.

Ameloblastoma arise from remnants of ameloblast or dental lamina, dentigerous cysts, or basal layer of oral mucosa. There is evidence that suppression of matrix metalloproteinase-2 may inhibit the local invasiveness of ameloblastoma. On gross pathology, the characteristic findings of ameloblastoma may include solid and cystic, multicystic and intraosseous or extraosseous, or rarely unicystic. On microscopic histopathological analysis, stellate reticulum, giant cells, subepithelial hyalinization, and columnar basal cells in palisading arrangement with vacuolated cytoplasm are characteristic findings of ameloblastoma. The exact pathophysiology of ameloblastoma is not fully understood. It is thought that ameloblastoma is the result of either suppression of matrix metalloproteinase-2 that may inhibit the local invasiveness of ameloblastoma, or there is also some research suggesting that α5β1 integrin may participate in the local invasiveness of ameloblastoma. Genes involved in the pathogenesis of ameloblastoma include BRAF V600E

There are no established causes for ameloblastoma. It is thought that ameloblastoma may be the result of either decreased expression of matrix metalloproteinase-2 which helps in inhibition of the local invasiveness of ameloblastoma, or it is may be due to increased expression of α5β1 integrin which participate in the local invasiveness of ameloblastoma.

Ameloblastoma must be differentiated from other diseases that cause symptoms similar to those of ameloblastoma, such as dentigerous cyst, odontogenic keratocyst, odontogenic myxoma, aneurysmal bone cyst, fibrous dysplasia, hard odontoma, osteosarcoma, and globulomaxillary cysts

The incidence of ameloblastoma is approximately 1.96, 1.20, 0.18, and 0.44 per 100,000 for black males, black females, white males, and white females respectively, worldwide. Ameloblastoma affects men and women equally. There is no racial predilection to the ameloblastoma. Ameloblastoma usually occur in middle age group i.e. 20-40 years; the median age at diagnosis is 39 years  

There are no established risk factors for ameloblastoma. It is thought that common risk factors in the development of ameloblastoma may be dentigerous cyst, impacted teeth, injury to the mouth or jaw, infections of the teeth or gums, inflammation of the teeth or gums, infections by viruses, and lack of protein or minerals in the person’s diet, and Gorlin-Goltz syndrome.

According to the United States Preventive Services Task Force, screening for ameloblastoma is not recommended.

In several cases, the patients with ameloblastoma are asymptomatic. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary.

Symptoms of ameloblastoma include mouth sores, painless swelling, loose teeth, facial deformity, swelling and numbness of the jaw, pain surrounding the teeth or jaw, and pain associated with the tissue growth, if ameloblastoma spreads to the sinus cavities and floor of the nasal cavity.  

Patients with ameloblastoma usually appear normal and clinical presentation of an ameloblastoma is usually limited. Common physical examination findings of ameloblastoma include facial asymmetry, swelling, and hemorrhage.

There are no diagnostic lab findings associated with ameloblastoma.

There are no ECG findings associated with amelobastoma.

A head x-ray may be helpful in the diagnosis of ameloblastoma. Findings on an x-ray suggestive of ameloblastoma include polycystic, honeycombed mass arising within the alveolar border of the jaw.

Head CT scan may be helpful in the diagnosis of ameloblastoma. Findings on CT scan suggestive of ameloblastoma include multiloculated, soap-bubble” lesion, erosion of the adjacent tooth roots and well demarcated borders with no matrix calcification.

Head and neck MRI may be helpful in the diagnosis of ameloblastoma. Findings on MRI diagnostic of ameloblastoma include mixed solid and cystic pattern, thick irregular walls with papillary solid structures projecting into the lesion.

Ultrasound may be helpful in the diagnosis of ameloblastoma. Findings on an ultrasound suggestive of ameloblastoma include cystic mass with solid contents, flow signals, multilocular and honeycomb appearance.

There are no other imaging findings findings associated with acoustic neuroma.

Other diagnostic studies for ameloblastoma include incisional biopsy. Incisional biopsy is diagnostic of ameloblastoma.

The mainstay of therapy for ameloblastoma is surgery. Adjunctive chemotherapy/radiation/chemoradiation may be required.

The mainstay of therapy for ameloblastoma is surgery. The predominant therapy for ameloblastoma is surgical resection. Adjunctive chemotherapy/radiation/chemoradiation may be required.

There are no primary preventive measures available for ameloblastoma.

Secondary prevention strategies following ameloblastoma include follow-up examination at regular intervals for at least 10 years.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2], Vamsikrishna Gunnam M.B.B.S [3]

Ameloblastoma was first described by Broca. This type of odontogenic neoplasm was designated as an adamantinoma by the French physician Louis-Charles Malassez.

• Ameloblastoma was recognized in 1827 by Cusack.^[1][2]
• Ameloblastoma was first described by Broca in 1868 and has been called adamantinoma, adamantoblastoma, epithelial odontoma, and a multilocular cyst.
• Ameloblastoma originates from the early English word ‘amel’, meaning enamel and the Greek word ‘blastos’, meaning germ.
• This type of odontogenic neoplasm was designated as an adamantinoma in 1885 by the French physician Louis-Charles Malassez.
• This tumor was previously called adamantinoma. However, this term is considered inaccurate now and is not used.
• It was finally renamed to the modern name ameloblastoma in 1930 by Ivey and Churchill.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2], Vamsikrishna Gunnam M.B.B.S [3]

Ameloblastoma may be classified based on histopathology into six subtypes including follicular, plexiform, acanthomatous, basal cell, granular cell, and desmoplastic. Based on the location, ameloblastoma may be divided into either intra-osseous or extra-osseous. Based on the radiologic features, ameloblastoma may be classified into four groups including solid or multicystic, unicystic, peripheral, and malignant.

Ameloblastoma may be classified into following subtypes based on the location:^{[1][2][3][4][5]}

• Intraosseous
  • Intraosseous ameloblastoma is locally aggressive
  • Intraosseous ameloblastoma may include the histological subtypes such as follicular, plexiform, acanthomatous, unicystic, granular cell, basal cell, or desmoplastic
• Extra-osseous
  • Extraosseous ameloblastoma may include the histological subtypes such as follicular, plexiform, or basal cell
  • Extraosseous ameloblastoma is benign
  • Extraosseous ameloblastoma is also known as peripheral ameloblastoma

Based on radiology, intraosseous ameloblastoma may be subclassified into two groups which includes the following:

• Solid/multicystic
  • More commonly reoccur
• Unicystic
  • Unlikely to reoccur
  • Classically found in younger individuals

Ameloblastoma may be classified into following subtypes based on the clinicoradiologic into four groups:^{[6][1][2][3][4][7]}

• Solid or multicystic
  • Solid ameloblastoma is the most common form of the lesion.
  • Approximately 86% of the ameloblastoma are solid. It has a tendency to be more aggressive than the other types and has a higher incidence of recurrence.
  • Multicystic ameloblastomacan infiltrate into the adjacent tissue and may metastasize and has the ability to recur.
  • It is prevalent in a slightly older age group than the unicystic ameloblastoma.
  • Radiographically, the appearance is generally multilocular or unilocular.
• Unicystic
  • Unicystic ameloblastoma has a large cystic cavity with intraluminal, luminal, or mural proliferation of ameloblastic cells.
  • Unicystic ameloblastoma is a less aggressive variant and it has a low rate of recurrence although lesions showing mural invasion are an exception and should be treated more aggressively.
  • The unicystic ameloblastoma usually appears as a “cystic” lesion with either an intramural or an intraluminal proliferation of the cystic lining.
  • Radiographically, it can resemble a well-circumscribed slow-growing radiolucency.^[7]
• Peripheral
  • Histologically, the peripheral ameloblastoma appears similar to the solid ameloblastoma.
  • Peripheral ameloblastoma is uncommon, usually presenting as a painless, non-ulcerated sessile or pedunculated gingival lesion on the alveolar ridge.
  • Peripheral ameloblastoma mostly appears in the alveolar mucosa. It is a soft-tissue version of an ameloblastoma but may also involve the underlying bone.
• Malignant
  • The malignant ameloblastoma is a rare entity. It is defined as an ameloblastoma that has already metastasized but still maintains its classical microscopic features.
  • The WHO classification of odontogenic tumors (2005) defines malignant ameloblastoma as, “an ameloblastoma that metastasizes in spite of a benign histological appearance”.
  • Even if metastasis is absent, ameloblastoma with cytological atypia is defined as ameloblastic carcinoma.
  • Thus, malignant ameloblastoma is defined as a retrospective diagnosis that can only be made when metastasis occurs.
  • In majority of cases, it not only maintains the histological characteristics of the parent tumor but also continues to display similarly indolent clinical behavior.

Differentiating features of three different subtypes of ameloblastoma is shown below in a tabular form:

Subtypes of Ameloblastoma	Percentage of Ameloblastoma	Age	Sites affected	Additional features
Multicystic/Conventional Ameloblastoma (also known as Solid Ameloblastoma)	Majority ofameloblastomas are multicystic/conventional ameloblastomas (over 80%)	The tumor is usually seen in middle-aged adults, around the age of 40 years		It is more prevalent among African-American population
Unicystic Ameloblastoma (also known as Cystic Ameloblastoma)	About 20% of all ameloblastomas are unicystic ameloblastomas	It affects men more than women, with 65% of the affected individuals being males It is usually seen in younger individuals with an average age of 25 years	A majority of these tumors occur in the lower jaw (over 90%)	The prognosis for unicystic ameloblastoma is better than conventional ameloblastoma, because they are less aggressive in growth However, they can recur after surgery, like conventional ameloblastomas
Peripheral Ameloblastoma	Generally, around 2% of ameloblastomas are of this type	Peripheral ameloblastoma typically affect individuals aged between 40-60 years Both men and women are equally affected	The common sites of tumor occurrence include: Soft tissues of jaw Gingiva Buccal mucosa	They are generally less aggressive than intraosseous tumors that arise in the bones (intraosseous ameloblastoma tumors)

Ameloblastoma may be classified into following subtypes based on the histology:^[8]

• Follicular
• Plexiform
• Acanthomatous
• Granular cell
• Basal cell
• Desmoplastic

Subtypes of Ameloblastoma	Features
Follicular	Histologically, follicular ameloblastoma are the most common type of ameloblastoma. The follicular pattern consist of islands of epithelial cells with a central mass of polyhedral cells or loosely arranged angular cells resembling stellate reticulum, which are surrounded by well organized single layer of cuboidal or tall columnar cells with nuclei placed at the opposite pole of basement membrane resembling pre-ameloblasts. This peripheral cell layer tends to show cytoplasmic vacuolization. Cystic formation is often seen in the center of the epithelial islands due to degeneration of stellate reticulum like cells.
Plexiform	The tumor epithelium is arranged in form of trabeculae which is bound by a layer of cuboidal or columnar cells and stellate reticulum like areas are usually minimal. Cyst formation occurs but is usually due to stromal degeneration rather than cystic change in the epithelium. The stroma consists of loose, vascular sparsely cellular connective tissue.
Acanthomatous	It resembles a typical follicular ameloblastoma except it shows extensive squamous metaplasia sometimes with keratin formation within the epithelial islands.
Granular cell	The tumors are referred to as granular cell ameloblastoma, when the central stellate reticulum cells show extensive granular cell transformation i.e. in the form of sheets of large eosinophilic granular cells. Ultrastructurally, it is seen that the granules consist of pleomorphic, osmiophilic, lysosome like organelles.
Basal cell	This variant shows predominant basaloid pattern consisting of darkly stained cells with minimal cytoplasm and little evidence of palisading at the periphery resembling those seen in basal cell carcinoma.
Desmoplastic	Desmoplastic ameloblastoma is characterized by extensive stromal collagenization or desmoplasia surrounding compressed small/irregular islands of odontogenic epithelium making it a distinct entity. Cyst formation is common and ameloblast like areas are present only in small foci. Calcification in the fibrous stroma and occasional bone formation can also be seen. Histochemical evaluation of the collagen suggests that the dense stroma is not scar tissue but represents active de novo synthesis of extracellular matrix proteins. It typically presents radiographically as a mixed radiolucency and radiopacity mimicking a fibro osseous lesion. In contrast to typical ameloblastoma, this variant frequents the maxilla and the anterior region of the jaws.
Unicystic	Unicystic ameloblastoma is considered as an in-situ or superficially invasive form of ameloblastoma and consists of a single cyst lined by ameloblastic epithelium. It presents clinically similar to a dentigerous cyst and is usually associated with an impacted tooth (usually 3rd molars). They are usually seen in younger patients with an average age of diagnosis being 22 years and generally involve the mandible. It histologically presents as a single cyst lined by ameloblastomatous epithelium and is divided into several subgroups based on pattern and extent of ameloblastomatous proliferation in relation to cyst wall. Unicystic ameloblastoma may be classified into four subtypes based on a classification by Reichart et al. which was modified by Ackermann et al. 1. Luminal unicystic ameloblastoma: It is a cystic lesion lined by epithelium which exhibits columnar differentiation and reverse polarization of the basal cell layer. The connective tissue adjacent to the epithelium often exhibits a uniform, thin band like area of hyalinization. 1.2. Luminal and intraluminal unicystic ameloblastoma: It is the simple type but exhibits one or more nodules projecting into the lumen. No extension is seen into the surrounding connective tissue wall. Occasionally, this form of unicystic ameloblastoma can produce an intraluminal plexiform pattern of odontogenic epithelium that lacks typical ameloblastomatous differentiation and is called as unicystic plexiform ameloblastoma. 1.2.3. Luminal, intraluminal and intramural unicystic ameloblastoma: Here there is occurrence of intramural proliferation of ameloblastoma along with subgroup 1.2 features. 1.3. Luminal and intramural unicystic ameloblastoma: It exhibits a cyst with a luminal lining in combination with intramural nodules of SMA tissues. The intramural ameloblastoma tissue may be seen as an infiltration from the cyst lining or as free islands of follicular ameloblastoma.
Peripheral	Peripheral ameloblastoma present histologically with follicular or plexiform pattern as well as acanthomatous pattern. In most cases, the tumor is well separated from the overlying epithelium but many are confluent with the overlying mucosa.
Other rare varients	Clear cell variant which may contain clear PAS positive cells are localized in the stellate reticulum like areas. Papilliferous keratoameloblastoma show occurrence of areas of ameloblastoma with keratinisation, tumor islands with papilliferous appearance along with cystic areas resembling odontogenic keratocysts. Mucous cells can also be demonstrated rarely in ameloblastoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivali Marketkar, M.B.B.S. [2], Vamsikrishna Gunnam M.B.B.S [3]

Ameloblastoma arise from remnants of ameloblast or dental lamina, dentigerous cysts, or basal layer of oral mucosa. There is evidence that suppression of matrix metalloproteinase-2 may inhibit the local invasiveness of ameloblastoma. On gross pathology, the characteristic findings of ameloblastoma may include solid and cystic, multicystic and intraosseous or extraosseous, or rarely unicystic. On microscopic histopathological analysis, stellate reticulum, giant cells, subepithelial hyalinization, and columnar basal cells in palisading arrangement with vacuolated cytoplasm are characteristic findings of ameloblastoma. The exact pathophysiology of ameloblastoma is not fully understood. It is thought that ameloblastoma is the result of either suppression of matrix metalloproteinase-2 that may inhibit the local invasiveness of ameloblastoma, or there is also some research suggesting that α5β1 integrin may participate in the local invasiveness of ameloblastoma. Genes involved in the pathogenesis of ameloblastoma include BRAF V600E.

• Ameloblastoma arise from remnants of ameloblast or dental lamina, dentigerous cysts, or basal layer of oral mucosa.^{[1][2][3][4][5]}
• Ameloblasts, which are part of the odontogenic epithelium, are responsible for enamel production and eventual crown formation.
• There is evidence that suppression of matrix metalloproteinase-2 may inhibit the local invasiveness of ameloblastoma, however, this was only demonstrated in vitro.
• There is also some research suggesting that α5β1 integrin may participate in the local invasiveness of ameloblastomas.
• The ameloblastoma is an ectodermal odontogenic tumor of the jaw which apparently originates from the Malassez rests in the periodontium, from the gingival epithelium, from the enamel organs, or from ordinary dental cysts (dentigerous cysts, follicular cysts, or radicular cysts).

Genes involved in the pathogenesis of ameloblastoma include:

• BRAF V600E ^[6]

On gross pathology the following are the characteristic findings of ameloblastoma:^[7][8][9]

• Solid and cystic
• Multicystic and intraosseous or extraosseous
• Rarely may be unicystic

On microscopic examination, the following characteristic findings of ameloblastoma are present:

• Stellate reticulum – star-shaped cells, found in a developing tooth^[10][11]
• Giant cells may or may not be present
• Subepithelial hyalinization may or may not be present
• Seen deep to the basement membrane
• Suprabasal cells loosely textured and noncohesive, resembling stellate reticulum
• The plexiform type has epithelium that proliferates in a “Fish Net Pattern”
• The follicular type will have outer arrangement of columnar or palisaded ameloblast like cells and inner zone of triangular shaped cells resembling stellate reticulum in bell stage. The central cells sometimes degenerate to form central microcysts
• No enamel or dentin formation
• Tall columnar cells
  • Palisaded nuclei with reverse polarization
    • Reverse polarization of nuclei = nuclei distant from the basement membrane/nuclei at pole opposite of basement membrane
    • Palisaded nuclei = picket fence appearance; columnar-shaped nuclei with long axis perpendicular to the basement membrane (key feature)
  • Subnuclear vacuolation
• The following are the different histopathological variants of ameloblastoma:^[2][1]
  • Intraosseous (follicular, plexiform, acanthomatous, multicystic, unicystic, granular cell [lysosomes by EM], basal cell, desmoplastic)
  • Extraosseous (follicular, plexiform, basal cell)

The image shows the characteristic features:^[12]

• Islands of cells with palisaded nuclei that have reverse polarization.
• Reverse polarization of nuclei : nuclei distant from the basement membrane/nuclei at pole opposite of basement membrane
• Palisaded nuclei: picket fence appearance; columnar-shaped nuclei with long axis perpendicular to the basement membrane

• Subnuclear vacuolation in palisading cell – vacuoles at the basement membrane aspect
• Loose stroma around the islands of cells
• Star-like cells at the centre of the islands of cells (stellate reticulum)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2], Simrat Sarai, M.D. [3]

There are no established causes for ameloblastoma. It is thought that ameloblastoma may be the result of either decreased expression of matrix metalloproteinase-2 which helps in inhibition of the local invasiveness of ameloblastoma, or it is may be due to increased expression of α5β1 integrin which participate in the local invasiveness of ameloblastoma.

Common causes of ameloblastoma may include:^[1][2]

• Decreased expression of of matrix metalloproteinase-2
• Increased expression α5β1 integrin

Less common causes of ameloblastoma may include:^[2]

• Mouth or jaw injury
• Infections
• Inflammation
• Diet lacks in protein or minerals

• Ameloblastoma is caused by a mutation in the FGFR2-RAS-BRAF V600E gene.^[3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Ameloblastoma must be differentiated from other diseases that cause symptoms similar to those of ameloblastoma, such as dentigerous cyst, odontogenic keratocyst, odontogenic myxoma, aneurysmal bone cyst, fibrous dysplasia, hard odontoma, osteosarcoma, and globulomaxillary cysts.

Differential diagnosis of ameloblastoma include the following:^[1]

• Dentigerous cyst
• Odontogenic keratocyst
• Odontogenic myxoma
• Aneurysmal bone cyst
• Fibrous dysplasia
• Hard odontoma
• Osteosarcoma
• Globulomaxillary cysts

Osteosarcoma must be differentiated from:Osteomyelitis, Pediatric Osteomyelitis, Rhabdomyosarcoma, Pediatric Rhabdomyosarcoma, Chondrosarcoma, Metastases from other malignancies, Fibrous dysplasia, Giant cell tumors, Ewing’s sarcoma, Malignant fibrous histiocytoma, Lymphoma Osteoblastoma, Aneurysmal bone cyst, Fibrosarcoma and Cortical desmoid.

Disease	History/demography	Symptoms			Physical examination		Diagnosis
		Palpable mass	Pain	Others	Mass tenderness	Others	Genetics	Imaging	Histology
Rhabdomyosarcoma[2][3][4][5]	Most common soft tissue cancer among children and adolescents The third most common extracranial solid tumors Two-third of all cases happen under 6 years old	+	+	Skin changes Respiratory difficulties Vomitting Hematuria	+/-	Fever Erythematous skin Proptosis Ophthalmoplegia Dysconjugate gaze	Loss of heterozygosity of 11p15. Mutations in: TP53 NRAS KRAS HRAS PIK3CA CTNNB1 FGFR4 Translocations in PAX3 or PAX7 genes with FOXO1	CT scan: Soft tissue density Enhancement with contrast Bone destruction Ultrasound: Well-defined and irregular mass Low to medium echogenicity MRI: T1: Low to intermediate intensity Hemorrhage areas are present in alveolar rhabdomyosarcoma T2: Hyperintense Prominent flow voids are present in extremity lesions of rhabdomyosarcoma T1 C+(Gd): Enhancement	An appearance of round blue cell tumors Myogenesis pathway has various types of differentiation Positive immunohistochemical results for: myoglobin actin desmin Myogenin
Wilms tumor[6][7][8][9][10]	Also called nephroblastoma The most common childhood abdominal malignancy Average age of 3.5 years old	+	+	Hematuria Respiratory symptoms ( due to lung metastases)	+/-	Fever Hypertension/ hypotension	Present mutations of: WT1 P53 FWT1 FWT2 11p15.5 loci	Ultrasound: The best initial diagnostic study. Distinguish tumor mass from other causes of renal swelling like hydronephrosis. Doppler ultrasonography can help to detect invasion of renal vein and IVC by the tumor. CT scan: Heterogeneous soft-tissue density mass Areas of calcification and fat density regions Lymph node metastasis Surrounding organs invasion Thrombus in renal vein or inferior vena cava	Arises from mesodermal precursors of the renal parenchyma Well-circumscribed/ macrolobulated lesion Hemorrhage/ central necrosis may be present It is comprised of 3 types of cells: Stromal Epithelial Blastemal The stroma may include: Striated muscle cartilage bone Fat tissue Fibrous tissue.
Ewing sarcoma[11][12][13][14]	Include ewing sarcoma, askin tumor, and peripheral neuroectodermal tumors primitive The second most common childhood malignant primary bone tumors Usually arises in the long bones of the extremities Common age between 10-20 years old	+	+	Weight loss Fatigue	+	Fever Pathologic fractures Petechiae/ purpura	Reciprocal translocation between chromosomes 11 and 22	Radiographic of region: Poorly marginated destructive lesion Permeative or “moth-eaten” appearance CT scan: Cortical destruction Demonstrate soft tissue disease MRI: Considered as a preferred diagnostic study Better shows tumor size/ intraosseous/extraosseous extent	Small/ round/ blue cell tumors May be undifferentiated or differentiated Regular sized primitive appearing cells
Pediatric neuroblastoma [15][16][17][18]	Most common extracranial solid tumor of infancy Arising from pluripotent sympathetic cells Age distribution: < 1 years old ( 40%) 1-2 years old (35%) > 2 years old (25%)	+ (Abdominal)	+	Constipation Weakness Diarrhea	+(Abdominal)	Proptosis Periorbital ecchymosis Horner syndrome Opsoclonus myoclonus syndrome	Chromosome 1p deletion N-myc amplification	CT scan: Heterogeneous mass Calcification Necrotic areas MRI: T1: heterogeneous mass T2: Heterogeneous/ hyperintense Cystic/ necrotic areas C+ (Gd): Heterogeneous mass	Well defined/ infiltrative mass Homer wright rosettes Secretion of vanillylmandelic acid (VMA) and homovanillic acid (HVA)
Pediatric pheochromocytoma[19][20][21][22]	Rare catecholamine-secreting tumor Occur in both children and adults Average age of 11 years old Associated with neurofibromatosis, von Hippel-Lindau disease, tuberous sclerosis, sturge-weber syndrome, and multiple endocrine neoplasia (MEN) syndromes	–	+/-	Headache Sweating Weakness Convulsion	–	Hypertension Tachycardia Pallor face	Genetic mutation in: NF1 RET VHL SDHD SDHC EGLN1 EGLN2 KIF1B SDHAF2 TMEM127 SDHA IDH1 SDHB MAX HIF2A FH	Ultrasound: Different appearance from solid to mixed cystic or solid to cystic CT scan: Large and heterogenous Calcification Necrosis Cystic changes MRI (in extra adrenal tumors): T1: Heterogenous enhancement Hypointense T2: Hyperintense T1 C+ (Gd): Heterogenous enhancement	Zellballen pattern on microscopy Well-defined clusters Eosinophilic cytoplasm Positive stains for: Chromogranin for zellballlen cells Neurospecific enolase markers for neuronal cells S-100 protein for sustentacular cells
Pediatric osteosarcoma[23][24][25]	The second most common primary bone tumor The third most common tumor among adolescents Can be primary or secondary Primary osteosarcoma occurs in age of 10-20 years old Secondary osteosarcoma occurs in older patients and is secondary to paget disease and bone infarcts Accompanied with positive history of trauma	+	+	Soft tissue swelling Fracture Night sweating	+	Mass swelling Fever Arthritis Decreased joint range of motion Lymphadenopathy	Alteration in retinoblastoma gene (Rb)	Radiography: Osteolytic/ osteoblastic feature Periosteum reaction Calcification or ossification CT scan: Primary lesion and chest CT are required Demonstrate tumor location and extension MRI: Exact assessment of tumor extension Involving joint to joint findings	Contain various cellular pleomorphism and mitoses Poorly trabecular bone formation Fibrocystic and chondroblastic features
Pediatric liposarcoma[26][27][28][29]	Considered as a nonrhabdomyosarcoma soft tissue sarcomas One of the least frequent tumors during childhood Rarely seen in adolescents and age of < 8 years old Average age is 50 years among adults Occur mostly in lower extremities, retroperitoneal region, and shoulder	+	+/-	Weight loss Fatigue	–	N/A	Amplification of 12q13–15 region in MDM2 and CDK4 genes Translocation of t (12;16) (q13;p11.2) in myxoid liposarcoma	CT scan: Inhomogenous fatty structure Tumor mineralization Cortical bone erosion Calcification Infiltration to mediastinum MRI: Adipose content mass Thin irregular septa Hemorrhage Necrosis areas	Divided into following subtypes: Well-differentiated Dedifferentiated, Myxoid/ round cell Pleomorphic Common findings: Lipoblasts presence Cytoplasmic lipid vacuoles Chromatin spikes
Pediatric acute myelocytic leukemia[30][31][32][33]	Replacement of normal bone marrow cells with abnormal cells Myeloblast is malignant cell Wide distribution among childhood to adults Survival rate of 60% Common in down syndrome	+/- ( Abdominal mass, mediastinal mass)	+ (bone pain, joint pain)	Bleeding Infectious	+/-	Lymphadenopathy Hepatosplenomegaly Bruising Petechiae Pallor face Anemia Fever	Genetic translocations include: t (8;21) t (3;21) t (15;17)	Radiography: Chest radiography: Diagnosis of mediastinal mass Extremities radiography: Metaphyseal bands Lytic lesions New periosteal bone formation Pathologic fractures CT scan/ MRI: Thickening/ edema of the bowel wall in presence of abdominal pain or bowel infection Detection of early sinusitis Intracranial hemorrhage in presence of neurological symptoms Radionuclide imaging: Detection of occult infection	Hyperplastic bone marrow with leukemia cells replacement Megaloblastic feature Decrease in normal hematopoietic cell
Pediatric acute lymphoblastic leukemia[34][35]	The most common malignancy among children Few cases may associated with down syndrome, wiskott- aldrich syndrome, and ataxia-telangiectasia Peak age of 2-5 years old Previous history of cancer/ drug exposure Bone marrow replaced with malignant lymphoblasts	+/-( Extramedullary mass in abdomen/ head/ neck)	+/- (Musculoskeletal pain)	Weakness Fatigue Weight loss Bleeding	–	Fever Lymphadenopathy Hepatosplenomegaly Pallor Papilledema Nuchal rigidity Cranial nerve palsy Dyspnea	Chromosomal translocations: t (9;22) t (12;21) t (5;14) t (1;19)	Radiography: Chest x ray: Nodular mass Central lymphadenopathy Bone x ray: Radiolucent metaphyseal bands Coarse trabeculation Periosteal reaction Osteopenia Brain MRI: Leukoencephalopathy Glial cell hyperplasia Meningitis	Divided into 3 subgroups: L1: Small lymphoblast cells Scant cytoplasm Invisible nucleoli L2: Larger lymphoblast cells Abundant cytoplasm Prominent nucleoli L3: Large lymphoblast cells Deep cytoplasmic basophilia Similar to Burkitt lymphoma
Pediatric non-hodgkin lymphoma[36][37][38]	Cancer derives from lymphocytes Diverse age of incidence Associated with autoimmune disorders, previous cancer therapy, and infection	+	–	Lymph node swelling Weight loss Anorexia Abdominal pain Nausea/ vomiting	+ (Chest tenderness)	Fever Hepatosplenomegaly Lymphadenopathy Seizure Petechiae	MLL2 MEF2B EZH2 EP300 KMT2D CDKN2A	Radiography: Chest x ray: Central lymphadenopathy Pleural effusion Pericardial effusion CT scan: Presence of enlarged lymph node in chest, abdomen, and pelvis Ultrasound: Hepatosplenomegaly	Histology findings of non-hodgkin lymphoma depend on: Cell differentiation Cell lineage Location of cell origin

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2], Vamsikrishna Gunnam M.B.B.S [3]

There are no established risk factors for ameloblastoma. It is thought that common risk factors in the development of ameloblastoma may be dentigerous cyst, impacted teeth, injury to the mouth or jaw, infections of the teeth or gums, inflammation of the teeth or gums, infections by viruses, and lack of protein or minerals in the person’s diet, and Gorlin-Goltz syndrome.

There are no established risk factors for ameloblastoma.

• The risk factors of ameloblastoma is not well understood.^[1][2]

• Risk factors may include the following:
  • Dentigerous cyst
  • Impacted teeth
  • Injury to the mouth or jaw
  • Infections of the teeth or gums
  • Inflammation of the teeth or gums

Less common risk factors in the development of ameloblastoma include:

• Infections by viruses
• Lack of protein or minerals in the diet

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2], Simrat Sarai, M.D. [3]

In several cases, the patients with ameloblastoma are asymptomatic. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary.

• In several cases, the patients with ameloblastoma are asymptomatic.^[1][2][3]
• Ameloblastoma most commonly diagnosed as an accidental finding on orthopantomography.
• The most common symptoms in patients with ameloblastoma are as following:
  • Facial swelling
  • Malocclusion
  • Loosening of teeth
  • ILL-fitting dentures
  • Periodontal diseases
  • Oroantral fistulas and
  • Nasal airway obstruction

• Ameloblastoma is regarded as a true neoplasm of enamel.
• Ameloblastoma described as unicentric, nonfunctional, intermittent in growth.
• Ameloblastoma is the second most common odontogenic neoplasm.
• Ameloblastoma histologically classified as six subtypes:
  • Follicular subtype
  • Plexiform subtype
  • Acanthomatous subtype
  • Granular subtype
  • Desmoplastic subtype and
  • Basilar subtype.

• Ameloblastoma most commonly affects mandible more than maxilla.
• Ameloblastomal progress as a slow growing, painless expansion of jaw

• Complications of ameloblastoma include the following:^[4][5]
  • Breathing difficulty
  • Pain and facial deformity
  • Secondary infection of the tumor
• The recurrence rate of these tumors is 25-30%.

• The prognosis of ameloblastoma was determined mainly by the method of surgical treatment, which means that patients receiving a radical treatment had a better prognosis than those who received a radical one. ^[6][7]

• In more than 50% patients receiving the conservative treatment had good prognosis without any recurrence.
• Ameloblastoma which has a well-defined edge with sclerosis is thought to grow slowly, and the normal bone has a strong reaction to form the sclerosis edge, and the prognosis is good.
• Ameloblastomawith the ill-defined radiographic boundary, the tumor has the highest proliferative ability and poorest prognosis.
• Radical surgery should be used for the multicystic ameloblastoma to prevent the recurrence.
• The follicular ameloblastoma were thought to have a higher recurrence rate than unicystic or plexiform.^[8]

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