Malignant Tumors of the Palate

Allen Young; Oluwafunmilola Okuyemi

Malignant Tumors of the Palate

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Free Review Questions

Continuing Education Activity

Malignant tumors of the palate incorporate a wide range of differing histologies with distinctive characteristics. The location is rich in minor salivary glands, with close interaction between the mucosa and underlying periosteum, which creates a unique array of tumor histologies from adjacent subsites. This activity reviews the evaluation and treatment of malignant tumors of the palate and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

Identify the etiology of malignant tumors of the palate.
Assess the physical evaluation of malignant tumors of the palate.
Differentiate the management options available for malignant tumors of the palate.

Introduction

Malignancies of the hard and soft palate have a wide variety of characteristics. The hard palate, a subsite of the oral cavity, comprises the palatine bone's horizontal plate and the palatine process of the maxillary bone. Its boundaries include the alveolar ridge anteriorly, the soft palate posteriorly, the nasal cavity superiorly, and the oral cavity inferiorly. The hard palate is rich in minor salivary glands with close interaction between its mucosa and the underlying periosteum. This unique composition creates a different array of malignancies than other oral subsites.[1][2][3]

The soft palate, on the other hand, is a subsite of the oropharynx. It is bordered by the hard palate anteriorly, palatoglossal and palatopharyngeal muscles laterally, and posterior uvula. The most common malignant tumor histologies of the hard and soft palate include squamous cell carcinoma (SCC), mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (AdCC), polymorphous low-grade adenocarcinoma (PLGA), low-grade papillary adenocarcinoma (LGPA), acinic cell carcinoma (ACC), mucosal melanoma, Kaposi sarcoma, and non-Hodgkin lymphoma (NHL).[1]

Etiology

Tobacco and alcohol are proven carcinogens and can be synergistic causes for the development of oral SCC.[4][5] Reverse smoking, where the lit end of the cigarette or cigar is placed inside the mouth, has been linked to the development of malignant lesions of the hard palate.[6][7] The temperature of the palate can reach up to 50 degrees Celsius with reverse smoking, and the heat is suspected to be a co-carcinogen.[8] Other risk factors such as poor oral hygiene, chronic oral mucosal trauma, ill-fitting dentures, Human Papilloma Virus (HPV) infection, irritative mouthwashes, and vitamin A deficiency were associated with palate lesions.[8][9][10][11][12]

The etiology of minor salivary gland malignancies such as AdCC, MEC, PLGA, LGPA, and ACC remains unknown but is theorized to be due to specific gene mutations with input from advancing age and hormonal influences.[13][14]

Mucosal melanoma comprises a rare and aggressive form of palatal malignancies. It is thought to arise from melanocytes found in the basal layer of the oral mucosa.[15] The etiology of mucosal melanoma of the palate is unclear. Still, risk factors proposed in the literature have included ill-fitting dentures, tobacco use, and pre-existing melanotic benign oral lesions.[15][16] In contrast to the cutaneous variant, ultraviolet radiation is unlikely to be a risk factor for mucosal melanoma due to its interior location.[17] Some may present without clinical evidence of pigmentation or Amelanotic melanoma.

Kaposi sarcoma is linked to the human herpesvirus 8 (HHV8) and human immunodeficiency virus (HIV).[18] It is associated with immunosuppression and is the first malignancy that is thought to develop from acquired immunodeficiency syndrome (AIDS).[18][19]

The risk factors for developing Non-Hodgkin's Lymphoma (NHL) are multifactorial, including immunosuppression (HIV, congenital immunodeficiency, organ transplant, chemotherapy, and radiation), viral infections (EBV, HTLV-1, Herpes, Hepatitis C), bacterial infections (such as Helicobacter pylori gastritis and Lyme disease), tobacco, animal fat consumption, obesity, hair dyes, ultraviolet radiation, pesticides, occupational toxin exposure, and genetic predisposition for B-cell survival and growth.[20][21][22][23][24][25][26][27][28]

Epidemiology

Within the oral cavity, about 1 to 5% of oral cavity malignancies are located on the hard palate.[1][29]

SCC is the most common malignancy in the oral cavity. Although the incidence of SCC of the palate is lower than other subsites, SCC remains the most common malignant lesion in the hard palate, accounting for 2% of all head and neck SCC, with a predilection for male patients in their 6th decade.[30][31][32][33][34][35][36] Studies have reported that 60-74% of hard palate SCCs are Stage IV on initial presentation, with 23% displaying cervical lymph node involvement.[37][38]

Minor salivary gland tumors are the most common neoplasms found in the hard palate, with malignancy rates ranging from 40 to 82%.[3][29][39][40][41][42] AdCC (415 to 51%) and MEC (26-40%) are the 1 most common minor salivary gland tumor malignancies found on the hard palate.[39][40][41][43][44][45]

AdCC is the palate's most common salivary gland malignancy, accounting for 17.7% of all malignant salivary gland tumors.[2][46] Intraorally, the palate is the most common subsite affected, followed by the tongue.[47] The incidence of ADCC in the minor salivary glands of the palate is much higher than that in the parotid or submandibular glands.[48] ADCC has a predilection for females.[36][47]

MEC is the most common salivary gland malignancy. The minor salivary glands of the hard palate are the 2nd most common location for MEC, following the parotid gland.[2] These tumors account for less than 3% of malignancies in the head and neck.[49] MEC has a predilection for younger female patients.[36][50]

PLGA accounts for 19% to 26% of minor salivary gland malignancies.[51][52] It is most commonly found in the palate and occurs more frequently in women in the 6th to 7th decade.[53]

LGPA is a rare oral minor salivary gland tumor with a predilection for the hard palate in patients in the 4th to 5th decade.[54]

ACC is a rare tumor found in 2.91% of minor salivary gland tumors in the palate.[43] It peaks in the 5th decade of life and has a slight predilection for females.[55]

Mucosal melanomas can present in the mucus membranes in the respiratory, gastrointestinal, and genitourinary tract and comprise only 0.8% to 3.7% of all melanoma cases.[56][57][58] They present at a mean age of 70 and have a predilection for females and those of Japanese, Indian, and African descent.[57][58][59][60][61]

Kaposi sarcoma most often involves cutaneous lesions and can involve the mucus membrane in the oral and gastrointestinal tract in up to 50% of all cases.[62] The oral mucosa is the initial site of disease in 22% of HIV patients with Kaposi sarcoma.[63] Intraoral Kaposi sarcoma most frequently affects the palate, gingiva, and dorsal tongue.[62]

NHL is the 7th most common cancer in the USA and can present in extra-nodal tissue in 25% to 40% of cases.[27][64] About 3% to 5% of extra-nodal NHL cases arise in the oral cavity, commonly at the junction of the hard and soft palate.[65][66][67][68] NHL is more common among White race individuals, males, and the elderly over age 65.[27] The most common subtypes of NHL in the palate are diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT).[2]

Pathophysiology

Palatal SCC pathogenesis is associated with an accumulation of genetic mutations and epigenetic anomalies in signaling pathways that promote uncontrolled cellular proliferation and cancer development. The genetic mutations associated with oral SCC are most often attributed to cigarette smoke, alcohol, and human papillomavirus.[69] Additional factors that may play a role in SCC development include oral microorganisms, vitamin deficiencies, immunosuppression, and environmental pollutants.[70]

The majority of AdCC tumors contain a recurrent t(6;9) translocation, which fuses the MYB Proto-Oncogene transcription factor (MYB) on chromosome 6q to the Nuclear Factor IB (NFIB) gene on chromosome 9p, resulting in an overexpression of MYB-NFIB fusion oncogene.[71][72][73]

Approximately 50% to 70% of MEC have specific chromosomal translocation t(11;19)(q21:p13) leading to MEC translocated protein 1 (MECT1) and mastermind-like protein 2 (MAML2) gene fusion. Low or intermediate-grade MEC tumors are more likely to display this translocation than high-grade tumors.[74][75]

ACC is theorized to evolve from serous acinic cell differentiation or pluripotent intercalated duct cells.[55][76][77]

Mucosal melanoma arises from precursor melanocytes, which develop from the neural crest cells.[78] The reason for the migration and presence of melanocytes in the mucosa membrane of the oral cavity is not clear. Still, it has been suspected to be an antimicrobial and immunologic function.[79] The pathogenesis of mucosal melanoma is unknown, but it is postulated to be due to genetic mutations with G-Protein Subunit Alpha Q (GNAQ/11) mutations found in 9.5% of patients and overexpression of tyrosin-protein kinase Kit (c-KIT) in over 80% of cases.[80][81]

Human herpesvirus 8 (HHV8) is a transforming virus found in several malignancies that can alter the genes of its infected cells. It is theorized that HHV8, along with immunosuppressive cytokines, induce the deterioration of the immune system and proliferation of Kaposi’s sarcoma.[82]

Diffuse large B-cell lymphoma (DLBCL) can develop from several de novo mutations and rearrangements of immunoglobulin chain genes such as B-Cell CLL/Lymphoma 2 (BLC2), B-Cell CLL/Lymphoma 6 (BLC6), tumor protein 53 (TP53), myc proto-oncogene protein (MYC), proto-oncogene C-Rel (REL), enhancer of zeste homolog 2 (EZH2), Notch Receptor 2 (NOTCH2), and 9p21/Cyclin Dependent Kinase Inhibitor 2A (9p21/CDKN2A). Extranodal marginal zone lymphomas (EMZL) involving the mucosa-associated lymphoid tissue (MALT) can arise from somatic translocation mutations in the immunoglobulin genes due to chronic infection or autoimmune disease. The most common abnormalities include t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32) which upregulate the nuclear factor kappa B (NF-kB) pathway, immunoglobulin heavy locus-forkhead box P1 (IGH-FOXP1) fusion, tumor necrosis factor, alpha-induced protein 3 (TNFAIp3) deletion, and myeloid differentiation primary response 88 (MYD88) mutation.[83]

Histopathology

Palatal SCC arises from the stratified squamous epithelium of the oral mucosa (see Image. Squamous Cell Carcinoma of the Palate Without P16 Staining). It often presents with bony erosion, perineural spread, invasion of the maxillary alveolus laterally or nasal cavity, and maxillary sinus superiorly.[84] Microscopically, SCC shows irregular dysplasia and infiltrative stromal invasion with varying cellular differentiation, mitotic figures, keratinization, and lymphovascular invasion.[70]

AdCC arises from the intercalated ducts of mucin-secreting glands and presents with 3 different histologic subtypes, including cribriform (most common), tubular, and solid (most aggressive).[47] See Image. Adenoid Cystic Carcinoma of the Palate. The cribriform variant presents a “Swiss-cheese” appearance, containing cylindrical pseudocysts lined with epithelial cells and hyaline material.[47] The tubular variant consists of ducts lined by 1 to 2 layers of myoepithelial-like cells.[47] The solid variant has epithelial islands with central areas of necrosis.[47][85] The solid variant is the most aggressive of the 3 and tends to hematogenous metastasis in 40 to 60% of cases. It also tends to the perineural invasion along the palatine nerves, extending into the pterygopalatine fossa and cavernous sinus.[47][86][87]

MEC contains varying amounts of mucin-producing cells, epidermoid (squamous), and intermediate cells.[50] Histologic variants are divided into low, intermediate, and high-grade. The low-grade variant has clearly defined margins with predominantly mucin-containing cystic components.[88] The cells have small nuclei with no pleomorphism and may have rare mitotic figures.[89] The intermediate-grade variant has more nests of solid epidermoid cells. There are moderate pleomorphisms, and mitotic figures are occasionally present. The high-grade variant has poorly defined margins and predominantly comprises solid nests of epidermoid cells. Cystic components are occasionally present, with significant pleomorphism, prominent nucleoli, and abundant mitotic figures.[89][90]

PLGA is a rare salivary gland tumor most commonly found in the palate.[91] It presents an infiltrative growth pattern with solid, cribriform, tubular, and cystic patterns. Uniformly sized cells are clustered with round clear nuclei with rare mitotic figures.[51][92] See Image. Polymorphous Low-grade Adenocarcinoma of the Palate.

LGPA was once considered under the spectrum of PLGA but has since been classified as a separate entity due to its more aggressive nature.[52][93] Compared with PLGA, it has a much more extensive papillary morphology. Due to its rarity and bland appearance on histology, it is often misdiagnosed as a mixed tumor, angioendothelioma, or papillary cystadenoma.[54] They have irregular cystic spaces that contain alternating complex hyalinized papillae with fibrovascular cores and solid nests of epithelial cells with clear cytoplasm. This architecture is similar to that seen in papillary thyroid carcinoma and papillary endothelial hyperplasia.[54][93]

ACC is encapsulated by a fibrous capsule and is divided into a mixture of nests containing solid, microcystic, papillary-cystic, and follicular components. Cells have a characteristic basophilic granular cytoplasm.[94][95] See Image. Acinic Cell Carcinoma of the Palate.

Mucosal melanoma consists of malignant melanocytes of varying phenotypes (epithelioid, spindle-cell, and plasmacytoid) arranged in a sheet-like, organoid, alveolar, solid, or desmoplastic architecture.[96]

Kaposi sarcoma presents with a mixture of vascular slits, extravasated erythrocytes, and proliferating spindle cells.[97]

NHL histopathology shows irregular lymphocytes mixed with plasma cells, histiocytes, and lymphoid follicles.[98] Mucosal-associated lymphoid tissue (MALT) presents with follicle-like structures surrounded by diffuse proliferation of small, round lymphoid cells.[67] On immunophenotyping, there is a predominant CD20+ B-cells with T-cells positive for CD3+.[98][99]

History and Physical

Patients with a palatal mass may present with a history of foul oral odor or halitosis, oral bleeding, poor-fitting dentures, dysphagia, odynophagia, changes in oral speech, and loose teeth. A detailed history, including pain symptoms, the time of onset of the palatal mass, growth rate, swallowing difficulties, bleeding episodes, and prior oral trauma, should be taken. Past medical history, surgical history, family history of malignancies, and social risk factors such as smoking, alcohol, drug use, and occupational hazards should be elicited. Physical examination consists of a comprehensive head and neck exam focusing on the oral cavity and its structures. Palatal malignancies are most commonly present as a palatal mass with or without oral bleeding and pain.[100][101] All neck levels should be palpated bilaterally for cervical lymphadenopathy. Hard palate SCC presents with cervical lymph node metastasis in 13.7% to 25.7% of cases, most frequently involving supra-omohyoid levels I to III.[35][43][102]

AdCC may present with pain before any visible lesion.[46] It has an indolent growth pattern and often extends beyond the visible and palpable limit of the mass.[103]

MEC presents as a slow-growing, painless, and red-bluish mass.[104] It has varying degrees of fluctuance on palpation due to the accumulation of the mucinous component within the tumor.[105]

PLGA presents as a painless, slow-growing mass with non-ulcerated mucosa and may resemble a benign tumor.[91]

LGPA is painless, lobulated, friable, yellow-tan, and firm mass.[54]

ACC is an uncommon salivary gland malignancy that rarely appears in the hard palate. It presents as a painless, slow-growing mass.[95]

Mucosal melanomas are macular or nodular lesions with pigmented brown-to-black coloration. Most tumors within the oral cavity are between 2 to 6 cm in size.[61]

Kaposi sarcoma presents with focal or widespread violaceous-brown patches, papules, plaques, or exophytic nodules. They can involve the mucosal membrane, skin, lymph nodes, and visceral organs.[18]

NHL often presents as a painless, submucosal mass at the junction of the hard and soft palates without ulceration and with cervical lymphadenopathy.[2]

Evaluation

Palatal malignancies are diagnosed through history, physical exam, imaging, and biopsy.

Computerized tomography (CT): Conventional CT has traditionally been used to evaluate tumor extent, bony erosion, and lymphadenopathy. However, it has lower soft-tissue resolution and precision than magnetic resonance imaging. Dental artifacts also limit it.[106][107][108]
Magnetic resonance imaging (MRI): MRI can show the extent of palatal tumors, signs of perineural spread, and cervical lymph node metastasis.[2][109] Signs of malignancy on MRI include ill-defined margins, perineural spread, invasion of surrounding structures, and a capsule's absence. Perineural spread of palatal malignancies can infiltrate along the greater and lesser palatine nerves into the pterygopalatine fossa and widen the palatine foramina on MRI.[36]
Panorex: A panoramic X-ray of the maxilla and mandible is utilized to determine any bone or tooth involvement.[110]
Positron emission tomography (PET): Although PET has a poor anatomical resolution, it is superior in detecting lymph node metastasis, occult metastases, and post-treatment surveillance.[111][112][113]
Biopsy: Punch biopsy, incisional biopsy, or fine-need aspiration (FNA) biopsy can be utilized to determine the specific histology of the palatal tumor and help dictate the treatment plan. The sensitivity and specificity of FNA biopsy may vary depending on the technique used and the pathologist's experience level.[100] Incisional biopsy and examination under anesthesia can provide additional information regarding the extent of the tumor.

Treatment / Management

Treatment of palatal malignancies often requires multimodal therapy depending on the specific histology, stage, and extent of disease, and patient tolerance of treatment. Wide local excision with negative margins treats most malignant palatal lesions.[1][100] Tumors with high-grade histology or cervical metastasis often mandate additional neck dissection for regional control.[114] Adjuvant chemotherapy and radiation therapy are often used after initial surgical resection for high-grade tumors, positive or close margins, cervical metastasis, perineural invasion, and recurrent disease.[1][43][100][115] Radiotherapy alone is ineffective for malignant salivary gland tumors due to its radio-resistance and frequent bony invasion.[1] For Kaposi sarcoma, antiretroviral therapy is indicated for patients with low CD4 counts or high viral loads.[18] NHL is primarily treated with chemoradiation.[116]

Differential Diagnosis

The differential diagnosis for palatal malignancies includes the following:

Neurofibroma
Neurilemmoma
Schwannoma
Lipoma
Pyogenic granuloma
Follicular lymphoid hyperplasia
Necrotizing sialometaplasia
Multiple myeloma
Ewing sarcoma
Langerhans cell histiocytosis
Leukemia
Osteosarcoma
Osteomyelitis
Abscess
Tuberculosis
Mucocele
Leiomyoma
Pleomorphic adenoma
Other rare benign minor salivary gland tumors, including basal cell adenoma, myoepithelioma, and cystadenoma

Surgical Oncology

Surgical resection is the treatment of choice for non-lymphoma palatal tumors. A Transoral approach can be used for most small, superficial palate malignancies. If the tumor involves the hard palate or alveolus bone, resection of the maxilla is necessary for oncologic clearance. The resection would depend on the tumor's extent, ranging from a central or partial palatectomy to some form of infrastructure maxillectomy. The resulting defect may be rehabilitated with a removable obturator or prosthesis to facilitate oncologic surveillance in the future, or it may be repaired with a local, regional, or free tissue transfer.

For more extensive tumors or those involving the infratemporal fossa, pterygopalatine fossa, parapharyngeal space, masticator space, or nasopharynx (areas where a transoral approach cannot be sufficient), an external approach such as an Upper Cheek flap, Lateral rhinotomy, Weber-Ferguson approach (upper lip-split incision extending along the nasal base into the nasomaxillary groove) or paramedian mandibulectomy may be required for adequate access.[100] These procedures may involve a subtotal or total maxillectomy for oncologic clearance. Intraoperatively, negative margins are confirmed on frozen section analyses. Tumors involving the greater and lesser palatine nerves should have a frozen specimen of the nerves performed to verify nerve margins and the extent of perineural spread.[100]

For extensive palatal tumors requiring palatectomy or maxillectomy, a defect between the nasal and oral cavities can lead to difficulties with talking, chewing, and swallowing. Reconstructive options for these defects include temporary prosthetic obturators, rotational flaps (such as buccal myomucosal flaps, temporoparietal fascia or temporalis muscle flap and facial artery myomucosal flaps) for smaller defects, and free-tissue transfer flaps (such as fibula, iliac crest, scapula, radial forearm, rectus abdominus, or anterolateral thigh free flaps) for larger defects.[117][118] Studies have shown that surgical intervention for palatal malignancies improves disease-free survival compared to non-surgical approaches.[35][119] Furthermore, palatal tumors tend to display early bony invasion due to the proximity of the underlying palatine periosteum, which is not very responsive to radiation therapy.[35]

Cervical metastasis of hard palate SCC was historically thought to be low, and many surgeons did not perform elective neck dissection for N0 disease. However, recent studies have shown that cervical metastasis rates range from 13.7% to 40%, with an occult nodal metastasis rate of 21.7% to 26%, both of which are comparable to other subsites of the oral cavity.[120][121][37][122] Elective neck dissection is now recommended for patients with T4 tumors due to an average occult nodal metastatic risk of 28.6%.[114] Prior studies have also shown that regional metastasis was seen exclusively in T3 and T4 disease. The need for elective neck dissection for T1 and T2 disease is still under investigation.[35]

Wide local excision with negative margins is the treatment for AdCC, MEC, PLGA, LGPA, ACC, and mucosal melanoma.[54][89][94][123][124][125] Elective neck dissection in AdCC has been shown to increase overall survival in advanced T4 disease.[126] High-grade MEC requires radical excision with neck dissection in the presence of cervical lymph node metastasis.[89] Patients with mucosal melanoma who undergo non-surgical intervention have a 21-fold increase in mortality.[61][80] Cryotherapy with curettage has been proposed in the literature as an adjuvant treatment for patients with extensive Kaposi’s sarcoma who do not have adequate cosmetic improvement with chemotherapy.[18]

Radiation Oncology

For high-grade SCC of the palate, adjuvant radiation is often used after surgical resection for positive or close margins, cervical metastasis, perineural invasion, and recurrent disease.[1][43][100][115] Large multicentered trials (European Organization for Research and Treatment of Cancer [EORTC] 22931 and Radiation Therapy Oncology Group [RTOG] 9501) have shown that postoperative radiation for advanced stage III and IV oral SCC affords improved overall survival and locoregional control.[127]

For AdCC, adjuvant chemoradiation is recommended after surgical resection for tumors with proximity to the skull base, cervical metastasis, perineural invasion, solid-variant histology, and recurrent tumors.[128][129]

Radiation therapy for MEC is recommended for patients with cervical lymph node metastasis, bony involvement, recurrent disease, positive margins on surgical resection, perineural invasion, lymphovascular invasion, and anaplasia.[130]

Radiation therapy for PLGA has been suggested for positive margins, perineural invasion, and lymph node metastasis cases.[91][131] However, radiotherapy was found in some studies to have no significant improvement in regional recurrence, distant metastasis, or overall survival.[125][132][133]

Unresectable LGPA lesions are treated with radiation therapy, with reports showing successful tumor shrinkage when doses of 4000 to 5000 rads are used.[54]

Radiation is not effective for ACC.[94][134]

Radiation therapy has been utilized in mucosal melanoma, with 1 report recommending 25 Gy over 25 fractions.[61] Postoperative adjuvant radiation therapy has been shown to improve loco-regional recurrence, but it has not significantly affected overall survival.[135]

NHL is treated with a combination of radiation and chemotherapy. Radiation is reportedly given at 24-45 Gy over 16-25 fractions.[116][136]

Medical Oncology

For hard palate, SCC with positive margins, or extracapsular nodal extension, the addition of concurrent cisplatin-based chemotherapy to radiation therapy has been shown to improve locoregional control and overall survival versus adjuvant radiation alone.[137] Chemotherapy alone has been reserved as a palliative option for metastatic or recurrent salivary gland tumors that are not amenable to surgery or radiation therapy. No specific chemotherapy regimens have been proposed by the National Comprehensive Cancer Network (NCCN), and few agents (such as cisplatin, 5-fluorouracil, and doxorubicin) are considered effective in improving overall or disease-free survival.[138][139][140] Chemotherapy alone is mostly ineffective for AdCC due to the slow rate of tumor growth.[141] Adjuvant chemotherapy has been found to have minimal benefit for PLGA.[125][132]

Systemic therapy for mucosal melanoma has included chemotherapy, targeted therapy, and immunotherapy. Chemotherapy regimens for mucosal melanoma have included 5-fluorouracil, cisplatin, dimethyl triazeno imidazole carboxamide (DTIC), interferon, dacarbazine, nimustine hydrochloride (ANCU), and vincristine.[142][143] Targeted therapies include imatinib and temozolomide. Immunotherapy regimens have included ipilimumab and pembrolizumab/nivolumab. The overall response rate for these regimens has been low, ranging from 23% to 37.5%, with a median overall survival rate of 3.9 to 9.7 months for most treatment regimens.[61][144][145] Chemotherapy is indicated for Kaposi’s sarcoma when there is widespread skin involvement, extensive intraoral disease, symptomatic edema, or rapidly progressive disease. Patients with high-risk factors such as advanced age and poorly controlled AIDS should undergo a combination of HAART and chemotherapy. Chemotherapy regimens have included bleomycin, vinca alkaloids, and Adriamycin.[18] In addition to radiation therapy, NHL is most commonly treated with a standard chemotherapy regimen involving cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) for 8 cycles for 3 weeks.[136]

Staging

Tumor-node-metastasis (TNM) staging of oral cavity cancers based on American Joint Committee on Cancer 8 edition.[146]

T Category	Tumor Size and Characteristics
Tx	Primary tumor cannot be assessed
Tis	Carcinoma in-situ
T0	No primary lesion identified
T1	Tumor <2 cm, Depth of Invasion (DOI) <5 mm
T2	Tumor <2 cm, DOI > 5 mm and <10 mm or Tumor >2 cm but <4 cm and DOI <10 mm
T3	Tumor >4 cm or Any tumor with DOI >10 mm but <20 mm
T4a	Tumor invades cortical bone of the mandible or maxilla, maxillary sinus, skin of the face, bilateral tongue, and/or DOI >20 mm
T4b	Tumor invades masticator space, pterygoid plates, skull base, and/or encases the internal carotid artery
Node Category	Node Criteria
cNx	Regional lymph node cannot be assessed
cN0	No regional lymph node metastasis
cN1	Single ipsilateral lymph node<3 cm and Extranodal Extension (ENE) negative
cN2a	Single ipsilateral metastatic node >3 cm but <6 cm, ENE negative
cN2b	Multiple ipsilateral nodes <6 cm, ENE negative
cN2c	Bilateral or contralateral lymph nodes <6 cm, ENE negative
cN3a	Metastatic in any lymph node >6 cm, ENE negative
cN3b	Metastasis in any lymph node, ENE positive
Metastasis Category	Metastasis Criteria
Mx	Metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis

TNM for mucosal melanoma based on the American Joint Committee on Cancer.[147]

T Category	Tumor Size and Characteristics
T3	Tumors limited to the mucosa and immediate underlying soft tissue
T4a	Tumor involves deep soft tissue, cartilage, bone, or overlying skin
T4b	Tumor involving the brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal structures
Node Category	Node Criteria
Nx	Regional lymph node cannot be assessed
N0	No regional lymph node metastases
N1	Regional lymphadenopathy present
Metastasis Category	Metastasis Criteria
Mx	Metastasis cannot be assessed
M0	No distant metastasis
cM1	Distant metastasis
pM1	Distant metastasis, microscopically confirmed

Staging for NHL based on the Lugano classification.[148]

Stage	Nodal Involvement	Extra-nodal Involvement
Stage 1	1 node or group of adjacent nodes	Single extra-nodal lesion without nodal involvement
Stage 2	2 or more nodal groups on the same side of the diaphragm	Stage 1 or 2 with limited contiguous extra-nodal spread
Stage 3	Nodes on both sides of the diaphragm, nodes above diaphragm with spleen involvement	N/A
Stage 4	Wide non-contiguous spread beyond lymph system to bone, liver, lung	N/A

Prognosis

Malignant tumors of the palate have a wide range of overall prognoses depending on the specific histologies, tumor grade, margin status, cervical metastasis, and recurrence.

Prognosis of specific palatal histologies.

SCC

Negative prognostic factors for SCC include high-grade tumors, advanced T stage, positive margins, cervical metastasis, and local recurrence.[13][120][121] HPV-positive tumors have been postulated to be possibly associated with higher overall survival in palatal SCC. However, it did not reach statistical significance in 1 study (see Image. HPV-Positive Squamous Cell Carcinoma of the Palate With P16 (+) Staining).[114] Adjuvant radiation therapy has also been shown to be a positive prognostic factor for overall survival.[120] Bony invasion occurs early in palatal SCC due to the thin layer of mucosal tissue and the proximity of the palatine bone.[121] However, this is not a poor prognostic factor in overall survival.[1] in 1 study, although only about 8% of patients with SCC displayed clinical cervical node disease at initial presentation, locoregional recurrence occurred in up to 30% of patients with N0 disease at a mean duration of 6 months from the initial presentation.[149] The 5-year overall survival rate for patients with regional recurrence is estimated to be about 41% compared to 81% for patients without regional recurrence, likely due to extracapsular nodal extension.[149][150]

AdCC

The overall 5-year survival rate for AdCC ranges from 60% to 90% but decreases to 40-50% after 10 years.[49][151] Its solid variant has the worst prognosis due to the increased risk of distant metastasis and local recurrence.[152][153][154] Poor prognosis and higher recurrence rates were associated with positive margins, cervical metastasis, advanced age, bony involvement, perineural invasion, and advanced T staging (tumors greater than 4 cm).[35][47][86][155][156][157][158] Intraoperatively, surgical margins may be difficult to clear superiorly due to the skull base's proximity, which may play a factor in a higher risk of recurrence.[29] Due to the indolent, slow-growing nature of ACC and predilection for late locoregional recurrence and distant metastasis, long-term surveillance is essential for AdCC.[47]

MEC:

Low-grade MEC has a 5-year survival rate of over 90%, whereas the high-grade variant tends to metastasize and recur locoregionally.[50][159] Overall survival rates for intermediate-grade MEC are comparable to low-grade tumors.[160][161] Patients who display MECT1 and MAML2 gene fusion have a better prognosis.[74]

PLGA

Local recurrence has been reported in 9-33% of cases, with cervical lymph node metastasis present in 6-35% of cases. Distant metastasis is rare at about 1%.[125] PLGA has an indolent growth pattern known to recur for decades after initial treatment.[162] The 5 and 10-year disease-specific survival rates are 98.6% and 96.4%, respectively.[163]

LGPA

LGPA has a more aggressive course than PLGA and has an increased tendency for recurrence due to a discontinuous growth pattern.[54] Studies show LGPA has a higher rate of local recurrence (46.6%) and cervical node metastasis (40%) compared with PLGA (19% and 6.6%, respectively).[164] Disease-free intervals between recurrences can last many years, with LGPA tending to produce cervical nodal metastasis and anaplastic transformation. Routine follow-up beyond 5 years is necessary.[52][54][93]

ACC

ACC has a 5-year overall survival rate of 88.6%. Poor prognostic factors included high tumor grade, advanced T stage, cervical lymph node metastasis, and advanced age.[165] It has a recurrence rate from 11% to 26.7% and may occur several years after tumor removal.[55][76][94]

Mucosal melanoma: The prognosis for mucosa melanoma is poor, with a 5-year survival rate of 15%-45%.[142][166] Negative prognostic factors include tumor thickness of more than 5 mm and cervical lymph node metastasis.[80]

Kaposi’s sarcoma

KS has a median survival of 18 months if left untreated.[167] Antiretroviral therapy has been shown to improve the overall survival of AIDS patients with Kaposi sarcoma with a 24-month survival rate of 58%.[168]

Non-Hodgkins Lymphoma (NHL)

Studies show a 5-year disease-free progression of 88% in NHL of the head and neck after radiation therapy.[169] At 10 years, the local control rate was 91-100%; disease-free survival was 43% to 53%, and overall survival was 64% to 79%.[116][170][171] Patients with high-stage disease (Stage II-IV) who undergo radiation and chemotherapy (CHOP and prednisolone) have an average survival of 38 months.[172] Prognostic factors of NHL depend on the extent of disease, tumor staging, histopathological subtype, and presence of HIV disease. The 5-year survival rate after chemoradiation is 59%, 34%, 14%, and 10% for stages I, II, III, and IV, respectively.[173] Among B-cell lymphomas, Burkitt's lymphoma and DLBCL have a more aggressive course, whereas follicular lymphoma and small lymphocytic lymphoma have a more indolent course.[174] Patients with HIV have a median survival time of 9 months, whereas those without HIV have a median survival time of 34 months.[174]

Complications

The most significant complication is a failure to cure the disease due to positive surgical margins, locoregional occurrence, distant metastasis, or the development of a second primary cancer.[175] Surgical resection of oral structures can cause difficulties in speech and swallowing, potentially requiring long-term enteral feeding, recurrent aspiration, and communication deficits.[175][176] The loss of sensation and the presence of soft tissue bulk from flap reconstruction can hinder the patient’s ability to manipulate food during chewing.[177] Patients who undergo neck dissection for cervical lymph node metastasis risk neurological damage to the spinal accessory nerve, phrenic nerve, hypoglossal nerve, lingual nerve, vagus nerve, sympathetic trunk, and a marginal mandibular branch of the facial nerve.[175][178][179]

Acute radiation toxicity is common after a standard course of adjuvant radiation therapy and is non-life-threatening. The introduction of 3D conformal radiation therapy (3D-radiation therapy) and intensity-modulated radiation therapy (IMRT) have significantly reduced the damage to salivary glands and subsequent xerostomia.[180][181] Patients may experience acute toxicities, including mucositis, pharyngitis, esophagitis, dysphagia, odynophagia, trismus, xerostomia, and dermatitis.[182][183] Delayed radiation toxicity such as mandibular osteoradionecrosis (ORN) can be a severe side effect of RT. Osteoradionecrosis is thought to occur due to radiation hampering osteoblastic replication, resulting in excessive myofibroblast proliferation and poor blood supply associated with fibrosis of the inferior alveolar artery, resulting in the atrophic, fibrotic bone.[184]

Chemotherapy for oral malignancies has been linked to several complications, such as mucositis, fungal and viral infections, xerostomia, dysgeusia, malnutrition, and pain.[185][186] Specific chemotherapy agents such as antimetabolites (5-Fluorouracil, 6-Mercaptopurine, Fludarabine, Gemcitabine, Methotrexate) and alkylating agents (cyclophosphamide, chlorambucil, chlormethine, busulfan) result in a higher incidence and severity of mucositis.[187] Reduced salivary production from chemotherapy agents increases the risk of oral candidiasis, periodontal disease, mucositis, dysgeusia, tongue fissures, halitosis, oral pain, and odynophagia.[187][188] Concurrent chemotherapy with radiation can further increase the risk of ORN through increased reactive oxygen species, which impede the DNA repair capability of bone cells.[189]

Postoperative and Rehabilitation Care

Patients who undergo treatment for oral malignancies often display long-term impairments in swallow and speech due to resection of anatomic oral structures, soft tissue fibrosis from radiation, and mucositis from chemoradiation. Early consultation with speech and swallow professionals is vital for assisting the patient in regaining some pre-treatment functions to prevent malnutrition, aspiration, long-term reliance on enteric feeding, and poor communication.[175][176][190] Recurrence often occurs many years after initial treatment and continuous follow-up is needed.[100] According to the National Comprehensive Cancer Network (NCCN) guidelines for post-treatment surveillance, patients should receive regular follow-ups every 1 to 3 months in the 1st year after treatment, 2 to 6 months in the 2nd year, 4 to 8 months in the 3rd to 5th year, and every 12 months after the 5th year.[191] Follow-up for over 10 years is recommended for these malignancies.[192]

Consultations

An interprofessional team would need to diagnose and manage palatal malignancies, including an otolaryngologist, plastic reconstructive surgeon, general surgeon, radiation oncologist, medical oncologist, speech-language pathologist, psychologist, and primary care physician.

Deterrence and Patient Education

Patient education on palatal cancer can be challenging due to the heterogeneous array of pathologic histologies and the need for multidisciplinary and multimodal management. Patients and their families should be educated on the different treatment options and timelines, including surgical resection, radiation therapy, and chemotherapy, as well as reconstructive surgery for significant palatal defects. Patients and parents (for minors) should be counseled on the possible risks and complications of all treatment modalities, and their comorbidities should be fully assessed by their primary care physicians to determine if they are candidates for surgical resection. Cessation counseling for social risk factors such as smoking and alcohol must be provided to reduce the risk of recurrent cancer and poor treatment outcomes. Long-term follow-up is crucial for oral malignancies, given the high recurrence rates and indolent growth patterns of certain pathologies, and must be emphasized to patients.

Enhancing Healthcare Team Outcomes

Patients with palatal malignancies should be managed by a multidisciplinary team of otolaryngologists, plastic surgeons, general surgeons, pathologists, radiation oncologists, medical oncologists, speech-language pathologists, psychologists, and primary care physicians. Oral palatal malignancies present with varying histologies and severities and often require multimodal therapy involving surgery, radiation, and chemotherapy. Close communication and collaboration between the surgeons, radiation oncologists, and medical oncologists can provide a tailored approach for each patient. Difficulties in swallow and speech are common complaints before and after treatment for oral malignancies. Therefore, patients may need a consultation with general surgery for gastric tube placement to ensure optimal nutrition perioperatively. Early post-treatment intervention by a speech-language pathologist can help patients regain some pre-treatment function to prevent malnutrition, dependence on enteric feeding, and communication difficulties. Recurrence of palatal malignancies can occur several years, even decades, after initial treatment. Thus, routine close follow-up by the otolaryngologist and primary care physician is advocated. Finally, patients may develop depression, social anxiety, and avoidance due to their cancer diagnosis, visible surgical scarring, and speech difficulties. Formal peer support groups and consultation with a psychologist can aid patients in addressing their concerns.

(Click Image to Enlarge)

Squamous Cell Carcinoma of the Palate Without P16 Staining

Contributed by J Ono, MD

(Click Image to Enlarge)

Acinic Cell Carcinoma of the Palate

Contributed by J Ono, MD

(Click Image to Enlarge)

Polymorphous Low-Grade Adenocarcinoma of the Palate

Contributed by J Ono, MD

(Click Image to Enlarge)

Adenoid Cystic Carcinoma of the Palate

Contributed by J Ono, MD

(Click Image to Enlarge)

HPV-Positive Squamous Cell Carcinoma of the Palate With P16 (+) Staining

Contributed by J Ono, MD

Details

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