Squamous cell carcinoma

Squamous cell carcinoma (SCC) of the oral cavity is a malignant epithelial neoplasm arising from the mucosal lining of the oral cavity. It is the most common malignancy of the oral cavity, accounting for approximately 90% of oral cancers.[1][2][3] The tumor is strongly associated with tobacco use, alcohol consumption, and betel nut chewing; these exposures act synergistically.[2][3] A stepwise molecular progression from normal mucosa through hyperplasia, dysplasia, and carcinoma in situ to invasive carcinoma is well established, driven by accumulating genetic alterations including loss of 9p21/p16, TP53 mutation, and cyclin D1 amplification.[4] Oral potentially malignant disorders—particularly leukoplakia, erythroplakia, and proliferative verrucous leukoplakia—carry a recognized risk of malignant transformation.[5]

SCC most commonly involves the jaws secondarily through direct invasion from overlying gingival or alveolar mucosal tumors, producing irregular bone destruction. Less commonly, primary intraosseous SCC arises centrally within the jaw from odontogenic epithelial remnants or malignant transformation of odontogenic cysts.[6] Management is primarily surgical, with adjuvant radiotherapy or chemoradiotherapy guided by pathologic risk features.[7]

The current WHO Classification of Head and Neck Tumours (5th edition, 2022) classifies this entity as squamous cell carcinoma of the oral cavity. Staging follows the AJCC/UICC TNM system, 8th edition (2017), which incorporates depth of invasion (DOI) into T classification and extranodal extension (ENE) into N classification.[7][8][9]

When SCC arises centrally within the jawbone without a mucosal primary, the WHO classifies it as primary intraosseous squamous cell carcinoma (PIOSCC), subdivided into solid type, carcinoma ex odontogenic keratocyst, and carcinoma ex odontogenic cyst.[6] Older literature may use the term "primary intraosseous carcinoma" (PIOC) or "intra-alveolar carcinoma." The term "gingival carcinoma" is sometimes used for SCC arising from the alveolar mucosa with secondary bone involvement.

• Age and sex: Pooled data indicate a mean age at diagnosis of approximately 57 years, with a male-to-female ratio of roughly 2–2.5:1. An increasing incidence in patients younger than 45 years has been noted in some populations.[2][10][11][12]
• Frequency: Globally, oral cavity and lip cancers account for approximately 389,000 new cases annually. In the United States, an estimated 36,600 new oral cavity cancers occur per year.[3][5]
• Anatomic distribution: The tongue (particularly the lateral border and ventral surface) is the most common subsite, followed by the floor of mouth, alveolar ridge/gingiva, buccal mucosa, retromolar trigone, and hard palate. When the alveolar ridge is involved, the posterior mandible is affected more frequently than the maxilla.[10][12][13]
• PIOSCC is rare, representing approximately 6% of malignant jaw tumors in one large series; it shows a strong predilection for the posterior mandible.[13][14]

Presentation and Symptoms

• Early lesions may present as a persistent mucosal ulcer, erythroplakic or leukoplakic patch, or an indurated mass that fails to heal within 2–3 weeks.
• Common symptoms include pain, dysphagia, bleeding, and loosening of teeth adjacent to the lesion.[1][12]
• Gingival and alveolar ridge SCC may mimic periodontal disease or a non-healing extraction socket, delaying diagnosis.
• Sensory disturbance (paresthesia or anesthesia) of the inferior alveolar nerve is a red flag for mandibular invasion and carries prognostic significance.[6][15]

Examination Findings

• An exophytic, endophytic, or ulceroproliferative mass with rolled, indurated borders is characteristic. Advanced tumors may be fixed to underlying bone.
• Cervical lymphadenopathy is common; regional nodal metastasis is present in approximately 39% of patients undergoing neck dissection. The lungs are the most frequent site of distant metastasis.[1][10]
• Trismus suggests involvement of the masticator space or pterygoid musculature and indicates very advanced (T4b) disease.[7]

Tempo and Complications

• Growth is typically progressive over weeks to months. Pathologic fracture of the mandible may occur with extensive bone destruction. Perineural spread along the inferior alveolar nerve or branches of the trigeminal nerve can extend disease beyond the clinically apparent margins.[16][17]

Oral SCC is primarily a soft-tissue malignancy; radiographic findings in the jaws reflect secondary invasion from an overlying mucosal tumor or, rarely, a primary intraosseous origin. Panoramic radiography is recommended in the workup of oral cavity cancers requiring mandibulotomy or mandibulectomy and as part of pre-radiation dental evaluation.[7]

Location and Distribution

• Bone involvement most commonly affects the posterior mandible (body, angle, retromolar region), corresponding to the frequent subsites of gingival, retromolar trigone, and floor-of-mouth SCC.[13][16]
• Maxillary involvement occurs less frequently and typically affects the alveolar ridge and hard palate, occasionally extending into the maxillary sinus.[7][13]
• PIOSCC shows a strong predilection for the posterior mandible; maxillary PIOSCC tends to involve the anterior region and may cross the midline.[14]

Periphery and Shape

• The characteristic appearance is an irregularly marginated radiolucency with ill-defined, non-corticated borders, reflecting aggressive, destructive growth.[13][14][18]
• Bone destruction follows recognized patterns: moth-eaten destruction (multiple small, coalescent areas of lysis with ragged margins) is common; permeative destruction (tiny lytic foci with indistinct transition to normal bone) indicates rapid, aggressive growth.[19]
• An erosive (saucerized) pattern of cortical resorption may be seen when the tumor advances on a broad front with osteoclastic activity at the tumor–bone interface.[17][20][21]
• Occasionally, particularly in PIOSCC or SCC arising within an odontogenic cyst, the lesion may show a deceptively well-defined or partially corticated border, mimicking a benign cystic process.[6][13][14]

Internal Architecture

• The internal structure is characteristically radiolucent without internal mineralization or septation.[14]
• Mixed radiolucent-radiopaque appearance is rare and has been reported in occasional cases of PIOSCC with reactive bone formation.[14][22]

Effects on Teeth and Adjacent Structures

• Root resorption of teeth within or adjacent to the lesion is common and may be irregular or "spiked" rather than the smooth resorption seen with benign lesions.[18]
• Tooth displacement and pathologic mobility occur as supporting alveolar bone is destroyed.
• Widening or destruction of the periodontal ligament space may be an early sign, sometimes mimicking periodontal disease.
• Loss of the lamina dura around involved teeth is a characteristic early finding.
• The inferior alveolar nerve canal may be widened, destroyed, or obscured; loss of canal cortication suggests perineural or direct tumor invasion.[16][23]

Extent and Cortical Involvement

• Cortical bone destruction is a hallmark feature. Initial involvement produces "cupping" or saucerization of the cortical plate directly beneath the tumor, progressing to frank cortical perforation.[17]
• Buccal and lingual cortical expansion is less prominent than in benign odontogenic tumors; instead, cortical destruction without significant expansion is more typical of malignancy.[18]
• Advanced lesions may extend to involve the inferior border of the mandible, with or without pathologic fracture.
• Panoramic radiography has moderate sensitivity (55–73%) but high specificity (88–92%) for detecting mandibular invasion; it tends to underestimate the width and depth of bone involvement. CBCT demonstrates significantly higher sensitivity (89–93%) than panoramic radiography for cortical bone invasion and mandibular canal involvement, with comparable or superior specificity. CBCT is particularly valuable for evaluating subtle alveolar invasion, though dental artifacts may limit assessment near the alveolar crest.[23][24][25][26][27][28]

Variants

• Primary intraosseous SCC presents as a central jaw radiolucency without an identifiable mucosal primary. Most cases appear as ill-defined unilocular osteolytic lesions; a minority show cyst-like radiolucency with partially defined borders, especially when arising from a pre-existing odontogenic cyst.[6][14][29]
• SCC arising in an odontogenic cyst may initially appear as a well-corticated unilocular radiolucency indistinguishable from a benign cyst; progressive loss of cortication, irregular margination, or rapid enlargement should raise suspicion for malignant transformation.[6]

Cortical Bone Erosion and Marrow Invasion

Contrast-enhanced CT with bone algorithm provides the highest specificity for cortical bone erosion and is complementary to MRI.[7][30] MRI is preferred for evaluating bone marrow invasion, as it can detect marrow replacement before cortical destruction is apparent; a negative MRI effectively excludes marrow invasion.[7][31] MRI is also superior for assessing perineural tumor spread along the inferior alveolar nerve and trigeminal branches, skull base invasion, and soft-tissue extent, particularly in the presence of dental amalgam artifact.[7][30][32]

Soft-Tissue Extent and Depth of Invasion

MRI with contrast provides superior soft-tissue resolution for delineating tumor extent in the tongue, floor of mouth, and extrinsic tongue musculature—features critical for T staging under the AJCC 8th edition DOI criteria.[7][30]

Nodal and Distant Staging

FDG-PET/CT is useful for detecting distant metastases in advanced disease and for mapping nodal extent in the clinically positive neck; it has limited value for the clinically N0 neck.[1][30] Chest CT is recommended to evaluate for pulmonary metastases.[1][7]

The differential diagnosis depends on whether the lesion presents as a mucosal-based destructive process invading bone or as a primary intraosseous radiolucency. Mucosal SCC with bone invasion is usually clinically apparent; the diagnostic challenge arises when bone destruction is the presenting or dominant radiographic finding.

The highest-risk diagnostic pitfall is misidentifying SCC as osteomyelitis or a benign odontogenic cyst, particularly when PIOSCC presents with cyst-like borders or when gingival SCC mimics a non-healing extraction socket. Any jaw radiolucency with progressive pain, paresthesia, rapid enlargement, or resistance to conventional therapy warrants incisional biopsy.[13][29][33]

Microscopic Features

Oral SCC is characterized by islands, cords, and sheets of malignant squamous epithelium invading the subepithelial connective tissue and, when present, underlying bone. Diagnostic features include intercellular bridges, variable keratinization, nuclear pleomorphism, increased mitotic activity, and loss of basement membrane integrity.[4][38]

Grading

The WHO classification endorses a three-tier differentiation-based grading system:[9]

• Well differentiated (G1): Prominent keratinization, keratin pearl formation, minimal nuclear atypia; resembles normal squamous epithelium.
• Moderately differentiated (G2): Intermediate keratinization and pleomorphism; the most common grade, accounting for approximately 50–55% of cases.[10][38]
• Poorly differentiated (G3): Minimal keratinization, marked pleomorphism, high mitotic rate; associated with higher rates of lymph node metastasis and worse survival.[39]

The prognostic value of the WHO grading system is limited.[9][40] Alternative systems incorporating tumor budding (small clusters or single cells at the invasive front) and worst pattern of invasion (WPOI) have demonstrated superior prognostic discrimination.[40][41][42]

Patterns of Bone Invasion

Two principal histologic patterns of mandibular invasion are recognized:[21][43][44]

• Erosive (indirect): Tumor advances on a broad front with osteoclastic bone resorption and an intervening connective tissue layer separating tumor from bone.
• Infiltrative (direct): Tumor islands penetrate directly into cancellous marrow spaces without an intervening connective tissue barrier; this pattern is associated with higher rates of marrow invasion, nodal metastasis, and worse survival.[21][43]

Aggressive soft-tissue WPOI (grades 4–5) significantly predicts an infiltrative pattern of bone invasion.[43]

Radiologic-Pathologic Correlation

Panoramic radiography and CT tend to underestimate the histologic extent of bone invasion.[25][26] The erosive pattern produces the saucerized cortical defects visible on imaging, whereas the infiltrative pattern—with tumor satellites advancing through marrow spaces—may extend beyond the radiographically apparent margins.[17][21] Superficial erosion of bone or tooth socket alone by a gingival primary is not sufficient to classify a tumor as T4 under AJCC 8th edition staging.[7]

Workup and Referral

The NCCN Guidelines recommend biopsy, complete head and neck examination, and cross-sectional imaging (CT with contrast and/or MRI) of the primary site and neck.[7] Panoramic radiography or dental CT is indicated for surgical planning and pre-radiation dental evaluation.[7] PD-L1 testing by immunohistochemistry (combined positive score) is recommended for treatment planning.[7] Multidisciplinary consultation is standard.[7]

Definitive Treatment

• Surgery is the preferred primary treatment for resectable oral cavity SCC. Resection of the primary tumor with adequate margins (≥1 cm) is the goal, with neck dissection guided by tumor location, depth of invasion, and nodal status.[7][45]
• Mandibular resection (marginal or segmental) is performed when tumor involves or is adherent to mandibular periosteum or bone. Segmental resection is indicated for medullary space invasion.[7]
• Sentinel lymph node biopsy is an emerging option for clinically N0 disease.[7]
• For PD-L1-positive (CPS ≥1) advanced disease (T3–T4a or node-positive), neoadjuvant pembrolizumab followed by surgery and adjuvant pembrolizumab with radiotherapy (± cisplatin for ENE or positive margins) is now included in NCCN recommendations.[7]

Adjuvant Therapy

• Concurrent chemoradiotherapy (cisplatin-based) is indicated for high-risk pathologic features: extranodal extension and/or positive margins (category 1).[7]
• Adjuvant radiotherapy alone is considered for other adverse features including close margins, pT3/pT4, pN2/pN3, perineural invasion, and lymphovascular invasion.[7]

Prognosis

• Early-stage (I–II) disease has a 5-year overall survival of approximately 70–80%.[46]
• Advanced-stage (III–IV) disease carries a 5-year overall survival below 50%, with high rates of locoregional recurrence (15–40%).[45][47]
• Independent adverse prognostic factors include poorly differentiated histology, extranodal extension, positive margins, perineural invasion, lymphovascular invasion, and increasing depth of invasion.[7][10][39][48]
• Recurrence is most common within the first year after treatment.[47]

Primary Intraosseous SCC

PIOSCC is classified separately from mucosal SCC and requires strict diagnostic criteria: absence of mucosal ulceration (except when caused by other factors), histologic evidence of SCC without another identifiable primary, and exclusion of metastatic disease by systemic imaging with a minimum 6-month follow-up.[6][34] The cystogenic subtype arises from malignant transformation of an odontogenic cyst (most commonly residual or dentigerous cysts) and may present with a deceptively benign radiographic appearance.[6] Any odontogenic cyst showing unexpected mural thickening, loss of cortication, or rapid recurrence should undergo thorough histologic examination to exclude PIOSCC.[6]