ACRT Journal

Introduction

Oral cancer is a malignant neoplasm that affects the oral cavity and its subsites like mucosal surfaces of the lips, floor of mouth, oral tongue, buccal mucosa, lower and upper gingiva, hard palate and retro molar trigone. It usually occurs after the 5th decade of life, even though cases in people younger than 40 years are increasing [1,2]. Although the incidence is higher in males, the male-female ratio is progressively decreasing, due to a proportional increase in the consumption of tobacco and alcohol in females [2,3]. If it is true that tobacco (including smokeless tobacco) and alcohol are nowadays the main etiological factors [1,4], chronic inflammation and repeated trauma of the mucosa and poor oral hygiene have to be considered important causes of oral cancer [5]. In fact, a review of the literature revealed that persistent irritation of the mucosa caused by dental trauma, as well as introduction of hot foods and beverages, can be regarded risk factors for the development of oral cancer [6,7]. More than 90% of oral cancers are squamous cell carcinomas (OSCCs) [2].

OSCCs begins as a superficial micro-papular lesion, but rapidly tends to ulcerate and infiltrate the adjacent structures (muscles, periosteum, bone). This occurs with variable frequency in relation to the subsite, the dimensions, and some histological characteristics of the primary lesion (thickness, degree of differentiation, perineural invasion). Although early diagnosis is possible with easy self-examination and physical examination, most patients are not symptomatic in the early stages and do not seek medical attention until the onset of pain, bleeding, oral cavity lesions or neck nodules, so that more than 50% of oral cancers are detected at an advanced stage (stage III and IV)[8]. OSCC can have varying degrees of differentiation and frequently presents with nodal involvement. The T stage, as well as the depth of invasion and tumor thickness, are all closely associated to lymphatic spreading into the neck [8,9]. According to staging and risk factors, treatment of OSCC includes single modality surgery, radiotherapy [external beam radiotherapy (EB-RT) and/ or brachytherapy], or various combinations of these modalities with or without systemic therapy (chemotherapy (CH) and/or target agents). Tumor site and size, nearby structures involvement, stage at diagnosis, functional and cosmetic outcomes, patient’s comorbidities, and the patient’s willingness are the main criteria of treatment decision [10]. Despite the advances in surgery, radiotherapy and chemotherapy have resulted in improved survival statistics over the past three decades, oral cancer still has poor prognosis, since the overall 5-year survival rate after treatment of oral cancer (all the stages included) is reported as 50–63% [2], due to aggressive local invasion and metastasis, leading to recurrence. [11].

DMs from OSCCs are quite rare, 6% to 9% of cases, and occur predominantly in organs such as the lung (commonest site for distant metastasis for HNSCCs) bone, mediastinal lymph nodes, brain, and liver [18,19,21,22]. Lung is the commonest site of DMs for HNSCCs, followed by bone, mediastinal lymph nodes, brain, and liver [12–14]. Invasion and metastasis of OSCC is favoured by overexpression of integrin αvβ6 in neoplastic cells [15]. This has also been documented in carcinomas arising from different organs (including serous ovarian cancer, colon, stomach, et al.), where it could become a possible target for antibody- and small-moleculemediated therapies [16,17].

Peritoneal metastasis (PMs) from a primary site in the upper aero digestive tract are extremely rare [18]. PMs are predominantly seen as a manifestation of intra-abdominal malignancy such as gastric, colon, pancreatic and ovarian cancer, and when they occur from an extra-abdominal primary cancer, breast and lung cancers are the most reported [18,19]. Molecularly, PM appear to be mediated by integrin α2 and β1 integrins [20,21]. Only a few cases have been reported in the literature of HNSCCs metastasizing specifically to the peritoneum, further illustrating its rarity [22]. We present the case of a 38-year-old patient with squamous cell carcinoma of the buccal mucosa, without any known preoperative distant metastases, who underwent surgical treatment followed by adjuvant therapy (radiotherapy and chemotherapy) and immediately at the end of the treatments, developed extensive peritoneal carcinosis and multiple bone metastases. Moreover, we performed a systematic review of literature to investigate eventual other similar cases and the molecular causes.

Material and Methods

In order to identify all potentially relevant scientific papers published from June 1954 until September 2023 and reporting original research on the uncommon sites of metastasis of OSCCs, a systematic search of the Medline databases (https://www.pubmed. ncb.nlm.nih.gov/) was carried based on the following criteria:

• Full text papers;
• Available abstracts;
• English text papers;
• Clinical studies, reviews and case reports related to uncommon sites of metastasis compared to the literature data.

Clinical studies were excluded if they met at least one of the following criteria:

• Pediatric or pregnancy patients;
• Interim reports;
• Not about squamous cell carcinoma (other histologies);
• Not uncommon sites of metastasis from OSCC
• Molecular studies;
• Preclinical studies;
• Non-English written language;
• No full text;
• Management of OSCC.

The following search string, sorted by “best match”, was used in Medline: oral cancer AND distant metastasis NOT lung NOT liver NOT melanoma. Two authors (AM and FM) independently selected the articles according to the inclusion and exclusion criteria. Any disagreements or differences in selection of the eligible articles were resolved by consultation and discussion with a third assessor (LG). 1954 to 2023 is the period frame that was taken into consideration for the search (the date last searched was 13 September 2023). The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram (http://prisma-statement.org/PRISMAStatement/FlowDiagram. aspx) (Figure 1) was followed, according to the specific guideline [23]. Consequently, 1896 out of 1944 papers were excluded after a preliminary screening that considered the language (only English texts were included), the accessibility of full texts, and the relevance determined by the title and abstract. Afterwards, out of the 68 full text papers that were evaluated for eligibility, 59 were disqualified, primarily due to their association with the typical sites of metastases from carcinomas of the oral cavity.

Tissue samples were fixed in buffered formalin and routinely processed to paraffin wax. Five-micrometer-thick sections were routinely stained with hematoxylin and eosin. Immunohistochemical (IHC) reactions were performed on additional 3-μm-thick sections using prediluted ready-to-use vials of the antibodies listed in Table 1 with an automated immunostainer (BenchMark Ultra, Ventana Roche Diagnostics) and standardized protocols (Ventana OptiView DAB IHC Detection Kit). Search for somatic variants in the TP53 gene was carried out using next generation sequencing (NGS) on the Illumina MiSeq platform (AmoyDx HANDLE Classic NGS Panel CE-IVD*, Amoy Diagnostics Co., Ltd.)

Table 1: Antibodies adopted for immunohistochemical reactions o formalin-fixed-paraffin-embedded tissue slides.

Figure 1: Prisma 2021 flow diagram.

Case Presentation

A 38-year-old man came to our attention in June 2021 for the appearance of an ulcerated lesion of the left buccal mucosa (specifically a squamous cell carcinoma on biopsy) with homolateral cervical lymphadenopathy causing reflex otalgia. The patient had no relevant past medical history without any familiarity for cancer. He had been e-cigarette smoker for 2 years till July 2021 (by 2019 he had been smoking 10-12 cigarettes per day for 20 years (10 p / y)). He stated that, over the previous two years, he had visited the dentist multiple times to have the second upper left molar filed since its contact had injured the buccal mucosa. Therefore, he had underestimated the emergence of a papule in the traumatize sites two months earlier. Clinical examination confirmed the presence of an ulcerated lesion of the posterior half of the left buccal mucosa at the level of first and second upper molar tooth, with discomfort and tenderness on palpation in apparent continuity with adenopathy package at levels Ib and IIa. On imaging (Magnetic Resonance Imaging, MRI with contrast), the lesion, which measured 30 x 14 x 26 mm in size (Figure 2a-b), appeared heteroproductive in the context of the adipose tissue of the buccal space and the Bichat’s fat pad, reaching close to the outlet of the Stensen duct; it had an extensive posterior contact with the masseter muscle and with the anterior margin of the upper branch of the mandible, occupying the region of the retro molar trigone up to the pterygomandibular raphe, and anteriorly infiltrating the buccinator muscle. Superiorly the tissue was infiltrating the gum and marginally the adjacent superior alveolar process surrounding the 1st molar. There wasn’t any sign of evident infiltration of the mandible, nor of the internal pterygoid muscle or of the pterygopalatine fissure. Several partial colliquated and confluent lymph node swellings, with a maximum diameter of 40 mm and inseparable from the submandibular gland and the lower region of the parotid gland, were observed postero-inferiorly to the mandibular body. An additional 17 mm lymph node nodulation was seen inferiorly contiguous with the anterior portion of the ipsilateral sternocleidomastoid muscle. In the right latero-cervical area, globally small lymph nodes including a more evident lymph node with irregular profiles at level IIa of 16x 8 mm, inhomogeneous after contrast of uncertain inflammatory significance.

Figure 2a-b: MRI showing the primary lesion (a= axial; b= coronal).

We completed the pre-operative staging with a Positron Emission Tomography (PET) scan, total body Computerized Tomography (CT) scan with contrast and cervical-lumbar spine CT scan with contrast without any evidence of distant metastases. His clinical TNM stage was determined as cT2N3bM0. In July 2021 the patient underwent surgery treatment with exeresis of the left buccal mucosa squamous cell carcinoma, complete left parotidectomy, left modified radical neck dissection (MRND) type III, right laterocervical lymphadenectomy (level IIa), temporary tracheostomy and reconstruction with right radial forearm free flap (RFFF). Histopathology report showed moderately differentiated squamous cell carcinoma (G2) infiltrating the buccinator muscle (DOI: 11 mm), with IHC hyper expression of p53 and integrin αvβ6 as well as negative p16 (Figure 3). The neoplasm reached the anterior resection margin of the operative piece and close (< 5 mm) to the posterior and inferior margin of the operative piece. Moreover, metastases were found in the lymph node of the deep left parotid lobe with extranodal spread and in 20 out of 40 left laterocervical lymph nodes, with extra nodal spread in 3 lymph nodes (ENE+). There was no evidence of lymph vascular invasion but perineural invasion was present. pT3 pN3b, R1, PNI + Stage IVB (AJCC, TNM 8 ^ ed. 2017).

Figure 3: Oral squamous cell carcinoma (OSCC) showing nests and cordons of neoplastic cells with abundant pinkish cytoplasm, round nuclei, intercellular bridges, and squamous pearls formation. Immunohistochemical profile features hyper expression of p53 and αvβ6, while p16 is negative. (A. EE, 5x; B. p53, 20x; C. αvβ6, 20x; D. p16, 5x).

Considering the histological outcome, the patient was given adjuvant radiotherapy for a total radiation dose of 66Gy in 30 fractions and concomitant chemotherapy with a total of 300mg/ m2 CDDP (from 30th August 2021 to 11th October 2021). Due to the patient’s intense actinic pharyngeal edema and mucositis, which was causing dysphagia and odynophagia, and because of the inadequate buccal opening brought on by the post-operative analgesic trismus, a nasogastric tube was placed during adjuvant therapy (September 23, 2021). So, from this point forward, the patient only received enteral nutrition. Blood tests were performed around one week after the therapy ended (October 20,2021), and the results were within normal ranges.

On 25th October 2021 the patient came to our attention for severe abdominal pain and vomiting. Upon clinical examination, he showed signs of weakness, severe suffering and fever with a flat abdomen, tense, pain, and tenderness in all four quadrants, as well as no peristalsis. In the suspicion of peritonitis, we sent the patient to the emergency room for appropriate management and treatment. Blood tests showed WBCs 10.8 x 10^9/L, RBCs 4,54 x 10^12/L, Hgb 12,9 g/dL, Hct 38.8 %, PLT 324 x 10^9/L, neutrophil 88,4 %, creatinine 0,65 mg/dL, Na+ 131,6 mmol/L, K+ 4.42 mmol/L, Ca2+ 2.41 mmol/L, PCR 148.3 mg/L. An abdominal CT scan was performed with the evidence of diffuse hyper density of the endoabdominal adipose tissue of dubious interpretation (inflammation? carcinosis?); lytic lesions of secondary substitutive significance affecting some of the skeletal segments included in the field of study, the most significant ones to the right hemi some of D10 and to the pelvic bones (Figure 4-5).

Figure 4: Axial CT scan showing hyper density of the endoabdominal adipose tissue due to peritoneal neoplastic involvement.

Figure 5: axial CT scan showing D10 hemisome’ lytic lesion.

The patient immediately underwent to an exploratory laparoscopic surgery, peritoneal washing and omental biopsy with macroscopic evidence of diffuse fibrinous peritonitis. Histopathology report showed squamous cell carcinoma metastasis with the same immunohistochemistry as the primary tumor in the buccal mucosa (p63+, p40+, CK34betaE12+, focal CK8-18+, calretinin-, CDX2-, BerEp4-) (Figure 6).

Figure 6: Peritoneal localization of a squamous cell carcinoma, which is immunophenotypically compatible with OSCC (A. and B. EE, 20x; C. IHC p40, 20x).

In the meantime, he was hospitalized in the general surgery department until November 5th, 2022, with a clinical course characterized by a slow recovery both of gastric emptying (frequent vomiting attacks) and intestinal canalization (digestive tube x-ray performed), which required prolonged maintenance of the nasogastric tube, and in general by a slow recovery of the general clinical picture. As a further investigation during hospitalization, a brain CT was performed which excluded the presence of intracranial metastases. Blood tests revealed an electrolyte imbalance including hyponatremia and hypercalcaemia (WBCs 13,2 10^9/L, RBCs 3.67 10^12/L, Hgb 10.1 g/dL, PLT 512 10^9/L, Na+ 132,8 mmol/L, K+ 3,64 mmol/L, Ca2+ 3,26 mmol/L, PCR 153.0 mg/L).

The hospitalization was then organized in the medical oncology department for the case’s investigation and treatment. Given the rarity of abdominal metastases from squamous cell carcinoma of the head and neck region, total body CT with contrast was performed on November 15th, which excluded the presence of other primary lesions (as well as dermatological examination and esophagogastroduodenoscopy). Moreover, it showed further rapid progression of the abdominal disease, a renal vein thrombosis and a minor peripheral pulmonary embolism. According to the tumor platin resistance, firstly, the patient underwent to immunotherapy with anti PDL1 (Nivolumab), but after the first two cycles, considering the rapid deterioration of patient’s general conditions (intestinal sub occlusion, paraneoplastic hypercalcemia, peripheral pulmonary embolism), was chosen best supportive care and the patient died 1.5 months later, due to disease progression.

Results

Of the sixty-eight full-text articles screened for uncommon sites of metastasis, fifty-nine were excluded due to the following reasons: (1) molecular studies about metastatic process (n = 6; 8,8 %); (2) not about uncommon metastasis (n = 40; 58,8%); (3) about the diagnostic and staging modalities (n = 13; 19,11%). In turn, nine papers about uncommon metastatization met the inclusion criteria and are listed in Table 2.

Table 2: Selection of articles regarding uncommon sites of OSCC metastasis.