Oral Squamous Cell Carcinoma Metastasising to Unusual Sites: A Case Series of Four Cases

1. Professor and Head, Department of Pathology, American International Institute of Medical Sciences, Udaipur, Rajasthan, India. 2. Assistant Professor, Department of Pathology, American International Institute of Medical Sciences, Udaipur, Rajasthan, India. 3. Associate Professor, Department of Radiodiagnosis, American International Institute of Medical Sciences, Udaipur, Rajasthan, India. 4. Associate Professor, Department of Pathology, American International Institute of Medical Sciences, Udaipur, Rajasthan, India. 5. Professor, Department of Pathology, American International Institute of Medical Sciences, Udaipur, Rajasthan, India.

Abstract

Oral cancer ranks as the sixth most common malignancy worldwide, with Squamous Cell Carcinoma (SCC) being the predominant type observed in the head and neck region. Incidence and mortality rates of SCC have significantly increased over the past few decades. Smoking and tobacco chewing are the most common aetiological factors, predominantly affecting elderly males. Distant metastasis at the time of diagnosis is a rare occurrence, typically disseminating through blood vessels or lymphatics. The lungs are the most frequent site for distant metastasis, followed by bone, mediastinal nodes, and occasionally the liver. However, in our cases, we observed metastasis to uncommon sites, excluding the liver. Accurate diagnosis necessitates the correlation with clinical history, radiological, histopathological, and immunohistochemical findings. Despite employing various surgical and radiotherapeutic modalities, distant metastasis diminishes the chances of survival, successful treatment, and worsens the prognosis. This article presents four cases of oral SCC that exhibited metastasis to unusual sites. Two cases had a primary tumour in the left lateral border of the tongue, with distant metastasis to the breast and skin (chest wall), while the other two cases had a primary tumour in the left buccal mucosa and left mandibular region, with distant metastasis to the kidney and liver.

and neck tumours, Metastasis, Oral squamous cell carcinoma, Rare sites

Oral cancer is the sixth most common malignancy worldwide (1). It is the most common cancer among Indian males and the fourth most common among Indian women. According to Global Cancer Observatory (GLOBOCAN) data from 2020, there were 377,713 new cancer cases of the oral cavity and lip registered, with 177,757 new deaths worldwide, accounting for 1.8% of all cancer deaths (2). In the head and neck region, Squamous Cell Carcinoma (SCC) is the most prevalent malignancy, accounting for over 90% of cases (3). The majority of cases are moderately or well-differentiated types (4). Loco-regional disease is common among such patients, with distant metastasis being a rare occurrence at the time of diagnosis (5). Approximately 40% of the cases show metastasis to lymph nodes (6), with cervical lymph nodes being commonly involved and reducing the survival rates by 50% (7). The most common site for distant metastasis is the lung, accounting for about 66% of cases, followed by the liver, mediastinal nodes, and bone (3),(8). This article presents four cases of oral SCC that exhibited metastasis to unusual sites.

Case Report

Case 1

A 50-year-old female patient presented to the Outpatient Department (OPD) with a complaint of an ulcerated lesion present over the left lateral border of the tongue for the past three months. Contrast-enhanced Computed Tomography of the neck revealed an ill-defined malignant mass lesion measuring 60×40.3×50.4 mm, involving the left lateral border of the tongue, crossing the midline, and infiltrating up to the right lateral border of the tongue, left hyoid bone, left myelohyoid, digastric, and suprathyroid strap muscles, with bilateral cervical lymphadenopathy (Table/Fig 1)a. Biopsy results showed invasive nests and sheets of atypical polygonal cells, exhibiting round to oval pleomorphic nuclei with vesicular chromatin, prominent nucleoli, eosinophilic cytoplasm, and individual cell keratinisation. Due to the advanced stage at diagnosis, surgery was not performed. The patient received six cycles of chemotherapy and 35 cycles of radiotherapy. During the course of treatment, the patient noticed a lump in the left breast. Mammography revealed an irregular-shaped high-density mass lesion in the upper outer quadrant of the left breast with spiculated margins, distortion of breast parenchyma, and no microcalcification, consistent with Breast Imaging Reporting And Data System 5 (BI-RADS 5) (Table/Fig 1)b. Fine needle aspiration cytology study of the mass showed clusters and a few singly dispersed atypical polygonal cells with pleomorphic hyperchromatic nuclei and moderate amount of cytoplasm, suggesting a malignant lesion with the possibility of metastatic SCC (Table/Fig 1)c. The patient underwent a trucut biopsy, which revealed an invasive tumour surrounding the mammary ducts, composed of nests and sheets of atypical polygonal cells with moderately pleomorphic nuclei, vesicular chromatin, prominent nucleoli, eosinophilic glassy cytoplasm, along with single-cell keratinisation. A histopathological diagnosis of metastatic SCC was made (Table/Fig 1)d. The patient was planned for adjuvant chemoradiotherapy, but her condition rapidly worsened, and she passed away.

Case 2

A 56-year-old male patient presented with a complaint of a mass in the oral cavity for the past month. The patient had a history of beedi smoking and tobacco chewing for 15 years. Contrast-enhanced Computed Tomography revealed an ill-defined heterogeneously enhancing mass measuring 70x40.5x50 mm, involving the left buccal mucosa, left inferior and superior gingivobuccal sulcus, likely neoplastic mass with left cervical lymphadenopathy (Table/Fig 2)a. Biopsy results showed invasive nests and sheets of moderately pleomorphic atypical polygonal cells, exhibiting individual cell keratinisation and focal keratin pearl formation, consistent with the diagnosis of moderately differentiated Squamous Cell Carcinoma (SCC). The patient underwent left composite hemimandibulectomy with modified neck dissection, and a diagnosis of moderately differentiated SCC was confirmed. The patient was staged as pT4aN3b, with skin involvement and extracapsular extension. Frozen section margins were negative, and the patient was discharged with stable vitals. Four months after surgery, the patient complained of abdominal pain and underwent imaging studies, including a Positron Emission Tomography and Computed Tomography scan, which revealed a hypermetabolic ill-defined heterogeneous enhancing soft tissue density lesion involving the lower pole of the left kidney, suggestive of metastasis (Table/Fig 2)b. A core needle biopsy from the same lesion was performed, showing the presence of invasive nests and sheets of atypical squamous epithelial cells, demonstrating moderate nuclear pleomorphism, moderate to abundant eosinophilic cytoplasm, individual cell keratinisation, and keratin pearl formation, suggesting a diagnosis of metastatic SCC (Table/Fig 2)c,d. The patient was then started on radiotherapy. However, during the course of treatment, the patient’s condition deteriorated markedly, and he passed away after receiving two cycles of radiotherapy.

Case 3

A 47-year-old male patient presented to the Outpatient Department (OPD) with complaints of an ulcer over the left lateral border of the tongue and difficulty in chewing for the past 1.5 months. The patient had a history of tobacco chewing. Contrast-enhanced Computed Tomography of the neck revealed an ulcerative heterogeneously enhancing irregular soft tissue density mass lesion measuring 40.2×20.2×10.3 mm involving the left lateral border of the tongue (Table/Fig 3)a. The patient underwent wide excision glossectomy with modified neck dissection, and the specimen was sent for histopathology. Microscopic examination revealed a tumour composed of invasive nests and sheets of moderately pleomorphic atypical squamous epithelial cells showing individual cell keratinisation and focal keratin pearl formation. A diagnosis of invasive moderately differentiated Squamous Cell Carcinoma (SCC) was made, and the tumour was staged as pT3N0. The patient received adjuvant chemotherapy and radiotherapy and was discharged with stable vitals. He was kept on regular follow-up. In the 7th month postoperatively, the patient reported a tender erythematous swelling over the posterior chest wall. Contrast-enhanced Computed Tomography of the thorax showed a heterogeneously enhancing soft tissue density mass lesion in the posterior chest wall (Table/Fig 3)b. Fine needle aspiration cytology revealed clusters of atypical cells comprising round to oval pleomorphic nuclei with fine granular chromatin, prominent nucleoli, and a moderate amount of cytoplasm, favoring poorly differentiated carcinoma (Table/Fig 3)c. An incisional biopsy was performed, which showed nests and sheets of atypical polygonal cells showing moderate nuclear pleomorphism, vesicular chromatin, prominent nucleoli, and eosinophilic cytoplasm with individual cell keratinisation (Table/Fig 3)d. A histopathological diagnosis suggestive of metastatic SCC was made. The patient was advised concurrent chemotherapy and radiotherapy, but due to financial constraints, he denied treatment and was lost to follow-up.

Case 4

A 38-year-old male patient presented to the outpatient department (OPD) with complaints of a mass over the left mandibular region for the past 1.5 months. The patient had a history of tobacco chewing for 10 years. Magnetic resonance imaging of the neck revealed a heterogeneously enhancing necrotic mass in the angle of the left mandible. Contrast-enhanced Computed Tomography of the neck revealed a mass lesion involving the left mandible measuring 80.3×70.6×10.7 mm, with destruction of the underlying mandible and enlarged left cervical level 1b and II nodes (Table/Fig 4)a. Biopsy results showed a tumour composed of invasive nests and sheets of atypical polygonal cells showing mild to moderate nuclear pleomorphism, vesicular chromatin, prominent nucleoli, and a moderate amount of eosinophilic cytoplasm with single cell keratinisation and focal keratin pearl formation, consistent with the diagnosis of moderately differentiated Squamous Cell Carcinoma (SCC). Contrast-enhanced Computed Tomography of the abdomen revealed multiple variably sized hypodense lesions in both lobes of the liver, with decreased enhancement relative to the background liver parenchyma, most conspicuous in the portal venous phase, suggesting metastases (Table/Fig 4)b. Ultrasound-guided fine needle aspiration cytology from a liver nodule was performed, showing atypical polygonal cells present in clusters comprising pleomorphic round to oval nuclei with vesicular chromatin, prominent nucleoli, and a moderate amount of cytoplasm. The features were suggestive of metastatic poorly differentiated carcinoma favoring SCC (Table/Fig 4)c. A biopsy was performed, revealing nests and sheets of atypical polygonal cells showing mild nuclear pleomorphism, round to oval nuclei with vesicular chromatin, prominent nucleoli, and moderate to abundant eosinophilic cytoplasm with individual cell keratinisation and intercellular bridges, suggesting metastatic SCC (Table/Fig 4)d. The patient was then planned for chemotherapy, following which he was discharged with stable vitals and advised regular follow-up.

The findings of all four cases have been summarised below (Table/Fig 5).

Discussion

In the head and neck region, Squamous Cell Carcinoma (SCC) is the most common type of malignancy worldwide. Patients who exhibit metastasis to regional lymph nodes during the initial diagnosis have a 30% risk of developing distant metastasis within 9 to 12 months (9). The tongue is the most common primary site for distant metastasis (10). In our study, two out of the four cases showed carcinoma in the left lateral border of the tongue. A review by Irani S indicated that the gingiva is the most frequent primary site of involvement for distant metastasis (10).

Metastases to the breast from extramammary tumours are very rare, comprising 0.5% to 6.6% of cases. The most common primary tumours metastasizing to the breast are contralateral breast carcinoma, followed by lung, gastrointestinal, gynaecological, haematological carcinomas, and melanoma (11). Breast metastases from SCCs of the head and neck region are extremely uncommon, and only a few cases have been reported in the literature (3). The mean age at diagnosis is usually 50 years, which is consistent with our case. The age range typically varies from 32-87 years (11). Metastases usually appear after 30 months of the primary extramammary malignancy diagnosis or during the course of treatment of the primary malignancy, as in our case (11). It is challenging to differentiate primary breast carcinoma from metastases because the clinical presentation might be similar to primary cancer, and it may be the initial presentation of a metastatic disease of unknown origin (12).

Radiology plays a critical role in diagnosing metastatic breast disease. On mammography, metastases present as single or multiple well-circumscribed masses, commonly located in the upper outer quadrant. Spiculations, calcifications, and desmoplastic reaction are absent, which are mainly seen in primary breast carcinomas (13). Histopathological and immunohistochemical examinations play an important role in accurately diagnosing the metastatic lesion and tailoring appropriate treatment (11). Surgery may be indicated only for symptom palliation or when an isolated breast metastasis is identified with a long interval from the diagnosis of the primary tumour (14). The prognosis is extremely poor, with an overall survival rate of less than a year from the time of diagnosis (14).

Metastases to the kidneys are very rare and are often erroneously diagnosed as primary tumours. The incidence of extrarenal tumours metastasizing to the kidneys varies from 2 to 20% (15). Distant metastasis of SCC of the tongue to the kidney is extremely uncommon, with only two reported cases in the literature (15). The median patient age is around 56.7 years, similar to our case, where the patient was a 56-year-old male. Imaging studies are the mainstay for diagnosing metastases (9). Radiologically, they are usually subcapsular in location, multicentric, small, and bilateral, with a known history of a primary tumour (15). Zhou C et al. reported a radiology pathology concordance of 51%, while Wu AJ et al. reported a concordance of 54% (16),(17).

In cases of secondary renal involvement, it is essential to rule out other possible differential diagnoses such as urothelial carcinoma with squamous differentiation and collecting duct carcinoma. Immunohistochemistry can be a useful tool, but it is not completely diagnostic due to overlapping features (9). SCCs usually show negativity for Cytokeratin 20 (CK20), whereas some urothelial carcinomas showing squamous differentiation are positive. Urothelial tumours are frequently CK7 positive, while SCCs are negative. Primary urothelial carcinoma typically exhibits strong diffuse expression of GATA3 (9). Paired-Box Gene 8 (PAX8) and CK7 can be helpful in distinguishing SCC from collecting duct carcinoma, with the latter being positive. A known history of a primary tumour can also be a helpful clue.

In a study by Wu AJ et al., the median time interval between primary diagnosis and metastases was reported to be three years, whereas Singh GK et al. and Elsarraj HS et al. reported a median interval of 18 months (17),(18),(9). In our study, the interval was 4 months, which was similar to the study by Thyavihally YB et al., who also reported a median time interval of four months (19). The median overall survival is about a year, and surgical interventions can help improve overall survival to more than two years (9).

The frequency of cutaneous metastasis from primary malignancies varies from 0.7% to 9%. In patients with head and neck SCC, the incidence of cutaneous metastasis is around 0.8-1.3% (20). The skin of the head and neck and chest region are the most common sites for metastasis (21). In our case, the site of metastasis was the posterior chest wall. One of the first reported cases of skin metastases was by Schultz and Schwartz in 1985, where a patient developed skin metastases secondary to carcinoma of the hypopharynx (22). Among all cancers of the head and neck region, laryngeal cancer is most often associated with skin metastasis (20).

FNAC and biopsy should be done to rule out the presence of malignancy even if the lesion appears clinically benign. Rastogi M et al. reported a case of SCC of the base of the tongue that showed multiple cutaneous metastases after 18 months of follow-up (20). Rahman T et al. reported cutaneous metastasis in a patient with carcinoma of the base of the tongue, in which lesions appeared one month after completion of treatment. This could possibly be due to the presence of occult skin metastasis during the course of treatment or at the time of diagnosis, which might have been missed (23). In our case, cutaneous metastasis occurred in the 7th month of follow-up. Treatment is usually palliative, and prognosis is very poor, with a survival of only a few months (20).

Metastases to the liver from head and neck cancers are rare, with an incidence of about 4.4% (24). Clinical history, imaging findings, FNAC, and biopsy can be used to accurately diagnose the metastatic lesion.

Metastatic nodules on ultrasonography are usually multiple and may be cystic, hypoechogenic, or hyperechogenic without a peripheral halo (24). Cases with isolated nodules in the liver and a history of head and neck cancer may show raised Lactate Dehydrogenase (LDH) levels, which could be the only alarming sign (23). Marcy PY et al. reported distant metastases from head and neck carcinomas to the liver in 0.9% of the studied population, while Merino E et al. reported liver metastasis in 0.7% of cases (24),(25). Prognosis is usually very poor, with a median survival of only four months (24).

Conclusion

Distant metastasis from oral SCCs is a rare event and mostly occurs during advanced stages. Careful evaluation of patient during the treatment of primary malignancy can have a remarkable impact on the overall survival and prognosis. Clinicopathological correlation can be immensely helpful in making a correct diagnosis and tailoring an appropriate cost-effective treatment.

DOI and Others

DOI: 10.7860/JCDR/2023/63502.18209

Date of Submission: Feb 15, 2023
Date of Peer Review: Apr 07, 2023
Date of Acceptance: May 26, 2023
Date of Publishing: Jul 01, 2023

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. No

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EMENDATIONS: 7