Mandibular tumour as the primary manifestation of an occult adenocarcinoma

Abstract

Oral cavity is an uncommon site for occurrence of metastasis and usually indicates widespread systemic disease. Primary tumours from the lung most commonly metastasise to oral soft tissues (31.3%) and jaw bones (22%) among men. It is quite challenging to diagnose a solitary metastatic lesion and to determine the site of primary lesion, due to the rarity of these occurrences. This case report describes the jaw bone as a first sign of occult primary lung adenocarcinoma with multiple metastases in 47-year-old man. The patient was treated with the combination of carboplatin and paclitaxel, and has completed two cycles till date with a stable clinical course. Diagnosis of metastatic carcinoma of jaw is very challenging. The pathologist must have knowledge of ancillary techniques along with clinical, radiological and histological correlation to determine the origin of distant primary.

Background

Metastasis to jaws and oral soft tissues is very uncommon and accounts for 1% of oral malignancies.¹ Oral metastasis is the first sign of occult malignancy at a distant site in 25% of cases. Furthermore, oral metastasis is revealed prior to detection of malignancy of distant primary in approximately 20% of cases.^{1 2} Metastatic lesions arising from carcinoma of unknown primary (CUP) pose a diagnostic conundrum in the oral cavity. CUP are heterogeneous group of histologically proven metastatic malignant neoplasms where primary site of tumour remains undefined, even after a wide array of investigations.² Between 3% and 5% of all newly diagnosed malignant tumours are CUP and they are the third to fourth most common causes of cancer death.^{2 3}

In this case report, we describe a rare case where a metastatic adenocarcinoma (ADC) of the mandible was the first sign of undetected primary malignancy with multiple occult metastases. Furthermore, this case highlights how histopathology and immunohistochemistry of a jaw lesion, in combination with advanced imaging techniques, helped to uncover an occult primary lung ADC.

Case presentation

A 47-year-old male patient presented with bony hard swelling on the left mandible for 3 months. The patient had been smoking 20 cigarettes/day for 30 years. On examination, there was bony hard swelling on the left mandible extending anteroposteriorly from angle of mouth to tragus of ear and superoinferiorly from the zygoma to submandibular region. Intraoral examination revealed fleshy, firm proliferative growth measuring approximately 3×2×1.5 cm on the gingivobuccal complex of left mandibular first premolar to first molar teeth region with associated grade III mobility of the involved teeth (figure 1).

Figure 1.

Clinical presentation of the patient, revealed soft fleshy growth on left alveologingival complex.

Investigations

Orthopantomogram showed radiolucent lytic lesions, ill-defined margins with ‘moth-eaten’ appearance suggestive of osteomyelitis affecting almost the entire mandible. Contrast-enhanced CT (CECT) showed permeative lytic destruction of the left mandible with periosteal reaction, cortical breach in few areas and erosion of the mandibular alveolar arches extending up to the temporomandibular joint. Significant soft tissue component involving the masticatory space, invading into the muscles of mastication and floor of mouth, was also seen (figure 2).

Figure 2.

Radiological features of the patient. (A) Orthopantomogram showed large, expansile lytic lesion (arrow) involving body and ramus of left hemimandible. (B) Axial bone window (CT) revealed predominantly lytic lesion with speculated (arrow) and multilayered (arrowhead) periosteal reaction. (C) Coronal soft tissue window (CT) showed significant soft tissue component (asterisk) involving masticatory space, invading into the muscles of mastication and floor of mouth.

Differential diagnosis

Radiological differential diagnosis of osteosarcoma, primary intraosseous carcinoma and a metastatic lesion were considered. Histology revealed atypical epithelial cells proliferating in glandular, cribriform arrangement and isolated tumour cells within dense fibrous stroma invading into bone. These glandular structures were lined by cuboidal to columnar cells exhibiting papillary projections in few areas. These cells showed marked nuclear pleomorphism, hyperchromatism, and abundant mucous and clear cell differentiation. Histomorphological features were compatible with malignancy of glandular origin (figures 3 and 4).

Figure 3.

Histopathology of the mandibular lesion in low power (10×) revealed (A–C) atypical glandular epithelial cells forming abortive glandular structures and isolated tumour cells and (D) bony invasion by atypical cells, H&E stain.

Figure 4.

Higher magnification of the lesion (40×) showed (A, B) tumour cells with marked nuclear pleomorphism, (C) invading into bone and (D) abundant clear and mucous cell differentiation.

Histological differential diagnosis of malignant salivary gland neoplasms (adenoid cystic carcinoma and mucoepidermoid carcinoma) followed by metastatic tumours were considered. Tumour cells were immunopositive for pan cytokeratin (CK), CK7, mucin 5AC in few mucus cells and immunonegative for smooth muscle actin (SMA), p40 and CD117. Ki67 proliferation index was approximately 62%. Immunonegativity for SMA, p40, CD117 and negativity for periodic acid–Schiff and mucicarmine stains ruled out mucoepidermoid carcinoma and adenoid cystic carcinoma. Further, negative CK20 ruled out other metastatic tumours from unknown primary. Narrowing our list of CUP subset (CK7+, CK20 and male patient), lung ADC was considered as most probable diagnosis (the most common cancer among males with smoking history). However, tumour cells were immunonegative for thyroid transcription factor-1 (TTF-1) and focal patchy positive for napsin (figure 5).

Figure 5.

Immunohistochemistry profile of tumour showed (A) immunopositivity for pan cytokeratin (CK) and (B) CK7. (C) Ki67 proliferation index and (D) focal patchy positivity for napsin.

Skeletal survey and ^99mTc-methylene diphosphonate whole body bone scan (with single-photon emission CT, figure 6) was performed to determine the primary site of metastasis. CECT chest (figure 7) revealed a conglomerate mass along left main bronchus, bronchial wall thickening extending along hilar lymph node causing collapse of left lung, multiple soft tissue nodules in contralateral lung and pleural nodules. Permeative destruction of right first rib along with infiltration in mediastinal vascular structures was also seen. There was no abnormality in abdomen and pelvis region (liver, kidney, spleen, prostate and urinary bladder). In view of imaging findings of nodules in the lung, a lung biopsy was performed which confirmed ADC of lung as primary lesion.

Figure 6.

Skeletal metastases on ^99mTc-methylene diphosphonate whole body bone scan (with single-photon emission CT). Focal increased radiotracer uptake is seen in the left half of mandible, medial end of left clavicle, few bilateral ribs, D8 and D12 vertebra and the neck of left femur.

Figure 7.

Contrast-enhanced CT chest. (A, B) Mediastinal window reveals heterogeneously enhancing mass (* in A) at left hilum with bronchial wall thickening and narrowing of left main bronchus (arrow in A). There is concentric pleural thickening (arrow in B) and pleural effusion (* in B). (C) Lung window shows multiple nodules (arrow) in right lung suggestive of pulmonary metastases. (D) Bone window shows permeative lytic destruction of right first rib (arrow) with soft tissue and lytic sclerotic lesion in medial end of left clavicle (arrowhead), suggestive of bone metastases.

Treatment

The patient was treated with the combination of carboplatin and paclitaxel (200 mg/m²), which is one of the standard chemotherapy for both lung ADC and CUP.

Outcome and follow-up

The patient had completed two cycles with a stable clinical course. However, after a period of 2 weeks, the patient succumbed to death.

Discussion

Most metastatic tumours to the orofacial region are detected in the fifth to seventh decade. Ninety per cent of cases involve the jaw bones, especially the mandible. Dissemination to the oral soft tissues is extremely rare and accounts for 0.1% of malignancies.⁴ The proportion of CUP metastasising to oral region varies from 5% to 17%.⁵ In autopsy findings, 50%–75% of patients of CUP had lung as the primary site of cancer and most patients with CUP had additional metastatic spread to viscera, bone and brain.⁶ Spread of lung cancer to the jaw bone (rare) indicates late-stage disease (table 1).⁷

Table 1.

10-Year review of literature showing lung adenocarcinoma metastasising to jaw bone (2011–2020)

Author and year	Age (years)	Sex	Site	Clinical presentation	Radiology	IHC and/or genetic profile	Survival time
Abe et al,10 2019	76	M	Palate	Swelling	MRI showed small localised mass on palatal mucosa	CK7+ CK20− TTF− Napsin− KRAS mutations	4 months
Savitri et al,11 2018	64	F	Anterior mandible	Pain	Irregular radiolucent lesion	CK7+ CK20− TTF+	Follow-up till 10 months, alive
Matsuda et al,6 2018	83	F	Right Mandible	Trismus, swelling, spontaneous pain	Bone destruction in ramus and condyle	CK7+ CK20− TTF+ Napsin+ Thyroglobin− Vimentin+	2 year follow-up, alive
Rogulj et al,12 2017	54	M	Mandible	–	Osteolytic lesion	–	1 month
Gultekin et al,13 2016	72	M	Right mandible	Pain, swelling	Extensive lytic lesion	CK7+ HMWK− P63− TTF+	6 months
Rajinikanth et al, 20154	60	M	Right mandible	Swelling	Well-defined osteolytic lesion with periosteal reaction and calcifications	–	NA
Dirican et al,14 2014	75	F	Right mandible	Pain, paraesthesia, swelling	–	CK7+ TTF+ EGFR, ALK−, no mutations	8 weeks
Misir et al,15 2013	55	M	Right mandible	Pain, swelling	Ill-defined radiolucent lytic lesion	–	5 months
Hashmi et al,16 2011	58	M	Left mandible	Pain, numb chin syndrome	Ill-defined radiolucency with radio-opaque foci	–	NA

ALK, anaplastic lymphoma kinase; CK, cytokeratin; EGFR, epidermal growth factor receptor; F, female; HMWK, high-molecular-weight kininogen; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma virus oncogene; M, male; NA, not available; TTF, thyroid transcription factor.

The pathogenesis of jaw bone metastasis is poorly understood but it is mainly attributed to haematogenous route with Batson venous plexus.⁶

Lung ADC particularly has been stated to be strongly associated with smoking which also promotes dissemination of disease.^{5 8} The present case was a known smoker; thus, widespread metastatic disease may be attributed to the smoking habit.

Advancement in imaging, immunohistochemical markers and molecular techniques have proven to be indispensable for diagnosing occult primary malignancies but workup for CUP is still perplexing. Pan CK and CK7/CK20 coordinated expression is used as primary screening panel to narrow down the differential diagnosis which is then confirmed by organ-restricted markers (table 2).

Table 2.

CK7+ CK20– profile in malignancies in male (pan CK+, vimentin–, S100– and LCA–) (modified from Lin and Liu¹⁷)

Lung adenocarcinoma	TTF+ napsin A+ Surfactant A+/–
Stomach adenocarcinoma	CEA+ CDX2–/+ MUC1–/+ MUC5AC–/+
Oesophageal adenocarcinoma	CDX2+/– CEA+, CDH17+ MUC1–/+ MUC5AC+/– SATB2-
Pancreatic adenocarcinoma	DPC4–/+ CK17±pVHL– Maspin+S100P+ IMP3+MUC5AC+
Thymic carcinoma	CD5±p63+/– PAX8+/–
Salivary ductal carcinoma	GATA3+ AR+ GCDFP-15+
Thyroid medullary carcinoma	TTF+ Calcitonin+ CEA+
Thyroid carcinoma (papillary and follicular)	PAX-8+ TTF-1+ Thyroglobulin+

AR, androgen receptor; CD5, cluster of differentiation 5; CDH17, cadherin-17; CDX2, caudal-type homeobox 2; CEA, carcinoembryonic antigen; CK, cytokeratin; DPC4, SMAD family member 4; GATA3, GATA binding protein 3; GCDFP-15, gross cystic disease fluid protein 15; IMP3, insulin-like growth factor; LCA, leucocyte common antigen; Maspin, mammary serine protease inhibitor; MUC, mucin; PAX, paired box gene; pVHL, von Hippel-Lindau protein; SATB2, special AT-rich sequence-binding protein 2; TTF, thyroid transcription factor.

The expression of CK7+ and CK20– profile in our case was suggestive of lung ADC; thus, its specific markers were employed. TTF-1 and napsin A are quite sensitive and specific markers for lung ADC; their co-expression strongly suggests possibility of lung ADC. However, positivity for both the markers is seen in 70%–80% and 75% of lung ADCs and also in some non-pulmonary carcinomas.⁹ The present case showed TTF-1 negativity and focal positivity for napsin. Skeletal survey further helped in locating the masses in lungs and excluding other differentials thereby finally diagnosing it as metastasis from primary lung ADC. Molecular techniques have also demonstrated mutations of epidermal growth factor receptor, anaplastic lymphoma kinase in non-smokers and Kirsten rat sarcoma virus oncogene in smokers with lung ADC. This may help further in characterisation and early diagnosis.⁴

Treatment in most cases is palliative care aimed at improving quality of life as malignant dissemination to oral cavity usually indicates widespread disease. The treatment options include surgical resection sometimes combined with chemotherapy and radiotherapy. The prognosis is poor with median survival in months.¹

Learning points.

• Diagnosis of metastatic carcinoma of jaw is very challenging due to non-specific symptoms further confounded by presentation of oral symptoms prior to occult primary and no history of previous malignancy.

• Clinicians must consider metastatic lesion in differential diagnosis of malignancies especially in older adults and determine the site of primary lesion.

• Oral and maxillofacial pathologists must have knowledge of immunohistochemical markers and molecular techniques along with clinical and radiological correlation to determine the origin of distant primary.