Peri-Implant Metastasis as First Manifestation of an Unknown Lung Cancer: Literature Review and Two New Cases

Metastatic tumors involving the orofacial tissues are infrequent, their incidence ranging between 1% and 8% of all oral malignant tumors.^1–4  With the exception of malignant tumors of childhood, their peak of incidence is in the fifth to seventh decades^1,4–6  and are the first sign of an occult cancer or manifest during the clinical follow-up of a patient with a known primary carcinoma.^1–6  Metastases to the orofacial tissues generally involve the oral mucosa, jawbones, and salivary glands, the most frequent primary localization being lung, kidney, prostate, and colon-rectum in males and uterus, breast, lung, and ovary in females.^2,3,7  Adenocarcinoma is the most common histological type of primary lung cancer (LC) with an increasing incidence all over the world.^8,9  LC most frequently metastasizes lymphogenous to regional lymph nodes and hematogenous to extrapulmonary organs like the brain, bones, liver, and adrenal glands.^10–13  Secondary localization to the head and neck are very infrequent and represent around 3% of all LC metastases and more rarely are recognized as early manifestation of metastatic disease.^10–12  Also, occurrence of both primary malignancies and metastases around the dental implant is reported to be a very rare event.¹⁴  Surely, the presence of a dental implant, associated or not to perimucositis and/or peri-implantisis, represents a peculiar clinical condition promoting metastatic cell implantation and facilitating metastatic growth.¹⁵ 

We report on 2 cases of maxillary metastases from an unknown LC occurring around dental implants and review the previous reports published in the international literature. The PubMed database of the US National Library of Medicine, the Web of Knowledge of Thomson Reuters, Google Scholar of Google, and the Excerpta Medica database (Embase) by Elsevier were screened by matching the relative key words. Expecting a relatively low number of cases, all kinds of papers were collected (case reports, case series, and systematic reviews), including clinical cases reported in oral/poster presentations published in special issues of scientific meetings and checking if not published elsewhere. The overall data are discussed in a narrative manner. This study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and approved by the Internal Ethical Committee (study no. 4575, protocol 1442/C.e).

A 62-year-old male without a relevant clinical history was referred to our attention with a history of recurrent dental implant failure in the maxilla after removal of all teeth as affected by diffuse periodontal disease with alveolar bone loss (Figure 1a and b) After the first insertion, the patient mentioned that 2 implants in the left hemimaxilla were lost 9 months after surgery and that, after a healing period of 1 month, new dental implants along with a bone substitute and absorbable membrane were repositioned in the same sites. Within 1 month, pain and swelling occurred. At this time, the patient showed a dehiscent wound of the left maxilla with exposition of the fixtures, signs of infection, and marginal bone necrosis (Figure 2a). Panoramic and periapical radiographs showed a poorly consistent bone around the implants (Figure 2b and c), while computed tomography (CT) with three-dimensional reconstruction revealed the presence of a wide osteolytic process completely incorporating the fixtures and extending to the left hemipalatal bone with both vestibular cortical bone and maxillary sinus floor erosion (Figure 2d–f). Implants were subsequently removed as “floating in bone.” An accurate bone curettage was also performed, and collected samples were sent for histological examination. Unexpectedly, small foci of adenocarcinoma were detectable along with spiculae of medullary bone, prominent inflammatory changes, and bacterial deposits (Figure 3a). With the suspicion of a secondary malignancy, immune-histochemical investigations became mandatory; the tumor positively stained for CK7+ and TTF1+ but not for CK20 and PSA (Figure 3b and c). Additional clinical-radiological investigations revealed the primary lung tumor (Figure 4), finally characterized as acinar adenocarcinoma with contextual metastases to loco-regional lymph nodes. The patient immediately started systemic therapy but died 7 months later from widespread metastatic involvement.

A 70-year-old female patient was sent to us for observation for a rapidly growing mass of the anterior maxillary adherent gingiva of brownish appearance, involving the palate and gingiva and also incorporating teeth (Figure 5a). The lesion extended outside the mouth, causing labial incontinence (Figure 5b). Panoramic radiograph showed an osteolytic lesion of the anterior maxilla with undefined borders along with the presence of a dental implant without final prosthetic rehabilitation completely involved in the lesion (Figure 5c). As reported by her general dentist, the fixture was inserted 6 months earlier in apparently safe (bone and gingiva) tissues. The patient reported a nonspecific discomfort in that area, probably related to perimucositis and/or peri-implantitis, starting about 4 months later. During the clinical examination, considering the difficulties in speaking and chewing and with the suspicion of an aggressive malignancy, a wide excision for mass reduction along with implant removal and bone curettage were suggested, and the patient agreed (Figure 5d). The following histological examination of the surgical sample showed the presence of foci of adenocarcinoma, which was definitively diagnosed as metastasis of lung adenocarcinoma after adjunctive chest radiograph, revealing the unknown primary neoplasm, and immunohistochemical investigations, as the neoplasm positive stained for CK7+ and TTF1+ and negatively for CK20 and PSA. The patient was referred to the oncology department to start systemic medical therapy. As for the follow-up, the patient died 11 months later from multiorgan involvement.

LC represents the most common cancer worldwide, amounting to 1.76 million deaths per year and thus representing a major public health problem, especially in males.¹⁶  As for epidemiology, in Western countries and most Asian countries, adenocarcinoma as a histological variant of LC has overtaken squamous cell carcinoma over the years. According to the data reported by the Surveillance, Epidemiology, and End Results Program (the 2011–2015 period among the US population), 47.9% of LCs are histologically adenocarcinoma, 23.2% are squamous cell carcinoma, 12.9% are small cell carcinoma, and 15.9% are other subtypes.^8,9,16  In 30% of cases, oral metastases are the first manifestation of an unknown cancer, and usually their recognition indicates an advanced and/or multiple-metastatic cancer.^1,2,4,6  The most common primary tumor in men is the lung in 36% of cases, the kidney in 16%, and the skin in 15%. In female patients, oral metastases most commonly originate from breast tumors (24%), followed by gynecological (17%), lung (12%), bone (10.3%), and renal (10.3%) tumors.^1,4,6  The median survival time of LC patients with gingival metastasis is only 4 months, as the prognosis is very poor.^{10,11,17–19}  Gingival metastases are usually treated by systemic chemotherapy or radiotherapy, neither of which, however, is particularly effective; surgical excision generally provides rapid relief of symptoms and may improve oral function too.^1,2,4,5  The jawbones and especially the molar and premolar regions are frequently involved in view of their rich vascularization and high bone marrow content.^2,7  In fact, metastatic neoplasms show a predilection for some specific sites in the orofacial region, and this may also be influenced by specific clinical conditions, such as gingival-parodontal soft tissues of dentates with periodontal inflammatory lesions or the same tissues in edentulous-bearing removable prostheses.^2–5  It has been postulated that in such instances, the reorganization of local blood flow along with inflammation or the pressure action of a removable prosthesis may potentially facilitate metastatic implantation and growth.^1,4–6  In addition, metastases may develop within postextraction sites as a possible consequence of increased blood flow during reorganization of the blood clot.^1,4–6,20 

Among all metastases to the oral cavity, their occurrence around dental implants is even rarer.^14,15  Their incidence remains undefined, as few reports (almost all single case reports) are available in the literature. Pfammatter et al,¹⁴  in a detailed review of the literature, reported a total number of 13 cases of pulmonary metastases to the gingiva with occurrence around a dental implant (mimicking peri-implantitis) in only 1 instance. More precisely, this case was a 67-year-old female affected by an untreatable LC with metastasis to the mandibular gingiva around an implant, placed 12 months earlier, as reported by Verhoeven et al.²¹  Kaplan et al¹⁵  added to the literature 7 cases of malignancies adjacent to dental implants, of which 1 was (probably as reported) a metastasis from LC to the posterior mandible with gingival overgrowth and bone loss in a 70-year-old female who experienced bleeding, pain, and paresthesia too. The last report in the literature, Allon et al,²²  described an unknown lung adenocarcinoma metastasized around 2 implants 8 months after insertion, clinically manifest as a soft tissue erythematous swelling associated to an ill-defined bone radiolucency on radiogram, completely absent at the time of implant surgery.

In Case 1 of the current report, recurrent dental implant failure was the clinical sign that led the surgeon to better investigate it; in fact, the subsequently performed CT showed a rapidly expansive lesion of the maxilla with all radiological signs of aggressive malignancy, thus making a bone biopsy mandatory. This being the case, it is hard to maintain whether implant insertion itself was the trigger of preexisting lesion progression or whether the metastatic process had set in after surgery, but, regardless, a condition promoting local inflammation in that specific area was induced. This is in complete accordance with the current theories, accepted worldwide, regarding metastatic implantation and/or growth and is further supported by the presence of healthy implants in both jaws.^{1,2,4,6,14,15,20,23}  Conversely, in Case 2, a large mass grew rapidly around a dental implant with alveolar bone destruction. As for the previous case, it is impossible to assess whether some (radiological or clinical) signs of malignancy were already possibly detectable on gingiva and/or bone at the time of implant insertion or whether the presence of an implant itself with a possible perifixture inflammation, as perimucositis or peri-implantitis, promoted the metastatic proliferation in that site. As for the previous case, considering as an in-patient comparison the presence of additional implants in the mandible also appearing in good radiological condition, we could endorse the theory of peri-implant inflammation as a potential factor that triggers proliferation in such a case.

For all the previously mentioned reasons, oral localization of an occult cancer always represents a diagnostic dilemma first for the clinician and then for the pathologist, especially when the clinical-diagnostic work-up is limited to the head and neck. Potential contributing factors, such as the insertion, presence, and/or inflammation around the dental implant as well as teeth extraction and the presence of teeth with or without periodontal inflammation, certainly further increase the diagnostic difficulties, resembling classical gingivitis or periodontitis.²³  Rapidly growing masses, mainly of the gingiva and palate, with periodontal or peri-implant involvement, especially when associated to any inflammation condition (gingival bleeding related to plaque/calculus, perimucositis/peri-implantitis, gingival enlargement with/or without concomitant infection or pus discharge, and so on), also in apparently healthy patients, should always raise the suspicion of a potentially malignant and aggressive neoplasm, including metastases.^{4–7,14,15,24}  In addition, their clinical/radiological differential diagnosis is challenging and should include aggressive primary carcinomas, malignant bone, or intraosseous salivary neoplasms and drug-induced (or not) bone necrosis. Additionally, conventional histological examination frequently may not allow a definitive diagnosis at a glance. Therefore, adjunctive immunohistochemical investigations with distinct combinations of antibodies become mandatory when histological findings on bioptic tissue are demonstrated not to be a diriment, especially for neoplasms with a typical and well-recognized head and neck localization.

Although rare, early and proper identification of metastatic lesions to the head and neck (including peri-implant hard and soft tissues) from a still unknown cancer could improve the life expectation in such patients. Therefore, a careful clinical and histological examination of whatever lesions arise around teeth and implants, when unresponsive to conventional instrumental periodontal treatments and/or medical therapies, is strongly suggested.