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A painful swelling of the mandible Nikolaos G. Nikitakis, MD, DDS, PhD,a Adamantia Vlachaki, DDS,b Vassilios Boussios, MD, DDS,c Alexandra Sklavounou, DDS, MSc, PhD,d and Fotios Tzermpos, MD, DDS, PhDe (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;-:1-5)
CLINICAL PRESENTATION A 54-year-old female patient presented to the Department of Oral and Maxillofacial Surgery with a chief complaint of lower jaw pain and a feeling of numbness in the lower lip, both on the right side. The patient reported that her symptoms started 3 months ago as numbness and feeling of swelling of the lower lip accompanied by ear pain on the right side; no treatment was administered. Fifteen days earlier, the patient had presented to a General Hospital complaining of gingival pyorrhea and swelling of the right mandible. Antibiotic treatment (amoxicillin 1 g two times daily and metronidazole 500 mg three times daily) was administered with limited improvement. At this point, the patient was referred to our Department for additional evaluation and management. Her medical history was significant for breast cancer diagnosed 5 years ago. Her initial treatment included chemotherapy with docetaxel, four cycles of cyclophosphamide, epirubicin, and 5-fluorouracil and radiotherapy, which resulted in full remission. For the last 4 years, the patient was receiving the aromataseinhibitor anastrazole for hormone manipulation. No use of bisphosphonates was reported. She was a light smoker (of approximately one to two cigarettes per day for several years) and a nondrinker. Intraoral clinical examination did not reveal significant findings, except for a palpable swelling of the buccal cortical plate in the right posterior mandible toward the angle. Extraoral examination revealed facial asymmetry due to swelling of the body of the right mandible extending to the angle (Figure 1). Review of a a Associate Professor, Department of Oral Medicine and Pathology, Dental School, National and Kapodistrian University of Athens, Greece. b Postgraduate Student, Department of Oral and Maxillofacial Surgery, Dental School, National and Kapodistrian University of Athens, Greece. c Oral and Maxillofacial Surgeon, Department of Oral and Maxillofacial Surgery, Dental School, National and Kapodistrian University of Athens, Greece. d Professor, Department of Oral Medicine and Pathology, Dental School, National and Kapodistrian University of Athens, Greece. e Associate Professor, Department of Oral and Maxillofacial Surgery, Dental School, National and Kapodistrian University of Athens, Greece. Received for publication Sep 22, 2015; returned for revision Nov 3, 2015; accepted for publication Nov 16, 2015. Ó 2016 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2015.11.010
panoramic radiograph performed a few weeks earlier revealed an ill-defined radiolucency of the right posterior body of the mandible with a diffuse alteration of the bone trabeculation pattern (Figure 2). A cone beam computed tomography scan of the mandible showed thinning and multiple areas of perforation of the cortical bone (“moth-eaten” appearance) of the body and ramus of the right mandible (Figure 3).
DIFFERENTIAL DIAGNOSIS A clinical presentation of painful swelling of the mandible elicits an extensive differential diagnosis. Taking into account the clinical and radiographic presentations of the present case, an infectious or inflammatory process, such as chronic osteomyelitis, was considered. Chronic osteomyelitis can cause pain, swelling, and intermittent purulent discharge. Radiographically, it may present as a patchy and ill-defined radiolucency that often contains central radiopaque areas, and the cortical surface can demonstrate significant periosteal reaction.1 However, the lack of association with a carious tooth or other local source of infection and the nonresponse to antibiotic treatment made the diagnosis of chronic osteomyelitis less likely. Certain benign but locally aggressive lesions could generate clinical and imaging findings similar to those of the present case. Ameloblastoma may present as a destructive radiolucent lesion frequently located in the posterior mandible; however, a painless, well-defined multilocular radiolucency is more typical.2 A similar presentation of a slow-growing, painless, and locally aggressive lesion may be caused by odontogenic myxomas, most of them being reported in female patients, especially in their second and third decades of life. Since pain and hypoesthesia are not common, the lesions may reach a considerable size before diagnosis.3 Central giant cell granuloma usually appears as an asymptomatic lesion. In most cases, it can be diagnosed as a painless expansion of the affected jaw during clinical examination or most frequently as a well-defined unilocular or multilocular radiolucency in a routine radiographic examination. Cortical bone plates are thinned, but perforation into surrounding soft tissue, as in our case, is rare. In addition, paresthesia is not a typical feature of central giant cell granuloma.4 Primary or metastatic bone tumors may manifest as destructive radiolucent jaw lesions causing cortical 1
CLINICOPATHOLOGIC CONFERENCE 2 Nikitakis et al.
Fig. 1. Extraoral view showing facial asymmetry as a result of swelling of the body of the right mandible extending to the angle.
perforation accompanied by neurologic symptoms, such as pain and paresthesia. Therefore, strong consideration was given to the possibility of a malignant process. Although oral mucosal squamous cell carcinoma (SCC) is, by far, the most common malignancy of the oral cavity and may invade the jaws, the presence of intact overlying mucosa excluded a primary mucosal origin. In the case of the relatively rare primary intraosseous SCC (PIOC), the most common presentation involves progressive painful swelling of the jaws along with loosening of teeth, trismus, and sensory disturbances, such as paresthesia and numbness; although the tumor may be asymptomatic during the early phases and only detected radiographically. In 61% of cases, primary intraosseous SCC presents as a unilocular radiolucency, resembling a cystic lesion in many sizes and shapes with poorly defined and irregular margins.5 Primary tumors of bone, such as osteosarcoma and chondrosarcoma, can be included in the differential diagnosis of an ill-defined radiolucent lesion, even in the absence of other typical radiographic findings, such as spiking root resorption, structural changes in the mandibular canal, and “sun ray” appearance. The patient’s symptoms were also consistent with malignancy, and her age was compatible, considering that jaw osteosarcomas tend to occur in older patients in comparison with extragnathic tumors.6,7 Extranodal malignant lymphomas, especially nonHodgkin lymphoma, may affect oral soft or hard tissues as a primary site of occurrence or as a component of widespread disease. Central lymphomas of the jaws tend to affect the maxilla more frequently. Clinically, a primary lymphoma of bone could manifest as localized bone swelling, possibly associated with ulceration of the overlying mucosa and tooth mobility; pain, numbness, and paresthesia are often reported. The radiographic presentation is not typical for this entity, which commonly appears as a nonspecific osteolysis.8
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Fig. 2. Panoramic radiograph revealing “moth-eaten” appearance of the body and ramus of the right mandible (arrow).
Metastatic tumors in the jaws usually appear as illdefined radiolucent lesions, although bone production has been associated with certain primary sites, particularly the prostate and the breast. Painful swelling and paresthesia are the most common clinical signs of metastatic tumors in the jaws, and the posterior mandible (mainly the molar and premolar areas) appears to be the site of predilection.9 Although metastatic disease to the jaws is not very common, corresponding to approximately 1% of all oral malignancies, a history of malignancy, similar to previous breast cancer in the present patient, should be a strong consideration.
DIAGNOSIS AND MANAGEMENT With the patient under local anesthesia, a full thickness mucoperiosteal flap was developed, and an incisional biopsy of the intrabony lesion was performed. Macroscopically, the biopsy specimen was red in color, had a smooth surface mass of elastic consistency, and measured 3.0 1.5 1.0 cm. Microscopically, a proliferation of neoplastic cells of epithelial origin within a dense fibrous connective tissue stroma was observed (Figure 4). The neoplastic cells were arranged in islands of variable size and shape or as isolated infiltrating cells. The tumor cells had eosinophilic cytoplasm and pleomorphic large, round or oval hyperchromatic nuclei showing focal duct formation (Figure 4). Vascular invasion was also noted. On the basis of these microscopic features, a provisional histopathologic diagnosis of epithelial malignancy that was consistent with metastatic breast cancer was made. Immunohistochemical testing showed positivity of the tumor cells for estrogen receptor and cytokeratin 7 (CK7), whereas CK20 was negative (Figure 4). Taking into account the patient’s history, a final diagnosis of metastatic breast adenocarcinoma was established. The patient was referred to her oncologist for a full metastatic workup and further management.
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Fig. 3. Cone beam computed tomography image of the mandible. A, Axial view. B, Coronal view. The images show thinning and multiple areas of perforation of the cortical bone in the right mandible (arrows). No pathologic fracture was observed.
DISCUSSION Secondary sites to the oral cavity are considered rare and usually constitute a sign of widespread disease.9 In the majority of patients, the primary tumor would have been detected before the development of oral metastasis.10 According to Hirshberg et al., oral metastases were the first evidence of metastatic dissemination in 25% of cases and the first indication of a previously unknown malignant disease in 23%.9,11 Oral metastatic lesions usually derive from epithelial malignancies (carcinomas) rather than mesenchymal tumors (sarcomas).12 The metastatic tumors, which represent approximately 1% of oral malignancies, show a predilection for the jaws than the soft tissues (2:1).11,13 When oral soft tissues are involved, the most common site is the gingiva with an overall frequency of 54%, followed by the tongue.14 In the jaws, the mandible is much more frequently involved compared with the maxilla.9,10 The posterior mandible, especially, is the site of predilection, and involvement of the condyle has been estimated in 5.7% of cases.9,11,15 The pathogenesis of the metastatic spread to the oral cavity has not been fully elucidated. It has been suggested that areas of red marrow are the preferred sites for metastatic deposits. Therefore, the persistence of active hematopoietic marrow in the posterior part of the mandible during adulthood offers an explanation for the predilection for metastasis to the jaws.11 According to Hirshberg et al., the breast is the principal primary tumor site giving rise to oral metastasis in female patients, followed by the adrenal glands and genital organs as the primary tumor sites.10 Breast carcinoma, in particular, has a predilection for bone metastasis rather than soft tissue metastasis. Compared with other malignancies, breast cancer metastasizes to the jaws three times more frequently.15 Similarly, D’Silva et al. reported that most metastases to the jaws in female patients (25.4%) were from a primary breast site.12 In contrast, in male patients, frequently the primary origins of oral metastatic tumors are the lungs, prostate gland, and kidney.9
With regard to patient age, metastatic oral tumors are more common in the fifth to seventh decades of life, with a mean age for metastasis to the jaws and oral soft tissues being 45 and 54 years, respectively.16,17 It has been suggested that the epidemiology of oral metastatic cancer may be affected by different local and geographic factors and genetic mutations, which possibly explains the reported differences among Western and Eastern populations.18 For example, in the study by Lim et al.,18 the mean age of 41 patients with oral metastatic tumors was 55.2 years, with a male-to-female ratio of 1.9:1; noticeably, the breast was not a common primary site for females in this study. Schwartz et al., however, reported that females have an increased risk of developing metastases to the jaws as a result of the predominance of primary breast lesions.19 Metastatic involvement of the jaws may be accompanied by a variety of clinical symptoms, the most common ones being pain, swelling, facial edema, bleeding, increasing tooth mobility and loosening, periodontal involvement, and trismus.10 The mechanisms responsible for pain have been linked to osteolysis.20 Metastasis to the mandible, with involvement of the inferior alveolar nerve, can produce an unexplained loss of sensation in the lower lip and chin, known as numb-chin syndrome.10 McClure et al. studied 26 patients with metastatic disorder to the maxillofacial area, and 11.5% of them had developed pathologic fractures in the mandible. In some instances, the patient may be asymptomatic.21 When the oral soft tissues (e.g., the gingival) are affected, the clinical appearance may be a hyperplastic mass, occasionally with an ulcerated surface.10 Radiographically, jaw metastatic disease may present as a well-defined radiolucency, although most cases will produce a poorly circumscribed radiolucency, described as “moth-eaten appearance.”12 Occasionally, oral metastatic jaw tumors, especially those of breast and prostate origin, may have a radiopaque or mixed radiolucent and radiopaque resolution as a result of
CLINICOPATHOLOGIC CONFERENCE 4 Nikitakis et al.
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Fig. 4. A and B, Low-power photomicrographs showing proliferation of neoplastic cells of epithelial origin forming islands of variable size and shape within a dense fibrous connective tissue stroma (H&E; 100). C, High-power photomicrograph demonstrating tumor cells with eosinophilic cytoplasm and pleomorphic, large, round or oval hyperchromatic nuclei showing focal duct formation (arrow) (H&E; 400). D and E, Immunohistochemical stains showing nuclear positivity for estrogen receptor (D, 100) and cytoplasmic positivity for cytokeratin 7 e (CK7) in the tumor cells (E, 100).
stimulation of new bone formation in the metastatic region.10 Histopathologically, the appearance of metastatic jaw disease is often that of a poorly differentiated tumor,
making the determination of the primary tumor location challenging. Thorough medical history taking, a high degree of suspicion, and appropriate selection of imaging and other diagnostic tests are necessary. In
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addition, the use of immunohistochemical staining can provide valuable information. As far as metastatic breast carcinomas are concerned, the usual immunohistochemical profile is positive for CK7 whereas it is negative for CK20.12 In addition, estrogen receptor and progesterone receptor markers are positive in the majority (70%-75%) of metastatic breast cancers. Other markers that can be used to confirm metastatic carcinoma from a breast primary are gross cystic disease fluid protein (GCDFP)-15, CEA and BCA225. Among these markers, GCDFP-15 is considered the most specific with a high positive predictive value of 95% and a sensitivity about 50-70%. According to recent literature, the combination of estrogen receptor, progesterone receptor, and GCDFP-15 is 83% sensitive and 93% specific, and is thus considered most valuable in establishing a diagnosis of metastatic breast cancer.22 Patients with oral metastatic disease have a dismal prognosis, most of them succumbing to their disease within a few months after diagnosis, and only 10% manage to survive for 4 years.21,23 In most cases, oral metastasis is a sign of widespread disease involving multiple additional sites, and the possibility of curative therapy is minimal. Therefore, therapeutic efforts are mainly focused on palliative care and interventions, such as radiotherapy and chemotherapy, which can improve the patient’s function and quality of life. Finally, in some selected cases, surgical intervention may be employed to at least temporarily alleviate the symptoms of the metastatic disease in the oral region.21
7.
8. 9.
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17. 18.
19. 20.
REFERENCES 1. Mehra H, Gupta S, Gupta H, Sinha V, Singh J. Chronic suppurative osteomyelitis of mandible: a case report. Craniomaxillofac Trauma Reconstr. 2013;6:197-200. 2. Santos Tde S, Piva MR, Andrade ES, Vajgel A, Vasconcelos RJ, Martins-Filho PR. Ameloblastoma in the Northeast region of Brazil: a review of 112 cases. J Oral Maxillofac Pathol. 2014;18: 66-71. 3. Manne RK, Kumar VS, Sarath PV, Anumula L, Mundlapudi S, Tanikonda R. Odontogenic myxoma of the mandible. Case Rep Dent. 2012;2012:214704. 4. Stavropoulos F, Katz J. Central giant cell granulomas: a systematic review of the radiographic characteristics with the addition of 20 new cases. Dentomaxillofac Radiol. 2002;31:213-217. 5. Shambhulingappa P, Sheikh S, Puri N, Jindal SK. Primary intraosseous carcinoma of mandible: an update on review of literature with a case report. J Clin Exp Dent. 2010;2:91-95. 6. Givol N, Buchner A, Taicher S, Kaffe I. Radiological features of osteogenic sarcoma of the jaws. A comparative study of different
21.
22.
23.
radiographic modalities. Dentomaxillofac Radiol. 1998;27: 313-320. Fernandes R, Nikitakis NG, Pazoki A, Ord RA. Osteogenic Sarcoma of the jaw: a 10-year experience. J Oral Maxillofac Surg. 2007;65:1286-1291. Steinbacher DM, Dolan RW. Isolated non-Hodgkin’s lymphoma of the mandible. Oral Oncology EXTRA. 2006;42:187-189. Hirshberg A, Shapiro AS, Kaplan I, Berger R. Metastatic tumours to the oral cavityd Pathogenesis and analysis of 673 cases. Oral Oncol. 2008;44:743-752. Hirshberg A, Berger R, Allon I, Kaplan I. Metastatic tumors to the jaws and mouth. Head and Neck Pathol. 2014:8463-8474. Hirshberg A, Buchner A. Metastatic tumours to the oral region. An overview. Oral Oncol. 1995;31:355-360. D’Silva NJ, Summerlin DJ, Cordell KG, et al. Metastatic tumors in the jaws: A retrospective study of 114 cases. J Am Dent Assoc. 2006;137:1667-1672. van der Waal RIF, Buter J, van der Waal I. Oral metastases: report of 24 cases. Br J Oral Maxillofac Surg. 2003;41:3-6. Scipio JE, Murti PR, Al-Bayaty HF, Matthews R, Scully C. Metastasis of breast carcinoma to mandibular gingiva. Oral Oncol. 2001;37:393-396. Qiu Y, Yang C, Chen M, Qiu W. Metastatic spread to the mandibular condyle as initial clinical presentation: radiographic diagnosis and surgical experience. J Oral Maxillofacial Surg. 2013;71:809-820. Hirshberg A, Leibovich P, Buchner A. Metastases to the oral mucosa: analysis of 157 cases. J Oral Pathol Med. 1993;22: 385-390. Hirshberg A, Leibovich P, Buchner A. Metastatic tumors to the jaws: analysis of 390 cases. J Oral Pathol Med. 1994;23:337-341. Lim SY, Kim SA, Ahn SG, et al. Metastatic tumours to the jaws and oral soft tissues: A retrospective analysis of 41 Korean patients. Int J Oral Maxillofac Surg. 2006;35:412-415. Schwartz ML, Baredes S, Mignogna FV. Metastatic disease to the mandible. Laryngoscope. 1988;98:270-273. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2:584-593. McClure SA, Movahed R, Salama A, Ord RA. Maxillofacial metastases: a retrospective review of one institution’s 15-year experience. J Oral Maxillofac Surg. 2013;71:178-188. O’Malley FP, Pinder SE, Mulligan AM. Breast Pathology: A Volume in the Foundations in Diagnostic Pathology. 2nd ed. Philadelphia, PA: Saunders; 2011:281-282. Zachariades N. Neoplasms metastatic to the mouth, jaws and surrounding tissues. J Cranio-Max-Fac Surg. 1989;17:283-290.
Reprint requests: Adamantia Vlachaki, DDS Dental School National and Kapodistrian University of Athens 168 Papadiamantopoulou St. Goudi 11527 Athens Greece [email protected]
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A painful swelling of the mandible Nikolaos G. Nikitakis, MD, DDS, PhD,a Adamantia Vlachaki, DDS,b Vassilios Boussios, MD, DDS,c Alexandra Sklavounou, DDS, MSc, PhD,d and Fotios Tzermpos, MD, DDS, PhDe (Oral Surg Oral Med Oral Pathol Oral Radiol 2016;-:1-5)
CLINICAL PRESENTATION A 54-year-old female patient presented to the Department of Oral and Maxillofacial Surgery with a chief complaint of lower jaw pain and a feeling of numbness in the lower lip, both on the right side. The patient reported that her symptoms started 3 months ago as numbness and feeling of swelling of the lower lip accompanied by ear pain on the right side; no treatment was administered. Fifteen days earlier, the patient had presented to a General Hospital complaining of gingival pyorrhea and swelling of the right mandible. Antibiotic treatment (amoxicillin 1 g two times daily and metronidazole 500 mg three times daily) was administered with limited improvement. At this point, the patient was referred to our Department for additional evaluation and management. Her medical history was significant for breast cancer diagnosed 5 years ago. Her initial treatment included chemotherapy with docetaxel, four cycles of cyclophosphamide, epirubicin, and 5-fluorouracil and radiotherapy, which resulted in full remission. For the last 4 years, the patient was receiving the aromataseinhibitor anastrazole for hormone manipulation. No use of bisphosphonates was reported. She was a light smoker (of approximately one to two cigarettes per day for several years) and a nondrinker. Intraoral clinical examination did not reveal significant findings, except for a palpable swelling of the buccal cortical plate in the right posterior mandible toward the angle. Extraoral examination revealed facial asymmetry due to swelling of the body of the right mandible extending to the angle (Figure 1). Review of a a Associate Professor, Department of Oral Medicine and Pathology, Dental School, National and Kapodistrian University of Athens, Greece. b Postgraduate Student, Department of Oral and Maxillofacial Surgery, Dental School, National and Kapodistrian University of Athens, Greece. c Oral and Maxillofacial Surgeon, Department of Oral and Maxillofacial Surgery, Dental School, National and Kapodistrian University of Athens, Greece. d Professor, Department of Oral Medicine and Pathology, Dental School, National and Kapodistrian University of Athens, Greece. e Associate Professor, Department of Oral and Maxillofacial Surgery, Dental School, National and Kapodistrian University of Athens, Greece. Received for publication Sep 22, 2015; returned for revision Nov 3, 2015; accepted for publication Nov 16, 2015. Ó 2016 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2015.11.010
panoramic radiograph performed a few weeks earlier revealed an ill-defined radiolucency of the right posterior body of the mandible with a diffuse alteration of the bone trabeculation pattern (Figure 2). A cone beam computed tomography scan of the mandible showed thinning and multiple areas of perforation of the cortical bone (“moth-eaten” appearance) of the body and ramus of the right mandible (Figure 3).
DIFFERENTIAL DIAGNOSIS A clinical presentation of painful swelling of the mandible elicits an extensive differential diagnosis. Taking into account the clinical and radiographic presentations of the present case, an infectious or inflammatory process, such as chronic osteomyelitis, was considered. Chronic osteomyelitis can cause pain, swelling, and intermittent purulent discharge. Radiographically, it may present as a patchy and ill-defined radiolucency that often contains central radiopaque areas, and the cortical surface can demonstrate significant periosteal reaction.1 However, the lack of association with a carious tooth or other local source of infection and the nonresponse to antibiotic treatment made the diagnosis of chronic osteomyelitis less likely. Certain benign but locally aggressive lesions could generate clinical and imaging findings similar to those of the present case. Ameloblastoma may present as a destructive radiolucent lesion frequently located in the posterior mandible; however, a painless, well-defined multilocular radiolucency is more typical.2 A similar presentation of a slow-growing, painless, and locally aggressive lesion may be caused by odontogenic myxomas, most of them being reported in female patients, especially in their second and third decades of life. Since pain and hypoesthesia are not common, the lesions may reach a considerable size before diagnosis.3 Central giant cell granuloma usually appears as an asymptomatic lesion. In most cases, it can be diagnosed as a painless expansion of the affected jaw during clinical examination or most frequently as a well-defined unilocular or multilocular radiolucency in a routine radiographic examination. Cortical bone plates are thinned, but perforation into surrounding soft tissue, as in our case, is rare. In addition, paresthesia is not a typical feature of central giant cell granuloma.4 Primary or metastatic bone tumors may manifest as destructive radiolucent jaw lesions causing cortical 1
CLINICOPATHOLOGIC CONFERENCE 2 Nikitakis et al.
Fig. 1. Extraoral view showing facial asymmetry as a result of swelling of the body of the right mandible extending to the angle.
perforation accompanied by neurologic symptoms, such as pain and paresthesia. Therefore, strong consideration was given to the possibility of a malignant process. Although oral mucosal squamous cell carcinoma (SCC) is, by far, the most common malignancy of the oral cavity and may invade the jaws, the presence of intact overlying mucosa excluded a primary mucosal origin. In the case of the relatively rare primary intraosseous SCC (PIOC), the most common presentation involves progressive painful swelling of the jaws along with loosening of teeth, trismus, and sensory disturbances, such as paresthesia and numbness; although the tumor may be asymptomatic during the early phases and only detected radiographically. In 61% of cases, primary intraosseous SCC presents as a unilocular radiolucency, resembling a cystic lesion in many sizes and shapes with poorly defined and irregular margins.5 Primary tumors of bone, such as osteosarcoma and chondrosarcoma, can be included in the differential diagnosis of an ill-defined radiolucent lesion, even in the absence of other typical radiographic findings, such as spiking root resorption, structural changes in the mandibular canal, and “sun ray” appearance. The patient’s symptoms were also consistent with malignancy, and her age was compatible, considering that jaw osteosarcomas tend to occur in older patients in comparison with extragnathic tumors.6,7 Extranodal malignant lymphomas, especially nonHodgkin lymphoma, may affect oral soft or hard tissues as a primary site of occurrence or as a component of widespread disease. Central lymphomas of the jaws tend to affect the maxilla more frequently. Clinically, a primary lymphoma of bone could manifest as localized bone swelling, possibly associated with ulceration of the overlying mucosa and tooth mobility; pain, numbness, and paresthesia are often reported. The radiographic presentation is not typical for this entity, which commonly appears as a nonspecific osteolysis.8
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Fig. 2. Panoramic radiograph revealing “moth-eaten” appearance of the body and ramus of the right mandible (arrow).
Metastatic tumors in the jaws usually appear as illdefined radiolucent lesions, although bone production has been associated with certain primary sites, particularly the prostate and the breast. Painful swelling and paresthesia are the most common clinical signs of metastatic tumors in the jaws, and the posterior mandible (mainly the molar and premolar areas) appears to be the site of predilection.9 Although metastatic disease to the jaws is not very common, corresponding to approximately 1% of all oral malignancies, a history of malignancy, similar to previous breast cancer in the present patient, should be a strong consideration.
DIAGNOSIS AND MANAGEMENT With the patient under local anesthesia, a full thickness mucoperiosteal flap was developed, and an incisional biopsy of the intrabony lesion was performed. Macroscopically, the biopsy specimen was red in color, had a smooth surface mass of elastic consistency, and measured 3.0 1.5 1.0 cm. Microscopically, a proliferation of neoplastic cells of epithelial origin within a dense fibrous connective tissue stroma was observed (Figure 4). The neoplastic cells were arranged in islands of variable size and shape or as isolated infiltrating cells. The tumor cells had eosinophilic cytoplasm and pleomorphic large, round or oval hyperchromatic nuclei showing focal duct formation (Figure 4). Vascular invasion was also noted. On the basis of these microscopic features, a provisional histopathologic diagnosis of epithelial malignancy that was consistent with metastatic breast cancer was made. Immunohistochemical testing showed positivity of the tumor cells for estrogen receptor and cytokeratin 7 (CK7), whereas CK20 was negative (Figure 4). Taking into account the patient’s history, a final diagnosis of metastatic breast adenocarcinoma was established. The patient was referred to her oncologist for a full metastatic workup and further management.
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Fig. 3. Cone beam computed tomography image of the mandible. A, Axial view. B, Coronal view. The images show thinning and multiple areas of perforation of the cortical bone in the right mandible (arrows). No pathologic fracture was observed.
DISCUSSION Secondary sites to the oral cavity are considered rare and usually constitute a sign of widespread disease.9 In the majority of patients, the primary tumor would have been detected before the development of oral metastasis.10 According to Hirshberg et al., oral metastases were the first evidence of metastatic dissemination in 25% of cases and the first indication of a previously unknown malignant disease in 23%.9,11 Oral metastatic lesions usually derive from epithelial malignancies (carcinomas) rather than mesenchymal tumors (sarcomas).12 The metastatic tumors, which represent approximately 1% of oral malignancies, show a predilection for the jaws than the soft tissues (2:1).11,13 When oral soft tissues are involved, the most common site is the gingiva with an overall frequency of 54%, followed by the tongue.14 In the jaws, the mandible is much more frequently involved compared with the maxilla.9,10 The posterior mandible, especially, is the site of predilection, and involvement of the condyle has been estimated in 5.7% of cases.9,11,15 The pathogenesis of the metastatic spread to the oral cavity has not been fully elucidated. It has been suggested that areas of red marrow are the preferred sites for metastatic deposits. Therefore, the persistence of active hematopoietic marrow in the posterior part of the mandible during adulthood offers an explanation for the predilection for metastasis to the jaws.11 According to Hirshberg et al., the breast is the principal primary tumor site giving rise to oral metastasis in female patients, followed by the adrenal glands and genital organs as the primary tumor sites.10 Breast carcinoma, in particular, has a predilection for bone metastasis rather than soft tissue metastasis. Compared with other malignancies, breast cancer metastasizes to the jaws three times more frequently.15 Similarly, D’Silva et al. reported that most metastases to the jaws in female patients (25.4%) were from a primary breast site.12 In contrast, in male patients, frequently the primary origins of oral metastatic tumors are the lungs, prostate gland, and kidney.9
With regard to patient age, metastatic oral tumors are more common in the fifth to seventh decades of life, with a mean age for metastasis to the jaws and oral soft tissues being 45 and 54 years, respectively.16,17 It has been suggested that the epidemiology of oral metastatic cancer may be affected by different local and geographic factors and genetic mutations, which possibly explains the reported differences among Western and Eastern populations.18 For example, in the study by Lim et al.,18 the mean age of 41 patients with oral metastatic tumors was 55.2 years, with a male-to-female ratio of 1.9:1; noticeably, the breast was not a common primary site for females in this study. Schwartz et al., however, reported that females have an increased risk of developing metastases to the jaws as a result of the predominance of primary breast lesions.19 Metastatic involvement of the jaws may be accompanied by a variety of clinical symptoms, the most common ones being pain, swelling, facial edema, bleeding, increasing tooth mobility and loosening, periodontal involvement, and trismus.10 The mechanisms responsible for pain have been linked to osteolysis.20 Metastasis to the mandible, with involvement of the inferior alveolar nerve, can produce an unexplained loss of sensation in the lower lip and chin, known as numb-chin syndrome.10 McClure et al. studied 26 patients with metastatic disorder to the maxillofacial area, and 11.5% of them had developed pathologic fractures in the mandible. In some instances, the patient may be asymptomatic.21 When the oral soft tissues (e.g., the gingival) are affected, the clinical appearance may be a hyperplastic mass, occasionally with an ulcerated surface.10 Radiographically, jaw metastatic disease may present as a well-defined radiolucency, although most cases will produce a poorly circumscribed radiolucency, described as “moth-eaten appearance.”12 Occasionally, oral metastatic jaw tumors, especially those of breast and prostate origin, may have a radiopaque or mixed radiolucent and radiopaque resolution as a result of
CLINICOPATHOLOGIC CONFERENCE 4 Nikitakis et al.
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Fig. 4. A and B, Low-power photomicrographs showing proliferation of neoplastic cells of epithelial origin forming islands of variable size and shape within a dense fibrous connective tissue stroma (H&E; 100). C, High-power photomicrograph demonstrating tumor cells with eosinophilic cytoplasm and pleomorphic, large, round or oval hyperchromatic nuclei showing focal duct formation (arrow) (H&E; 400). D and E, Immunohistochemical stains showing nuclear positivity for estrogen receptor (D, 100) and cytoplasmic positivity for cytokeratin 7 e (CK7) in the tumor cells (E, 100).
stimulation of new bone formation in the metastatic region.10 Histopathologically, the appearance of metastatic jaw disease is often that of a poorly differentiated tumor,
making the determination of the primary tumor location challenging. Thorough medical history taking, a high degree of suspicion, and appropriate selection of imaging and other diagnostic tests are necessary. In
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CLINICOPATHOLOGIC CONFERENCE Nikitakis et al. 5
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addition, the use of immunohistochemical staining can provide valuable information. As far as metastatic breast carcinomas are concerned, the usual immunohistochemical profile is positive for CK7 whereas it is negative for CK20.12 In addition, estrogen receptor and progesterone receptor markers are positive in the majority (70%-75%) of metastatic breast cancers. Other markers that can be used to confirm metastatic carcinoma from a breast primary are gross cystic disease fluid protein (GCDFP)-15, CEA and BCA225. Among these markers, GCDFP-15 is considered the most specific with a high positive predictive value of 95% and a sensitivity about 50-70%. According to recent literature, the combination of estrogen receptor, progesterone receptor, and GCDFP-15 is 83% sensitive and 93% specific, and is thus considered most valuable in establishing a diagnosis of metastatic breast cancer.22 Patients with oral metastatic disease have a dismal prognosis, most of them succumbing to their disease within a few months after diagnosis, and only 10% manage to survive for 4 years.21,23 In most cases, oral metastasis is a sign of widespread disease involving multiple additional sites, and the possibility of curative therapy is minimal. Therefore, therapeutic efforts are mainly focused on palliative care and interventions, such as radiotherapy and chemotherapy, which can improve the patient’s function and quality of life. Finally, in some selected cases, surgical intervention may be employed to at least temporarily alleviate the symptoms of the metastatic disease in the oral region.21
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Reprint requests: Adamantia Vlachaki, DDS Dental School National and Kapodistrian University of Athens 168 Papadiamantopoulou St. Goudi 11527 Athens Greece [email protected]
