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Revista Românã de Anatomie funcþionalã ºi clinicã, macro- ºi microscopicã ºi de Antropologie Cervical Squamous Cell Carcinoma Metastases to the Brain, Skin and Upper Jaw CLINICAL ANATOMY Vol. XII Nr. 1 2013 CERVICAL SQUAMOUS CELL CARCINOMA METASTASES TO THE BRAIN, SKIN AND UPPER JAW. CASE PRESENTATION AND LITERATURE REVIEW Gabriela Dumitrescu1, Anca Sava2, Delia Ciobanu3, Doina Butcovan3, Corina Ursulescu4, Danisia Haba5, Eugenia Popescu6, I. Poeatã7 1. Emergency Clinical Hospital Prof. dr. N. Oblu Iaºi Department of Pathology University of Medicine and Pharmacy Gr. T. Popa Iaºi 2. Department of Anatomy and Embriology 3. Department of Pathology 5.Department of General and Dental Radiology 6. Department of Maxillo-Facial Surgery 7. Department of Neurosurgery 4. Emergency County Hospital St. Spiridon Iaºi Radiology Clinic Prof. Dr. Gh. Chisleag CERVICAL SQUAMOUS CELL CARCINOMA METASTASES TO THE BRAIN, SKIN AND UPPER JAW. CASE PRESENTATION AND LITERATURE REVIEW (Abstract): OBJECTIVE: Even though the squamous carcinoma of the cervix is a very common gynecologic malignancy in Romania, its metastases to maxillary bone, skin and brain are extremely rare. CASE REPORT: A 46-yearold woman was diagnosed with moderately differentiated squamous cell carcinoma of the uterine cervix, FIGO stage, IIB, which was treated with concurrent chemoradiation. Fifteen months later, a thoraco-abdominal computed tomography (CT) detected a right pulmonary metastasis, and mediastinal and retroclavicular adenopathies. The patient received chemotherapy, but after 25 months she presented intense headache and vomiting. Computed thomography (CT) of the brain showed a frontal expansive lesion. A total excision was performed. The histopathological exam revealed a cerebral metastasis from a moderately differentiated squamous cell carcinoma. The patient received postoperative chemoradiotherapy. Four months later, the patient showed an ulcerative, painful, bleeding lesion with irregular borders, localized on the 2.1.-2.4. alveolar ridge. Head and neck CT revealed an expansive osteolytic lesion, located in the left upper jaw. Thoraco-abdominal CT also showed metastases in the lung, the liver, and cutaneous, on the left posterolateral chest wall. An incisional biopsy of the jaw tumor was performed and the histopathological exam established the diagnosis of metastasis of a moderately differentiated squamous carcinoma with keratinization. CONCLUSION: The case presented here is an example of successful management of squamous carcinoma of the cervix, and demonstrates the possibility that, in conditions of long-term survival of the patient, the tumor cells could spread in completely unusual locations for cervical cancer, such as skin, brain and oral cavity. Key words: SQUAMOUS CELL CARCINOMA, UTERINE CERVIX, METASTASES INTRODUCTION In 2008, Romania had the highest standardized incidence rate of cervical cancer - 29 0/0000 women, and this places our country in the first place in Europe (1). In region of Moldavia, there is an average incidence of 31.49 0/0000, and the incidence of cervical cancer in Galati County is even higher (45.80 0/0000.) (2). In recent decades, surgery, chemotherapy and radiotherapy have prolonged survival of these patients, but they have limited metastatic disease that typically occurs by local extension and lymphatic dissemination to the retroperitoneal lymph nodes. Hematogenous metastases usually occur less frequently and mostly localized in the lung, liver and bones. Intracerebral 49 Gabriela Dumitrescu et al. Fig. 1. Brain MRI: heterogenous tumoral lesion in the frontal lobe Fig. 2. Histopathological aspects of the frontal metastasis: a moderately differentiated squamous cell carcinoma (HE, x200) Fig. 3. Ulcerative, painful, and bleeding lesion, localized on the 2.1.-2.4. alveolar ridge. Fig. 4. Orthopantomography: radiolucent area in the central part of the dental arch. metastases and maxillary bones are rarely identified. Due to the rarity of these conditions, little is known about the management and prognosis of these patients. The aim of this case presentation was to show the clinical aspects and treatment modalities of a patient with squamous cervical carcinoma treated with chemotherapy and radiotherapy, which developed metastases into the lymph nodes, liver and lung, but also into the brain and the maxillary bone later in the evolution of the disease. metastasis, and mediastinal and retroclavicular adenopathies, and the patient received six sequences of chemotherapy (Carboplatin + Taxol) followed at 6 months by a second-line chemotherapy (Carboplatin + Hycamtin) administrated in six sequences, too. In 2011, she followed the oral chemotherapy (20mg/day) at 3 weeks. In March 2012, the patient experienced intense headache and vomiting for 15 days. Computed thomography (CT) of the brain showed an expansive infiltrative lesion located in the right fronto-basal region. The tumour had a maximum diameter 55mm, was heterogeneous, and showed perilesional vasogenic edema and significant mass effect on adjacent frontal horn. The lesion was diagnosed as intracerebral metastasis and a biopsy has been done. Pathological diagnosis was metastasis from a moderately differentiated squamous cell carcinoma that was considered to be compatible with a metastasis of a cervix cancer. In May 2012, the patient followed postoperative radiotherapy on CASE REPORT A woman, aged 46 years, whose father died of a esophageal cancer, was diagnosed by a biopsy, in December 2008, with moderately differentiated squamous cell carcinoma of the cervix, FIGO stage, IIB. Without a surgical treatment, in February 2009 she began radioand chemotherapy (Cisplatin) simultaneously. After a year, in February 2010, thoraco-abdominal tomography detected a right pulmonary 50 Cervical Squamous Cell Carcinoma Metastases to the Brain, Skin and Upper Jaw a b c Fig. 5 (a, b, c). Cranial CT: expansive osteolytic tumour in the left jaw with destruction of the alveolar and palatine processes, with extension into the hard palate, the floor of the left maxillary sinus, and to the lower third of the nasal vestibule and left oral cavity. b a c Fig. 6. (a, b, c) Thoraco-abdominal CT: cervical and mediastinal adenopathy with superior mediastinal and right upper paratraheal adenopathy block that encompasses and occluded the brachio-cephalic venous trunk, as well as pulmonary and hepatic metastases. encephalon for a total radiation dose of 30 Gy given in 10 fractions, and corticosteroids, followed by a fourth-line chemotherapy with capecitabine (Xeloda) (1500mg / 2 times a day, for 14 days, in 6 secqences, but she supported only one. In July 2012 the patient experienced malaise, headache, nausea, vomiting, but she also accused pain and bleeding from an intraoral tumor located on the upper left alveolar ridge. In August 2012, a magnetic resonance ima51 Gabriela Dumitrescu et al. Fig. 7. Histopathological aspects of the jaw bone tumor: metastasis of a moderately differentiated squamous carcinoma with keratinization (HE, x200). Fig. 8. Histopathological aspects of the jaw bone tumor: tumoral emboli in lymphatic vessels of the oral mucosa (HE, x200). ging (MRI) of the brain showed an intraaxial heterogeneous tumoral lesion, with cystic and necrotic areas, located in the right frontal lobe (45/44/35mm - ap/t/cc). The lesion showed peripheral edema and mass effect on the right frontal horn of the lateral ventricle, shifting the midline to the left by approx. 9.4 mm (Fig. 1). The surgical intervention reopened the old scar. Microsurgical tumor resection was performed with CUSA, and a macroscopical total ablation was done. Postoperative evolution was favorable. Histopathological exam showed an intracerebral metastasis of moderately differentiated squamous carcinoma with gliosis in the adjacent nervous tissue, with a possible starting point in a cervical carcinoma (Fig. 2). As the patient presented swelling and pain in her left maxillar bone, in October 2012 she was admitted at Emergency Hospital St. Spiridon, Oro-Maxillo-Facial Clinic. Personal history and local examination showed an ulcerative, painful, bleeding lesion with irregular borders, localized on the alveolar ridge at 21-24, developed rapidly in the last 3 months (Fig. 3). Orthopantomography revealed a radiolucent area in the central part of the dental arch, 2.1. roots remnants, and discontinuity of 1/3 internal bottom edge of the left maxillary sinus. There was also vertical and horizontal periodontal retraction at 1.3, 4.4 and 4.3, which is mesial moved (Fig. 4). Head and neck CT revealed: an expansive osteolytic lesion ( 31/37/ 30mm - AP / T / CC), located in the upper jaw, alveolar and palatin processes, with extension to the hard palate, to the left maxillary sinus floor, to the nasal vestibule floor, and to oral cavity and left oral vestibule (Fig. 5). Thoraco-abdominal CT showed left laterocervical and submandibular lymph nodes adenopathies with 15-25 mm in diameters, and an extended mediastinal adenopathic block that encompassed the aortic emergences, aortic putter, descending aorta, tracheal fork and esophagus, and was firmly attached with bilateral hilar lymphadenopathy. There was also a superior mediastinal adenopathy block that encompassed and determined the stenosis of mediastinal right brachiocephalic venous trunk, and metastases in the left lower pulmonary lobe, in the liver, and cutaneous, on the left posterolateral chest wall (Fig. 6). An incisional biopsy of the jaw tumor was performed and the histopathological exam established the diagnosis of metastasis of a moderately differentiated squamous carcinoma with keratinization, with a possible starting point in the cervix (Fig. 7 and Fig. 8) 52 DISCUSSIONS Cervical carcinoma usually spreads by contiguity to adjacent organs and disseminates through the rich lymphatic network to pelvic and para-aortic lymph nodes. In rare instances, tumoral cells can spread via a hematogenous route to distant organs such as lung, liver and bone (3), but also unusual location, as the skin (4), central nervous system (3) or jaw (5). In adults, the most common origins of brain metastasis are lung cancer, breast cancer, melanoma, and kidney cancer, colorectal cancer, lymphoma or other unknown primary tumors (6, 7). Cancers of the genital area and especially the cervix are reported as having little Cervical Squamous Cell Carcinoma Metastases to the Brain, Skin and Upper Jaw ability to spread in the nervous system as the intracerebral metastases incidence of this cancer ranging between 0.45% and 1.20% (8-12), which demonstrates the importance of our case as it allows the monitoring of the metastatic process. Of all hystotypes of cervical cancer, it appears that the squamous carcinoma spreads lesser in the brain comparative with the uterine adenocarcinomas (11), and this fact provide new evidence of the rarity of this case. Our case developed, subsequently to the brain metastasis, a metastasis in the upper jaw. In the medical literature, there are reports of intraoral metastases from cancers of various thoracic or abdominal-pelvic organs, but these situations represent only 1-3% of all oral cancers (13). The majority of these cases are published sporadically because of their rarity. The reported cases demonstrated as a starting point a hepatocellular carcinoma, thyroid cancer, colon adenocarcinoma, breast carcinoma, lung or prostate carcinoma (14-23). An analysis of 24 cases of oral carcinomatous metastases reported by van der Waal et al. showed that primary locations were breast (25%), lung (21%), kidney (17%), and prostate (13%) (24). Taking into consideration 110 carcinomatous metastases located only in the mandible, Harrison and Lund found its origin to be located in kidney (44%), lung (13%), breast (9%), testicle (7%), uterus (6%) , thyroid (5%), colon and rectum (5%), stomach (5%), and prostate (3%) (25). However, all the studies and articles published stresses that gynecological cancer bone metastases are a rare entity and their location in the jaws is even rarer (5, 26). Various cancers spread into the jaw bones via the bloodstream by embolization because the jaws lack lymphatics (27). In the case of tumoral seeding in the bones, bone marrow is considered necessary for the establishment and proliferation of metastases (28). Because the marrow is poorly represented in the jaw bones, metastatic carcinomas are rare in these locations. However, secondary deposits occur more frequently in the mandible (83%) than in the maxilla (17%) (23, 24). The mechanism was explained by the fact that the mandible is richer in hematopoietic tissue, and as the metastasis spread hematogenous, cancer cells can be stored easily in this area. Reduced blood flow in this area may help to deposit the tumoral cells (29). Moharil et al. defined the criteria by which one can establish the diagnosis of a metastatic lesion of the jaws: a) histological verification; b) if metastatic tumor is not in a typical area of an oral primary tumor; c) if one can exclude the possibility of a direct extension of primary tumors into the jaws; d) if genetic tests of the primary tumor are identical with those of the metastatic lesions in the jaw (19). In our case, histological verification was performed for both primary tumor and the intracerebral and intramaxillary metastases, and we excluded a possible oral primary tumor because all tumors showed the same histological appearance: moderately differentiated squamous cell carcinoma. In 1992, Kumar et al. reported that brain metastases developed between 7 and 35 months after the primary diagnosis (30). In our case, the patient was diagnosed with brain metastases after 40 months from the diagnosis of primary disease probably because she received a well managed oncological treatment. Analyzing our case, but also the medical literature, we tried a possible explanation for these rare distant metastases of the cervical squamous cell carcinoma. Because thoraco-abdominal CT showed enlarged mediastinal block encompassing aortic emergences we can hypothesize that tumoral cells could pass from the mediastinal adenopathy block by contiguity into the aortic emergences, respectively brachiocephalic trunk, common carotid artery, the internal carotid artery and then to the anterior cerebral artery and could seed in the right frontal lobe, just where the intracerebral metastasis was identified. The tumoral cell from the mediastinal adenopathy block could also pass into the left common carotid artery, left external carotid artery, left maxillary artery and then into left posterior superior alveolar artery to seed in the left maxillary alveolar area. It is possible, however, a second mechanism based on the lymphatic route. The tumoral emboli could enter into the left lymphatic duct that ends in the inferior vena cava and tumoral cells reach the right atrium. Tumoral emboli pass then in the right ventricle and enter into the pulmonary artery, arrive to the lungs where it could seed and then continue to move through the pulmonary veins until reaching the left atrium. From the left atrium, tumoral emboli could enter into the systemic circulation and may seed in any location, probably depending on certain anatomical variants of the organs. 53 Gabriela Dumitrescu et al. This hypothesis is mainly plausible as our patient has had a pulmonary metastasis 25 months before having cerebral, cutaneous and maxillary metastases. The proof for this hypothesis comes from the articles published in the last twenty years and demonstrating the intracardiac metastases from cervical squamous cell carcinoma. Nakao et al. reported a pedunculated tumor in the right atrium (31) and Senzaki et al. showed an extensive right ventricle metastasis associated with multiple organ involvement (32). Lee and Park presented a case with a cervical squamous cell carcinoma that has spread into the lungs and then was followed by a secondary seeding into the left atrium through the pulmonary veins (33). However, once the tumoral cells enter the systemic circulation, they spread even in unsual location such as the brain, skin, and upper jaw as in our case, or, as reported in literature, the tumoral emboli could disseminate into the fibula (34), the femur (35), the humerus (36), the orbit (37), the pericardium (38), the scalp (39) etc. Because of their rarity, brain, cutaneous and intramaxillary metastases of a squamous carcinoma of the cervix are real challenges for clinicians and for the pathologists as well. These metastases have bad prognosis as primary tumor cells already seeded in many other locations (lymph nodes, lung, liver, etc.). There are also difficulties in treatment as oral and cutaneous metastases are usually resistant to chemotherapy and radiotherapy (19), but palliative treatment can improve the quality of life. CONCLUSIONS The case presented here is an example of successful management of squamous carcinoma of the cervix, using surgery, chemotherapy and radiotherapy as these treatments prolonged the life of our patient with at least four years. At the same time, this case demonstrates the possibility that, in conditions of long-term survival of the patient, the tumor cells could spread in completely unusual locations for cervical cancer, such as skin, brain and oral cavity. REFERENCES 1. Stoenescu TM, Prognosticul cancerului de col uterin în contextul unor abordãri epidemiologice, clinice ºi imunohistochimice, Rezumatul Tezei de doctorat, UMF Gr. T. Popa Iaºi, 2011, p. 4. 2. Bratu Mariana. Aspecte epidemiologice, factori de risc ºi screening în neoplaziile colului uterin, Rezumatul Tezei de doctorat, UMF Gr. T. Popa Iaºi, 2011, p. 9. 3. 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