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INTRODUCTION Adenoneuroendocrine carcinoma includes both endocrine and exocrine components. The histopathologic classification of these tumors was defined by Lewin(1) as listed below: 1. Mixed tumors (both tissues exist together), 2. Both tissues exist completely separately, 3. Tumors that exist of amphricrine cells. These tumors may occur in the sinonasal cavity, larynx, lungs, gastrointestinal system, and uterine cervix. Neuroendocrine tumors account for one percent of all cervical carcinomas and are classified into three groups histopathologically; (i) carcinoid tumor, (ii) atypical carcinoid tumor, and (iii) high grade neuroendocrine carcinoma; small cell or large cell types(2). Early nodal and distant metastases are typical for these tumors. Between all pathologic groups, small-cell carcinomas show the worst prognosis and have similar survival to small cell carcinomas of the lungs. Compared with other cervical carcinoma histopathologies, distant metastases occur frequently and there are shorter survival periods in neuroendocrine carcinoma(3). Due to the lack of data, there is no consensus on the definitive treatment of the disease. Surgery alone is not adequate because of the frequent metastases and aggressive behavior. Following surgery, adjuvant chemotherapy and radiotherapy present better survivals in patients with non-small cell disease(4).

arcinoma(3). Due to the lack of data, there is no consensus on the definitive treatment of the disease. Surgery alone is not adequate because of the frequent metastases and aggressive behavior. Following surgery, adjuvant chemotherapy and radiotherapy present better survivals in patients with non-small cell disease(4). The definitive diagnosis of neuroendocrine tumors can be achieved through immunohistochemical staining. Epithelial membrane antigen (EMA), cytokeratin 7 (CK7), cytokeratin 19 (CK19), chromogranin, and synaptophysin staining are diagnostic. Polymerase chain reaction (PCR) study of these viruses is also crucial because of the strong relationship with human papillomavirus (HPV) type 16 and 18. Cervical adenoneuroendocrine carcinoma can be very similar to adenocarcinoma of the cervix. The differential diagnosis is very important because of the aggressive behavior of these tumors and the need for a more aggressive treatment than with other cervix carcinomas.

The definitive diagnosis of neuroendocrine tumors can be achieved through immunohistochemical staining. Epithelial membrane antigen (EMA), cytokeratin 7 (CK7), cytokeratin 19 (CK19), chromogranin, and synaptophysin staining are diagnostic. Polymerase chain reaction (PCR) study of these viruses is also crucial because of the strong relationship with human papillomavirus (HPV) type 16 and 18. Cervical adenoneuroendocrine carcinoma can be very similar to adenocarcinoma of the cervix. The differential diagnosis is very important because of the aggressive behavior of these tumors and the need for a more aggressive treatment than with other cervix carcinomas. CASE REPORT A woman aged 50 years who had been post-menopausal for 8 years was admitted to the hospital with abdominal pain and ongoing postmenopausal vaginal bleeding, which had lasted for ten days. A gynecologic examination revealed a 2x1.5-cm polypoid lesion that originated from the endocervical canal. Also, the whole vagina seemed fragile and the cervix seemed to fuse with the vagina, and the vaginal fornix appeared to be erased. A 3x4-cm cervical tumor was diagnosed. The left parametrium was shortened and there was suspected involvement seen in the right parametrium. Abdominal ultrasonography showed normal uterine fundus and corpus with an endometrial thickness of 15 mm. The right adnexal area included a solid lesion that was 89x50 mm in diameter with cystic areas, and a 72x74 mm complicated cystic mass was seen in the left adnexal area, which was adjacent to the other mass. Abdominopelvic tomography revealed increased dimensions of uterus and cervix with heterogeneous structure. There was minimal fluid in the endometrial cavity. The right adnexal area included a mass of 80 mm that could not be distinguished from the uterus and showed retention of contrast matter. This mass was regular-edged and hypo-dense. The left adnexal area included a 90 mm complicated cyst. The peritoneal surfaces had implants, the largest of which was 53 mm. Massive ascites was present. The right lobe of the liver had 15 and 20 mm lesions that retained contrast matter.

showed retention of contrast matter. This mass was regular-edged and hypo-dense. The left adnexal area included a 90 mm complicated cyst. The peritoneal surfaces had implants, the largest of which was 53 mm. Massive ascites was present. The right lobe of the liver had 15 and 20 mm lesions that retained contrast matter. The tumor marker results were as follows; CA-125: 1870 IU/mL, CA 19-9: 234 IU/mL, CA 15-3: 36.7 IU/mL, and carcinoembryonic antigen: 1.98 IU/mL. A cervical and endometrial biopsy were performed and both results were reported as adenocarcinoma. Accordingly, a laparotomy with a midline incision was performed. Nearly 7000 mL of serous ascites was explored. Adnexal masses were explored as they had been imaged on ultrasonography and tomography. Tumoral implants were seen on the peritoneum of the douglas pouch, hepatorenal area and paracolic area, serosa of rectosigmoid colon, and mesothelium of the bowel. The pancreas and spleen were normal and omental cake was observed. Right unilateral salpingo-oophorectomy was performed and frozen sections were reported as “poorly differentiated adenocarcinoma of the cervix.” As a result, surgery was expanded to type 2 radical hysterectomy, left unilateral salpingo-oophorectomy, resection of the sigmoid colon, right hepatorenal peritoneum, and tumoral implants both on the liver and mesothelium of bowel and appendectomy. Right diaphragm stripping was performed due to the tumoral implants of the right diaphragm. Bilateral pelvic and para-aortic complete lymphadenectomy was performed until the level of left renal vein. The operation was completed with optimal cytoreduction, which resulted with the existence only of residual tumor with a greatest diameter of 5 mm.

was performed due to the tumoral implants of the right diaphragm. Bilateral pelvic and para-aortic complete lymphadenectomy was performed until the level of left renal vein. The operation was completed with optimal cytoreduction, which resulted with the existence only of residual tumor with a greatest diameter of 5 mm. Pathology Macroscopic: The first examined tissue was frozen sections of right salpingo-oophorectomy. The tumoral lesion was a solid structure with minimal cystic structures within, with white-yellowish color and necrosis. Ovarian and tubal tissues were had tumoral nodules on their surface. Microscopic: After fixation with 10% formalin and staining with Hematoxylin and Eosin on paraffin sections, two different malignant tissue was remarkable on cervix. The first tumor was characterized with pseudo-stratified prismatic epithelium with hyperchromatic nuclei and different diameters of atypical glands with mitosis. These atypical glands were at a random distribution both at mucinous stroma and desmoplastic stroma. The second tumor comprised large cells with atypical nuclei and significant nucleoli. There were a high number of mitotic cells forming trabecular, cordon-like structures with a palisade sequence. Necrosis and lymphovascular invasion were also noticed (Figure 1). More than 50% percent of cervical muscle tissue was invaded with tumoral tissue. The vagina, both parametrium, uterine and cervical peritoneum were also showing invasion. The endometrium was inactive and only adenomyosis was noticeable in the myometrium.

The second tumor comprised large cells with atypical nuclei and significant nucleoli. There were a high number of mitotic cells forming trabecular, cordon-like structures with a palisade sequence. Necrosis and lymphovascular invasion were also noticed (Figure 1). More than 50% percent of cervical muscle tissue was invaded with tumoral tissue. The vagina, both parametrium, uterine and cervical peritoneum were also showing invasion. The endometrium was inactive and only adenomyosis was noticeable in the myometrium. The tumoral tissue on the right ovary was also showing characteristics of the second tumor described above. The cystic structure on left ovary and tumoral tissues on both tuba uterine, serosa of the recto-sigmoid colon and adjacent adipose tissue were showing the same structural features (Figure 2).

More than 50% percent of cervical muscle tissue was invaded with tumoral tissue. The vagina, both parametrium, uterine and cervical peritoneum were also showing invasion. The endometrium was inactive and only adenomyosis was noticeable in the myometrium. The tumoral tissue on the right ovary was also showing characteristics of the second tumor described above. The cystic structure on left ovary and tumoral tissues on both tuba uterine, serosa of the recto-sigmoid colon and adjacent adipose tissue were showing the same structural features (Figure 2). Immunohistochemical Study: For the definitive diagnosis, proper immunohistochemical tests were performed. The tumoral tissue on right ovary was stained diffusely positive with EMA, CK7, chromogranin, synaptophysin, focally positive for progesterone receptor, and negative for estrogen receptor, thyroid transcription factor-1 (TTF-1), CK, gross cystic disease fluid protein 15 (GCDFP15), CK K-20, CD-56. These results were compatible; both the ovarian and cervical tumors were large cell neuroendocrine carcinoma. HPV PCR studies also revealed HPV type 16 positivity for both tumors. The Ki 67 proliferation index was 80%. According to all of these data, the ovarian tumor was a metastasis of cervical neuroendocrine carcinoma. The definitive pathologic diagnosis was reported as mixed adenoneuroendocrine carcinoma of the cervix (mucinous adenocarcinoma, endocervical type + large cell neuroendocrine carcinoma). The stage of disease was 4B according to 2009 International Federation of Gynecology and Obstetrics criteria.

euroendocrine carcinoma. The definitive pathologic diagnosis was reported as mixed adenoneuroendocrine carcinoma of the cervix (mucinous adenocarcinoma, endocervical type + large cell neuroendocrine carcinoma). The stage of disease was 4B according to 2009 International Federation of Gynecology and Obstetrics criteria. The other tumoral implants were metastasis of the cervical primary tumor. Also 1 right hypogastric and 1 presacral lymph node were infiltrated with tumor. Other lymph nodes and abdominal cytology were clear. After the operation, 6 cycles of etoposide + cisplatin combined chemotherapy were given with 2-week intervals. During that period, abdominal and thoracic tomography showed no new tumor lesions. Tumor markers 6 months after the surgery were: Carcinoembryonic antigen: 0.30 ng/mL, CA 15-3: 10.6 IU/mL, and CA 125: 14.3 IU/mL. DISCUSSION Cervical adenoneuroendocrine carcinomas are extremely rare. These malignancies progress aggressively with distant metastasis and high mortality rates. There is no consensus on suitable therapeutic protocols because of the lack of data(5). According to the available data, the most important prognostic factor is the stage of the disease(6). Studies reflecting data about small-cell neuroendocrine carcinoma suggest multidrug aggressive chemotherapeutic protocols including cisplatin and etoposide(7). Despite the higher stage of the presented case, 6 months of follow-up showed a very good prognosis with surgery and cisplatin + etoposide chemotherapy regimen.

Studies reflecting data about small-cell neuroendocrine carcinoma suggest multidrug aggressive chemotherapeutic protocols including cisplatin and etoposide(7). Despite the higher stage of the presented case, 6 months of follow-up showed a very good prognosis with surgery and cisplatin + etoposide chemotherapy regimen. One of the most important prognostic features of adenoneuroendocrine carcinomas is that the malignant potential is mostly related to the neuroendocrine component. The presented case was consistent with this and the metastases originated from neuroendocrine component. Despite these data, ovarian metastasis may rarely originate from lower grade adenocarcinoma components and the differential diagnosis of these malignancies with primary ovarian carcinomas can be made through HPV DNA positivity(8). An association between cervical neuroendocrine carcinomas and high-risk HPV (type 16 and 18) has been described(9). HPV produces E6 oncoprotein, which causes the demolition of p53 rather than the effects on retinoblastoma(10). Another molecular mechanism is the loss of heterozygosity on 3p loci as seen in the pathophysiology of small-cell lung cancers(11). Considering all of these pathways, it may be speculated that the malignant transformation of a cervical cell is a multifactorial process. Another point is that neuroendocrine carcinomas may cause paraneoplastic syndromes. No paraneoplastic syndromes were observed in our follow-up, but different syndromes have been experienced(12).

An association between cervical neuroendocrine carcinomas and high-risk HPV (type 16 and 18) has been described(9). HPV produces E6 oncoprotein, which causes the demolition of p53 rather than the effects on retinoblastoma(10). Another molecular mechanism is the loss of heterozygosity on 3p loci as seen in the pathophysiology of small-cell lung cancers(11). Considering all of these pathways, it may be speculated that the malignant transformation of a cervical cell is a multifactorial process. Another point is that neuroendocrine carcinomas may cause paraneoplastic syndromes. No paraneoplastic syndromes were observed in our follow-up, but different syndromes have been experienced(12). CONCLUSION Cervical adenoneuroendocrine carcinoma is a very rare form of cervical malignancies and there is no consensus for proper treatment. The prognosis is mostly related to neuroendocrine component. The most important prognostic factor is indicated as the stage of the disease. The association between neuroendocrine malignancies and HPV subtypes are clinically important for diagnosis. It must be highlighted that differential diagnosis between adenocarcinoma and adenoneuroendocrine carcinomas may be challenging, but is essential because of the different clinical approach and prognosis. Immunohistochemistry is widely used in the differential diagnosis. More extended data should be presented to provide for definitive treatment protocols and clinical approaches.

denocarcinoma and adenoneuroendocrine carcinomas may be challenging, but is essential because of the different clinical approach and prognosis. Immunohistochemistry is widely used in the differential diagnosis. More extended data should be presented to provide for definitive treatment protocols and clinical approaches. Ethics: Ethics Committee Approval: The study was approved by the Local Ethics Committee of Etlik Zübeyde Hanım Women’s Health Training and Research Hospital, Informed Consent: Consent form was filled out by all participants. Peer-review: Externally peer-reviewed. Authorship Contributions: Surgical and Medical Practices: Taner Turan, Heyecan Ökten, Reyhan Öçalan, Concept: Taner Turan, Gökhan Tulunay, Design: Taner Turan, Gökhan Tulunay, Data Collection or Processing: Erdem Fadıloğlu, Şeyma Asiltürk, Analysis or Interpretation: Nurettin Boran, Literature Search: Erdem Fadıloğlu, Şeyma Asiltürk, Writing: Erdem Fadıloğlu, Alper Karalök, Osman Türkmen. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Figure 1 Mix cervical adenocarcinoma and large cell neuroendocrine carcinoma Figure 2 Large cell neuroendocrine carcinoma (ovarian metastasis)

PRECIS: To identify the possible risk factors for postpartum urinary retention. Introduction Uterine cervical cancer (CC) is the third most common cause of cancer having the highest mortality rate in the female reproductive system(1). Prognostic factors of CC are based on stage, patient age, type and size of tumor, lymph node metastases, parametrial invasion, and lymphovascular space invasion(2,3). Mostly, recurrence occurs within 2 years after primary treatment and 90% of patients with recurrence die(4,5). The 10-year recurrence rate is reported as 3% for stage IA, 16% for stage IB, 31% for stage IIA, 26% for stage IIB, 39% for stage III, and 75% for stage IVA(6).

nvasion, and lymphovascular space invasion(2,3). Mostly, recurrence occurs within 2 years after primary treatment and 90% of patients with recurrence die(4,5). The 10-year recurrence rate is reported as 3% for stage IA, 16% for stage IB, 31% for stage IIA, 26% for stage IIB, 39% for stage III, and 75% for stage IVA(6). Just like other solid tumors, CC spreads through direct invasion, and lymphatic and hematogenous dissemination. Distant metastasis to other organs such as lung, bone, braini and liver uses the hematogenous route primarily(7,8). Distant organ metastasis is most commonly seen in lungs (21%), bone (16%), para aortic nodes (11%), the intestinal space (8%), and supraclavicular lymph nodes (7%). The number and site of metastasis are important for survival. The median survival is 24 weeks in lymphatic recurrence, whereas it is only 12 weeks in metastasis to other organs(6). Patients with stage I-IIA CC who undergo surgery have bone recurrence in the first 2 years of the postoperative period, and usually the recurrence occurs in axial bone, especially in the vertebra(9,10). The median survival after bone recurrence is reported as between 5 and 12 months(9,10,11,12). In this research, our aim was to evaluate the clinical, surgical, and pathologic factors in patients with bone recurrence after type III radical hysterectomy with pelvic ± para aortic lymphadenectomy for CC.

he vertebra(9,10). The median survival after bone recurrence is reported as between 5 and 12 months(9,10,11,12). In this research, our aim was to evaluate the clinical, surgical, and pathologic factors in patients with bone recurrence after type III radical hysterectomy with pelvic ± para aortic lymphadenectomy for CC. Materials and Methods Between 1993 and 2018, 412 patients with stage IB-IIA epithelial CC as classified by the International Federation of Obstetricians and Gynecologists (2014) were treated with laparotomy and type III radical hysterectomy with pelvic ± paraaortic lymphadenectomy, and their data were reviewed. Seven (1.7%) patients who had the first recurrence in bone were included. Data of the patients’ clinical findings, site of recurrence, time to recurrence, treatment modality, and the response rates were obtained from the patient files and pathology reports in our gynecologic oncology clinic electronic database system.

Seven (1.7%) patients who had the first recurrence in bone were included. Data of the patients’ clinical findings, site of recurrence, time to recurrence, treatment modality, and the response rates were obtained from the patient files and pathology reports in our gynecologic oncology clinic electronic database system. Bone scintigraphy, magnetic resonance imaging, and positron emission tomography-computed tomography (PET-CT) were used in the diagnosis of metastatic lesions. For the differential diagnosis of metastasis, systemic examination, chest X-ray, abdominopelvic and thoracic CT and PET-CT were performed. Recurrence that developed only in bone was classified as “isolated recurrence” and bone and other sites were classified as “multiple recurrences”. Recurrence of the bone was classified as “axial skeleton”, which included cranium, sternum, vertebra and costa, and “appendicular skeleton”, which included the upper and lower extremities, scapula, and the pelvic bones. The size of the tumor was defined by the largest diameter of the tumor in the cervix at the initial treatment.

of the bone was classified as “axial skeleton”, which included cranium, sternum, vertebra and costa, and “appendicular skeleton”, which included the upper and lower extremities, scapula, and the pelvic bones. The size of the tumor was defined by the largest diameter of the tumor in the cervix at the initial treatment. The plan of treatment in the patients with recurrence was decided by the council of gynecology and oncology. Treatment results were evaluated according to the guidelines of the World Health Organization. We defined the clinical response as follows: (I) complete clinical response: disappearance of the macroscopic tumor; (II) partial clinical response: shrinkage over 50% of the macroscopic tumor, (III) stable disease: macroscopic shrinkage of the tumor less than 50% or not less than 25% growth; (IV) progressive disease: more than 25% growth of the macroscopic tumor or macroscopic appearance of new tumor foci(13). The factors indicating the bone recurrence could not be recognized at this point, because the number of the patients with bone recurrence were only 7 (1.7%). The time of from surgery until recurrence was defined as time-to-recurrence (TTR), the time until the death of the patient was defined as overall survival, and the time of recurrence until the death of patient or until the last date was defined as post recurrence survival.

ients with bone recurrence were only 7 (1.7%). The time of from surgery until recurrence was defined as time-to-recurrence (TTR), the time until the death of the patient was defined as overall survival, and the time of recurrence until the death of patient or until the last date was defined as post recurrence survival. All patients were followed up after the initial treatment for the CC. Patients who had complete clinical response with salvage treatment for recurrence were followed up quarterly in the first 2 years, semi-annually for up to 5 years, and annually thereafter. Pelvic examination, abdominopelvic ultrasonography, Papanicolaou smear, complete blood count, and biochemistry profile were performed in the follow-up. Chest X-ray was used annually unless there was clinical suspicion. Thoracic and\or abdominal CT were used when needed.

ually for up to 5 years, and annually thereafter. Pelvic examination, abdominopelvic ultrasonography, Papanicolaou smear, complete blood count, and biochemistry profile were performed in the follow-up. Chest X-ray was used annually unless there was clinical suspicion. Thoracic and\or abdominal CT were used when needed. Results The median follow-up of the main cohort (n=412) was 46 (range=1-300) months. In this period, recurrence developed in 53 (12.9%) patients, and the recurrence rate in bone was observed as 13.2% (7 of 53). Tumor type was squamous carcinoma in six patients and mixed type in one patient (squamous + adenocarcinoma). Paraaortic lymphadenectomy was added to the surgical procedures in six patients and pelvic lymphadenectomy alone was performed in one patient. The number of lymph nodes removed was between 42 and 102. It was determined that there was spread to the pelvic lymph nodes in two patients and pelvic and paraaortic lymph nodes in one patient. There was parametrial invasion in one patient, surgical border positivity in one, and lymphovascular space invasion in two patients. The surgical-pathologic features are shown in Table 1. One patient (patient #7) received neo-adjuvant chemotherapy. As neoadjuvant chemotherapy, the patient received a combination of cisplatin + tegafur-uracil for 2 cycles. Adjuvant therapy was given to three patients as concurrent chemo-radiotherapy (CCRT) and three patients received no adjuvant therapy. One patient (patient #4) refused adjuvant therapy.

neo-adjuvant chemotherapy. As neoadjuvant chemotherapy, the patient received a combination of cisplatin + tegafur-uracil for 2 cycles. Adjuvant therapy was given to three patients as concurrent chemo-radiotherapy (CCRT) and three patients received no adjuvant therapy. One patient (patient #4) refused adjuvant therapy. TTR ranged from 9 to 45 months. Five of the recurrences were in the axial skeleton and two were in the appendicular skeleton. Recurrence was observed in three patients in the lumbar vertebrae, one in the thoracic vertebrae, one in the sacral vertebrae, one in the lumbosacral vertebrae, and two in the left femur. Three patients (patient #1, #6, and #7) had isolated bone recurrence and four patients had multiple recurrence. Except for the bone, one of them had it in the inguinal and supraclavicular lymph nodes, one in pelvic-paraaortic lymph nodes, one in lung and paraaortic lymph nodes and one in lung (Table 2). Recurrence was in the axial skeleton in all isolated bone recurrences.

ne recurrence and four patients had multiple recurrence. Except for the bone, one of them had it in the inguinal and supraclavicular lymph nodes, one in pelvic-paraaortic lymph nodes, one in lung and paraaortic lymph nodes and one in lung (Table 2). Recurrence was in the axial skeleton in all isolated bone recurrences. After recurrence, six patients received salvage therapy for curative intent and one patient received palliative therapy (patient #4). Two of the patients who received salvage therapy were given only systemic treatment (cisplatin + 5 fluorouracil). Four patients received radiotherapy, two of whom were given systemic treatment after radiotherapy. Radiotherapy was performed in one patient with weekly cisplatin (CCRT) and one patient received radiotherapy only (Table 2). In salvage therapy, one patient with only systemic treatment and one patient with radiotherapy had a complete clinical response (patients #1 and #7). These two patients had isolated bone recurrence and their post recurrence survival was 129 months and 11 months, respectively. During the follow-up period, four patients died because of the disease (patient #2, #3, #4 and #5). The recurrence type of these four patients was multiple recurrence, and in two the disease recurred in the lung (Table 2). These patients died within 6-25 months after recurrence. Recurrence was seen in the femur and pelvic paraaortic lymph nodes of the patient who lived up to 25 months after recurrence and was treated with concurrent chemo-radiotherapy.

tients was multiple recurrence, and in two the disease recurred in the lung (Table 2). These patients died within 6-25 months after recurrence. Recurrence was seen in the femur and pelvic paraaortic lymph nodes of the patient who lived up to 25 months after recurrence and was treated with concurrent chemo-radiotherapy. Discussion The results of bone recurrence in uterine CC vary widely. Drescher(14) reported bone metastasis in 1.2%. However, this rate was 16% in the study of Fagundes et al.(6). In our case series, the rate of bone recurrence was 1.3% in the main cohort where the median follow-up was 46 months.

tients was multiple recurrence, and in two the disease recurred in the lung (Table 2). These patients died within 6-25 months after recurrence. Recurrence was seen in the femur and pelvic paraaortic lymph nodes of the patient who lived up to 25 months after recurrence and was treated with concurrent chemo-radiotherapy. Discussion The results of bone recurrence in uterine CC vary widely. Drescher(14) reported bone metastasis in 1.2%. However, this rate was 16% in the study of Fagundes et al.(6). In our case series, the rate of bone recurrence was 1.3% in the main cohort where the median follow-up was 46 months. The site and number of recurrences are the main factors affecting prognosis and treatment(15). It is known that the success of treatment is low when recurrence occurs in others site accompanying the bone recurrence(16). In the current case series, all patients with multiple recurrences died of recurrent disease. The choice of treatment for recurrent disease is primarily dependent on previous treatment and should be evaluated together with the location of the recurrent tumor and the patient’s performance(17,18). In patients with CC who have distant and multiple recurrent disease, the primary aim of treatment is mostly not-curative intent but palliative(19). However, in a study presented by Makino et al.(20)of 75 patients with uterine CC and bone recurrence, the overall survival (OS) of 16 patients who received chemotherapy and CCRT after RT was 18 months and 2 months, respectively, compared with 25 patients receiving palliative treatment (p<0.05). In our case series, complete clinical response was obtained with salvage treatment in two patients in the presence of isolated recurrence. Salvage treatment was applied to one of them with systemic treatment, and with cisplatin and radiotherapy to the other. In recurrent CC, cisplatin is preferred for most patients. Systemic treatment success rate is 12-22% in recurrent CC(21,22,23,24,25,26). Unlike other anti-angiogenic agents, bevacizumab has been used as a part of cisplatin-based combination therapy for recurrent, persistent or metastatic CC, and its addition to the cisplatin-paclitaxel protocol has been shown to increase OS from 13 months to 17 months (p=0.008)(27,28). Surgical treatment has been applied in selected cases with solitary bone recurrence in the literature. Ida et al.(29) were able to control the disease by surgical resection in a solitary femur recurrence that developed 22 months after the first treatment. However, Makino et al.(20) reported that in two patients with solitary bone recurrence, complete resection could not be achieved. We had no patients who could be managed surgically in this series.

ontrol the disease by surgical resection in a solitary femur recurrence that developed 22 months after the first treatment. However, Makino et al.(20) reported that in two patients with solitary bone recurrence, complete resection could not be achieved. We had no patients who could be managed surgically in this series. The retrospective nature is the main limitation of the study. The number of patients was low and this prevented clear results to change clinical practice. However, the study evaluated patients who had a median follow-up of approximately 4 years and who had undergone radical surgery from among more than 400 early-stage cancers. Conclusion In conclusion, complete clinical response and long postoperative survival can be achieved with salvage treatment when bone recurrence is solitary. However, the effect of surgery in this patient group should be evaluated. Multimodal treatment options including surgery in CC with bone recurrence, especially solitary recurrence, need to be evaluated in further studies. Ethics Ethics Committee Approval: Local ethics committee approval was obtained. Informed Consent: Approval from all patients. Peer-review: External and internal peer-reviewed. Authorship Contributions Surgical and Medical Practices: C.Ç., T.T., Concept: C.Ç., R.D., D.Y., Ç.K., Design: C.Ç., Data Collection or Processing: C.Ç., M.Ü., Analysis or Interpretation: C.Ç., Literature Search: C.Ç., G.B., A.K., Ö.M.T., T.T., Writing: C.Ç. Conflict of Interest: No conflict of interest was declared by the authors.

Authorship Contributions Surgical and Medical Practices: C.Ç., T.T., Concept: C.Ç., R.D., D.Y., Ç.K., Design: C.Ç., Data Collection or Processing: C.Ç., M.Ü., Analysis or Interpretation: C.Ç., Literature Search: C.Ç., G.B., A.K., Ö.M.T., T.T., Writing: C.Ç. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study received no financial support. Table 1 Clinical, pathologic, and surgical features Table 2 Bone metastasis site, treatment and outcome