out. 1 cannot be, because there would be infectious signs.

This one has been difficult for me, we are going to rule it out. 1 cannot be, because there would be infectious signs. Answer 2 is possible because bisphosphonates create mandibular necrosis. 3 seems unlikely to me because the radiotherapy that the patient received would be oriented on the breast and not on the mandible. I rule out number 4, as it is not a case of dental root involvement. 5 is possible; after all, the patient already has bone metastases. So, I hesitate between 2 and 5, which one to choose? I am certainly not sure what a bone sclerosis means on a CT scan, but a bone metastasis would be more destructive than sclerotizing. On the other hand, using reverse psychology, what did the questioner want me to know? That bisphosphonates can create mandibular necrosis? Or that a woman with several bone metastases can have a metastasis also in the mandible? The latter seems too simple, and would make me lean more towards 2, but it's not clear to me. Be that as it may, between two possible answers you have to always answer, and between 2 and 5, you have to check 2, which is more likely.

This one has been difficult for me, we are going to rule it out. 1 cannot be, because [HIDDEN]. Answer 2 is possible because bisphosphonates create mandibular necrosis. 3 seems unlikely to me because [HIDDEN]. I rule out number 4, as [HIDDEN]. 5 is possible; after all, the patient already has bone metastases. So, I hesitate between 2 and 5, which one to choose? I am certainly not sure what a bone sclerosis means on a CT scan, but [HIDDEN]. On the other hand, using reverse psychology, what did the questioner want me to know? That bisphosphonates can create mandibular necrosis? Or that [HIDDEN]? The latter seems too simple, and [HIDDEN], but it's not clear to me. Be that as it may, between two possible answers you have to always answer, and between 2 and 5, [HIDDEN].

60-year-old woman, diagnosed with breast cancer treated with surgery and radiotherapy 10 years ago. Currently with metastases in the dorsal spine and sacroiliac joint, for which she has received monthly treatment with i.v. zoledronic acid for the last two years. The patient presented spontaneous bone exposure at the level of the mandibular bone of approximately 2 cm. There are no signs of acute infection and the gum around the bone exposure is strictly normal. The mandibular CT scan shows an area of bone sclerosis. What would be the diagnosis?

OTORHINOLARYNGOLOGY AND MAXILLOFACIAL SURGERY

Successful conservative treatment of jaw osteonecrosis caused by denosumab in patients with multiple bone metastasis.

We report a case of osteonecrosis of the jaw (ONJ) associated with denosumab therapy in a 62-year-old female patient being treated for bone metastases from breast cancer. Upon initial presentation at the Department of Oral Medicine, Hokkaido University Hospital, the patient's mandibular molar teeth were extracted because of severe periodontal disease. Two months later, epithelialization of the sockets was observed and treatment with anti-resorptive drugs was started for bone metastases. One year after tooth extraction, bone exposure in the right lower first molar region was observed, and stage 2 medication-related ONJ (MRONJ) was diagnosed. Up to this time, the patient had received zoledronic acid twice and denosumab 22 times. Denosumab was discontinued by the oncologist, and oral antibiotics with rinsing of the exposed bone area were prescribed. By 36 weeks after discontinuation of denosumab, a sequestrum in the posterior part of the mandible was naturally shed, and the site was healed. Bisphosphonate is deposited in bones, whereas denosumab functions extracellularly and circulates in the blood. The effect of denosumab on bone remodeling is reversed shortly after the drug has been discontinued.

A case of osteonecrosis of the jaw in a breast cancer patient with bone metastases receiving long-term treatment with bisphosphonates.

Bisphosphonates (BPs) are often used for the treatment of several diseases such as osteoporosis, cancer-associated hypercalcemia, and osteolytic bone metastasis. Recently, there have been reports of osteonecrosis of the jaw (ONJ) in cancer patients whose treatment regimens include BPs. In this case report, we describe complications and treatment of ONJ in a breast cancer patient with bone metastases who received long-term treatment with BPs. A 70-year-old woman underwent modified radical mastectomy on her left breast cancer and received oral 5-fluorouracil derivatives for 2 years in another hospital. Eleven years after the surgery, she came to our hospital complaining of spinalgia and was diagnosed with recurrent breast cancer with multiple metastases to the stomach, liver, multiple lymph nodes, and spine. After surgery for spine metastases, she was given a combination therapy of trastuzumab (initial bolus: 170 mg/body, followed by two or more cycles of 85 mg/body) every week, docetaxel (100 mg/body) every 3 weeks, and BPs (90 mg/body) every 4 weeks. About 1 year and 4 months later, she complained of pain in her right maxilla; biopsy revealed ONJ. Medical oncologists need to recognize ONJ as a serious side effect of BP treatment; dentists and oral and maxillofacial surgeons need to thoroughly consult patients regarding the administration of BPs and have them make an informed consent.

[A case of bisphosphonate-associated osteonecrosis of the jaw in a patient with bone metastasis of breast cancer].

A 5 6-year-old woman underwent modified radical mastectomy for left breast cancer in 2002. Bone metastases developed in November 2005, and she received pamidronate from February 2006. Pamidronate was changed to zoledronate in November 2006. In November 2007, she was referred to a dentist for pain and swelling of the right lower gum. Conservative therapy with local irrigation and antibiotics was performed, but the lesion progressed and showed ulceration with exposed bone. She was diagnosed as bisphosphonate-associated osteonecrosis of the jaws, and zoledronate was withdrawn in January 2008. Conservative therapy was continued but the necrotic lesion caused pathological fracture and fistula. In February 2009, surgical intervention was performed for the improvement of her QOL.

Bisphosphonate-related osteonecrosis of the jaw in metastatic breast cancer patients: a review of 25 cases.

Intravenous bisphosphonates have been used in metastatic breast cancer patients to reduce pathologic bone fracture and bone pain. However, necrosis of the jaw has been reported in those who received intravenous bisphosphonates. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is caused by dental extraction, dental implant surgery, and denture wearing; however, it occurs spontaneously. The purpose of this study was to report BRONJ in metastatic breast cancer patients. Consecutive 25 female patients were referred from the Department of Oncology from 2008 to 2014 for jaw bone discomfort. Staging of breast cancer, history of bisphosphonate infusion, etiology of BRONJ, and treatment results were reviewed. Average age of the patients was 55.4 years old (38-74). Twelve maxillae and 16 mandibles were involved. Conservative treatments such as irrigation, antibiotic medication, analgesics, and oral gargle were applied for all patients for the initial treatment. Patients who had sequestrum underwent debridement and primary closure. The etiologies of BRONJ were dental extraction (19 cases), dental implant (2 cases), and endodontic treatment (1 case). However, three patients did not have any risk factors to cause BRONJ. Three patients died of progression of metastasis during follow-up periods. Surgical debridement was performed in 21 patients with success in 18 patients. Three patients showed recurred bone exposure and infection after operation. Prevention of the BRONJ is critical in metastatic breast cancer patients. Conservative treatment to reduce pain, discomfort, and infection is recommended for the initial therapy. However, if there is a sequestrum, surgical debridement and primary closure is the key to treat the BRONJ.

Metastatic Breast Cancer in Medication-Related Osteonecrosis Around Mandibular Implants.

Many authors have considered dental implants to be unrelated to increased risk of medication-related osteonecrosis of the jaw (MRONJ). Nevertheless, more recently, more cases of peri-implant MRONJ (PI-MRONJ) have been described, thus becoming a challenging health problem. Also, metastatic cancer deposits are not infrequently found at peri-implant sites and this may represent an additional complication for such treatments. We present the case of a breast cancer patient with PI-MRONJ, presenting a clinically and radiologically undetected metastasis within the necrotic bone, and highlight the necessity of an accurate histopathological analysis. A 66-year-old female patient, who had received intravenous bisphosphonates for bone breast cancer metastases, came to our attention for a non-implant surgery-triggered PI-MRONJ. After surgical resection of the necrotic bone, conventional and immunohistochemical examinations were performed, which showed breast cancer deposits within the necrotic bone. Cancer patients with metastatic disease, who are undergoing bisphosphonate treatment, may develop unusual complications, including MRONJ, which is a site at risk for hosting additional metastatic deposits that may be clinically and radiologically overlooked. Such risk is increased by previous or concomitant implant procedures. Consequently, clinicians should be prudent when performing implant surgery in cancer patients with advanced-stage disease and consider the possible occurrence of peri-implant metastases while planning adequate treatments in such patients.

Use of bone scintigraphy in the early diagnosis of bisphosphonate related osteonecrosis of the jaw. Case report and review of the literature.

The main aim of the present report is to show the potential utility of bone scintigraphy for the diagnosis of jaw osteonecrosis. We report the history of a 62-year-old woman underwent breast cancer surgery in 2010. Moreover, patient received postoperative radiotherapy and chemotherapy. Intravenous bisphosphonates were also added to the treatment strategy to reduce the risk of bone metastasis. However, a hypermetabolic focus on left hemimandible was evidenced with a bone scintigraphy during follow up. After a careful study, the diagnosis of Bisphosphonate Related Ostneonecrosis of the Jaw (BRONJ) was carried out. This case highlights that bone scintigraphy may be extremely helpful for the early detection of BRONJ in high risk patient. <bKey words:</bBone scintigraphy, mandibular osteonecrosis, bisphosphonates.

Bisphosphonates and jaw osteonecrosis in patients with advanced breast cancer.

In recent years, several cases of mandibular necrosis associated with long-term use of bisphosphonates have been reported. The estimated incidence varies from 1% to 4.6%. We conducted an observational study with the aim of determining the incidence of jaw osteonecrosis in advanced breast cancer patients with bone metastases under bisphosphonate treatment and to identify subjects at higher risk of developing this complication evaluating preclinical signs. We considered two groups of patients. All the patients complaining of odontostomatological symptoms underwent maxillary CT scan and maxillo-surgeon clinical examination. Asymptomatic patients were asked to perform a standard orthopantomography (OPT). From February 2005 to October 2005, we observed five patients with jaw bone necrosis (6%). Diagnosis was radiological and clinical. In two patients a confirmatory biopsy was performed. In the same time interval, OPTs were collected from 76 asymptomatic patients. Three OPTs revealed radiological features of suspicious mandibular necrosis. Maxillary CT scan confirmed the presence of an osteolityc area with signs of periosteal reaction. All the three patients were referred to maxillo-surgeon and two out of three patients underwent mandibular biopsy, but histopathological results were not conclusive. In our experience, the incidence of jaw bone necrosis in breast cancer patients seems to be higher than in other reports (6%). Radiological features of suspicious jaw necrosis were observed in three asymptomatic patients. We do not know how these findings should be considered. Anyway, standard OPT is a simple procedure, and may allow identification of periodontal conditions that in some way can predispose to the development of this uncommon event.

Spontaneous regeneration of the mandible following hemimandibulectomy for medication-related osteonecrosis of the jaw: A case report.

Medication-related osteonecrosis of the jaw decreases quality of life of patients with cancer. The debate about it continues regarding the risk factors, etiology, and treatment methods, and so on. Also, spontaneous regeneration of the mandible is clinically rare. A 67-year-old woman presented to the authors' department complaining of pain, swelling, and pus discharge from a fistula. She previously had breast cancer bone metastases and had received antiresorptive intravenous bisphosphonate. The patient was diagnosed with medication-related osteonecrosis of the jaw. She received conservative therapy with antibiotics and surgical therapy as sequestrectomy under general anesthesia; however, the lesion did not heal. Thirty months after the MRONJ diagnosis, when she was 70 years' old, she underwent a left hemimandibulectomy without reconstruction under general anesthesia. Spontaneous regeneration of the mandible was observed by follow-up imaging examinations. The patient has no current subjective or objective symptoms. This is the first case report of the spontaneous mandibular regeneration after surgery for medication-related osteonecrosis of the jaw. Additionally, this case was the oldest patient among the published mandibular regeneration cases.

Medication-related osteonecrosis of the jaw

There is no known prevention for bisphosphonate-associated osteonecrosis of the jaw. Avoiding the use of bisphosphonates is not a viable preventive strategy on a general-population basis because the medications are beneficial in the treatment and prevention of osteoporosis (including prevention of bony fractures) and treatment of bone cancers. Current recommendations are for a 2-month drug holiday prior to dental surgery for those who are at risk (intravenous drug therapy, greater than 4 years of by-mouth drug therapy, other factors that increase risk such as steroid therapy). It usually develops after dental treatments involving exposure of bone or trauma, but may arise spontaneously. Patients who develop MRONJ may experience prolonged healing, pain, swelling, infection and exposed bone after dental procedures, though some patients may have no signs/symptoms.

[A case of osteonecrosis of the lower jaw due to bisphosphonates in a breast cancer patient with bone metastasis].

Recently, osteonecrosis of the jaw (ONJ) with bisphosphonates is frequently reported. ONJ due to bisphosphonate is an adverse event in the treatment of breast cancer with bone metastasis. We report a case of ONJ due to bisphosphonates. A 66-year-old woman was admitted to our hospital due to right advanced breast cancer with bone metastasis. She received neo-adjuvant chemotherapy consisting of paclitaxel 70 mg/m2, qw, trastuzumab 2 mg/m2, qw. After chemotherapy, we performed modified mastectomy for local control. Postoperative adjuvant chemotherapy was added with bisphosphonate for bone metastasis of breast cancer. After bisphosphonate was used 14 times, she had a pain and pus-discharge in her lower jaw. The dentists' diagnosis was ONJ. We treated her with antibiotics and local minor curettage. The inflammatory symptoms almost disappeared. In this case, the administration of bisphosphonates was thought to be a major risk factor for ONJ. We think that special precautions for ONJ should be taken in patients administered bisphosphonates for bone metastasis of breast cancer.

Avascular mandibular osteonecrosis in association with bisphosphonate therapy: a report on four patients.

Over the past three years, several reports have been published on jaw osteonecrosis possibly being associated with the administration of bisphosphonates. Bisphosphonates are highly active inhibitors of osteoclasts. These drugs are used for the treatment of multiple myeloma, bone resorption in the case of metastatic malignant diseases, tumor-associated hypercalcaemia, and in the treatment of osteoporosis. Due to the importance of this presumed side-effect of bisphosphonates for the dentist and the maxillofacial surgeon, we report four cases. Four patients (two women and two men aged 56, 62, 67 and 75 years, respectively) were diagnosed with osteonecrosis of the mandible. These osteonecroses did not react adequately to local treatment and systemic therapy with antibiotics. One patient suffered from non-Hodgkin's lymphoma, one from breast cancer, one from prostate cancer and one from sarcoidosis. Besides cytostatic chemotherapies, all patients received bisphosphonates over an extended period. Bisphosphonates are considered an established standard in the treatment of multiple myeloma and bone metastases. Over the past few years, a rapidly increasing number of reports have been published describing patients with a history of bisphosphonate therapy in whom therapy-resistant osteonecrosis of jaw bones occurred either after dental extractions or spontaneously. Since then, bisphosphonate therapy has come under scrutiny as a cause of osteonecrosis. However, the multiplicity of drugs prescribed for the treatment of cancer requires caution when determining a cause-and-action effect. Since patients with malignant diseases receive cytostatic therapy and a range of other drugs, including bisphosphonates, enhancement of the side-effects may be presumed. The case report of an osteonecrosis of the jaw following multi-drug therapy for sarcoidosis adds a further and non-cancerous condition to the newly described entity of bisphosphonate-associated jaw necrosis. The probable association of the therapeutic use of bisphosphonates and the development of jaw necrosis has to be studied in further investigations. Patients who will undergo bisphosphonate therapy should receive a careful dental check-up prior to drug application. Patients receiving bisphosphonates should be followed up carefully to avoid the occurrence of extended osteonecrotic lesions. Moreover, established jaw lesions must be diagnosed precisely in order to exclude metastatic disease.

Descending necrotizing mediastinitis after sequestrectomy in a patient with bisphosphonate-induced osteonecrosis of the jaw: A case report.

An 83-year-old woman underwent mastectomy for breast cancer of the right breast in 2008. In addition to hormone therapy and irradiation, zoledronate was started for bone metastasis 6 months postoperatively. Five years after the operation, the patient developed osteonecrosis of the jaw, and underwent sequestrectomy because of uncontrollable pain in the mandible. The patient visited our hospital for a 1-week history of fever and right facial swelling with pain, and was diagnosed with right mandibular cellulitis. Despite antibiotic therapy, the patient fell into shock. Follow-up computed tomography showed gas formation extending down to the posterior mediastinum, which was compatible with descending necrotizing mediastinitis (DNM). The patient succumbed to septicemia on the third hospital day. The mortality rate of DNM greatly increases in patients with advanced cancer because clinicians cannot perform radical treatment due to the impaired general condition and limited life expectancy. DNM advances by the hour; therefore, repeated computed tomography is essential when antibiotic therapy does not improve the patient's condition. Attention must be paid to detect signs of DNM in such patients. To the best of our knowledge, this is the first report in English regarding DNM caused by bisphosphonate-induced osteonecrosis of the jaw.

Prevalence of bisphosphonate-associated osteonecrosis of the jaw after intravenous zoledronate infusions in patients with early breast cancer.

The definite incidence rate of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is still unknown. The aim of this study was to investigate prevalence of BRONJ in a group of breast cancer patients applying the classification of the Association of Oral and Maxillofacial Surgeons 2009. Between 2000 and 2008, 63 premenopausal early breast cancer patients who were free of metastases were treated with 4 mg zoledronic acid every 6 months over 3 years as participants of a multicenter, randomized, controlled, adjuvant breast cancer medication trial. Patients were not informed about the risk of jaw necrosis. None reported tooth or jaw complaints during the breast cancer follow-up examinations. In 2010, 48 patients of this cohort were investigated concerning BRONJ by clinical and radiological examinations. No advanced stages (AAOMS 2009)were detected. However, five patients (10.4%) presented purulent (2) and nonpurulent (3) fistulas and radiological signs correlating to BRONJ stage 0. Although no case of advanced BRONJ was detected, the study revealed a high prevalence of BRONJ stage 0. This supports the need for tight cooperation between dentists and medical specialists prescribing bisphosphonates including dental pre-therapeutic and follow-up examinations. Adaption of the BRONJ classification taking account to bone exposure via fistulas is recommended. BRONJ is said to be a complication linked to high-dosage bisphosphonate therapy. The study demonstrates that even after application of zoledronate in a low-dose protocol, early BRONJ occurred. Radiological signs solely are not sufficient to confirm BRONJ; clinical signs are mandatory.

Medication-related osteonecrosis (MRONJ) of the mandible and maxilla.

In 2003, Marx reported the first case of osteonecrosis of the jaw in 36 cases related to zoledronic acid or pamidronate. Painful bone exposure in the mandible or maxilla unresponsive to medical or surgical management was observed. In 2014, the American Association of Oral and Maxillofacial Surgeons proposed the term 'medication-related osteonecrosis of the jaw' (MRONJ). However, a non-exposed variant may also occur. MRONJ can lead to debilitating clinical sequelae with limited treatment options. We present the case of a 73-year-old woman with metastatic breast cancer and MRONJ of her mandible and maxilla following treatment with intravenous zoledronic acid and denosumab. Six months following dental extractions, she was referred to the Department of Oral and Maxillofacial Surgery for assessment of extensive necrosis of her maxilla and mandible. Extraoral draining sinuses were observed. A CT mandible showed cortical destruction with an ill-defined mixed sclerotic-lucent pattern in keeping with osteonecrosis. Due to her metastatic breast cancer, the extent of her necrosis and poor performance status, free flap reconstruction of her mandible was ruled out. She was treated conservatively.

Osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) in an osteoporotic patient chronically treated with bisphosphonates.

The aim of the study is to report the rare association of two complications of long-term treatment of osteoporosis with bisphosphonates in the same Caucasian elderly patient. A female patient of Italian descent, age 87 years, consulted in February 2013. She had a history of osteoporosis and had taken alendronate weekly for 7 years (1999-2006). Due to low back pain, an orthopedist had indicated i.v. zoledronic acid, 5 mg/year for 3 years (2006-2008). She received occasional supplements of ergocalciferol. In 2009, she suffered a fall and sustained a subtrochanteric fracture of the left femur. She was operated on and recovered uneventfully. In 2012, she consulted a dentist due to loose teeth. She underwent the removal of a molar and was given a denture. She had discomfort when using the prosthesis, and developed an ulceration in the gum of the mandible, which exposed the bone and did not heal for 2 months. After radiologic studies, the diagnosis was osteonecrosis of the jaw. She improved after surgical debridement and local and systemic antibiotics. In early 2013, laboratory tests were normal except for a slight elevation of serum PTH and CTX-I. Calcitriol 0.25 mcg/day was prescribed; after 3 months serum calcium, phosphate, PTH, and CTX-I showed no variation. Two years later, she experienced acute low back pain after a fall; MRI showed recent crushing of D12, and chronic deformities of D11 and L1. Bone densitometry of her right hip (DXA) showed a T-score of -2.3 at the femoral neck. An X-ray film of the right femur showed diffuse thickening of both cortices. She was treated with nasal calcitonin and analgesics. After the back pain subsided, she was treated with s.c. denosumab. Although the association of ONJ and AFF was known in cancer patients treated with high doses of bisphosphonates, it is very rare in patients with osteoporosis receiving these drugs at usual doses. Only three cases have been reported, all in oriental women. This appears to be the first reported case in a Caucasian woman.

[Two bedridden patients with bone metastases from breast cancer effectively treated with pamidronate therapy].

Case 1: A 43-year-old woman underwent mastectomy because of locally advanced breast cancer with multiple bone metastases. She was treated with CMF therapy but developed a compression fracture of a thoracic vertebra after 10 months and received pamidronate therapy. Pamidronate administration relived her back pain after 2 months and she was able to walk again after 3 months. However, she developed a resistance to the treatment, and then refused another treatment. She was found to have hypercalcemia 6 months later and received pamidronate again, but died 9 months after the treatment. Case 2: A 52-year-old woman underwent mastectomy because of breast cancer (T2) and was diagnosed as having multiple bone metastases 24 months after the operation. She could not turn over in bed due to progressing bone pain and received pamidronate therapy with CMF therapy at home 23 months after the diagnosis. After 2 months, pamidronate administration relieved her bone pain and she was free of pain after 4 months. After 5 months, X-rays revealed that lytic lesions showed sclerosis, and the pamidronate therapy was assessed as producing a PR. Pamidronate therapy improved her quality of life and activities of daily living, and she continues to receive it this time as an outpatient. Pamidronate therapy is promising as an effective treatment for bedridden patients with bone metastasis from breast cancer.

Metastatic breast carcinoma in the mandible presenting as a periodontal abscess: a case report.

Tumors can metastasize to the oral cavity and affect the jaws, soft tissue and salivary glands. Oral cavity metastases are considered rare and represent approximately 1% of all oral malignancies. Because of their rarity and atypical clinical and radiographic appearance, metastatic lesions are considered a diagnostic challenge. The purpose of this report is to present a rare case of a metastatic breast carcinoma mimicking a periodontal abscess in the mandible. A 55-year-old Caucasian woman was referred to our clinic for evaluation of bisphosphonate-induced jaw osteonecrosis. She had undergone modified radical mastectomy with axillary lymph node dissection for invasive ductal carcinoma of the left breast. Her clinical examination showed diffuse swelling and a periodontal pocket of 6 mm exhibiting suppuration in the posterior right mandible. Moreover, paresthesia of the lower right lip and chin was noted. There were no significant radiographic findings other than alveolar bone loss due to her periodontal disease. Although the lesion resembled a periodontal abscess, metastatic carcinoma of the breast was suspected on the basis of the patient's medical history. The area was biopsied, and histological analysis confirmed the final diagnosis of metastatic breast carcinoma. The general dentist or dental specialist should maintain a high level of suspicion while evaluating patients with a history of cancer. Paresthesias of the lower lip and the chin should be considered ominous signs of metastatic disease. This case highlights the importance of the value of a detailed medical history and thorough clinical examination for the early detection of metastatic tumors in the oral cavity.

18F-Fluoride PET/CT Imaging of Medication-Related Osteonecrosis of the Jaw in Conservative Treatment-A Case Report.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect in antiresorptive treatment. Treatment of MRONJ is considered primarily conservative with oral mouth rinses and antibiotics but may demand surgery, depending on the complaints and general condition of the patient, the extent of the necrosis, and the overall prognosis with respect to the underlying disease. A 77 year old female patient with invasive ductal breast cancer and bone metastases was treated with intravenous bisphosphonate (BP) zoledronic acid. During therapy, she developed MRONJ in the mandible with severe pain. Clinical examination revealed confluent exposed bone of the lower left jaw and a fistula at the right molar region. The panoramic radiograph revealed a mandibular osseous involvement with diffuse radiopaque areas between radiolucent areas. For preoperative planning, <sup18</supF-fluoride positron emission tomography/computed tomography (PET/CT) of the jaw was performed, showing substantially increased <sup18</supF-fluoride uptake in regions 38 to 47 of the mandible with a focal gap in region 36 (area of clinically exposed bone). CT revealed medullary sclerosis and cortical thickening with confluent periosteal reaction and focal cortical erosion in the regions 37 to 42, whereas the regions 43 to 47 were only subtly sclerotic without cortical thickening. After systemic antibiotic therapy with sultamicillin following significant symptom and pain relief, <sup18</supF-fluoride PET/CT imaging was performed again after 5 months. No changes in either CT and PET were observed in regions 38 to 42, whereas the bony sclerosis was slightly increased in regions 43 to 47 with a slight reduction of <sup18</supF-fluoride uptake. <sup18</supF-fluoride PET/CT showed no significant changes assessing the extent of MRONJ prior and after systemic antibiotic therapy, providing no evidence that conservative treatment reduced the extent of the MRONJ-affected jawbone. The additional information of <sup18</supF-fluoride PET enables to identify the true extent of MRONJ which may be underestimated by CT imaging alone. Patients with MRONJ undergoing conservative treatment could benefit because additional imaging may be avoided as the pre-therapeutic <sup18</supF-fluoride PET/CT delivers all information needed for further treatment. Our findings support the recommendation of a surgical approach as long-term antibiotics cannot downsize the extent of MRONJ.

Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307).

Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis. SWOG 0307 randomized women with stage I-III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided. Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ. ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this. NCT00127205 REGISTRATION DATE: July 2005.

Synchronous antiresorptive osteonecrosis of the jaws and breast cancer metastasis.

Antiresorptive osteonecrosis of the jaws (ARONJ) is a significant and poorly understood oral complication that may affect patients receiving antiresorptive agents, such as intravenous bisphosphonate therapy. There are scarce reports of the coexistence of ARONJ and metastasis at the same jaw site in the English-language literature. In the present case, a 60-year-old white woman was referred for the evaluation of a nonhealing extraction socket. The patient was undergoing treatment with intravenous zoledronic acid to metastatic breast cancer in bone, and her medical history and clinical characteristics led to the diagnosis of ARONJ. Nevertheless, histologic analysis showed a fragment of necrotic bone and bacterial colonies associated with malignant epithelial cells that were confirmed to be metastatic breast adenocarcinoma. This case showed that jaw metastasis can occur at the same time and site of ARONJ, making diagnosis and management challenging.

Metastatic breast cancer to bilateral mandibular ramus regions.

Metastatic carcinomas to the jaw bones are uncommon and comprise to about 1% of all malignant oral neoplasms. The purpose of this report is to present a rare case of metastatic breast carcinoma to bilateral mandibular ramus regions. The present case report is about a 40-year-old female patient with the complaints of a paresthesia in the right mandibular area of the last month duration. She was referred to our department by her oncologist with the differential diagnosis of osteonecrosis or metastasis. She had undergone modified radical mastectomy for invasive lobular carcinoma of the left breast. Oral cavity examination did not reveal the existence of any ulcer or fistula. Panoramic, cone-beam computed tomography (CBCT), and positron-emission tomography (PET) were used for diagnosing the lesions. In panoramic radiography and CBCT images, there were lytic lesions on the both of right and left coronoid, condyle, and ramus of the mandible. PET results showed us fluoro-2-deoxy-D-glucose uptake in the mandible and vertebrae. On the basis of the patient's medical history and paresthesia of the lower lip and chin, the metastatic disease was highly suspected. The patient was referred to her oncologist for further treatment since it was not amenable to the surgical management. The general dentist or dental specialist should maintain a high level of suspicion while evaluating patients with a history of cancer. Paresthesias of the lower lip and the chin should be considered ominous signs of metastatic disease.

Metastatic breast cancer

Bone metastases. The bones are a very common site of metastatic disease from breast cancer, and bone metastases can cause severe pain, hypercalcemia and pathologic fracture. Radiotherapy is indicated to prevent pathologic fracture; it is also part of postoperative treatment following repair of a pathologic fracture. Strontium 89, a radiopharmaceutical which is injected into the bloodstream, is under investigation for the treatment of bone metastases from breast cancer; there is evidence that it can relieve pain for up to three months after its administration. It is unknown whether or not it can prevent pathologic fracture, but it should be considered in patients who have three or more sites of painful bone metastases who cannot be treated with external-beam radiotherapy. In some patients with estrogen-receptor-positive breast carcinoma metastatic to the bone only, external-beam radiotherapy followed by tamoxifen or another anti-estrogen may be sufficient to control disease, at least

Hormonal therapy in the treatment of mandibular metastasis of breast carcinoma. Report of a case.

We present the clinical history of a 39-year-old woman, who has survived for over 10 years with metastatic breast cancer. After combined surgery and radiotherapy of the primary tumor and the regional lymph nodes, all bone metastases gradually disappeared under chemotherapy and continuing hormonal treatment. This complete remission included a large mandibular metastasis, which had received additional radiotherapy of 21 Gy. Spontaneous reossification was observed in this location.

Bisphosphonate

Bisphosphonates, when administered intravenously for the treatment of cancer, have been associated with osteonecrosis of the jaw (ONJ), with the mandible twice as frequently affected as the maxilla and most cases occurring following high-dose intravenous administration used for some cancer patients. Some 60% of cases are preceded by a dental surgical procedure (that involves the bone), and it has been suggested that bisphosphonate treatment should be postponed until after any dental work to eliminate potential sites of infection (the use of antibiotics may otherwise be indicated prior to any surgery). A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes.

Risk factors include: Dental treatment (e.g. dentoalveolar surgery/procedure that impacts bone) – it is possible for MRONJ to occur spontaneously without any recent invasive dental treatment Duration of bisphosphonate drug therapy – increased risk with increased cumulative dose of drug Other concurrent medication – use of chronic systemic glucocorticoid increases risk when they are taken in combination with anti-resorptive drugs Dental implants Drug holidays – no evidence to support a reduction in MRONJ risk if patients stop taking bisphosphonates temporarily/permanently, as drugs can persist in skeletal tissues for many years Treatment in the past with anti-resorptive/anti-angiogenic drugs Patient being treated for cancer – higher risk Patients being treated for osteoporosis/non-malignant bone diseases (e.g. Paget's disease) – lower risk Research findings

Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy.

The current report presented 17 patients with cancer with bone metastases and 1 patient with osteopenia who received treatment with bisphosphonates and who subsequently developed osteonecrosis of the mandible and/or maxilla. The authors reviewed information on 18 patients who were referred to oral medicine or oral surgery specialists for evaluation and treatment of mandibular and/or maxillary bone necrosis from June 2002 to September 2004. To be included in the current review, patients must have been treated with either pamidronate or zoledronic acid to control or prevent metastatic disease, or with alendronate for osteoporosis. All patients with cancer had received chemotherapy while receiving bisphosphonate management. The 17 patients with cancer were receiving active medical care for a malignancy. Cancer treatment included a variety of chemotherapeutic agents. They presented with metastatic disease to bone and were treated intravenously with the bisphosphonates pamidronate or zoledronic acid for a mean time of 25 months (range, 4-41 mos). There were 14 females and 4 males with a mean age of 62 years (range, 37-74 yrs). Malignancies included breast carcinoma (n = 10), multiple myeloma (n = 3), prostate carcinoma (n = 1), ovarian carcinoma (n = 1), prostate carcinoma/lymphoma (n = 1), and breast/ovarian carcinoma (n = 1). One female patient with osteopenia received alendronate. The most common clinical osteonecrosis presentations included infection and necrotic bone in the mandible. Associated events included dental extractions, infection, and trauma. Two patients appeared to develop disease spontaneously, without any clinical or radiographic evidence of local pathology. Despite surgical intervention, antibiotic therapy, hyperbaric oxygen therapy, and topical use of chemotherapeutic mouth rinses, most of the lesions did not respond well to therapy. Discontinuation of bisphosphonate therapy did not assure healing. However, 1 patient with cancer healed after discontinuation of bisphosphonate therapy for 4 months. The findings in the patient population combined with recent literature reports suggested that bisphosphonates may contribute to the pathogenesis of the oral lesions. The risk factors and precise mechanism involved in the formation of the osteonecrosis are not known. This condition represents a new oral complication in patients with cancer and can be termed bisphosphonate-associated osteonecrosis. Lesions in patients with osteoporosis are worrisome and need to be further evaluated.

[Drug-induced osteonecrosis of the jaw - not just bisphosphonates].

Metastatic bone disease and osteoporosis have a large impact on quality of life and are associated with the development of skeletal-related events (SREs), such as fractures and spinal cord compression. Pharmacologic managing of metastatic bone disease and osteoporosis typically involves antiresorptive agents such as bisphosphonates and RANKL inhibitors. Undesired adverse effects resulting from the use of these drugs include osteonecrosis of the jaw (ONJ). Dentoalveolar surgery, particularly tooth extraction, appears to increase the risk of ONJ. However, spontaneous events were also documented. Therefore, it is of upmost importance for the general practitioner to have updated knowledge in order to prevent and early diagnose ONJ. We present a case of a metastatic breast cancer patient who spontaneously developed ONJ following the use of Denosumab, a monoclonal RANKL antibody.

Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment.

Bisphosphonates inhibit bone resorption and thus bone renewal by suppressing the recruitment and activity of osteoclasts thus shortening their life span. Recently three bisphosphonates, Pamidronate (Aredia; Novartis Pharmaceuticals, East Haven, NJ), Zoledronate (Zometa; Novartis Pharmaceuticals), and Alendronate (Fosamax; Merck Co, West Point, VA) have been linked to painful refractory bone exposures in the jaws. One hundred-nineteen total cases of bisphosphonate-related bone exposure were reviewed. Thirty-two of 119 patients (26%) received Aredia, 48 (40.3%) received Zometa, 36 (30.2%) received Aredia later changed to Zometa, and 3 (2.5%) received Fosamax. The mean induction time for clinical bone exposure and symptoms was 14.3 months for those who received Aredia, 12.1 months for those who received both, 9.4 months for those who received Zometa, and 3 years for those who received Fosamax. Sixty-two (52.1%) were treated for multiple myeloma, 50 (42%) for metastatic breast cancer, 4 (3.4%) for metastatic prostate cancer and 3 (2.5%) for osteoporosis. Presenting findings in addition to exposed bone were 37 (31.1%) asymptomatic, 82 (68.9%) with pain, 28 (23.5%) mobile teeth, and 21 (17.6%) with nonhealing fistulas. Eighty-one (68.1%) bone exposures occurred in the mandible alone, 33 (27.7%) in the maxilla, and 5 (4.2%) occurred in both jaws. Medical comorbidities included the malignancy itself 97.5%, previous and/or maintenance chemotherapy 97.5%, Dexamethasone 59.7%. Dental comorbidities included the presence of periodontitis 84%, dental caries 28.6%, abscessed teeth 13.4% root canal treatments 10.9%, and the presence of mandibular tori 9.2%. The precipitating event that produced the bone exposures were spontaneous 25.2%, tooth removals 37.8%, advanced periodontitis 28.6%, periodontal surgery 11.2%, dental implants 3.4% and root canal surgery 0.8%. Complete prevention of this complication in not currently possible. However, pre-therapy dental care reduces this incidence, and non-surgical dental procedures can prevent new cases. For those who present with painful exposed bone, effective control to a pain free state without resolution of the exposed bone is 90.1% effective using a regimen of antibiotics along with 0.12% chlorohexidine antiseptic mouth.

[Clinical features of osteonecrosis of jaws after bisphosphonates therapy for bone metastasis of breast cancer].

To understand the clinical features of osteonecrosis of the jaw after bisphosphonates use for therapy of breast cancer patients with bone metastasis. The cases diagnosed as bisphosphonates-related osteonecrosis of the jaws (BRONJ) were retrospectively analyzed from January 2011 to August 2015 in the Peking University School and Hospital of Stomatology, and those breast cancer patients with bone metastasis were selected. The clinical symptoms, imaging characteristics and treatment results were summarized. A total of 14 cases of breast cancer patients with bone metastasis were selected, with an average age of 60.21 years. The average time of suffering from breast cancer was 9.77 years, and the average time of bone metastasis and bisphosphonates drugs use was 5.67 and 3.29 years individually. There was no patient with systemic application history of hormone therapy, and no history of diabetes. There were 9 patients with tooth extractions history, and the mean time of bone necrosis symptoms was 8.58 months. There were 10 cases with bone necrosis occurring on mandible, 3 cases on maxilla, and one case with both upper and lower jaws involved. Among the 10 patients with surgical treatment, there were 3 cases cured, and 6 cases improved. However, the clinical symptoms of 2 cases with conservative treatment were significantly aggravated. The medication time between the bisphosphonates use beginning and the occurrence of BRONJ is relatively long. The history of diabetes and long-time hormone use did not exist in this group. Tooth extraction itself does not determine the severity of BRONJ. Mandible is the most common site involved by BRONJ. Surgical treatment can alleviate the clinical symptoms of BRONJ with breast cancer to some extent.

Mandibular osteonecrosis due to bisphosphonate use.

Due to their efficient osteoclastic inhibitor effect in bone metabolism and antiangiogenic activity, bisphosphonates are widely used in many cancer diseases particularly in prostate cancers with bone metastasis, lung cancer, breast cancer and multiple myeloma, as well as in systemic diseases such as osteoporosis, osteopenia, Paget disease and osteogenesis imperfect for the last 13 years. Prostate cancer is a common cancer in males and it is the leading cause of bone metastasis. Mandibular metastasis is rarely encountered during the course of prostate cancer. Mandibular osteonecrosis as well has begun to be observed along with the availability of more efficient and stronger formulations developed following the use of bisphosphonates. Zolendronic acid, which has been used also by our patient, has widely come into practice as a 3(rd) generation bisphosphonate. Because of prostate cancer and widespread bone metastases, our patient has been receiving zolendronic acid with maximum androgen blockage for 4 years. Tomography of the patient, who has undergone intensive treatment because of submandibular abscess, demonstrated extensive osteonecrosis in the fovea sublingual region of the mandible corpus. In large series, although, mandibular osteonecrosis was widely seen due to bisphosphonate use for the metastases of lung and breast cancers, this rate was between 9.6% and 11% for prostate cancer within the series. Although our patient had no mandibular metastasis before, mandibular necrosis was observed due to long-term bisphosphonate use. We are going to present our patient who had this rare complication with his clinical picture.

[Natural history and development of bone metastasis. Apropos of 429 cases].

The records of 429 patients seen at the Centre Alexis-Vautrin in 1979 and 1980 with bony metastases were retrospectively reviewed to assess their natural history and survival. Breast was the location of primary lesion in 140 patients (32.6%), lung in 95 patients (22.1%) and prostate in 33 patients (7.7%). The primary tumor was of unknown origin in 42 cases (10.9%). The median survival from time of diagnosis was 5 months. Two and 5-year survival rates were 17.5 and 5.1% respectively. According to the nature of the primary tumor, 2 and 5-year survival periods for bony metastases were 36.4 and 7.9% in breast cancer, 33.3 and 15.2% in prostatic cancer, 4.3 and 2.1% in metastases of unknown origin, 2.1 and 0% in pulmonary carcinoma. Multivariate analysis revealed four factors to be of prognostic significance for survival: the nature of the primary tumor, the absence of local relapse, the disease-free interval and the absence of metastases in other sites. Patients with hormone-sensitive lesions or slowly-growing tumors had a better prognosis.

Bilateral femoral head osteonecrosis in a patient with metastatic breast cancer receiving long-term zoledronic acid treatment: A case report.

Bone-modifying agents (BMAs), including bisphosphonate and anti-receptor activator of NF-κB ligand (RANKL) antibodies, are effective in treating bone metastases. The present study is a case report on the efficacy and side effects of long-term treatment with zoledronic acid, a BMA, in a 57-year-old woman. The patient was diagnosed with concurrent stage IV triple-negative breast cancer and stage II colon cancer. The patient experienced complete remission of both these cancers following chemotherapy, zoledronic acid treatment and irradiation for breast cancer and surgery for colon cancer. The patient received long-term zoledronic acid treatment and has survived >7 years after her initial diagnosis. The patient subsequently reported bilateral hip pain that was diagnosed as osteonecrosis of the femoral head, after the presence of bone metastases was ruled out using magnetic resonance imaging. The patient underwent bilateral artificial hip joint replacements. After orthopedic surgery, the multiple distant metastases, including a brain metastasis, remained in complete remission. It is well established that BMAs, such as zoledronic acid, increase the risk of osteonecrosis of the jaw, but it is not well understood if they can increase this risk in other anatomical locations. The findings of the present case study suggested that while long-term use of BMAs may be effective in managing bone metastases, it may increase the risk of osteonecrosis in anatomical locations other than the jaw.


The endoscopic appearance of trachealized esophagus is very typical of eosinophilic esophagitis, which presents with dysphagia and repeated food impactions.

What disease would we suspect in a young patient with a frequent history of dysphagia to solids and liquids with repeated food impactions, without symptoms of heartburn and in whom oral endoscopy shows multiple concentric esophageal rings with normal mucosa (trachealized appearance)?

Esophagitis

Some lifestyle indicators for this disease include stress, unhealthy eating, smoking, drinking, family history, allergies, and immunodeficiency. Types Reflux esophagitis Although it usually assumed that inflammation from acid reflux is caused by the irritant action on the mucosa by hydrochloric acid, one study suggests that the pathogenesis of reflux esophagitis may be cytokine-mediated. Infectious esophagitis Esophagitis happens due to a viral, fungal, parasitic or bacterial infection. More likely to happen to people who have an immunodeficiency. Types include: Fungal Candida (Esophageal candidiasis) Viral Herpes simplex (Herpes esophagitis) Cytomegalovirus Drug-induced esophagitis Damage to the esophagus due to medications. If the esophagus is not coated or if the medicine is not taken with enough liquid, it can damage the tissues. Eosinophilic esophagitis

Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features.

Eosinophilic esophagitis is an inflammatory condition in which there is dense eosinophilic infiltration of the surface lining of the esophagus. Reports of eosinophilic esophagitis pertain almost exclusively to pediatric populations. However, eosinophilic esophagitis is emerging as a clinical affliction of adults. This report describes the clinical and endoscopic findings of eosinophilic esophagitis in the largest cohort of adult patients reported to date. Twenty-nine patients (21 men, 8 women; mean age 35 years) with documented eosinophilic esophagitis (>/=15 eosinophils per high-power field in biopsy specimens) and a significant history of chronic dysphagia for solid food (24 patients) were evaluated clinically and endoscopically during a 3-year period (1999-2002). Fourteen patients (48%) had a history of asthma, environmental allergy, or atopy. In a subset of 15 patients, the diagnostic accuracy of endoscopy was compared with that of barium contrast esophagography. Twenty-seven patients (93%) had abnormal endoscopic findings; 25 (86%) had unique esophageal structural changes, associated with a preserved mucosal surface, that were highly atypical for acid reflux injury. Structural alterations seen in adult patients with eosinophilic esophagitis may occur in combination or as a primary characteristic, e.g., uniform small-caliber esophagus, single or multiple corrugations (rings), proximal esophageal stenosis, or 1 to 2 mm whitish vesicles scattered over the mucosal surface. Barium contrast radiography combined with swallow of a barium-coated marshmallow identified 10 (67%) of the primary features observed endoscopically in 15 patients. However, radiography failed to detect other features noted at endoscopy (e.g., only 3/6 patients with proximal stenosis, 5/9 patients with concentric rings and none of 4 patients with small caliber esophagus). Eight of the 29 patients (20%) had a history of chronic heartburn. Twelve patients had been treated with a proton pump inhibitor and only 3 reported some improvement in the severity of dysphagia. Relatively young age, a history of chronic dysphagia for solid food, and endoscopic detection of unique structural alterations atypical for GERD in an adult patient should prompt a suspicion of EE and subsequent biopsy confirmation. Acid reflux appears to have a secondary role in eosinophilic esophagitis. In an uncontrolled comparison, endoscopy was superior to barium contrast radiography for the diagnosis of eosinophilic esophagitis. The incidence of eosinophilic esophagitis in adults appears to be increasing.

Heartburn

Esophagus GERD (most common cause of heartburn) occurs when acid refluxes from the stomach and inflames the esophagus. Esophageal spasms typically occur after eating or drinking and may be combined with difficulty swallowing. Esophageal strictures Esophageal cancers Esophagitis GERD Eosinophilic esophagitis - a disease commonly associated with other atopic diseases such as asthma, food allergies, seasonal allergies, and atopic skin disease Mallory-Weis tears - tears of the superficial mucosa of the esophagus that are subsequently exposed to gastric acid commonly due to vomiting and/or retching Chemical esophagitis - related to the intake of caustic substances, excessive amounts of hot liquids, alcohol, or tobacco smoke Infections may explain heartburn symptoms. These especially include CMV and certain fungal infections, most common in immunocompromised persons Stomach

Esophagitis -- Evaluation

The endoscopic appearance of the mucosal lesions can help with diagnosis. In patients with suspected eosinophilic esophagitis, endoscopy may reveal white exudates or papules, red furrows, corrugated concentric rings, and strictures; but endoscopy may be normal in up to 10% of patients. Endoscopic signs of candidiasis are small, diffuse, linear, yellow-white "cheese-like" plaques adherent to the mucosa. CMV esophagitis is characterized by several large, shallow, superficial ulcerations. HSV esophagitis results in multiple small, deep ulcerations.

Infectious Esophagitis in Romanian Children: From Etiology and Risk Factors to Clinical Characteristics and Endoscopic Features.

The aim of this study is to provide information about prevalence, etiology, risk factors, clinical characteristics and endoscopic features of various types of infectious esophagitis in children. We performed a total of 520 upper gastrointestinal tract endoscopies in Pediatric Clinic II, Emergency Hospital for Children, Cluj-Napoca. Indications for endoscopy in our cohort were gastrointestinal tract symptoms such as dysphagia, heartburn, or appetite loss. The prevalence of infectious esophagitis in the study population was 2.11% (11 patients). Candida albicans (<iC. albicans</i) was the most frequent cause. Our data illustrates that herpes simplex virus (HSV)-induced esophagitis is common in immunocompromised patients and should be systematically suspected in cases of severe dysphagia, heartburn, or hematemesis. In the present study, all cytomegalovirus (CMV) esophagitis patients were immunocompromised. Immunodeficiency (81.8%) and prolonged antibiotic therapy with broad-spectrum antibiotics were by far the most important risk factors involved in the pathogenicity of the disease. Dysphagia, appetite loss, heartburn, epigastralgia, and hematemesis were the main clinical manifestations. Infectious esophagitis was associated with significant mortality. In four patients, endoscopy during life showed signs of infectious esophagitis; however, the precise etiology was only established post-mortem, in the pathological anatomy laboratory department. A risk factor involved in pathogenesis of post-mortem diagnosed infectious esophagitis is the DiGeorge syndrome for CMV and HSV patients. The study illustrates that infectious esophagitis should be considered in immunocompromised infants with prolonged antibiotic therapy with broad-spectrum antibiotics.

Esophagus

Inflammation Inflammation of the esophagus is known as esophagitis. Reflux of gastric acids from the stomach, infection, substances ingested (for example, corrosives), some medications (such as bisphosphonates), and food allergies can all lead to esophagitis. Esophageal candidiasis is an infection of the yeast Candida albicans that may occur when a person is immunocompromised. the causes of some forms of esophagitis, such as eosinophilic esophagitis, are not well-characterized, but may include Th2-mediated atopies or genetic factors. There appear to be correlations between eosinophilic esophagitis, asthma (itself with an eosinophilic component), eczema, and allergic rhinitis, though it is not clear whether these conditions contribute to eosinophilic esophagitis or vice versa, or if they are symptoms of mutual underlying factors. Esophagitis can cause painful swallowing and is usually treated by managing the cause of the esophagitis - such as managing reflux or treating infection.

[Eosinophilic esophagitis : a cause of dysphagia].

Eosinophilic esophagitis (EE) is a chronic, interleukin-5-driven inflammatory disease of the esophagus, causing dysphagia and esophageal food impactions. We analyzed the diagnostic results of patients with suspected or proven EE and in this article discuss the relevant aspects of this disease. Sixteen patients suffering from dysphagia or recurrent esophageal food impactions underwent rigid esophagoscopy to exclude EE. In six patients, 24-h pH monitoring was performed to exclude laryngopharyngeal reflux (LPR). EE was diagnosed in only one patient, a boy with a history of peanut allergy and recurrent esophageal food impactions. In six patients, histological examination of biopsies revealed reflux esophagitis indicating gastroesophageal reflux disease (GERD). Using 24-h pH monitoring, LPR was diagnosed in four of six patients. Even in patients presenting with typical symptoms of EE, this disease is rarely found. However, in male patients with asthma, allergies, or a history of recurrent esophageal food impactions, EE must be excluded. The most important differential diagnoses of EE are GERD and LPR.

Eosinophilic esophagitis in adults, an emerging cause of dysphagia. Description of 9 cases.

Eosinophilic esophagitis is a rare condition mainly affecting children, although the number of cases reported in adults is on the increase. It is characterized by intense infiltration of eosinophilic leukocytes in the esophageal mucosa, without involvement of other sections of the alimentary canal. Over the past year, following the performance of endoscopies and biopsies, our service identified nine patients who were diagnosed with suffering from this disorder. Each patient sought medical help for episodes of long-term, self-limited dysphagia or food impaction in the alimentary canal. Endoscopy revealed esophageal stenosis in the form of simultaneous contraction rings or regular stenosis. In six cases, the manometric study showed a nonspecific motor disorder of severe intensity affecting the esophageal body, and another patient had a disorder characterized by the presence of simultaneous waves and secondary peristaltic waves in the three thirds of the organ. These disorders are presumably due to eosinophilic infiltration of the muscular layer or ganglionar cells of the esophagus, and account for symptoms in these patients. Although the etiopathogenesis of this illness is uncertain, it is clearly an immunoallergic manifestation. As the number of diagnosed cases is on the increase, eosinophilic esophagitis is in adults a specific entity within the differential diagnosis of dysphagia in young males with a history of allergies. Eosiniphilic esophagitis responds in a different number of ways to therapies used. We successfully used fluticasone propionate, a synthetic corticoid applied topically, which proved to be efficient in the treatment of this illness by acting on the pathophysiological basis of the process. It does not have any adverse effects, thus offering advantages over other therapies such as systematic corticoids or endoscopic dilations.

Esophageal candidiasis

Some patients present with esophageal candidiasis as a first presentation of systemic candidiasis. Diagnosis In most cases, the diagnosis is established based on response to therapy. Patients in whom esophageal candidiasis is suspected should receive a brief course of antifungal therapy with fluconazole. If the infection resolves after treatment with fluconazole, then the diagnosis of esophageal candidiasis is made and no further investigation is needed. However, if the infection persists or if there are other factors involved which may warrant further investigation, then patient will undergo an esophagogastroduodenoscopy if it is safe to do so. Endoscopy often reveals classic diffuse raised plaques that characteristically can be removed from the mucosa by the endoscope. Brushing or biopsy of the plaques shows yeast and pseudohyphae by histology that are characteristic of Candida species.

InternalMed_Harrison

FIguRE 53-2 Approach to the patient with dysphagia. Etiologies in bold print are the most common. ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease. agents or pills, previous radiation or chemotherapy, or associated mucocutaneous diseases may help isolate the cause of dysphagia. With accompanying odynophagia, which usually is indicative of ulceration, infectious or pill-induced esophagitis should be suspected. In patients with AIDS or other immunocompromised states, esophagitis due to opportunistic infections such as Candida, herpes simplex virus, or cytomegalovirus and to tumors such as Kaposi’s sarcoma and lymphoma should be considered. A strong history of atopy increases concerns for eosinophilic esophagitis.

Esophageal dysphagia

Esophageal rings and webs, are actual rings and webs of tissue that may occlude the esophageal lumen. Rings --- Also known as Schatzki rings from the discoverer, these rings are usually mucosal rings rather than muscular rings, and are located near the gastroesophageal junction at the squamo-columnar junction. Presence of multiple rings may suggest eosinophilic esophagitis. Rings cause intermittent mechanical dysphagia, meaning patients will usually present with transient discomfort and regurgitation while swallowing solids and then liquids, depending on the constriction of the ring. Webs --- Usually squamous mucosal protrusion into the esophageal lumen, especially anterior cervical esophagus behind the cricoid area. Patients are usually asymptomatic or have intermittent dysphagia. An important association of esophageal webs is to the Plummer–Vinson syndrome in iron deficiency, in which case patients will also have anemia, koilonychia, fatigue, and other symptoms of anemia.

Cytomegalovirus esophagitis

Cytomegalovirus esophagitis is a form of esophagitis associated with cytomegalovirus. Symptoms include dysphagia, upper abdominal pain, diarrhea, nausea, vomiting, and sometimes hematemesis. This condition occurs in the setting of patients with a weakened immune system who are susceptible to both infections by CMV and the manifestation of symptoms. A large majority of patient that have CMV Esophagitis are diagnosed with HIV. Another significant segment of the population have weakened immune systems through transplant surgery, diabetes, or due to medication. Diagnosis is done primarily by endoscopy with biopsy, as CMV Esophagitis has a distinctive pathology pattern of linear ulcers. Signs and Symptoms Dysphagia: Difficulty or pain while swallowing Hematemesis: Blood while vomiting Abdominal Pain: Pain in the upper abdominal area, usually exacerbated by swallowing. Pain can also manifest as heartburn symptoms Nausea/vomiting Fever

InternalMed_Harrison

EoE is diagnosed based on the combination of typical esophageal symptoms and esophageal mucosal biopsies demonstrating squamous epithelial eosinophil-predominant inflammation. Alternative etiologies of esophageal eosinophilia include GERD, drug hypersensitivity, connective tissue disorders, hypereosinophilic syndrome, and infection. Current evidence indicates that EoE is an immunologic disorder induced by antigen sensitization in susceptible individuals. Dietary factors play an important role in both the pathogenesis and treatment of EoE. Aeroallergens may also contribute, but the evidence is weaker. The natural history of EoE is unclear, but an increased risk of esophageal stricture development paralleling the duration of untreated disease has been noted. Diseases of the Esophagus FIGURE 347-11 Endoscopic features of (A) eosinophilic esophagitis (EoE), (B) Candida esophagitis, (C) giant ulcer associated with HIV, (D) and a Schatzki ring.

Esophageal web

Esophageal webs are thin membranes occurring anywhere along the esophagus. Presentation Its main symptoms are pain and difficulty in swallowing (dysphagia). Esophageal webs are thin membranes of normal esophageal tissue consisting of mucosa and submucosa that can partially protrude/obstruct the esophagus. They can be congenital or acquired. Congenital webs commonly appear in the middle and inferior third of the esophagus, and they are more likely to be circumferential with a central or eccentric orifice. Acquired webs are much more common than congenital webs and typically appear in the cervical area (postcricoid). Clinical symptoms of this condition are selective (solid more than liquids) dysphagia, thoracic pain, nasopharyngeal reflux, aspiration, perforation and food impaction (the last two are very rare).

Eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. In healthy individuals, the esophagus is typically devoid of eosinophils. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartburn. Eosinophilic esophagitis was first described in children but also occurs in adults. The condition is not well understood, but food allergy may play a significant role. The treatment may consist of removal of known or suspected triggers and medication to suppress the immune response. In severe cases, it may be necessary to enlarge the esophagus with an endoscopy procedure. While knowledge about EoE has been increasing rapidly, diagnosis of EoE can be challenging because the symptoms and histo-pathologic findings are not specific.

Cytomegalovirus Esophagitis -- Differential Diagnosis

Cytomegalovirus esophagitis more commonly presents as a single, isolated large ulcer in the distal esophagus but can also manifest as diffuse esophagitis. [1] The diffuse presentation can be difficult to distinguish from other disorders such as herpes simplex virus (HSV) esophagitis and acid peptic disease. The differentiating factor is that HSV esophagitis typically presents as multiple, small, shallow ulcerations more so than large ulcerations. HSV esophagitis also affects the entire esophagus, whereas CMV esophagitis more commonly affects the mid to distal esophagus. [10] Achalasia Acid peptic disease Aphthous ulcers Barrett esophagus and Barrett ulcer Candidiasis Cryptococcosis Drug-induced dysphagia Epstein-Barr virus infection Esophageal cancer Gastroesophageal reflux disease Herpes simplex esophagitis Histoplasmosis Tuberculosis

Esophageal food bolus obstruction

Risk factors Food bolus obstruction is most commonly caused by Schatzki rings, which are mucosal rings of unknown cause in the lower esophagus. Foodstuff jams into the esophagus due to the narrowing caused by the ring. An increasingly commonly recognized cause for esophageal food bolus obstruction is eosinophilic esophagitis, which is an inflammatory disorder of the mucosa of the esophagus, of unknown cause. Many alterations caused by eosinophilic esophagitis can predispose to food boluses; these include the presence of multiple rings and narrowing of the lumen. When considering esophageal dilation to treat a patient with food bolus obstruction, care must be made to look for features of eosinophilic esophagitis, as these patients are at a higher risk of dilation-associated complications.

Dysphagia

Differential diagnosis All causes of dysphagia are considered as differential diagnoses. Some common ones are: Esophageal atresia Paterson-Kelly syndrome Zenker's diverticulum Esophageal varices Benign strictures Achalasia Esophageal diverticula Scleroderma Diffuse esophageal spasm Polymyositis Webs and rings Esophageal cancer Eosinophilic esophagitis Hiatus hernia, especially paraesophageal type Dysphagia lusoria Stroke Fahr's disease Wernicke encephalopathy Charcot–Marie–Tooth disease Parkinson's disease Multiple sclerosis Amyotrophic lateral sclerosis Rabies Cervical Spondylosis

Drug-Induced Esophagitis -- Differential Diagnosis

Eosinophilic esophagitis: Eosinophilic infiltration presents in drug-induced esophagitis as well as eosinophilic esophagitis. The two are separated based on the clinical picture and pathological diagnostic criteria. Herpes esophagitis: It most commonly presents in immunocompromised patients, such as acquired immune deficiency symptoms (AIDS). Esophagogastroduodenoscopy may show lesions such as small erosions or ulcers in the distal or mid esophagus. Twenty-six percent of the cases involve the entire esophagus. Diagnosis requires biopsies and a viral culture of the lesion. [19] Infectious esophagitis such as esophageal candidiasis Malignancy Gastroesophageal reflux disease and peptic ulcer disease Achalasia and esophageal motility disorder Acute coronary syndrome with atypical chest pain Acute necrotizing esophagitis (black esophagus) in the elderly [1] [18] [2]

Eosinophilic esophagitis

Predominant symptoms in school-aged children and adolescents include difficulty swallowing, food impaction, and choking/gagging with meals- particularly when eating foods with coarse textures. Other symptoms in this age group can include abdominal/chest pain, vomiting, and regurgitation. The predominant symptom in adults is difficulty swallowing; however, intractable heartburn and food avoidance may also be present. Due to the long-standing inflammation and possible resultant scarring that may have gone unrecognized, adults presenting with EoE tend to have more episodes of esophageal food impaction as well as other esophageal abnormalities such as Schatzki ring, esophageal webs, and in some cases, achalasia.

Esophageal motility disorder

Types Dysphagia could be for solid only or for solid and liquid. Solid dysphagia is due to obstruction such as esophageal cancer, esophageal web, or stricture. Solid plus liquid dysphagia is due to esophageal motility disorder (or dysmotility) either in the upper esophagus (myasthenia gravis, stroke, or dermatomyositis) or lower esophagus (systemic sclerosis, CREST syndrome, or achalasia). The Most common dysphagia is Achalasia which is caused by degeneration of the nerves in the esophagus. This causes the muscles to stop working and prevents the valve at the bottom of the esophagus from being able to open properly. If there is a food allergy causing an EMD, then physicians recommend an elimination diet. If this fails, then physicians will prescribe special types of Medication to help resolve this problem. Diagnostics Testing to diagnose an EMD include: Barium Esophagography, Upper Endoscopy, and Esophageal Manometry. Treatments

Esophagitis

Lymphocytic esophagitis Lymphocytic esophagitis is a rare and poorly understood entity associated with an increased amount of lymphocytes in the lining of the esophagus. It was first described in 2006. Disease associations may include Crohn's disease, gastroesophageal reflux disease and coeliac disease. It causes similar changes on endoscopy as eosinophilic esophagitis including esophageal rings, narrow-lumen esophagus, and linear furrows. Caustic esophagitis Caustic esophagitis is the damage of tissue via chemical origin. This occasionally occurs through occupational exposure (via breathing of fumes that mix into the saliva which is then swallowed) or through pica. It occurred in some teenagers during the fad of intentionally eating Tide pods. By severity The severity of reflux esophagitis is commonly classified into four grades according to the Los Angeles Classification:

Eosinophilic esophagitis: a newly established cause of dysphagia.

Eosinophilic esophagitis has rapidly become a recognized entity causing dysphagia in young adults. This review summarizes the current knowledge of eosinophilic esophagitis including the epidemiology, clinical presentation, diagnostic criteria, pathophysiology, treatment, and prognosis. An extensive search of PubMed/Medline (1966-December 2005) for available English literature in humans for eosinophilic esophagitis was completed. Appropriate articles listed in the bibliographies were also attained. The estimated incidence is 43/10(5) in children and 2.5/10(5) in adults. Clinically, patients have a long history of intermittent solid food dysphagia or food impaction. Some have a history of atopy. Subtle endoscopic features may be easily overlooked, including a "feline" or corrugated esophagus with fine rings, a diffusely narrowed esophagus that may have proximal strictures, the presence of linear furrows, adherent white plaques, or a friable (crepe paper) mucosa, prone to tearing with minimal contact. Although no pathologic consensus has been established, a histologic diagnosis is critical. The accepted criteria are a dense eosinophilic infiltrate (>20/high power field) within the superficial esophageal mucosa. In contrast, the esophagitis associated with acid reflux disease can also possess eosinophils but they are fewer in number. Once the diagnosis is established, treatment options may include specific food avoidance, topical corticosteroids, systemic corticosteroids, leukotriene inhibitors, or biologic treatment. The long-term prognosis of EE is uncertain; however available data suggests a benign, albeit inconvenient, course. With increasing recognition, this entity is taking its place as an established cause of solid food dysphagia.

Eosinophilic esophagitis

Esophageal strictures and rings can be safely dilated in EoE. It is recommended to use a graduated balloon catheter for gradual dilation. The patient should be informed that after dilation they might experience chest pain and in addition risk of esophageal perforation and bleeding. Prognosis The long-term prognosis for patients with EoE is unknown. Some patients may follow a “waxing and waning” course characterized by symptomatic episodes followed by periods of remission. There have also been reports of apparent spontaneous disease remission in some patients; however, the risk of recurrence in these patients is unknown. It is possible that long-standing, untreated disease may result in esophageal remodeling, leading to strictures, Schatzki ring and, eventually, achalasia. History The first case of eosinophilic esophagitis was reported in 1978. In the early 1990s, it became recognized as a distinct disease. See also Eosinophilic gastroenteritis References External links

InternalMed_Harrison

to the development of copy with mucosal biopsies, which are necessary tion. In terms of endoscopic appearance, infectious esophagitis is diffuse and tends to involve the proximal esophagus far more frequently than does reflux esophagitis. The ulcerations seen in peptic esophagitis are usually solitary and distal, whereas infectious ulcerations are punctate and diffuse. Eosinophilic esophagitis characteristically exhibits multiple esophageal rings, linear furrows, or white punctate exudate. Esophageal ulcerations from pill esophagitis are usually singular and deep at points of luminal narrowing, especially near the carina, with sparing of the distal esophagus.

Lymphocytic esophagitis

While the diagnosis of lymphocytic esophagitis depends on the biopsy results, certain changes can be visualized directly at the time of endoscopy. The esophagus may be narrow in calibre, may show multiple rings, redness, linear furrows or the mucosal lining may slide demonstrating a "crepe-paper" appearance. Complications such as strictures of the esophagus can also be detected with endoscopy. These changes are very similar to those found in eosinophilic esophagitis, a more common and better understood esophageal disorder thought to be of allergic origin. Narrow-band imaging with magnification endoscopy is another imaging modality that can show characteristic changes of lymphocytic esophagitis.

Eosinophils in the esophagus--peptic or allergic eosinophilic esophagitis? Case series of three patients with esophageal eosinophilia.

Scattered eosinophils in the distal esophagus traditionally provide the hallmark for peptic esophagitis, but the upper limit of eosinophils and the longitudinal extent of peptic inflammation along the esophagus are unknown. Recently, adults and children with upper intestinal symptoms and >20 eosinophils/high-power field (eos/HPF) have been given the diagnosis of allergic esophagitis. Standardized diagnostic criteria for allergic esophagitis are lacking and the isolated finding of large numbers of eosinophils in the squamous epithelium has been used as the defining feature. We cared for three patients with symptoms and endoscopic features of esophagitis with >20 eos/HPF in their esophageal mucosa. Symptoms, endoscopic features, and histologic findings resolved after 2 months of proton pump inhibitor (PPI) treatment. The aim of this case series is to demonstrate that features thought to be consistent with a diagnosis of allergic esophagitis are also observed in peptic esophagitis. A retrospective chart review of three patients with esophagitis (>20 eos/HPF) whose symptoms and eosinophilia resolved with PPI treatment was performed. Esophageal biopsies were reviewed in a blinded manner by one pathologist. Patients (aged 14, 25, and 5 yr) presented with dysphagia, food impaction, and vomiting. Endoscopic features included white exudates and linear furrows. None of the patients received antiallergic treatments or dietary eliminations prior to endoscopy. Following treatment with PPIs alone, all patients became asymptomatic and endoscopic findings reverted to normal. In all three patients, pre- and post-PPI treatment eosinophil numbers/HPF decreased to normal/near normal (37 to 1, 21 to 3, and 52 to 0 eosinophils/HPF in patients 1, 2, and 3, respectively). Large numbers of eosinophils can be seen in peptic esophagitis. This histologic finding must be interpreted in the context of the clinical setting in which it is obtained.

Esophageal dysphagia

Esophageal stricture, or narrowing of the esophagus, is usually a complication of acid reflux, most commonly due to gastroesophageal reflux disease (GERD). These patients are usually older and have had GERD for a long time. Esophageal stricture can also be due to other causes, such as acid reflux from Zollinger–Ellison syndrome, trauma from a nasogastric tube placement, and chronic acid exposure in patients with poor esophageal motility from scleroderma. Other non-acid related causes of peptic strictures include infectious esophagitis, ingestion of chemical irritant, pill irritation, and radiation. Peptic stricture is a progressive mechanical dysphagia, meaning patients will complain of initial intolerance to solids followed by inability to tolerate liquids. When the diameter of the stricture is less than 12 mm the patient will always have dysphagia, while dysphagia is not seen when the diameter of the stricture is above 30 mm. Symptoms relating to the underlying cause of the

Eosinophilic esophagitis

At a tissue level, EoE is characterized by a dense infiltrate with white blood cells of the eosinophil type into the epithelial lining of the esophagus. This is thought to be an allergic reaction against ingested food, based on the important role eosinophils play in allergic reactions. The eosinophils are recruited into the tissue in response to local production of eotaxin-3 by IL-13 stimulated esophageal epithelial cells. Eosinophils are inflammatory cells that release a variety of chemical signals which inflame the surrounding esophageal tissue. This results in the signs and symptoms of pain, visible redness on endoscopy, and a natural history that may include stricturing. Diagnosis The diagnosis of EoE is typically made on the combination of symptoms and findings on diagnostic testing. To properly diagnose EoE, various diseases such as GERD, esophageal cancer, achalasia, hypereosinophilic syndrome, infection, Crohn's disease, and drug allergies need to be ruled out.

An uncommon case of herpetic esophagitis in a small child with allergic rhinitis: A case report and literature review (CARE compliant).

Herpetic esophagitis (HE) is a common condition in immunosuppressed patients, but a rare entity in immunocompetent patients affecting especially male teenagers and young adults. We report the case of a 5-year-old male patient, with a history of allergic rhinitis admitted in our clinic for acute onset fever refractory to antipyretics, chest pain, anorexia, refusal of solid food, accepting only small amounts of fluids, odynophagia, and epigastric pain. The clinical exam revealed severe malaise, pallor, decreased skin turgor, abdominal epigastric tenderness, heartburn at palpation within the epigastric area. The laboratory tests showed leukocytosis, monocytosis, hypoglycaemia, and elevated inflammatory biomarkers. The serology tests for human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV) were negative, except for immunoglobulin G (IgG) anti-EBV which was positive. The chest radiography was normal, and the abdominal ultrasound showed abdominal bloating. The upper digestive endoscopy revealed friable esophageal mucosa, with multiple ulceration on the entire esophagus, and whitish exudates especially on the middle and lower part of the esophagus suggesting a possible eosinophilic esophagitis or caused by Candida. Despite the empirical initiated treatment, the patient's evolution was only slowly favorable. The histological exam established the diagnosis of HE. We initiated acyclovir therapy with an outstandingly favorable evolution. After 1 month, we detected the seroconversion of IgG anti-HSV. The patient's follow-up revealed no additional complaints. Despite its rarity in immunocompetent individuals, HE must be taken into account even in otherwise healthy small children. Allergic conditions might represent a predisposing factor for HE.

Esophageal pH monitoring

Clinical application Gastroesophageal reflux disease (GERD) is a common disease in western countries. In the United States, 7% of the population experiences heartburn daily and 44% at least once a month. Heartburn occurs when esophageal mucosa is exposed to the acidic gastric content, but the complaint of heartburn is not always a reliable guide to the presence of acid reflux in the esophagus. Further, only half of the patients with increased esophageal acid exposure will have esophagitis. Therefore, the diagnosis of gastroesophageal reflux disease (GERD) on the basis of symptoms or endoscopic findings is problematic.

Lymphocytic esophagitis

Prognosis There has been little studied about the natural history of lymphocytic esophagitis. The longest study of the condition involved a median follow-up of 3.3 years, wherein participants were surveyed, and demonstrated that 87% of patients were alive but that the vast majority (97%) of patients still had symptoms. There have been two reports of esophageal perforation associated with the condition, one case occurring during endoscopic treatment of complications. Epidemiology The percentage of individuals with lymphocytic esophagitis is uncertain. Early studies indicated that the prevalence was 0.1% in adults. However, reports in children indicate a higher prevalence of 8.5%, perhaps suggestive of incidental findings of lymphocytes in endoscopies performed for other reasons. The disease may occur more frequently in women over the age of 60.