[Updates to the WHO classification of bone tumours]. / Neues zur WHO-Klassifikation der Knochentumoren.

The fourth edition of the WHO Classification of Soft Tissue and Bone Tumours, published in 2013, extends the approach to describe genetics and pathology of these tumours in the context of epidemiological, clinical and imaging data, which was adopted in the third edition. Added are a few new entities, reclassifications and renamings. The most important point, also of clinical relevance and with consequences for treatment, is the introduction of a stratification of bone tumours based on their biological behaviour into three groups (benign, intermediate, malignant) in analogy to soft tissue tumours.

[Chondroblastoma]. / Chondroblastom.

Chondroblastomas are very rare benign primary bone tumors occurring preferentially in the epiphyses or apophyses of long bones in children and adolescents. In most cases the typical histological and imaging findings lead to a correct diagnosis that may be substantiated by demonstrating the highly specific point mutation in the H3F3B gene (p.K36M), either by sequencing or immunohistochemistry. Recurrences occur in 5-15% of cases, postsurgical metastatic deposits to the lungs are very rare (<1%). Histologically "malignant" chondroblastomas have been reported as single case reports. The treatment of choice is a thorough curettage, also in the case of local relapses.

[Tumor-like lesions of bone]. / Tumorähnliche Knochenläsionen.

Historically, tumor-like lesions of bone were defined as non-neoplastic bone lesions. Today, however, some of them are considered real neoplasms. They are among the most frequent bone lesions. They usually grow slowly, but occasionally they grow rapidly. Many of them can be diagnosed by plain films alone; in others, CT and MRI yield additional features for a correct diagnosis. Some lesions do not need treatment; others should be resected, and some may even recur. Non-ossifying fibroma, juvenile and aneurysmal bone cysts, fibrous and osteofibrous dysplasia and eosinophilic granuloma are presented.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

[Pathological assessment of bone sarcomas]. / Pathologische Begutachtung von Knochensarkomen.

Bone tumors are very rare. Diagnosis and treatment is an interdisciplinary task for experienced radiologists, pathologist, and surgeons that is ideally performed in specialized centers. For optimal processing of bone specimens, basic laboratory equipment and special techniques are required. The cornerstone of the histological diagnosis remains H&E staining, supplemented by special stains, immunohistochemistry, and molecular techniques. For an appropriate diagnosis, data on clinical history, age, location, topography within bone, and imaging are required. Major differences between histological and radiological diagnosis have to be clarified before starting treatment (e.g., by involving a reference registry).

Lung cancer in the Swiss HIV Cohort Study: role of smoking, immunodeficiency and pulmonary infection.

BACKGROUND: Immunodeficiency and AIDS-related pulmonary infections have been suggested as independent causes of lung cancer among HIV-infected persons, in addition to smoking. METHODS: A total of 68 lung cancers were identified in the Swiss HIV Cohort Study (SHCS) or through linkage with Swiss Cancer Registries (1985-2010), and were individually matched to 337 controls by centre, gender, HIV-transmission category, age and calendar period. Odds ratios (ORs) were estimated by conditional logistic regression. RESULTS: Overall, 96.2% of lung cancers and 72.9% of controls were ever smokers, confirming the high prevalence of smoking and its strong association with lung cancer (OR for current vs never=14.4, 95% confidence interval (95% CI): 3.36-62.1). No significant associations were observed between CD4+ cell count and lung cancer, neither when measured within 1 year (OR for <200 vs ≥500=1.21, 95% CI: 0.49-2.96) nor further back in time, before lung cancer diagnosis. Combined antiretroviral therapy was not significantly associated with lung cancer (OR for ever vs never=0.67, 95% CI: 0.29-1.52), and nor was a history of AIDS with (OR=0.49, 95% CI: 0.19-1.28) or without (OR=0.53, 95% CI: 0.24-1.18) pulmonary involvement. CONCLUSION: Lung cancer in the SHCS does not seem to be clearly associated with immunodeficiency or AIDS-related pulmonary disease, but seems to be attributable to heavy smoking.

High STEAP1 expression is associated with improved outcome of Ewing's sarcoma patients.

BACKGROUND: Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. PATIENTS AND METHODS: Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). RESULTS: A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). CONCLUSION: High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimens.

Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors.

BACKGROUND: Synovial sarcoma (SS) is a malignant soft tissue sarcoma with a poor prognosis because of late local recurrence and distant metastases. To our knowledge, no studies have minimum follow-up of 10 years that evaluate long-term outcomes for survivors. PATIENTS AND METHODS: Data on 62 patients who had been treated for SS from 1968 to 1999 were studied retrospectively in a multicenter study. Mean follow-up of living patients was 17.2 years and of dead patients 7.7 years. RESULTS: Mean age at diagnosis was 35.4 years (range 6-82 years). Overall survival was 38.7%. The 5-year survival was 74.2%; 10-year survival was 61.2%; and 15-year survival was 46.5%. Fifteen patients (24%) died of disease after 10 years of follow-up. Local recurrence occurred after a mean of 3.6 years (range 0.5-14.9 years) and metastases at a mean of 5.7 years (range 0.5-16.3 years). Only four patients were treated technically correctly with a planned biopsy followed by a wide resection or amputation. Factors associated with significantly worse prognosis included larger tumor size, metastases at the time of diagnosis, high-grade histology, trunk-related disease, and lack of wide resection as primary surgical treatment. CONCLUSIONS: In SS, metastases develop late with high mortality. Patients with SS should be followed for >10 years.

The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

BACKGROUND: Local recurrence (LR) in osteosarcoma is associated with very poor prognosis. We sought to evaluate which factors correlate with LR in patients who achieved complete surgical remission with adequate margins. PATIENTS AND METHODS: We analyzed 1355 patients with previously untreated high-grade central osteosarcoma of the extremities, the shoulder and the pelvis registered in neoadjuvant Cooperative Osteosarcoma Study Group trials between 1986 and 2005. Seventy-six patients developed LR. RESULTS: Median follow-up was 5.56 years. No participation in a study, pelvic tumor site, limb-sparing surgery, soft tissue infiltration beyond the periosteum, poor response to neoadjuvant chemotherapy, failure to complete the planned chemotherapy protocol and biopsy at a center other than the one performing the tumor resection were significantly associated with a higher LR rate. No differences were found for varying surgical margin widths. Surgical treatment at centers with small patient volume and additional surgery in the primary tumor area, other than biopsy and tumor resection, were significantly associated with a higher rate of ablative surgery. CONCLUSIONS: Patient enrollment in clinical trials and performing the biopsy at experienced institutions capable of undertaking the tumor resection without compromising the oncological and functional outcome should be pursued in the future.

[Ectomesenchymal chondromyxoid tumor of the anterior tongue]. / Ektomesenchymaler chondromyxoider Tumor des vorderen Zungenabschnitts.

Ectomesenchymal chondromyxoid tumor of the anterior tongue is a rare entity. To date, 37 cases have been reported in the literature. We present the case of a 52-year-old male patient with an ectomesenchymal chondromyxoid tumor at the typical location with a characteristic lobular proliferation of ovoid and fusiform uniform tumor cells on a chondromyxoid background and showing expression of typical immunohistochemical markers GFAP and S-100. Despite its rarity, this special tumor should be considered in the differential diagnosis when dealing with localized swellings of the anterior tongue.

Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study.

BACKGROUND: The advent of highly active antiretroviral therapy (HAART) in 1996 led to a decrease in the incidence of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL), but not of other cancers, among people with HIV or AIDS (PWHA). It also led to marked increases in their life expectancy. METHODS: We conducted a record-linkage study between the Swiss HIV Cohort Study and nine Swiss cantonal cancer registries. In total, 9429 PWHA provided 20,615, 17,690, and 15,410 person-years in the pre-, early-, and late-HAART periods, respectively. Standardised incidence ratios in PWHA vs the general population, as well as age-standardised, and age-specific incidence rates were computed for different periods. RESULTS: Incidence of KS and NHL decreased by several fold between the pre- and early-HAART periods, and additionally declined from the early- to the late-HAART period. Incidence of cancers of the anus, liver, non-melanomatous skin, and Hodgkin's lymphoma increased in the early- compared with the pre-HAART period, but not during the late-HAART period. The incidence of all non-AIDS-defining cancers (NADCs) combined was similar in all periods, and approximately double that in the general population. CONCLUSIONS: Increases in the incidence of selected NADCs after the introduction of HAART were largely accounted for by the ageing of PWHA.

[Hereditary bone tumors]. / Familiäre Tumorerkrankungen im Knochen.

Familial diseases leading to bone tumor formation are rare. They are mainly caused by genetic alterations of cell cycle constituent genes, such as retinoblastoma syndrome (RB1) and Li-Fraumeni syndrome (p53), of genes involved in growth-regulating transcriptional cascades, such as enchondromatosis (PTHR1) and multiple hereditary exostoses (EXT1, EXT2) or of genes maintaining chromosomal stability, such as Rothmund-Thomson (RECQL4), Werner (WRN) and Bloom syndromes (BLM). This leads to multiple benign bone tumors, which may undergo secondary malignant transformation (enchondromatosis: enchondromas, multiple hereditary exostoses: osteochondromas) or bone sarcomas, mainly osteosarcomas, such as primary (Li-Fraumeni, Rothmund-Thomson, Werner and Bloom syndromes) or secondary manifestations (retinoblastoma syndrome) of the underlying disease. Some of these lesions also carry an increased risk for developing additional malignant diseases. In contrast to sporadically occurring similar tumors, differences in manifestation in time, topography or histology may be present which can aid in the correct recognition of the underlying syndrome.

Tumour and tumour-like lesions of the patella--a multicentre experience.

Fifty-nine cases of lesions presenting in the patella were identified after review of the databases of four European bone tumour registries. Of the 59 cases, 46% were non neoplastic, 39% were benign and 15% were malignant. The commonest benign neoplasm was giant cell tumour (GCT) (11 cases). Younger patients were more likely to have a benign neoplasm. Lesions in patients less than 40 years of age included giant cell tumour, chondroblastoma, aneurysmal bone cyst (ABC), osteomyelitis, osteoid osteoma and solitary bone cyst. In patients older than 40 years, the following were common lesions: intra-osseous gout, metastasis and intra-osseous ganglion. Expansion of the patella with thinning of cortex was seen more commonly in GCT and brown tumour in hyperparathyroidism. There was associated soft tissue extension in gout and malignant lesions.

[Warthin tumor with carcinoma: malignant transformation or metastasis?]. / Warthin-Tumor mit Karzinom: Maligne Transformation oder Metastase?

We present the unusual case of a cytologically diagnosed Warthin tumor (WT) of long standing with sudden enlargement und subsequent resection. Histologically, the diagnosis of WT was confirmed, but the tumor additionally showed diffuse infiltrates of an adenocarcinoma undergoing unrestrained growth. Warthin tumor with malignant transformation was suspected and radiological staging examinations were conducted. PET scans detected a metastasizing carcinoma of the breast, morphologically identical to the WT infiltrates. Care should always be taken when the diagnosis of malignant WT is made to exclude metastatic disease.

[Musculoskeletal tumors: significance of morphological diagnostics]. / Tumoren des Bewegungsapparats: Bedeutung der morphologischen Diagnostik.

Musculoskeletal tumors, particularly bone neoplasms, are very rare. Diagnosis and treatment require an interdisciplinary concept as well as wide experience of all physicians involved. The final histopathologic diagnosis should not be confirmed without information regarding the patient's age, exact localization, and radiological findings. The requirements of additional diagnostic procedures (molecular pathology) have to be taken into consideration when planning a biopsy.

Kaposi sarcoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy.

Between 1984 and 2006, 12 959 people with HIV/AIDS (PWHA) in the Swiss HIV Cohort Study contributed a total of 73 412 person-years (py) of follow-up, 35 551 of which derived from PWHA treated with highly active antiretroviral therapy (HAART). Five hundred and ninety-seven incident Kaposi sarcoma (KS) cases were identified of whom 52 were among HAART users. Cox regression was used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Kaposi sarcoma incidence fell abruptly in 1996-1998 to reach a plateau at 1.4 per 1000 py afterwards. Men having sex with men and birth in Africa or the Middle East were associated with KS in both non-users and users of HAART but the risk pattern by CD4 cell count differed. Only very low CD4 cell count (<50 cells microl(-1)) at enrollment or at HAART initiation were significantly associated with KS among HAART users. The HR for KS declined steeply in the first months after HAART initiation and continued to be low 7-10 years afterwards (HR, 0.06; 95% CI, 0.02-0.17). Thirty-three out of 52 (63.5%) KS cases among HAART users arose among PWHA who had stopped treatment or used HAART for less than 6 months.

[Cartilage tumors of the skeleton]. / Chondrogene Tumoren des Skeletts.

Although the spectrum of benign and malignant cartilaginous bone tumors is extremely wide, a distinct diagnosis, even from small biopsy specimens, is almost always possible if radiological findings, age, clinical data, and localization within the skeleton as well as within the bone are considered. With limitations, this also holds true for distinguishing enchondromas from low-grade chondrosarcomas; however, extensive experience in multidisciplinary bone tumor diagnosis is required. In single cases, immunohistochemical findings may be helpful in the differential diagnosis if they are integrated into the context of all other findings. Because of treatment-related or prognosis-related consequences, collaboration with a reference center is recommended.

[Benign "mixed" odontogenic tumors]. / Benigne "gemischte" odontogene Tumoren.

Benign "mixed"odontogenic tumors consist of an epithelial and ectomesenchymal tumor component, distinguishing them from pure epithelial and pure ectomesenchymal odontogenic tumors. In addition, they may have the ability to produce dentin, enamel or cementum. Therefore, they can sometimes already be differentiated radiologically from epithelial odontogenic tumors. Some of the mixed odontogenic lesions are regarded as true tumors (ameloblastic fibroma, odontoameloblastoma, dentinogenic ghost cell tumor), while others are assumed to represent hamartomatous lesions (complex and compound odontoma, probably also ameloblastic fibrodentinoma and ameloblastic fibroodontoma). Preceded by keratocystic odontogenic tumor, complex and compound odontomas are the second most common odontogenic tumors, while other members of the "mixed" odontogenic tumor group are far less frequently diagnosed. Odontoameloblastoma and dentinogenic ghost cell tumors are locally aggressive lesions that require total resection. All other lesions of this group are treated by local excision. Since ameloblastic fibrosarcoma may evolve from ameloblastic fibroma, patients with ameloblastic fibroma should remain in long-term follow-up.

[Malignant odontogenic tumors]. / Maligne odontogene Tumoren.

Malignant odontogenic tumors are extremely rare. As with benign odontogenic tumors, malignant epithelial odontogenic tumors or odontogenic carcinomas are distinguished from the even rarer mesenchymal ones, the odontogenic sarcomas. The existence of odontogenic carcinosarcomas is not yet acknowledged by the World Health Organization. Odontogenic carcinomas comprise ameloblastic carcinoma (AmCa), primary intraosseous carcinoma (PIOC), clear cell odontogenic carcinoma, odontogenic ghost cell carcinoma (OGCC), and the special case of metastasizing ameloblastoma. Odontogenic sarcomas consist of ameloblastic fibrosarcoma and ameloblastic fibrodentinosarcoma and fibroodontosarcoma. Whereas metastasizing ameloblastoma can be diagnosed only after having metastasized, all other malignant odontogenic tumors present with atypia, increased cellularity and mitoses, and invasion. Odontogenic sarcomas are regarded as low-grade tumors that rarely metastasize. Odontogenic carcinomas, however, especially AmCa, OGCC, and PIOC, are more aggressive, with a 5-year survival rate of about 70% for AmCa and OGCC and a 3-year survival rate of about 37% for PIOC. Radical surgery, eventually in combination with radiotherapy, is the treatment of choice.