IDH mutations in G2-3 conventional central bone chondrosarcoma: a mono institutional experience.

BACKGROUND: Heterozygous isocitrate dehydrogenase (IDH) mutations occur in about half of conventional central bone chondrosarcomas (CCBC). Aim of this study was to assess the frequency and prognostic impact of IDH mutations in high grade CCBC patients. METHODS: 64 patients with G2 and G3 CCBC were included. DNA extraction, PCR amplification of IDH1/2 exon 4s, and sequencing analysis with Sanger were performed. RESULTS: IDH mutations were detected in 24/54 patients (44%): IDH1 in 18, IDH2 in 4, and both IDH1/2 in 2 patients. The frequency of mutations was 37% in G2 vs. 69% in G3 (p = 0.039), and 100% in three Ollier disease associated chondrosarcoma. 5-year overall survival (OS) at 124 months (range 1-166) was 51%, with no significant difference based on the IDH mutational status: 61% in IDHmut vs. 44% in IDH wild type (IDHwt). The 5-year relapse free survival (RFS) was 33% (95% CI:10-57) for IDHmut vs. 57% (95%CI: 30-77) for IDHwt. Progression free survival (PFS) was 25% (95%CI:1-65) IDHmut vs. 16% (95%CI: 0.7-52) IDHwt. 55% (5/9) of IDHmut G2 became higher grade at the recurrence, as compared with 25% (3/12) of G2 IDHwt. CONCLUSIONS: This study shows a higher frequency of IDH mutations in G3 CCBC as compared with G2. No significant differences in OS, RFS, and PFS by mutational status were detected. After relapse, a higher rate of G3 for IDH mutated CCBC was observed.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Extra-axial chordoma: a clinicopathologic analysis of six cases.

Extra-axial chordoma is an exceedingly rare tumor, with only 28 cases reported in the literature to date. Axial and extra-axial chordoma exhibits complete morphologic and immunophenotypic (expression of brachyury) overlap. However, in consideration of the non-canonical presentation, extra-axial chordoma is under-recognized and often misdiagnosed, most often as extraskeletal myxoid chondrosarcoma or myoepithelioma. To increase our understanding of the clinicopathologic features of extra-axial chordoma, six cases have been retrieved from the files of the Istituto Ortopedico Rizzoli and of the General Hospital of Treviso. The clinicoradiologic, morphologic, and molecular features have been analyzed, and the follow-up was updated. Our series included four female and two male patients; their ages ranged from 20 to 67 years (mean 45.8 years). All patients presented with a single mass localized in four cases in the soft tissue (posterior arm, left leg, dorsal aspect of the foot, and popliteal fossa), and in two cases in the bone (radius and second metacarpal bone). Grossly, the neoplasm was lobulated, with a fleshy cut surface and a diameter ranging between 0.8 and 8 cm (mean 3.4 cm). Morphologically, all six cases showed an epithelioid cell proliferation organized in nests and cords demarcated by fibrous septa and set in an abundant extracellular myxoid matrix. Neoplastic cells featured hyperchromatic nuclei and abundant vacuolated cytoplasm. Immunohistochemically, all six cases were strongly positive for EMA, cytokeratin AE1/AE3, S100, and brachyury. INI1 nuclear expression was retained. Smooth muscle actin, calponin, p63, and GFAP were all negative. Fluorescent in situ hybridization (FISH) analysis did not reveal rearrangements involving NR4A3, FUS, and EWSR1 genes. At follow-up (mean 55 months), all patients were alive without disease after local surgical treatment. One patient underwent thigh amputation following multiple local recurrences and inguinal node metastases treated with marginal resection. In conclusion, primary extra-axial chordoma is an extremely rare neoplasm with distinct morphological and immunohistochemical features. Immunomorphology and molecular analysis allow distinction from both extraskeletal myxoid chondrosarcoma and myoepithelioma. Complete surgical resection appears to be curative.

Dedifferentiated chondrosarcoma with "adamantinoma-like" features: A case report and review of literature.

Dedifferentiated chondrosarcoma is defined by the presence of a low grade malignant cartilaginous component juxtaposed to a high grade malignant non-cartilaginous sarcomatous components. Only 4 cases in which the high grade component showed epithelial differentiation have been reported in the literature; three featured a squamous and the one a glandular epithelial component. Here we describe a case of dedifferentiated chondrosarcoma exhibiting epithelial "adamantinoma-like" basaloid features. The patient underwent wide resection of the proximal tibia and post-operative chemotherapy and died 8 months after the diagnosis due to lung and bone metastases.

Primary extraskeletal myxoid chondrosarcoma of bone: Report of three cases and review of the literature.

Extraskeletal myxoid chondrosarcoma is a rare neoplasm of soft tissue. The usual location is in deep parts of the proximal extremities and limb girdles in middle-aged adults. The bone location as primary location is extremely rare and few cases are reported. We present three cases arising in bone with molecular confirmation using both RT-PCR and FISH analysis. Patients include two men and one woman with an age of 62, 69 and 73 years old. The mean size of the lesion was 13cm (range 8-18cm). Tumors arose in the iliac bone in two cases and in the proximal humerus in the other case. At time of diagnosis the three cases show bone cortex and soft tissue involvement. On imaging, lesions have a lobular pattern, are purely lytic, but take up contrast medium after injection. Two patients are alive with disease (local recurrence and lung metastasis) after five years and five years and six months, respectively and one patient died of disease two years after the diagnosis. The primary extraskeletal myxoid chondrosarcoma of bone seems to have a more aggressive behavior than the soft tissue counterpart. The molecular confirmation of diagnosis using RT-PCR is necessary to do the differential diagnosis with other entities, in particular with myoepithelioma that shows similar morphological features and EWSR1 and FUS genes rearrangement.

Elastofibroma of the gluteal region with a concomitant contralateral lesion: case report and review of the literature.

A 51-year-old man presented with elastofibroma (EF) of the gluteal region with a concomitant contralateral lesion. The patient presented with a slow growing mass of the proximal third of the right buttock and had swelling, discomfort in sitting, and right-hip pain during walking for 2 months. On MRI, a soft-tissue mass was noted between the gluteus maximus and the gluteus medius muscle. The mass showed similar signal intensity to the surrounding tissue on T1- and T2-weighted images and with linear hyperintense areas in its internal structure. At surgery, a soft, non-encapsulated, irregular, and rubber-like mass was found attached to the gluteus medius muscles. It was pathologically confirmed to be an EF. This unusual manifestation of an EF is discussed.

Sclerosing epithelioid fibrosarcoma of the thigh: report of two cases with synchronous bone metastases.

We report two cases of sclerosing epithelioid fibrosarcoma occurring in the deep soft tissue of the thigh, confirmed by molecular analysis and associated with bone metastases in the lumbar vertebrae and the iliac wing at the time of diagnosis. Synchronous bone metastases of sclerosing epithelioid fibrosarcoma are extremely difficult to diagnose because clinical and radiological features are not specific. In addition, the range of differential diagnoses is very wide, including metastatic carcinoma and osteosarcoma. At present, all but three published cases of sclerosing epithelioid fibrosarcoma with bone metastases showed bone metastases during follow-up. We confirm in our two cases that the distinct pattern of immunohistochemical staining for MUC4, associated with the absence of staining for both SATB2, a marker of osteoblastic differentiation, and pan-cytokeratin, allows differentiating between sclerosing epithelioid fibrosarcoma and metastatic carcinoma or osteosarcoma.

Metastasizing tenosynovial giant cell tumour, diffuse type/pigmented villonodular synovitis.

Tenosynovial giant cell tumour, diffuse type, also known under a variety of other terms including diffuse pigmented villonodular synovitis, tends to be locally aggressive and not infrequently can show multiple recurrences. The differential diagnosis with the extremely rare and somewhat controversial malignant variant of tenosynovial giant cell tumour, diffuse type, is challenging due to overlapping radiologic features of these two entities. Malignant tenosynovial giant cell tumour is defined by the presence of overtly malignant sarcomatous areas. We describe a very unusual case of a 63-year-old man affected by tenosynovial giant cell tumour, diffuse type of the knee that, despite absence of morphologic evidence of sarcomatous transformation, developed inguinal lymph node metastases following multiple surgical procedures.

Leiomyosarcoma of the hand.

Soft-tissue sarcomas of the hand are rare and the devastating effect of an undiagnosed sarcoma warrants clinical vigilance. We present the case of an unsuspected leiomyosarcoma localised in the hand in order to underline (i) the rarity of the disease in this site, (ii) the role of adequate surgical treatment in the first step, (iii) the relationship with adjuvant treatments, lymph node metastasis and the poor prognosis of this tumour.

Myoepithelioma of the spine: first case in the literature.

Myoepithelioma is a very rare tumour. This tumor type has been reported in the soft tissue, ear, sinonasal cavity, breast and lung. Although rare, myoepithelioma can occur in bone. We present the first case of myoepithelioma in the spine, documenting the clinical, radiographic and pathological features.

The importance of radiographic imaging in the microscopic assessment of bone tumors.

INTRODUCTION: Primary bone tumors are rare and require a multidisciplinary approach. Diagnosis involves primarily the radiologist and the pathologist. Bone lesions are often heterogeneous and the microscopic diagnostic component(s) may be in the minority, especially on core needle biopsies. Reactive processes, benign, and malignant tumors may have similar microscopic aspects. For these challenging cases, the correlation of microscopic and radiologic information is critical, or diagnostic mistakes may be made with severe clinical consequences for the patient. The purpose of this article is to explain how pathologists can best use imaging studies to improve the diagnostic accuracy of bone lesions. DIAGNOSIS: Many bone lesions are microscopically and/or radiographically heterogeneous, especially those with both lytic and matrix components. Final diagnosis may require specific microscopic diagnostic features that may be present in the lesion, but not the biopsy specimen. A review of the imaging helps assess if sampling was adequate. The existence of a pre-existing bone lesion, syndrome (such as Ollier disease or multiple hereditary exostosis), or oncologic history may be of crucial importance. Finally, imaging information is very useful for the pathologist to perform accurate local and regional staging during gross examination. CONCLUSION: Close teamwork between pathologists, radiologists, and clinicians is of utmost importance in the evaluation and management of bone tumors. These lesions can be very difficult to interpret microscopically; imaging studies therefore play a crucial role in their accurate diagnosis.

Severe osteolysis and soft tissue mass around total hip arthroplasty: description of four cases and review of the literature with respect to clinico-radiographic and pathologic differential diagnosis.

Periprosthetic osteolysis is a well known phenomenon caused by wear particle-induced bone resorption, particularly common and extensively reported in total hip arthroplasty. Its typical radiographic feature is a radiolucent area adjacent to an implant, sometimes associated with a soft tissue mass. Osteolytic changes may be caused by numerous other pathologic processes, including infection, metabolic disease, and neoplasia. Four cases of massive periprosthetic bone destruction associated with a large soft tissue mass around a failed total hip replacement are presented. In three cases, a diagnosis of periprosthetic osteolysis was correctly made and managed by revision surgery. However, in one case angiosarcoma of the ipsilateral hemipelvis went long unrecognized despite aggressive clinical course, requiring hind-quarter amputation and ultimately resulting in the patient's death. Periprosthetic malignancy in the form of either primary sarcoma or metastatic cancer is a very rare yet reported event in the setting of previous hip replacement, likely leading to catastrophic consequences when diagnosis is not established in a timely manner. The differential diagnosis of periprosthetic osteolysis should consider the entire spectrum of conditions that can present with radiolucent changes. Thorough review of patient's history and course of symptoms, along with careful evaluation of standard roentgenograms should be always performed and possibly integrated with imaging modalities such as CT, MRI, and bone scintigraphy in order to increase diagnostic accuracy. If uncertainty remains, biopsy should always be considered to rule out malignancy.

Comparison of the Marsh-Oberhuber classification with a new grading system in identifying patients with latent celiac disease.

AIM: The diagnosis of celiac disease (CD) is still mainly based on pathological description. However, these descriptions are often unable to identify latent CD. The aim of this study was to evaluate whether the Marsh-Oberhuber classification and a recently proposed classification may help to identify patients with latent CD. METHODS: Biopsy samples from twelve patients with latent CD (age range 3-32 years) defined as having normal duodenal mucosa when ingesting a free diet, and subsequently developing severe villous atrophy, were retrospectively reviewed in blind according to the Marsh-Oberhuber classification and the new grading system. RESULTS: In 67% of patients the Marsh-Oberhuber and the new classification could have yielded a diagnosis of CD soon after the first biopsy (3a-3c score when reviewed according to this classification, and B2 score when reviewed according to the new grading system), thereby avoiding further (up to two more in four cases) unnecessary endoscopic procedures. CONCLUSION: Both the Marsh-Oberhuber and the new classification allow to discriminate latent CD from patients with normal mucosa. Thus, these classifications may help in identifying and treating patients at an early stage.

High grade malignant peripheral nerve sheath tumors: outcome of 62 patients with localized disease and review of the literature.

Malignant peripheral nerve sheath tumours (MPNST) are rare sarcomas with one of the poorest prognoses of all the soft tissue sarcomas. Information about adjuvant treatment is scarce and not homogeneous for this diagnosis. We analyzed retrospectively the outcome of patients with localized high grade MPNST admitted to our institute from 1969 to 2008. A review of the literature is also reported. Of 62 evaluable patients, 23 were females and 39 males, median age 39 years (17-71), 22/62 had neurofibromatosis type I. Median follow-up was 54 months (range 12-194). A total of 22/62 are alive; 26 patients had surgery alone, 18 received radiation therapy, 12 received radiation therapy and chemotherapy, and 6 received only adjuvant chemotherapy. The 5-year disease-free survival was 30% and 5-year overall survival was 38%. A positive trend for adjuvant radiation, but not for chemotherapy was observed according to univariate analysis only for disease-free survival and overall survival. Multivariate analysis indicated that primary site, size and surgical margins remained significant for disease-free survival and only site and size were significant for overall survival. New drugs employed successfully in advanced mpNSt should be employed also in the adjuvant setting.

The incidental skeletal lesion: ignore or explore?

The 'leave me alone' bone lesions are very classical, and, as indicated by their name, do not require any further investigation. There are very typical cases, and there are also more difficult ones, and they can be especially difficult to manage if the patient has a known cancer.

Coeliac disease: a histological follow-up study.

AIMS: To assess the histological response to a gluten-free diet (GFD) in a series of coeliac patients in clinical remission, of different ages and with varying degrees of mucosal damage at diagnosis. METHODS AND RESULTS: Biopsy samples from 249 coeliac patients (F 165, M 84) were analysed basally and after clinical and biochemical remission following a GFD. All patients showed an improvement in mucosal findings after starting a GFD, but complete histological normalization was observed in 74.1% of paediatric cases (diagnosed before 14 years of age) and in only 17.5% of adults. Statistical analysis showed that sex, the clinical picture at diagnosis and the length of time between biopsy at the time of diagnosis and on a GFD were not related to histological normalization. In contrast, the age at diagnosis was statistically significantly related to it (P < 0.0001). In addition, the presence/absence of Helicobacter pylori was independent of the normalization of the duodenal mucosa. CONCLUSIONS: In clinical practice the criteria for diagnosis of coeliac disease are sufficiently standardized, whereas for follow-up they are less well defined. We suggest that in order to compare the results from different studies, it should be stated whether remission after treatment is based on clinical or histological criteria or both.

[Tardive cecal metastasis from ovarian cancer: a case report]. / Metastasi colica tardiva da carcinoma ovarico. A proposito di un caso clinico.

Intestinal insolvement is a frequent sequela of metastatic ovarian cancer may be syncronous or following ovaric resection, after several years of disease free condition. The authors herein describe a clinical report of a case of cecal metastatic neoplasm due to ovarian cancer treated with surgical resection 24 years before.