A Rare Co-Occurrence of Maffucci Syndrome and Astrocytoma with IDH1 R132H Mutation: A Case Report.

Background: Maffucci syndrome is a rare genetic disorder associated with the development of multiple enchondromas and soft tissue cavernous hemangiomas, as well as an increased risk of malignant tumors. Case Description: Here we report a case of Maffucci syndrome in a patient who presented with a giant left frontal lobe tumor. Molecular genetic analysis of the tumor revealed an isocitrate dehydrogenase (IDH) mutation p.R132H (c.395C>A) mutation in the IDH1 gene and a heterozygous duplication of the CDKN2A genes. Conclusions: The presence of an IDH1 mutation is notable because this mutation is frequently seen in glial tumors and other neoplasms, and its co-occurrence with Maffucci syndrome may represent a novel risk factor for the development of gliomas. This case underscores the importance of genetic testing in patients with Maffucci syndrome who present with central nervous system tumors, as well as the need for further research to understand the relationship between IDH1 mutations and the development of gliomas in this population.

Supratentorial multifocal gliomas associated with Ollier disease harboring IDH1 R132H mutation: A case report.

Somatic mosaicism of isocitrate dehydrogenase 1/2 (IDH1/2) mutation is a cause of Ollier disease (OD), characterized by multiple enchondromatosis. A 35-year-old woman who was diagnosed with OD at age 24 underwent resection surgery for multifocal tumors located at the right and left frontal lobes that were discovered incidentally. No apparent spatial connection was observed on preoperative magnetic resonance imaging. Pathological examinations revealed tumor cells with a perinuclear halo in the left frontal lobe tumor, whereas astrocytic tumor cells were observed in the right frontal lobe tumor. Based on positive IDH1 R132H immunostaining and the result of 1p/19q fluorescent in situ hybridization, pathological diagnoses were IDH mutant and 1p/19q-codeleted oligodendroglioma in the right frontal lobe tumor and IDH mutant astrocytoma in the left frontal lobe tumor, respectively. The DNA sequencing revealed IDH1 R132H mutation in the peripheral blood sample and frontal lobe tumors. This case suggested that in patients with OD, astrocytoma and oligodendroglioma can co-occur within the same individual simultaneously, and IDH1 R132H mutation was associated with supratentorial development of gliomas.

A possible case of "kissing" osteochondroma and multiple enchondromas in a medieval skeleton from the church of Sant' Agostino in Caravate (Northern Italy).

This work presents the neoplastic bone changes found in the lower limb of a medieval skeleton from the church of Sant' Agostino in Caravate (Northern Italy). After briefly assessing the individual's overall pathological picture, a differential diagnosis for the neoplastic changes is now proposed. These changes were analysed macroscopically and radiographically and subsequently evaluated considering the paleopathological and clinical literature available. The differential diagnosis allowed us to recognize a tibiofibular osteochondroma and some enchondromas in the medullary cavity of the tibia. The results presented here highlight the importance of radiological analyses in the recognition and study of bone neoplasms in the paleopathological field, further contributing to our knowledge of the presence of neoplasms in Medieval Northern Italy.

Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome.

Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in IDH1 and IDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in HIF1A, 6 had rare germline missense variants in VHL, and 3 had IDH1 variants including 2 with mosaic IDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in HIF1A, VHL, and IDH1 were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in HIF1A, VHL, and IDH1 in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.

Co-existence of lung carcinoma metastasis and enchondroma in the femur of a patient with Ollier disease.

Tumour-to-tumour metastasis is very unusual and has been defined as a tumour metastasis into another histologically different tumour. It is extremely rare in bone. We report a case of lung squamous cell carcinoma metastasized to an enchondroma in the femur of a patient with Ollier disease. A 60-year-old female had a history of a poorly differentiated squamous cell carcinoma of the lung. She underwent a video-assisted thoracoscopic lobectomy, and a follow-up MRI scan showed three lesions in the left distal femur and proximal tibia, which were initially interpreted as metastasis on radiology. Resection of the left proximal tibial lesion was performed, and the pathological findings were consistent with enchondroma with no evidence of metastasis. Subsequent curettage of lesions in the distal left femur revealed metastatic poorly differentiated carcinoma with foci of hyaline cartilage, which was most consistent with metastatic carcinoma in a pre-existing enchondroma. The MRI films were re-reviewed. Characteristic MRI features of enchondroma were found in the lesion in the left proximal tibia and one of the lesions in the left distal femur, while the features of the other lesion in the left distal femur included cortical destruction and extensive oedema in surrounding soft tissue, which were consistent with a malignant tumour. In addition, the enchondroma in the lateral condyle showed blurring and irregular inner margin and adjacent bone oedema, which likely represents a co-existing metastatic tumour and enchondroma. The difference in lineage was confirmed by immunohistochemistry. The final diagnosis was metastatic poorly differentiated carcinoma of the lung into a co-existent enchondroma. The diagnosis can be challenging and could be easily overlooked both radiologically and histologically. Thorough clinical and radiological information is critical for the diagnosis, and despite a very unusual event, awareness of the tumour-to-tumour metastasis phenomenon can avoid an inaccurate diagnosis by the pathologist, therefore preventing inappropriate clinical intervention.

Whole-body MRI in assessing malignant transformation in multiple hereditary exostoses and enchondromatosis: audit results and literature review.

OBJECTIVE: To analyze the results of annual screening using whole-body magnetic resonance imaging (WBMRI) in patients with multiple hereditary exostoses (MHE) and enchondromatosis (EC), and estimate the risk for transformation to chondrosarcoma (CS) in these disorders. MATERIALS AND METHODS: A total of 62 patients (57 with MHE and five with EC) screened during a mean follow-up period of 4.6 years (range, 1-10 years) using 253 WBMRIs (median four WBMRIs per patient, range, 1-10) were analyzed retrospectively. The time of WBMRIs was compared with dates for diagnosed CSs. A supplementary literature review was performed focusing on the risk of malignant transformation. RESULTS: Ten patients had CS before being enrolled in the screening program, nine with MHE and one with EC. Three asymptomatic CSs were detected by screening; one in a patient with EC and two in patients with MHE, one of whom had CS previously. During the screening period, there was no occurrence of CS not detected by WBMRI in the study group. Histopathologically, the CSs were predominantly grade 1 and were, except for in two patients, located at the truncus, proximal femur, and shoulder girdle. Based on the current material and literature review, the risk of CS seems to be in the range of 2-3.7% for MHE and up to 50% for EC patients. CONCLUSIONS: MRI may be used as a screening method detecting malignant transformation in MHE and EC patients, but the efficacy has to be confirmed in long-term follow-up studies including cost analysis.

IDH1 immunohistochemistry reactivity and mosaic IDH1 or IDH2 somatic mutations in pediatric sporadic enchondroma and enchondromatosis.

Mosaic somatic mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes have been identified in most enchondromas by targeted mutation analysis. Next-generation sequencing (NGS), that may detect even low-level mosaic mutation rates, has not previously been applied to enchondromas. Immunohistochemistry using the H09 clone is routinely used as a surrogate for the common R132H IDH1 mutation in gliomas. We compared immunohistochemistry and NGS results in a series of 13 enchondromas from 8 pediatric patients. NGS identified a heterozygous IDH mutation in all enchondromas, showing identical mutation status in patients with multiple tumors assessed, thereby confirming somatic mosaicism. A majority of the tumors harbored an IDH1 mutation (p.R132H in 3 tumors; p.R132C in 4 tumors from 2 patients; p.R132L and p.R132G in one tumor each). A p.R172S IDH2 mutation was identified in 4 enchondromas, but not in the ependymoma from one patient with Ollier disease, who further displayed a heterozygous STK11 missense mutation. IDH mutation rates varied between 14% (indicative of mutations in 28% of the cells and of intratumoral mosaicism) and 45% (tumor content was close to 100%). Cytoplasmic H09 reactivity was observed as expected in tumors with an IDH1 p.R132H mutation; cross-reactivity was seen with the p.R132L variant. This first NGS study of pediatric enchondromas confirms that IDH mutations may occur in a mosaic fashion. STK11 gene mutations may provide insights in the development of multiple cartilaginous tumors in enchondromatosis, this tumor suppressor gene having been shown in animal models to regulate both chondrocyte maturation and growth plate organization during development.

Skull Base Enchondroma and Chondrosarcoma in Ollier Disease and Maffucci Syndrome.

BACKGROUND: Maffucci syndrome (MS) and Ollier disease (OD) are rare diseases characterized by multiple benign enchondromas. The incidence of skull base (SB) enchondromas and the risk of malignant transformation remain unknown. Most SB lesions are asymptomatic, and surgical resection carries significant morbidity. Observation may be a reasonable strategy. We report our experience with observation of probable SB enchondromas in MS/OD patients. METHODS: Retrospective review of OD/MS patients with cranial imaging between 1995 and 2018 at 1 institution. RESULTS: 14 patients were included: 3 with MS (21.4%) and 11 with OD (78.6%). The median age was 28 years (range, 11-74 years) and 57.1% were female. Extracranial chondrosarcoma was reported in 3 (21.4%) patients. Seven (50%) patients with SB enchondroma or chondrosarcoma were identified on initial imaging. In patients with SB lesions, the indications for imaging were headache (n=3), seizure (n=1), and diplopia (n=1); 2 cases were incidental findings. The most commonly involved structures were petroclival fissure (86%) and clivus (71%). Treatment included observation (6/7) and resection (1/7). Follow-up imaging was available for all SB lesions, with a mean interval of 50.7 months (range, 5-225 months) and was negative for progression in all patients. CONCLUSIONS: Primary SB lesions in OD/MS patients frequently present in the petroclival junction. Cranial screening and close observation should be considered in MS/OD patients, given the increased risk of intra-axial intracranial tumors, de novo chondrosarcomas, or malignant degeneration of previously known lesions. In asymptomatic patients, observation appears to be a safe strategy in this cohort. Further case accumulation and follow-up are required to better understand the long-term outcomes.

[Chondromucinous tumors involving craniocerebral slope area: a clinicopathological analysis of eight cases].

Objective: To investigate the histological type and clinicopathological characteristics of the craniocerebral slope tumors with chondromucinous features. Methods: Retrospective analysis was conducted to analyze chondromucinous tumors in the slope area diagnosed at Henan Provincial People's Hospital from October 2011 to June 2018. Relevant clinical and pathological data were reviewed, and immunohistochemistry was used to investigate the immunophenotype of the tumors. Results: Eight cases were identified, including 4 males and 4 females with patient age ranging from 20 to 48 years. Histologically, there were 1 case of chordoid meningioma, 1 chondromyxoid fibroma, 1 mucinous chondrosarcoma, 1 Maffucci syndrome, and 4 chondroid chordomas. Conclusion: Chondromucinous tumors of the slope area include chordoma, chordoid meningioma, chondromyxoid fibroma, and myxoid chondrosarcoma and their correct diagnosis is mainly based on the morphological characteristics, immunophenotype and comprehensive analysis of clinical data.

Unsatisfactory response to sirolimus in Maffucci syndrome-associated spindle cell hemangiomas.

Maffucci syndrome is characterized by multiple benign vascular anomalies and enchondromas present on the distal extremities. Effective treatment options are currently not available for Maffucci syndrome-associated vascular lesions. Sirolimus is a mTOR pathway inhibitor, and has been tried successfully in the treatment of various vascular anomalies. We treated a 23-year-old female with Maffucci syndrome-associated spindle cell hemangiomas with oral sirolimus (2mg/day, 0.04mg/kg/day). There was improvement in pain, but no change in colour or size of the vascular nodules. In view of unsatisfactory response and treatment-related adverse effects (oral aphthae, mild transaminitis), sirolimus was stopped after 6 months.

Coexistence of secondary chondrosarcoma and lung carcinoma metastasis in the humerus of a patient with Ollier's disease: A case report.

Tumor-to-tumor metastasis in the same bone is an extremely rare condition. Limited number of case reports exists for coincidence of benign and malign neoplasms but none for malignant to malignant metastasis. Occurrence of several individual malignancies in the same patient may eventually cause such coexistences. We report an Ollier's disease patient with malignant transformation to chondrosarcoma complicated by a pathologic fracture and eventually whose pathological examination revealed that the lesion was not only the chondrosarcoma but an accompanying metastasis from existing lung adenocarcinoma. This report includes clinical, radiological, histological diagnostic challenges in an unexpected lesion and a review of literature.

Molecular profiling of different glioma specimens from an Ollier disease patient suggests a multifocal disease process in the setting of IDH mosaicism.

Ollier disease (OD) and Maffucci syndrome are rare conditions due to a post-zygotic somatic mutation that results in mosaicism. In addition to enchondromas and hemangiomas, some of these patients also develop other unrelated tumors, such as gliomas, that harbor IDH mutations, suggesting that an IDH mutation is a common genetic event in the tumorigenesis in this group of patients. We illustrate an interesting case of multifocal IDH-mutant astrocytomas in an OD patient with 8 years of follow-up. We first demonstrated identical IDH mutations in the brain tumor samples from various locations in this patient, but different 1p,19q results by fluorescent in-situ hybridization, different whole genome copy number profiles by OncoScan analysis, and a discrepant IDH2M131I mutation unique to one tumor, supporting a multifocal disease process in the setting of somatic IDH mosaicism.

Bilateral Forearm Pseudotumors in an Adult with Hemophilia A and Ollier Disease: A Case Report.

CASE: A 29-year-old man with mild hemophilia A and Ollier disease presented with bilateral atraumatic forearm pseudotumors. Both forearm pseudotumors were successfully treated surgically with staged radical extirpation and factor VIII replacement therapy. CONCLUSION: Pseudotumors typically occur in adolescents with severe, poorly controlled hemophilia A. The development of factor VIII replacement therapy has progressively reduced the incidence of pseudotumors in patients in the developed world. No standardized therapy exists for pseudotumors that continue to bleed into the muscles despite nonoperative measures. Persistent masses require surgical removal with careful preoperative planning and a team approach.

Chondrosarcomas of the phalanges of the hand.

OBJECTIVES: This study aims to evaluate the diagnosis and treatment approaches of the rarely seen chondrosarcomas of the phalanges of the hand. PATIENTS AND METHODS: Fifty-two patients (27 males, 25 females; mean age 41.2 years; range 12 to 70 years) with chondroid lesions localized in hand phalanges who were performed surgical treatment between December 2012 and September 2016 were retrospectively reviewed. The study included 62 phalangeal chondroid lesions. Patients' mean follow-up duration was 60.6 months (range 13 to 165 months). Incisional biopsy was performed for the diagnosis. One patient with bilateral and multiple involvement was performed tru-cut biopsy. Phalangeal chondrosarcoma was diagnosed in five patients (9.6%). RESULTS: Of the chondroid lesions, 37 were localized in proximal phalanges (59.6%), 16 in midphalanges (25.8%), and nine in distal phalanges (14.6%). Chondrosarcoma was detected in 15 phalanges of five patients. Of the two patients with Ollier disease, localization was detected in nine phalanges (four proximal, two mid, three distal phalanges) of one patient and in three phalanges (one proximal, two midphalanges) of the other patient. None of the patients had distant metastasis on diagnosis. Ray amputation was performed in two patients under general anesthesia and amputation was performed in one patient. One patient did not give consent for operation. The other patient with Ollier disease gave consent for amputation of only one finger. No local recurrence was seen. CONCLUSION: The hand localization of chondrosarcomas is rare with scarce information in the literature. Their metastasis potential is low but local recurrence rates are high after insufficient surgery. Amputation or ray amputation is the applicable treatment.

Multiple Enchondromas of the Hand in Children: Long-Term Follow-Up of Mean 15.4 Years.

BACKGROUND: Multiple enchodromatosis of bone, termed Ollier's disease, or Maffucci syndrome when associated with hemangiomas, is a rare disease that can affect the pediatric hand. This condition often causes a finger mass, deformity, pain and possible pathologic fractures, and has been associated with malignant transformation to chondrosarcoma. The aim of our study is to describe the long-term sequela of multiple enchondromatosis of the hand in the pediatric population, specifically the rates of malignant transformation, tumor recurrence, rates of pathologic fracture, and phalangeal growth arrest. METHODS: We examined 15 pediatric patients who were treated in our institute with a total of 127 phalanges and metacarpals lesions. Only patients with follow-up of at least 4 years were included. We retrospectively reviewed patients' chart and hand radiograph for symptoms including pathologic fractures, indications for surgery, and postoperative complications including tumor recurrence, and malignant transformation. We assessed phalangeal growth arrest with radiographs and normalized phalangeal growth charts. RESULTS: Mean age of diagnosis was 5.8 years and mean follow-up time was 15.4 years. Pathologic fractures were common at 46% of pediatric patients, but ceased to occur once reaching adulthood. Outcomes of pathologic fractures were excellent, regardless of treatment. Malignant transformation occurred in 1 patient and did not occur during childhood. A total of 80% of patients and 29% of lesions underwent surgical treatment of curettage and bone graft for the lesion, yet recurrence was common and affected 33% of treated patients. Phalangeal growth arrest was the most common long-term sequela and affected 11% of phalanxes and metacarpals. This sequela was significantly more prevalent in patients who had surgical excision of the tumor. CONCLUSIONS: Our findings reassure that malignant transformation of enchodromatosis of the hand is unlikely in the pediatric population. Pathologic fracture is common, but has excellent outcomes. When considering surgery, parents should be counseled about the possibility of phalangeal growth arrest and recurrence of the lesion. TYPE OF STUDY/LEVEL OF EVIDENCE: Level IV-therapeutic.

Enchondromatosis-associated oligodendroglioma: case report and literature review.

Enchondromatosis is a rare skeletal disorder characterized by the development of multiple enchondromas, which can also manifest non-cartilage tumors including gliomas. Here, we describe a genetic analysis of a low-grade glioma that developed in an enchondromatosis case. A 32-year-old man with a long history of enchondromatosis developed a left frontal tumor. The histopathological findings of his surgical specimen revealed characteristics of a low-grade glioma with an IDH1 c.395G>A (R132H) mutation and 1p/19q codeletion, which led to a definitive diagnosis of oligodendroglioma. A common point mutation in IDH1 (R132H) was detected in the patient's enchondroma and glioma-matched pair specimens. To the best of our knowledge, this is the first case of molecularly confirmed oligodendroglioma associated with enchondromatosis. Furthermore, identification of a common IDH1 mutation in enchondroma and oligodendroglioma-matched pair specimens supports the hypothesis that IDH1/2 mosaicism initiates tumorigenesis.