Epithelioid and spindle cell rhabdomyosarcoma with FUS-TFCP2 or EWSR1-TFCP2 fusion: report of two cases.

The WHO Classification of Tumors of Soft Tissue and Bone divides rhabdomyosarcoma (RMS) into alveolar, embryonal, pleomorphic, and spindle cell/sclerosing types. Advances in molecular diagnostics have allowed for further refinement of RMS classification including the identification of new subtypes. Very rare RMS with epithelioid and spindle cell morphology, female predominance, marked osseous predilection, ALK expression, EWSR1/FUS-TFCP2 gene fusions, and highly aggressive clinical behavior have recently been recognized with only 23 cases reported in the English language literature. Herein, we report two additional cases with detailed clinicopathologic description and molecular confirmation. In brief, two young women presented each with a primary bone tumor-one with a frontal bone tumor and another with an osseous pelvic tumor. Both tumors showed epithelioid to spindle cell morphology, ALK expression, and EWSR1/FUS-TFCP2 gene fusions. Both patients died of disease less than 17 months from diagnosis despite administration of multiple lines of aggressive treatment. In addition, we review the literature and discuss differential diagnostic and potential treatment considerations.

Middle Ear and Temporal Bone Nonkeratinizing Squamous Cell Carcinomas With DEK-AFF2 Fusion: An Emerging Entity.

Primary squamous cell carcinomas (SCCs) of the middle ear and temporal bone are rare and usually keratinizing by morphology. Nonkeratinizing, basaloid SCCs arising in this area are exceedingly rare, and, due to the anatomic proximity to the skull base, nasopharynx, and nasal sinuses, the differential diagnosis is broad. Most tumors with squamous differentiation arising in these subsites are either viral-induced (human papillomavirus/Epstein-Barr virus) or rarely may have specific molecular alterations (BRD4-NUT, EWSR1-FLI translocations). Occasional tumors are negative for these findings, and their pathogenesis is unknown. A recently discovered DEK-AFF2 fusion was clinically detected in a series of 2 cases known to the authors. This fusion has been previously reported in the literature in a patient with a base of skull tumor who was an exceptional responder to programmed cell death protein 1 inhibitor therapy. We examine here the histomorphologic and molecular findings of 2 additional cases of an emerging entity. Two male patients were identified. Each had a primary middle ear/temporal bone mass with locally advanced disease. The histology was reviewed, and immunohistochemistry was performed. RNA-based next-generation sequencing was performed for clinical detection of diagnostic or actionable fusions. Both patients had basaloid/nonkeratinizing tumors on biopsy. They were positive for markers of squamous differentiation (HMWK, CK5, and p40). By RNA sequencing, they demonstrated the presence of a DEK-AFF2 fusion and were negative for EWSR1 and NUT translocations. The DEK-AFF2 fusion may define a novel diagnostic category of middle ear and temporal bone nonkeratinizing/basaloid SCCs. This fusion also may represent a potential avenue for immunotherapy in these patients. Further studies are needed to fully explore whether this fusion defines a location-specific clinicopathologic entity.

A Novel COL1A1-CAMTA1 Rearrangement in Cranial Fasciitis.

Cranial fasciitis is an uncommon benign fibroblastic tumor, generally histologically identical to nodular fasciitis. It develops almost exclusively in children. Cranial fasciitis manifests clinically as a painless rapidly growing solitary nodule in the head and neck area, frequently eroding the underlying bone. Thus, this entity is often confused with aggressive lesions such as sarcomas, both clinically and radiologically. Histopathologic examination is essential to differentiate between cranial fasciitis and fibrohistiocytic or even sarcomatous lesions observed in children. In this article, we present a case of cranial fasciitis with intracranial extension in a 2-year-old boy. Although USP6 rearrangement has recently been recognized as a recurring alteration in nodular fasciitis, we present a novel COL1A1-CAMTA1 fusion in this lesion.

Congenital dermoid inclusion cyst over the anterior fontanel in Chinese children.

Congenital dermoid inclusion cyst (CDIC) over the anterior fontanel is a rare and benign tumor. This study reports nine Chinese cases (three females and six males) with CDIC over the anterior fontanel. The clinical manifestations and imaging were analyzed retrospectively. Surgical resection was undertaken in all cases. The diagnosis of CDIC over the anterior fontanel was confirmed by histological examination. The cysts were all noticed soon after birth and enlarged gradually. They were soft, nontender with a sessile base without inflammatory signs and breaking. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed soft tissue mass over the anterior fontanel without intracranial extensions. The histopathological examination displayed stratified squamous epithelium with skin appendages. There were no complications or recurrence after operation during a follow-up for one year. CDIC over the anterior fontanel is a benign tumor. Imaging is recommended preoperatively to aid differential diagnosis. The main management is total excision with good prognosis.

Molecular findings in maxillofacial bone tumours and its diagnostic value.

According to the WHO, mesenchymal tumours of the maxillofacial bones are subdivided in benign and malignant maxillofacial bone and cartilage tumours, fibro-osseous and osteochondromatous lesions as well as giant cell lesions and bone cysts. The histology always needs to be evaluated considering also the clinical and radiological context which remains an important cornerstone in the classification of these lesions. Nevertheless, the diagnosis of maxillofacial bone tumours is often challenging for radiologists as well as pathologists, while an accurate diagnosis is essential for adequate clinical decision-making. The integration of new molecular markers in a multidisciplinary diagnostic approach may not only increase the diagnostic accuracy but potentially also identify new druggable targets for precision medicine. The current review provides an overview of the clinicopathological and molecular findings in maxillofacial bone tumours and discusses the diagnostic value of these genetic aberrations.

Primary Low-Grade B-Cell Lymphoma of Skull With Translocation Between Immunoglobulin and Interferon Regulatory Factor 4 Genes.

Low-grade B-cell lymphoma with immunoglobulin (IG) and interferon regulatory factor 4 (IRF4) gene rearrangement is extremely rare, with only 4 cases being previously reported. In this article, we report one additional case that arises from the skull and review the literature. The patient was a 69-year-old man who presented with recurrent and disabling vertigo and was found to have a 5.0 × 1.7 cm lesion within the left posterior parietal bone. Histological examination revealed a bone lesion with diffuse lymphoid infiltrate comprising of mostly small lymphocytes with scant cytoplasm, slightly irregular nuclei and inconspicuous nucleoli, and scattered larger cells resembling prolymphocytes and paraimmunoblasts. Immunohistochemical studies showed that the neoplastic cells were positive for CD20, CD79a, PAX5, CD23, CD43, BCL-2, BCL-6, MUM-1, LEF-1, and IgM and negative for CD5, CD10, cyclinD1, SOX11, and IgD. Flow cytometric analysis identified CD5 negative and CD10 negative monoclonal B cells with lambda light chain restriction. Fluorescence in situ hybridization analysis revealed del(13q) abnormality, but was negative for IGH/BCL2, IGH/CCND1, and BIRC3/MALT1 translocations. Next-generation sequencing identified IGK-IRF4 rearrangement and BRD4 E1113 del abnormalities. Given a low clinical stage (IE) of the disease, the patient did not receive additional treatments and was free of disease at 1 year after the diagnosis.

Giant Cell Lesions of the Maxillofacial Skeleton Express RANKL by RNA In Situ Hybridization Regardless of Histologic Pattern.

Maxillofacial central giant cell lesions (CGCLs) are often locally aggressive tumors in young patients that may be histologically very similar to or quite distinct when compared with giant cell tumors (GCTs) of long bones. It has been well established that GCTs express high levels of receptor activator of nuclear factor-kappa B ligand (RANKL) and are amenable to treatment with denosumab. To assess the predictive value of morphology, we evaluated CGCLs with GCT-like or non-GCT-like histology for RANKL expression by RNA in situ hybridization. Tumors were classified by clinical and radiographic criteria as aggressive or nonaggressive and histopathologically as resembling GCT or non-GCT-like. RNA in situ hybridization for RANKL mRNA was performed and scored semiquantitatively based on the magnification at which the signal was first detected. There were 17 patients (M:F=8:9) with a median age of 15 years. Nine patients were children under 18 years of age. In 10 patients, tumors were characterized as GCT-like and in 7, non-GCT-like; 6 occurred in the setting of a known associated syndrome. Of the sporadic tumors, 9/11 (82%) were classified as aggressive. Fifteen of 17 (88%) tumors strongly expressed RANKL (8/9 aggressive, 2/2 nonaggressive; 10/10 GCT-like and 5/7 non-GCT-like). Two patients with clinically aggressive CGCL, GCT-like histology and high tumor RANKL expression were identified as candidates for a trial of denosumab with notable clinical response. CGCLs demonstrate strong and diffuse RANKL mRNA expression in mononuclear stromal cells, regardless of histology or presence of an associated syndrome. Denosumab may be clinically beneficial in aggressive CGCLs.

Intra-Extracranial Primary Clear Cell Sarcoma: The First Report and Review of the Literature.

BACKGROUND: Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor with poor prognosis owing to metastasis and insensitive response to chemotherapy and radiotherapy. METHODS: We first searched PubMed and Embase using the terms "clear cell sarcoma," "malignant melanoma of soft tissue," "head," and "neck." In the 15 articles selected for literature review, only 27% (4/15) of patients were diagnosed with primary CCS of the head. Pathologically, those tumors arose from either the scalp or the superficial temporal fascia, but none invaded the skull and brain. Next, the search was performed in the same database using the terms "clear cell sarcoma," "malignant melanoma of soft tissue," and "bone," and only 24 articles were selected. RESULTS: In the case reported here, a 36-year-old woman was found to have a palpable mass located at the left temporal-occipital region, and surgical finding confirmed the invasion into the skull and the brain. The diagnosis of primary CCS was made because of the detection of t(12;22)(q13;q12) in >50% of tumor cells by fluorescence in situ hybridization, and metastasis to the lymph nodes and lungs was discovered by postoperative positron emission tomography-computed tomography. CONCLUSIONS: To the best of our knowledge, this is the first case of primary central nervous system CCS. Primary CCS may involve the skull and should be one of the differential diagnoses for intra-extracranial communicating tumors. Further research on biological characteristics and molecular targeted therapy of CCS are needed to improve its poor prognosis.

Double-Hit Lymphoma (MYC and BCL6) with Involvement of Skull and Adnexal Lesions: A Case Report and a Review of the Literature.

BACKGROUND Double-hit lymphomas (DHL) belong to a category of very aggressive lymphomas characterized by MYC translocation and either BCL2, or less commonly, BCL6 translocations. Those with BCL6 translocations have a predilection for rare extranodal sites such as the gastrointestinal tract, nasopharynx, and tonsils. Involvement of the skull and adnexal structures is rare. Here we report a case of a young female with both skull and adnexal involvement. CASE REPORT A 20-year-old female who presented with hypercalcemia was found to have adnexal, skull, and jaw masses. Workup revealed a stage IV high grade B-cell lymphoma (HGBL) with MYC and BCL6 rearrangements. She was subsequently treated with R-EPOCH and attained complete remission 9 months after her initial presentation. To the best of our knowledge, our patient represents the first reported case of skull and adnexal involvement in HGBL with MYC and BCL6 rearrangement. CONCLUSIONS Rare extranodal presentations of HGBL with MYC and BCL6 rearrangement should be considered in the differential diagnosis of masses found in unusual sites such as the skull and adnexa. Due to their aggressive nature, early and prompt recognition of these lymphomas is essential for timely administration of appropriate therapy.

Targeted next-generation sequencing of malignant peripheral nerve sheath tumor of the pterygopalatine fossa with intracranial metastatic recurrence.

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon neoplasm that rarely involves the head and neck region. Intracranial MPNSTs unrelated to cranial nerves are highly malignant tumors with poor overall survival, probably because of infiltrating growth into surrounding brain tissue. The pathogenesis of MPNST remains unclear. There are no conclusive explanations for the mechanisms underlying the initiation, progression, and metastasis of MPNST. In this paper, we describe a case of MPNST in the pterygopalatine fossa with intracranial metastatic recurrence and review related literatures. Meanwhile, targeted next-generation sequencing (NGS) revealed the presence of both a beta-catenin (CTNNB1) missense mutation p.Ser33Phe and a mediator complex subunit 12 (MED12) frameshift mutation p.Tyr1278fs in the recurrent intracranial tumor. Therapies that target CTNNB1 mutation, MED12 mutation, CTNNB1 activation, or Wnt pathway activation are worth future studying.

Poorly differentiated chordoma with loss of SMARCB1/INI1 expression in pediatric patients: A report of two cases and review of the literature.

Identification of loss of SMARCB1/INI1 expression in poorly differentiated (PD) chordoma in pediatric patients suggests that PD chordoma is an entity molecularly distinct from conventional chordoma or atypical teratoid/rhabdoid tumor, which is also characterized by loss of SMARCB1/INI1 expression by inactivating mutation of the SMARCB1/INI gene. So far, around 20 cases of pediatric PD chordoma with loss of SMARCB1/INI1 expression have been reported. Here, we report two cases of pediatric PD chordoma with loss of SMARCB1/INI1 expression, which is very rare among the pediatric chordoma types. Both patients presented clival masses on preoperative MRI. Histologically, both tumors had nonclassic histologic features for conventional chordoma: sheets of large epithelioid to spindle cells with vesicular nuclei and prominent nucleoli. Both cases revealed nuclear expression of brachyury, loss of SMARCB1/INI1 expression and lack of embryonal, neuroectodermal, or epithelial component. One case showed heterozygous loss of EWSR1 gene by break-apart fluorescence in situ hybridization that reflected loss of SMARCB1/INI1 gene. Based on the clival location and histologic findings along with the loss of SMARCB1/INI1 expression and positivity for nuclear brachyury staining, the final pathologic diagnosis for both cases was PD chordoma.

Unusual skull tumors with psammomatoid bodies: a diagnostic challenge.

AIM: We describe a series of three diagnostically challenging, histologically similar fibro-osseous skull masses. METHODS: The cases were identified in our archives among 50,000 neuropathology specimens. A comprehensive review of the histological, immunohistochemical, ultrastructural, and imaging features as well as the clinical outcome was performed. RESULTS: The routine histology was similar in all 3 cases and showed spindle cell proliferations with frequent calcospheres or psammomatoid bodies. There was no evidence of an underlying subdural component. Immunohistochemistry for the meningioma markers EMA and SSTR2A raised the possibility of intraosseous meningioma, as all 3 lesions were convincingly positive for epithelial membrane antigen (EMA) and 1 lesion was convincingly positive for the somatostatin receptor subtype 2A (SSTR2A); weak, questionable positivity for SSTR2 was present in the remaining 2 cases. In addition, electron microscopy was available in 1 case and showed features consistent with meningioma. CONCLUSIONS: Overall, the findings were most consistent with intraosseous meningioma. Primary intraosseous meningiomas are rare lesions that may present a diagnostic challenge. It is important to consider meningiomas in the differential diagnosis, as extradural meningiomas are associated with an increased risk of recurrence and may occasionally undergo malignant transformation.
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AN AGGRESSIVE TEMPORAL BONE SDHC PARAGANGLIOMA ASSOCIATED WITH INCREASED HIF-2α SIGNALING.

OBJECTIVE: To describe a patient with a germline succinate dehydrogenase (SDHC) gene mutation presenting with primary hyperparathyroidism and a large catecholamine-producing temporal bone paraganglioma (PGL). METHODS: Evaluation of a SDHC mutation-positive PGL tumor biology using staining for tyrosine hydroxylase (TH), hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α). RESULTS: A 66-year-old man was noted to have a lytic skull base mass during work-up for his primary hyperparathyroidism. Biochemical evaluation with 24-hour urine catecholamines and metanephrines revealed marked elevation of norepinephrine and normetanephrine. Genetic testing revealed a germline SDHC mutation. A partial excision of skull base tumor was performed, which upon further examination revealed PGL. Immunohistochemistry of skull base PGL demonstrated heavy expression of TH and HIF-2α but reduced expression of HIF-1α. The remaining skull base PGL was treated with adjuvant radiation therapy. The patient's normetanephrine levels significantly decreased after surgery and radiation. CONCLUSION: Here, we report an unusual case of a patient presenting with a germline SDHC mutation-related functional PGL along with concomitant primary hyperparathyroidism. The present case illustrates that overexpression of HIF-2α but not of HIF-1α is linked to the pathogenesis of SDHC mutation-related PGL, and it may be responsible for the aggressive clinical behavior of a usually indolent course of SDHC-related PGLs.

Atypical cartilaginous tumor/chondrosarcoma, grade 1, of the mastoid in three family members: A new entity.

We present a case series of a family with three members having cartilaginous tumors of the mastoid. All patients presented between the ages of 9 to 12 years with acute onset facial nerve paralysis. Histologic analysis of all tumors showed similar features, consistent with atypical cartilaginous tumors/chondrosarcoma, low-grade. Conventional cytogenetic analysis performed on one of the sons' tumor showed no evidence of chromosomal abnormality. High-resolution array comparative genomic hybridization performed on the same patient's blood also showed no unbalanced chromosomal abnormality. This is the first report of family members with this unusual combination of clinical, radiologic, and histologic finding. Laryngoscope, 126:E310-E313, 2016.

Benign Fibro-Osseous Lesions of the Craniofacial Area in Children and Adolescents: A Review.

Benign fibro-osseous lesions (BFOL) of the craniofacial area are represented by a variety of morphologic processes that are characterized by pathologic ossifications and calcifications in association with a hypercellular fibroblastic marrow element. The current classification includes neoplasms, developmental dysplastic lesions and inflammatory/reactive processes [5]. The final diagnosis depends on-clinical, radiological and pathological features. The clinico-pathologic features of this heterogeneous group of diseases are presented in this article.

Chromosome 12 long arm rearrangement covering MDM2 and RASAL1 is associated with aggressive craniofacial juvenile ossifying fibroma and extracranial psammomatoid fibro-osseous lesions.

To evaluate the diagnostic value of MDM2 status in craniofacial fibro-osseous lesions, we investigated MDM2 expression by immunohistochemistry and analyzed MDM2 amplification by qPCR in 30 cases of ossifying fibroma (including 13 cases of the juvenile variant) and 17 cases of fibrous dysplasia. Two cases of uncommon extragnathic psammomatoid fibrous dysplasia and a mixed control group of 15 cases of low-grade osteosarcoma and 15 cases of well-differentiated/dedifferentiated liposarcoma were included. MDM2 amplification was found in 33% of ossifying fibromas (peak of 69% for the juvenile variant) and in 12% of fibrous dysplasia, in none of which was MDM2 overexpressed. All control cases exhibited MDM2 amplification and overexpression. To investigate possible polysomy of chromosome 12, we studied RASAL1 amplification, a gene telomeric to MDM2 on the long arm of chromosome 12. RASAL1 amplification was reported in all benign fibro-osseous lesions exhibiting MDM2 amplification but not in controls. Simultaneous amplification of these two genes was significantly higher in juvenile ossifying fibromas compared with fibrous dysplasia (P=0.004), non-juvenile ossifying fibromas (P=0.001), and all other benign craniofacial fibro-osseous lesions combined (P=0.0001). Of the nine cases of juvenile ossifying fibroma exhibiting amplification, three were locally invasive and four were recurrent, suggesting aggressive disease. The two cases of extragnathic psammomatoid fibrous dysplasia also showed MDM2 and RASAL1 amplification with no MDM2 overexpression. This large chromosome 12 rearrangement, spanning MDM2 and RASAL1, is the first recurrent molecular abnormality to be reported in juvenile ossifying fibroma. It may represent both a molecular diagnostic marker and a characteristic of more aggressive forms with a higher risk of recurrence. Finally, the presence of this rearrangement in extragnathic psammomatoid fibro-osseous lesions mimicking ossifying fibromas might reflect a common molecular pathway in their pathogenesis and calls into question the classification of such lesions within fibrous dysplasia.

Protuberant fibro-osseous lesions of the temporal bone: two additional case reports.

The most commonly encountered fibro-osseous lesions of the skull bone are fibrous dysplasia and ossifying fibroma. Two cases of a unique "protuberant fibro-osseous lesion of the temporal bone" were first described by Selesnick and colleagues in 1999, and 2 further cases were reported in 2010 under the name "Bullough lesion". We recently found 2 new cases of this rare entity. Two Korean female patients aged 70 and 54 years presented with slow growing postauricular masses without pain or tenderness for 6 and 7 years, respectively. Computed tomography revealed a 2.9 cm calcified mass in the temporal bone of the first patient, and a 5.5 cm enhancing mass with internal cartilaginous matrix in the temporal bone of the second patient. Intramedullary or intracranial extension was not found in either case, and en bloc removals were performed. Microscopically, multiple round to oval osseous islands were scattered throughout the bland fibrous stroma in both cases. The osseous islands varied in size and were lamellar or woven, without osteoblastic rimming, and surrounded by fibroblastic bands. Neither patient has shown evidence of postoperative recurrence for 18 months. The location, histology, and clinical course of these 2 cases were identical to the 4 cases previously reported, although age and sex varied. The lesions were tested for the R201H mutation in the GNAS gene, which is present in fibrous dysplasia. No mutations were found, suggesting a different genetic background for these lesions.

Gardner's syndrome: a clinical and genetic study of a family.

OBJECTIVE: Gardner syndrome (GS) is an autosomal dominant genetic disorder with almost complete penetrance (80%) and variable expression. GS is a variant of familial adenomatous polyposis and characterized by extracolonic manifestations including osteomas and soft tissue tumors (desmoid tumors, epidermoid cysts). We describe clinical and surgical approaches in a family in which the genetic disorder was diagnosed in 3 generations. STUDY DESIGN: The studied family underwent clinical history and instrumental and genomic studies. Two members of this family, affected with GS, underwent surgery for skeletal osteomas. RESULTS: The patients that we treated with clinical-instrumental monitoring for a period of 5 years had no major disturbances of the stomatognathic system and no clinical signs of pathology of the gastrointestinal tract, eyes, or endocrine systems. CONCLUSIONS: The orofacial complex disorders are exclusively functional and esthetic, concerning primarily the stomatognathic system. We had no cases of malignant transformation of osteomatosis lesions. Clinical sequelae are manly facial eumorphy and occlusion problems of the temporomandibular joint.

Myoepithelioma of the skull: a case report.

BACKGROUND AND IMPORTANCE: Myoepithelioma of bone is a rare osseous tumor thought to be related to myoepithelial lesions found at other anatomic sites such as the salivary gland and skin. These tumors are composed of varying proportions of epithelial and myoepithelial cells and exhibit a spectrum of biologic behavior ranging from benign to malignant. We present the first reported case of myoepithelioma of the skull. CLINICAL PRESENTATION: A 20-year-old white woman presented with a persistent right parieto-occipital skull nodule, relating its presence to a fall on the site 2 years previously. The nodule had become painful in the past 2 months. Her past medical history and workup were otherwise unremarkable. The initial biopsy was inconclusive for diagnosis. The lytic bone lesion was subsequently resected, and histopathological examination showed a proliferation of epithelioid cells in a myxochondroid background. Fluorescence in situ hybridization studies revealed a rearrangement of the EWSR1 locus. The morphologic and molecular findings were consistent with the diagnosis of myoepithelioma of bone. CONCLUSION: Six months after surgery, the patient is doing well with no evidence of recurrence. This case illustrates the clinical presentation, histopathology, and molecular findings of a myoepithelioma of the skull with successful surgical treatment. Because myoepitheliomas with benign morphological appearance may rarely act aggressively, long-term clinical follow-up is warranted.