An Unusual Bump on the Head: Intracranial and Extracranial Cytokeratin-Positive Interstitial Reticular Cell Tumor.

BACKGROUND: We describe a cytokeratin positive interstitial reticulum cell tumor (CPIRCT) as the cause of a large and defacing scalp tumor. Clinically these tumors manifest as progressive, painless swelling. Treatment usually consists of surgery with or without irradiation; chemotherapy is applied in metastatic disease. CASE DESCRIPTION: A patient was referred after attempted removal of a large bump on the head. The tumor was initially noted about 12 months earlier. Assuming a benign lipoma, resection without prior imaging was attempted. During surgery, the underlying bone was found to be profoundly destroyed. Cranial magnetic resonance imaging revealed a large mass with an extracranial and intracranial component. Subsequent extensive resection finally led to the diagnosis of CPIRCT. CONCLUSIONS: Most CPIRCTs manifest as progressive palpable or visible masses. Radical excision is usually the mainstay of treatment, although there is no generally accepted treatment strategy. A needle biopsy might not be diagnostic and can complicate future curative surgery. Especially in fast-growing lesions, imaging studies should be considered before surgery. Their potential recurrence and metastatic spread render CPIRCTs an interdisciplinary challenge and highlight the need for long-term follow-up.

Clinical Characteristics and Surgical Features of Intracranial Fibrosarcoma.

BACKGROUND: Intracranial fibrosarcoma is an extremely rare neoplasm in the central nervous system. Insofar there were only sporadic case reports describing its features. The purpose of this study is to review the clinical and surgical features of cases who were treated in our department. METHOD: The authors retrospectively reviewed and detailed the clinical and surgical data obtained from 5 patients with fibrosarcoma who underwent treatment at our institute between January 2009 and January 2019. RESULTS: There were 3 males and 2 females including 2 juvenile and 3 senior patients. The most frequent sign was intermittent pain and vomiting. The location of the tumor included middle fossa, thalamus and midbrain, sellar and suprasellar region and right parietal-occipital lobe. Surgical observation demonstrated the consistency of the tumor was tenacious with abundant blood supply. Gross total resection was achieved in 2 cases. Pathological analysis showed spindle cells in a herringbone form with positive Vimentin staining in all 5 cases, with the absence of GFAP or S-100. All 5 patients were deceased eventually after a varied period of time after the first surgery. CONCLUSION: Intracranial fibrosarcoma was a highly malignant entity presented in the central nervous system. Surgery still remains the first-line treatment followed by radiotherapy, however, the prognostic outcome was very poor. Future studies should be more focused on accumulation of the relevant information on this disease thus hopefully in assisting to developing more optimized treatment.

Myeloid sarcoma involving the greater wing of the sphenoid bone and additional skeletal sites presenting with unilateral proptosis and fevers.

We report a case of myeloid sarcoma with multifocal skeletal involvement, including the greater wing of the sphenoid bone. A 23-month-old boy presented with left-sided proptosis and fevers, and was found to have an infiltrative mass involving the left sphenoid bone on orbital imaging. Full body imaging further demonstrated multiple bony lesions in the pelvis, thoracic and lumbar vertebrae, bilateral femura, and left humerus, and biopsies of the humerus were consistent with myeloid sarcoma. The patient was started on a standard chemotherapy regimen and is responding well. Myeloid sarcoma presenting with proptosis due to sphenoid bone involvement with simultaneous multifocal skeletal involvement is very uncommon and highlights the importance of biopsy for establishing a definitive diagnosis.

Co-existence of Langerhans cell histiocytosis and reticulohistiocytosis with initial presentation of skull lesions: A case report.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder resulting from dysregulated clonal proliferation of Langerhans cells. Reticulohistiocytosis (RH) is another rare histiocytosis caused by the proliferation of histiocytes other than Langerhans cells. Co-existence of LCH and RH in different organs and in the same skin area has not been reported. We present the case of a 20-year-old woman who initially had co-existing bone LCH and cutaneous RH. After 1 year of chemotherapy with cytarabine, bone LCH significantly improved but cutaneous LCH developed in the same area where cutaneous RH was, resulting in hybrid LCH and RH of the skin. This unique history provides some evidence to support the theory that LCH and RH originate from the same stem cells and subsequently develop into hybrid LCH and RH of the skin in a cytokine environment influenced by chemotherapy. Repeat skin biopsies may be considered for adjusting treatment regimens in LCH patients whenever pre-existing skin lesions progress.

Reappraisal of morphological and immunohistochemical spectrum of intracranial and spinal solitary fibrous tumors/hemangiopericytomas with impact on long-term follow-up.

BACKGROUND: Hemangiopericytomas (HPCs) and solitary fibrous tumors (SFTs) are unique entities in the central nervous system (CNS) and even rarer in the spine with propensity to recurrence and metastasis. Both these tumors were detected to share the NAB2-STAT6 fusion gene with frequent morphologic overlap that necessitated the need for the combined term SFT/HPC in the CNS by the World Health Organization (WHO) in 2016. AIMS: This study aims to describe the clinical outcome of intracranial and spinal SFT/HPCs based on detailed histomorphologic and immunohistochemical features. MATERIALS AND METHODS: A retrospective analysis of these tumors was conducted over a period of 10 years from January 2006 to January 2017 at our institute. Based on the elaborative assessment of morphology and immunohistochemistry, these tumors were categorized into three grades as per WHO criteria. RESULTS: A total of 13 cases were encountered involving mainly extra-axial and supratentorial regions. Among intracranial HPCs, anaplastic subtypes constituted significantly higher proportion (39%) when compared with peripheral HPCs. Peculiar morphological patterns like micropapillae and pseudoangiomatous arrangement of tumor cells were observed in high-grade tumors. A panel of immunomarkers were used to confirm the diagnosis and rule out other mimickers. Gross total resection was achieved in 54% (7/13) of the cases with local recurrence observed in 31% (4/13). Grade II tumors showed recurrence in 28% cases. No case showed distant metastasis. CONCLUSION: To conclude, not just clinical parameters but morphologic features such as unusual patterns, mitosis, and proliferative index also play a pivotal role in predicting the clinical behaviour of SFT/HPC.

Multiple Recurrent Fibromatosis With Cranial Fasciitis Characteristics in a Pediatric Patient.

Cranial fasciitis is a rare, rapidly growing, but benign fibroblastic tumor of the skull that generally presents in childhood. Local resection or curettage of the affected bone is generally curative and the tumor is thought not to recur. Cranial fasciitis is distinguished by positive cytoplasmic and nuclear beta-catenin staining. Fibromatosis is a clonal myofibroblastic nonmalignant proliferation that generally demonstrates positive nuclear beta-catenin staining. In this report, the authors present a patient with fibromatosis with cranial fasciitis characteristics in a 2.5-month-old boy who has had 7 recurrences (total 8 resections) of this fibroblastic neoplasm over 6 years of follow-up.

Serotonin, ATRX, and DAXX Expression in Pituitary Adenomas: Markers in the Differential Diagnosis of Neuroendocrine Tumors of the Sellar Region.

Differential diagnosis based on morphology and immunohistochemistry between a clinically nonfunctioning pituitary neuroendocrine tumor (NET)/pituitary adenoma and a primary or secondary NET of nonpituitary origin in the sellar region may be difficult. Serotonin, a frequently expressed marker in the NETs, has not been systematically evaluated in pituitary NETs. Although mutations in ATRX or DAXX have been reported in a significant proportion of pancreatic NETs, the mutational status of ATRX and DAXX and their possible pathogenetic role in pituitary NETs are unknown. Facing a difficult diagnostic case of an invasive serotonin and adrenocorticotroph hormone immunoreactive NET in the sellar region, we explored the immunohistochemical expression of serotonin, ATRX, and DAXX in a large series of pituitary endocrine tumors of different types from 246 patients and in 2 corticotroph carcinomas. None of the pituitary tumors expressed serotonin, suggesting that serotonin immunoreactive sellar tumors represent primary or secondary NETs of nonpituitary origin. Normal expression of ATRX and DAXX in pituitary tumors suggests that ATRX and DAXX do not play a role in the pathogenesis of pituitary endocrine tumors that remain localized to the sellar and perisellar region. A lack of ATRX or DAXX in a sellar NET suggests a nonpituitary NET, probably of pancreatic origin. One of the 2 examined corticotroph carcinomas, however, demonstrated negative ATRX immunolabeling due to an ATRX gene mutation. Further studies on a larger cohort of pituitary carcinomas are needed to clarify whether ATRX mutations may contribute to the metastatic potential in a subset of pituitary NETs.

Real-Time In Vivo Confocal Fluorescence Imaging of Prostate Cancer Bone-Marrow Micrometastasis Development at the Cellular Level in Nude Mice.

In the present report, we demonstrate in vivo fluorescence imaging of bone-marrow micrometastasis of prostate cancer at the cellular level in nude mice. PC-3 human prostate cancer cells labeled with green fluorescent protein (GFP) or red fluorescent protein (RFP) were injected into the left ventricle or intratibial bone marrow of nude mice. PC-3-GFP, as well as selected high metastatic variants of PC-3-GFP, PC-3-GFP-BM6 or PC-3-RFP were visualized by real-time fluorescence imaging, to traffic and grow in the bone marrow. Formation of bone marrow micrometastasis could be imaged at the single-cell level in live mice, using confocal microscopy. The ability to track bone marrow micrometastasis in real time at the cellular level provides a visual target for evaluating new therapeutics for this recalcitrant disease. J. Cell. Biochem. 117: 2533-2537, 2016. © 2016 Wiley Periodicals, Inc.

LPA Increases Tumor Growth and Bone Destruction Through Enhancement of Osteoclastogenic Cytokines.

BACKGROUND: Lysophosphatidic acid (LPA) production in osteoblasts has multiple effects on osteoclast formation and function and raises the possibility that LPA may serve as a signaling molecule for the reciprocal conversation of both osteoblasts and osteoclasts within the tumor-bone microenvironment for bone resorption. However, little is known on the effect of LPA in regulating the function of both cancer cells and osteoclasts in the bone microenvironment. MATERIALS AND METHODS: PC-3 tumor growth and bone destruction upon LPA administration were observed in a mouse calvarium xenograft. The osteoclastogenic cytokines produced by LPA-stimulated prostate cancer cells were also defined. RESULTS: LPA administration was found to increase PC-3 tumor growth and bone destruction in a mouse calvarium xenograft. Using a cytokine antibody array, LPA highly stimulated the expression and release of osteoclastogenic cytokines from PC-3 cells. Conditioned medium from LPA-stimulated PC-3 cells containing enhanced levels of osteoclastogenic cytokines facilitated osteoclast formation. Histopathologically, LPA administration supports the erosive type of bone destruction by PC-3 prostate cancer cells. CONCLUSION: LPA is a critical regulator in the tumor-bone microenvironment and may be a therapeutic target for patients with prostate cancer. In addition, LPA-enhanced osteoclastogenic cytokines are critical to therapeutic strategies targeting osteolytic prostate cancer.

Temporal bone carcinoma: a first glance beyond the conventional clinical and pathological prognostic factors.

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a poor prognosis in advanced cases. The dismal outcome is partially related to: the lack of reliable clinical or pathological prognostic factors and the largely unstandardized surgical and integrated treatments adopted. There is an undeniable need for novel diagnostic/therapeutic strategies to improve the prognosis. The purpose of this critical review was to explore the level of available knowledge concerning the molecular markers involved in the biology of TBSCC that have a prognostic potential. The Pub-Med and Scopus electronic databases were searched without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: "temporal bone cancer", "temporal bone carcinoma", "temporal bone malignancy", "ear cancer", "ear carcinoma", and "ear malignancy". We decided preliminarily not to consider series with less than five cases. Nine retrospective case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers (HPV, vimentin, transforming growth factor ß, CD105, RECK, matrix metalloproteinase-9, MASPIN, EBV, p16, TP53 mutation, pSTAT3, relaxin-2). CD105 expression (in tumor vessel endothelial cells) and MASPIN cytoplasmic expression (in carcinoma cells) were, respectively, found directly and inversely related with the neoplasm's recurrence rate. CD105 expression was also inversely related with disease-free survival in TBSCC. A future goal of such analyses should be to ascertain the radio- and chemo-sensitivity profiles of individual TBSCCs, enabling truly personalized therapies. A further, more ambitious goal will be to find targets for therapeutic agents that might prove crucial in improving the disease-specific survival for patients with advanced TBSCC.

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.

Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone.

Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms.

Examination of survivin expression in 50 chordoma specimens--A histological and in vitro study.

Chordomas mainly arise along the axial skeleton and are characterized by their slow but destructive growth. Prognosis and quality of life are poor because treatment options are mainly limited to surgery and radiotherapy. Survivin, a member of the apoptosis inhibitor protein family, functions as a key regulator of mitosis and programmed cell death, and is overexpressed in many tumor types. The aim of this study was to determine the role of survivin in chordomas. Survivin expression was investigated in 50 chordoma samples and three chordoma cell lines using immunohistochemistry. The intensity of immunostaining was evaluated in regard to the development of recurrences. The immunohistochemical results were correlated with clinical parameters like gender, age, tumor size, and location and were performed in primary chordomas as well as in recurrent lesions. Furthermore, survivin knockdown experiments on chordoma cell lines were performed. YM155 decreased the growth behavior of chordoma cells dose- and time dependently. Transient knockdown of survivin led to a G2/M arrest, decreased proliferation, consistently induced an increase of polyploidy and morphological changes, and induced apoptosis. The resultant data from this study suggest that survivin plays a cell cycle-progressive role in chordomas. Hence, regulation of survivin by YM155 is a promising new target for the development of new therapeutic drugs.

Primary platelet-derived growth factor-producing, spindle-shaped diffuse large B-cell lymphoma of the skull: a case report and literature review.

A 39-year-old woman with a right frontal mass underwent a cranial bone tumor biopsy. Histopathologic examination of hematoxylin and eosin-stained slides showed spindle-shaped tumor cells in a storiform pattern, appearing somewhat like a sarcoma. However, the tumor cells were CD20-positive by immunohistochemical staining. Therefore, a diagnosis of spindle-shaped diffuse large B-cell lymphoma (Sp-DLBCL) was made. There have been at least 35 cases of Sp-DLBCL documented in the literature, and most were of the germinal center type, while the present case is the first report of a vimentin-positive primary Sp-DLBCL of the skull. The DLBCL in this case was immunohistochemically stained for six representative cytokines that might give rise to fibrosis, due to the evidence of fibroblastic proliferation. The DLBCL cells were positive for platelet-derived growth factor (PDGF), and some cells were also positive for tumor necrosis factor (TNF) α. Based on these findings, it was inferred that the PDGF and TNFα produced by DLBCL cells induced fibroblastic proliferation. The resultant conspicuous fibrosis caused interfibrous impingement on the DLBCL cells, which deformed them into a spindle shape. The present case is the first reported case of a PDGF-producing Sp-DLBCL.

Spontaneous subperiosteal orbital hematoma as initial presentation of metastatic lung adenocarcinoma to the skull: case report.

INTRODUCTION: Subperiosteal orbital hematoma is a rare occurrence, typically developing as a result of orbital trauma. The spontaneous formation of a subperiosteal orbital hematoma (sSOH) may also occur but is less frequent. To date there has been no documented cases of sSOH as the initial presentation of an unknown metastatic neoplasm to the skull. We provide a case of a woman with unknown lung adenocarcinoma that metastasized to the skull which caused the formation of a sSOH resulting in orbital compression syndrome. CASE REPORT: A 57-year-old female presented with double vision, retro-orbital right eye pain, and vision loss in the right eye. A magnetic resonance imaging revealed a right orbital compressive lesion with an adjacent supraorbital skull lesion and separate left frontal skull lesion. Intra-operative findings along with post-operative immunohistochemistry staining revealed sSOH resulting from a metastatic lung adenocarcinoma to the skull. Further metastatic work up also revealed an occult lung mass and multiple spinal lesions. CONCLUSION: Differential diagnosis of etiologies causing the formation of sSOH in an adult without history of trauma should include metastatic neoplasm to the skull and warrants metastatic workup. Treatment options of sSOH have included observation with spontaneous resolution; however, we opted for surgical decompression of the eye and biopsy of the skull mass.

Evaluation of the prognostic role of pSTAT3 expression in temporal bone squamous cell carcinoma.

OBJECTIVE: Temporal bone squamous cell carcinoma (SCC) accounts for less than 0.2% of all head and neck tumors. Although some progress has been made in treating this aggressive tumor, the prognosis in advanced cases remains poor. More effective therapeutic strategies need to be considered, including receptor-mediated carcinoma-targeted therapy. Phosphorylated STAT3 (pSTAT3) regulates many genes that are necessarily expressed in cancer initiation, development, and progression, being involved in proliferation, anti-apoptosis, invasion, angiogenesis, and immune surveillance evasion. The aim of the present study was to preliminarily investigate the potential prognostic role of pSTAT3 expression in temporal bone SCC. STUDY DESIGN: Retrospective clinicopathologic investigation. SETTING: Tertiary referral centers. PATIENTS: Twenty-five consecutively operated patients with primary temporal bone SCC. INTERVENTION: pSTAT3 immunohistochemical expression in primary temporal bone SCCs was assessed with the aid of computer-based image analysis. MAIN OUTCOME MEASURES: Conventional clinicopathologic parameters and pSTAT3 expression were correlated with SCC prognosis. RESULTS: pT, stage, and surgical margin status were significantly related with recurrence rate (p = 0.002, p = 0.01, and p = 0.047, respectively) and disease-free survival (DFS) (p = 0.0049, p = 0.031, and p = 0.035, respectively). pT classification was also related with disease-specific survival (DSS) (p = 0.035). The SCC recurrence rate did not correlate with pSTAT3 expression. Statistical analyses ruled out any significant difference in DFS or DSS when patients were stratified by pSTAT3 expression (>80.0% or ≤80.0%). CONCLUSION: Despite our preliminary results, the role of pSTAT3 in temporal bone SCC warrants further investigation in larger series because there is increasing evidence in preclinical models to indicate that inhibiting STAT3 phosphorylation can be a useful addition to different anticancer strategies.

Expression of the tumour-suppressor maspin in temporal bone carcinoma.

AIMS: Although it accounts for fewer than 0.2% of all head and neck tumours, temporal bone squamous cell carcinoma (SCC) is an aggressive malignancy with a poor prognosis in advanced cases. Novel therapeutic strategies should be developed focusing on specific targeted therapies. Maspin is a serpin showing tumour-suppressing activity which has therapeutic potential. The present study is the first to investigate maspin expression in temporal bone SCCs, using a series of 29 cases. METHODS AND RESULTS: Cytoplasmic maspin expression was significantly higher in the group of patients whose SCC did not recur than in the group experiencing recurrences (P = 0.029), and in G1-G2 SCCs than in G3 cases (P = 0.001). cT correlated with recurrence rate (P = 0.05), disease-free survival (DFS) (P = 0.008) and disease-specific survival (DSS) (P = 0.0043), and pT and pathological regional lymph node status correlated with recurrence rate (P = 0.008 and P = 0.03, respectively), DFS (P = 0.017 and P = 0.0049, respectively) and DSS (P = 0.008 and P = 0.0009, respectively). CONCLUSIONS: Although further studies using larger series are required, our preliminary findings suggest that cytoplasmic maspin expression has promise as a prognostic indicator of disease recurrence in temporal bone SCC, and that reactivating maspin functions in association with apoptosis-inducing or anti-angiogenic chemotherapeutic agents might be an important goal in the treatment of temporal bone SCC.