TERT gene rearrangement in chordomas and comparison to other TERT-rearranged solid tumors.

Chordomas are rare, slow-growing neoplasms thought to arise from the foetal notochord remnant. A limited number of studies that examined the mutational profiles in chordomas identified potential driver mutations, including duplication in the TBXT gene (encoding brachyury), mutations in the PI3K/AKT signaling pathway, and loss of the CDKN2A gene. Most chordomas remain without clear driver mutations, and no fusion genes have been identified thus far. We discovered a novel TERT in-frame fusion involving RPH3AL (exon 5) and TERT (exon 2) in the index chordoma case. We screened a discovery cohort of 18 additional chordoma cases for TERT gene rearrangement by FISH, in which TERT rearrangement was identified in one additional case. In our independent, validation cohort of 36 chordomas, no TERT rearrangement was observed by FISH. Immunohistochemistry optimized for nuclear TERT expression showed at least focal TERT expression in 40/55 (72.7%) chordomas. Selected cases underwent molecular genetic profiling, which showed low tumor mutational burdens (TMBs) without obvious driver oncogenic mutations. We next examined a cohort of 1,913 solid tumor patients for TERT rearrangements, and TERT fusions involving exon 2 were observed in 7/1,913 (0.4%) cases. The seven tumors comprised five glial tumors, and two poorly differentiated carcinomas. In contrast to chordomas, the other TERT-rearranged tumors were notable for higher TMBs, frequent TP53 mutations (6/7) and presence of other driver oncogenic mutations, including a concurrent fusion (TRIM24-MET). In conclusion, TERT gene rearrangements are seen in a small subset (2/55, 3.6%) of chordomas. In contrast to other TERT-rearranged tumors, where the TERT rearrangements are likely passenger events, the possibility that TERT protein overexpression representing a key event in chordoma tumorigenesis is left open.

PD-L1 Expression Reveals Significant Association With Squamous Differentiation in Upper Tract Urothelial Carcinoma.

OBJECTIVES: Limited literature is available on the tumor microenvironment (TM) of upper tract urothelial carcinoma (UTUC). This study comprehensively reviews programmed death 1 receptor (PD-1)-positive and CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression on tumor epithelium (TE). METHODS: Seventy-two nephroureterectomy specimens were analyzed for PD-L1, PD-1, and CD8. One percent or more tumor and lymphohistiocyte PD-L1 expression was considered positive. TIL density by H&E was scored semiquantitatively from 0 to 3, and CD8+ and PD-1+ TILs were quantified in hotspots. RESULTS: Of the cases, 37.5% demonstrated PD-L1+ on TE. PD-L1+ TE showed an association with pathologic stage (P = .01), squamous differentiation (SqD) (P < .001), TILs by H&E (P = .02), PD-1+ peritumoral TILs (P = .01), and PD-L1+ peritumoral lymphohistiocytes (P = .002). Finally, there was a significant difference in PD-1+ peritumoral TILs in cases with SqD vs no SqD (P = .03). CONCLUSIONS: Aggressive UTUC is associated with a distinct TM. Furthermore, TM of UTUC-SqD was distinctly different from those with no SqD, warranting study in a larger cohort.

Primary Cutaneous Angiosarcoma of the Eyelid: A Diagnostic and Therapeutic Challenge.

Primary cutaneous angiosarcoma is a rare vasoformative malignant neoplasm that can present a diagnostic and therapeutic challenge. We describe a 76-year-old Caucasian man with right upper eyelid swelling and nodularity, initially suspected clinically to represent either ocular adnexal lymphoma or basal cell carcinoma. Incisional biopsy and wide resection of the mass with frozen section control of margins were interpreted as compatible with hobnail (Dabska-retiform) hemangioendothelioma. Foci of atypia were noted in the tumor, raising speculation of evolution into a more aggressive neoplasm, such as conventional angiosarcoma. The patient subsequently underwent two additional wide resections with frozen section control of margins in an attempt to obtain complete excision of residual tumor, which demonstrated histopathologic features favoring angiosarcoma. The histologic material from the original and subsequent resections was sent in consultation to several soft tissue pathology experts and the final diagnosis of low-grade cutaneous angiosarcoma was established. Despite repeated surgical interventions, there was continued persistence of the tumor in the deep orbital tissues. Various management options, including adjuvant radiotherapy/chemotherapy with and without orbital exenteration, were discussed. The patient decided against further surgical intervention and is currently undergoing adjuvant radiotherapy/chemotherapy. This case illustrates the diagnostic and management difficulties of ocular adnexal angiosarcoma.

Angiosarcoma Arising in Chronic Expanding Hematoma: Five Cases of an Underrecognized Association.

Little is known about the etiology or pathogenesis of angiosarcoma (AS). We describe a series of 5 cases of AS arising in chronic expanding hematomas. Inclusion criteria were the presence of a hematoma of at least 1-year duration and a thick fibrous wall surrounding the hematoma. Patients were 4 men and 1 woman; ages ranged from 43 to 71 years. Locations were the thigh (3), chest wall (1), and pelvic soft tissue involving the ischial bone (1). Hematoma duration ranged from 2 to 25 years. All cases had large cystic hematomas >10 cm; 2 had prior radiation. Thick fibrous walls surrounded the hematomas, with foci of hemosiderin and foamy histiocytes. Wall thickness ranged from 0.2 to 1.0 cm and varied within lesions. All AS were epithelioid, and in 3 cases the tumor invaded through the cyst wall. Immunoreactive nuclear c-myc was noted in 3/3 cases available for testing. Follow-up disclosed 4 patients developed metastatic disease, 3 of whom died of disease, 4, 8, and 15 months after diagnosis; the fourth patient is alive without disease after chemotherapy at 59 months. One patient without metastases is alive without disease 18 months after diagnosis; this tumor was confined to the cyst without penetration through the wall. We identified 4 similar cases in the literature, 3 as individual case reports (all epithelioid AS), and 1 as part of a series of AS. To our knowledge, this is the first series of AS arising in chronic expanding hematomas. Recognition of this unusual complication should alert clinicians to provide periodic clinical follow-up to these patients and to biopsy any case with sudden or uncontrolled enlargement. We recommend that excised chronic hematomas be well sampled histologically to search for AS and, if identified, to determine its extent and invasiveness.

Contemporary diagnostics: sarcoma pathology update.

Sarcoma diagnosis continues to evolve as new information is discovered. Certain tumors have been downgraded (dermal leiomyosarcoma) and an atypical category designed for others. Recently entities include myxoinflammatory fibroblastic sarcoma, myoepithelioma, and pseudomyogenic hemangioendothelioma. The terms malignant fibrous histiocytoma and hemangiopericytoma are outdated. New immunostains (STAT6, SOX10, ERG) add diagnostic specificity, and new risk assessment models are described for sarcomas where grading and staging has failed to provide adequate prognosis.

Primary intranodal epithelioid rhabdomyosarcoma.

We report an unusual, rare case of primary epithelioid rhabdomyosarcoma of a lymph node in the parotid basin. A 72-year-old man with a history of squamous cell carcinoma of the forehead and cheek had a 5-cm mobile nontender mass of the parotid tail and right level II region. A positron emission tomography/computed tomography scan confirmed a hypermetabolic soft tissue mass in the right parotid gland. Histologic sections showed an intraparotid lymph node almost completely effaced by a centrally necrotic malignant epithelioid neoplasm consisting of uniform-appearing dyshesive cells exhibiting rhabdoid morphologic features with abundant eosinophilic fibrillary cytoplasm, eccentric nuclei, and prominent nucleoli. Bizarre cells were not seen. In immunohistochemical studies, neoplastic cells expressed desmin and myogenin. Electron microscopy showed a mixture of thick and thin filaments, primitive Z-band formation, and well-formed sarcomeres. Fluorescence in situ hybridization studies for FOXO1, PAX3, and/or PAX7 rearrangements were negative. An extensive clinical and radiologic workup showed no evidence of primary tumor elsewhere. Complete resection of the tumor was performed, and adjuvant chemotherapy was given; patient was disease free 12 months after surgery.

Cervical hibernoma, a rare, benign tumor: case report.

Hibernomas are rare, benign tumors that contain neoplastic cells that are histologically similar to those of brown adipose tissue. The most common sites of these tumors have been the back and thighs; head and neck involvement has been rare. We describe the case of a 54-year-old woman who presented with a 1-year history of a large, asymptomatic, lateral neck mass. Based on imaging findings and fine-needle aspiration cytology, a hibernoma was suspected, although a liposarcoma could not be ruled out prior to surgery. The mass was completely resected. On postoperative analysis, the tumor was grossly and microscopically consistent with a cervical hibernoma. Although hibernomas are rare, they are important entities and should be considered in the differential diagnosis of a soft-tissue mass of the head or neck.

Early pleomorphic hyalinizing angiectatic tumor: precursor or distinct lesion?

Early pleomorphic hyalinizing angiectatic tumor is a rare and recently described soft tissue lesion. Originally believed to be a precursor lesion to neoplastic pleomorphic hyalinizing angiectatic tumor, and possibly identical to hemosiderotic fibrohistiocytic lipomatous lesion/tumor, there have been recent suggestions that it is distinct from pleomorphic hyalinizing angiectatic tumor and is instead a reactive process. This article reports a case of a mass in the foot of a 45-year-old woman, which is 1 of only 15 published cases of early pleomorphic hyalinizing angiectatic tumor and is the first case to describe its radiographic appearance. Early pleomorphic hyalinizing angiectatic tumor predominantly develops in the fourth to sixth decades (average age, 45 years, range, 10-67 years). Females predominate 4 to 1. The foot/ankle is the most common site (67%). On magnetic resonance imaging (MRI), the mass appeared inhomogeneously dark on T1-weighted sequences and inhomogeneously bright on fat-suppressed T2-weighted sequences. Forty-four percent of resected lesions recur locally, but no early pleomorphic hyalinizing angiectatic tumor lesion has ever metastasized. These clinical characteristics of early pleomorphic hyalinizing angiectatic tumors closely mirror those of hemosiderotic fibrohistiocytic lipomatous lesions/tumors and are dissimilar to those for classic pleomorphic hyalinizing angiectatic tumors. Therefore, although the 3 entities share several histologic features, we believe early pleomorphic hyalinizing angiectatic tumor is equivalent to hemosiderotic fibrohistiocytic lipomatous lesion/tumor and is not a true precursor to classic pleomorphic hyalinizing angiectatic tumor.

Case report: hemosiderotic fibrohistiocytic lipomatous lesion: a clinicopathologic characterization.

BACKGROUND: A hemosiderotic fibrohistiocytic lipomatous lesion, also called hemosiderotic fibrolipomatous tumor, is a rare and recently described fibrolipomatous entity. Initially considered the result of a reactive inflammatory process from trauma or vascular disease, newer evidence suggests it may be neoplastic in origin. CASE REPORT: We report the case of a 56-year-old woman with a painful mass in the dorsal aspect of the foot diagnosed as a hemosiderotic fibrohistiocytic lipomatous lesion. LITERATURE REVIEW: We reviewed all 31 published cases of hemosiderotic fibrohistiocytic lipomatous lesions looking for common clinical, imaging, and histologic patterns. Hemosiderotic fibrohistiocytic lipomatous lesions occur predominantly in the fifth and sixth decades of life (average age, 49.5 years; range, 0.67-74 years). Females predominate 22 to 9. Thirteen of 28 patients had histories of trauma or vasculopathy. Twenty-six of 31 lesions were in the foot. The MRI signal of a hemosiderotic fibrohistiocytic lipomatous lesion follows fat in all sequences. Stranding or septations also frequently are seen. Histologically, the lesions are composed of three main elements in varying proportions: mature adipocytes, spindle cells, and hemosiderin pigment. Ten of 27 resected lesions recurred. Resection types are not reported in many cases. Four of 15 lesions recurred after marginal/intralesional excision, whereas none of three lesions treated by wide excision recurred. PURPOSE AND CLINICAL RELEVANCE: The high recurrence rate may be related to the difficulty in determining intraoperatively that a resection is complete, secondary to the lack of anatomic boundaries such as a pseudocapsule. Any attempt at wide resection must weigh the morbidity of this surgery against that of a recurrence after a resection which seemed complete intraoperatively. There have been no reports of metastasis.

Spindle-cell hibernoma: a clinicopathologic comparison of this new variant.

Spindle-cell hibernoma is 1 of 4 histologic variants of hibernomas, which are rare lipomatous tumors distinguished from other lipomas by their brown fat component. This article presents a case of a spindle-cell hibernoma that developed in the groin of a 58-year-old man, and is 1 of only 5 known cases of spindle-cell hibernoma published in the scientific literature. Minimal information is available regarding the clinicopathologic characteristics of the 4 hibernoma variants: typical, lipoma-like, myxoid, and spindle-cell. Spindle-cell hibernoma is believed to be the rarest variant, accounting for approximately 2% of hibernomas. The spindle-cell variant predominantly develops in the fourth and fifth decades, with an average age at diagnosis of 42.5 years (range, 28-59 years). It has a male predilection of 4:1. Previously reported only in the posterior neck and scalp, the groin is now added to the sites of spindle-cell hibernoma occurrence. Our patient's tumor demonstrated low-attenuation on computed tomography and contained moderately-attenuating internal septae. Histologically, in addition to the multivacuolated brown fat component common to all hibernomas, spindle-cell hibernoma has a spindle-cell element without vacuolization that is CD34 positive. No prior treatment details are available on this particular variant. Our patient was treated by marginal excision and was disease free through 13 months of follow-up.

Trisomy 21 enhances human fetal erythro-megakaryocytic development.

Children with Down syndrome exhibit 2 related hematopoietic diseases: transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AMKL). Both exhibit clonal expansion of blasts with biphenotypic erythroid and megakaryocytic features and contain somatic GATA1 mutations. While altered GATA1 inhibits erythro-megakaryocytic development, less is known about how trisomy 21 impacts blood formation, particularly in the human fetus where TMD and AMKL originate. We used in vitro and mouse transplantation assays to study hematopoiesis in trisomy 21 fetal livers with normal GATA1 alleles. Remarkably, trisomy 21 progenitors exhibited enhanced production of erythroid and megakaryocytic cells that proliferated excessively. Our findings indicate that trisomy 21 itself is associated with cell-autonomous expansion of erythro-megakaryocytic progenitors. This may predispose to TMD and AMKL by increasing the pool of cells susceptible to malignant transformation through acquired mutations in GATA1 and other cooperating genes.

Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy.

Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway thought to have a key role in controlling cancer growth and thus is an important target for cancer therapy. Several inhibitors of mTOR are in clinical trials, including AP23573, which is being tested on metastatic sarcomas and other tumors. We hypothesized that a marker for the activity of mTOR, phosphorylated S6 ribosomal protein, would be predictive of clinical response to the drug, that is, high tumor expression would signify better response than low expression. This was a blinded study. Of 26 patients treated, 20 remained on study, with available paraffin blocks. Fourteen patients received AP23573 alone and six patients received AP23573 in combination with adriamycin. An antibody to the phosphorylated S6 ribosomal protein was used to stain the tumors, all high-grade sarcomas. Pretreatment biopsy or resection material was tested: the original tumor (n=6) or tumor recurrence/metastasis (n=14); either of these may have been after treatment with other agents. Staining was scored for both quantity/percentage of tumor cells and intensity. Scoring was performed without knowledge of tumor response. Staining quantity could be categorized into two natural groups: high expressors (> or =20% of tumor cells, 11 cases) and low expressors (0-10% of tumor cells, 9 cases). The high-expression group had eight stable and three progressive cases (73% stable disease); the low-expression group had three stable and six progressive cases (67% progressive disease). Chi-square analysis showed statistical significance (P< or =0.05) at this initial cutoff (10%) selected blindly. The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mTOR inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy.

Prognostic significance of MCM2, Ki-67 and gelsolin in non-small cell lung cancer.

BACKGROUND: Uncontrolled proliferation and increased motility are hallmarks of neoplastic cells, therefore markers of proliferation and motility may be valuable in assessing tumor progression and prognosis. MCM2 is a member of the minichromosome maintenance (MCM) protein family. It plays critical roles in the initiation of DNA replication and in replication fork movement, and is intimately related to cell proliferation. Ki-67 is a proliferation antigen that is expressed during all but G0 phases of the cell cycle. Gelsolin is an actin-binding protein that regulates the integrity of the actin cytoskeletal structure and facilitates cell motility. In this study, we assessed the prognostic significance of MCM2 and Ki-67, two markers of proliferation, and gelsolin, a marker of motility, in non-small cell lung cancer (NSCLC). METHODS: 128 patients with pathologically confirmed, resectable NSCLC (stage I-IIIA) were included. Immunohistochemistry was utilized to measure the expressions of these markers in formalin-fixed, paraffin-embedded tumor tissues. Staining and scoring of MCM2, Ki-67 and gelsolin was independently performed. Analyses were performed to evaluate the prognostic significance of single expression of each marker, as well as the prognostic significance of composite expressions of MCM2 and gelsolin. Cox regression and Kaplan-Meier survival analysis were used for statistical analysis. RESULTS: Of the three markers, higher levels of gelsolin were significantly associated with an increased risk of death (adjusted RR = 1.89, 95% CI = 1.17-3.05, p = 0.01), and higher levels of MCM2 were associated with a non-significant increased risk of death (adjusted RR = 1.36, 95% CI = 0.84-2.20, p = 0.22). Combined, adjusted analyses revealed a significantly poor prognostic effect for higher expression of MCM2 and gelsolin compared to low expression of both biomarkers (RR = 2.32, 95% CI = 1.21-4.45, p = 0.01). Ki-67 did not display apparent prognostic effect in this study sample. CONCLUSION: The results suggest that higher tumor proliferation and motility may be important in the prognosis of NSCLC, and composite application of biomarkers might be of greater value than single marker application in assessing tumor prognosis.

Endoscopic resection of a venous hemangioma of the optic nerve sheath.

We describe a case of a venous hemangioma that arose in the optic nerve sheath of the orbital apex in a 28-year-old man who presented with progressive vision loss. To the best of our knowledge, this is the first reported case of a venous hemangioma occurring at this location. A definitive diagnosis and partial excision was achieved via an endoscopic transsphenoethmoid approach with interactive, computer-assisted, frameless stereotactic surgical navigation. The intervention resulted in minimal morbidity, demonstrating yet again that this surgical approach is a safe and effective way to treat lesions of the orbital apex.