BizarreParosteal Osteochondromatous Proliferation (Nora's lesion) with translocation t(1;17)(q32;q21): a case report and role of cytogenetic studies on diagnosis.

Bizarre Parosteal Osteochondromatous Proliferation (BPOP) is a benign tumor-like lesion that has recently been reported to have an association with a specific translocation t(1:17)(q32;q21)[1]. Like other reactive periosteal lesions, BPOP can be diagnostically challenging, with the ever-present possibility of a potentially devastating erroneous diagnosis of malignancy. These lesions are often clinically, radiologically and histopathologically ambiguous, with rapid but circumscribed, non-infiltrative growth patterns, and histological atypia, but without overt features of malignancy. However, recent published reports have better characterized radiological [2] as well as histological features that aid in making an accurate diagnosis. In spite of all these advances, one of the biggest challenges in making the correct diagnosis still remains the inexperience of the practicing pathologist with this lesion, simply due to its rarity. We present a case of Nora's lesion in the distal ulna of an 8 year-old girl, in which, besides the histological features, we were able to demonstrate the translocation t(1:17)(q32;q21). Thus, we would like to emphasize the utility of cytogenetic studies in the correct and rapid diagnosis of clinically and radiologically ambiguous periosteal-based lesion.

Intraneural parachordoma of the arm with regional metastases.

Parachordoma is a rare tumor, with fewer than 100 cases reported. We present an unusual presentation of a long tumor tracking along the median nerve, with regional metastasis to the axillary nodes in a 67-year-old woman. The tumor extended from the wrist proximally along the forearm to the elbow, coursing intraneurally along the median nerve. We present this case due its rarity, interesting radiographic appearance, and atypical presentation.

Non-epiphyseal chondroblastoma arising in the iliac bone, and complicated by an aneurysmal bone cyst: a case report and review of the literature.

Chondroblastoma is a benign bone tumor that typically arises in the epiphysis of a long bone. However, when it occurs in non-epiphyseal location in flat bones, it may create a diagnostic problem. We describe such a case of chondroblastoma arising in the iliac bone. A 29-year-old man was incidentally found to have a bony pelvic lesion while undergoing evaluation for Crohn's disease. The radiographs and CT revealed an expansile lytic lesion in the right iliac bone. A core biopsy of the lesion was performed. The histopathology revealed the lesion to be a chondroblastoma with secondary features of aneurysmal bone cyst. An en bloc surgical resection of the tumor was performed.

Tumor necrosis in osteosarcoma: inclusion of the point of greatest metabolic activity from F-18 FDG PET/CT in the histopathologic analysis.

OBJECTIVE: To determine if the location of the point of maximum standardized uptake value (SUVmax) being included in or not included in the histopathologic slab section corresponded to tumor necrosis or survival. MATERIALS AND METHODS: Twenty-nine osteosarcoma patients underwent post-chemotherapy [fluorine-18]-fluoro-2-deoxy-D: -glucose (FDG) positron-emission tomography-computed tomography (PET/CT) prior to resection. PET/CT images were correlated with slab-section location as determined by photographs or knowledge of specimen processing. The location of the point of SUVmax was then assigned as being 'in' or 'out' of the slab section. Cox's proportional hazard regression was used to evaluate relationships between the location and value of SUVmax and survival. Logistic regression was employed to evaluate tumor necrosis. RESULTS: No correlation was found between the SUVmax location and survival or tumor necrosis. High SUVmax correlated to poor survival. CONCLUSION: High SUVmax value correlated to poor survival. Minimal viable tumor (> 10%) following chemotherapy is a known indicator of poor survival. No correlation was found between the location of SUVmax and survival or tumor necrosis. Therefore, the SUVmax value either does not correspond to a sufficient number of tumor cells to influence tumor necrosis measurement or it was included in the out-of-slab samples that were directed to viable-appearing areas of the gross specimen. Since high SUVmax has been previously found to correspond to poor tumor necrosis, and tumor necrosis is simply an estimate of the amount of viable tumor, SUVmax likely represents many viable tumor cells. Therefore, when not in the slab section, SUVmax was likely included in the tumor necrosis measurement through directed sampling, validating our current method of osteosarcoma specimen analysis.

Targeted mutation of p53 and Rb in mesenchymal cells of the limb bud produces sarcomas in mice.

Mice bearing germ line mutations of p53 develop sarcomas at a significant rate. Since they are susceptible to a variety of other malignancies, they are not ideally suited to the study of sarcomas. To test the possibility that targeted mutation of tumor suppressor genes in early mesenchymal cells would induce formation of sarcomas, the Prx1-cre transgenic mouse was crossed to mice-bearing floxed alleles of p53 and Rb. Mice with homozygous deletion of p53 (Prx1-cre p53(lox/lox)) developed sarcomas in the extremities at a mean time of 50 weeks. Osteosarcomas (OS) were the most common type of sarcoma (61%) followed by poorly differentiated soft tissue sarcomas (PDSTS) (32%). Homozygous deletion of p53 produced sarcomas significantly more rapidly than heterozygous deletion, which resulted in sarcoma formation after a mean of 96 weeks. Mice with homozygous Rb mutation (Prx1-cre Rb(lox/lox)) developed normally and had no ostensible defects in the limbs. In contrast to p53, targeted deletion of Rb did not produce sarcomas in the limbs. However, simultaneous deletion of Rb and p53 accelerated the time to sarcoma formation, and a greater percentage of PDSTS were found. Deletion of p53 in committed osteoblasts by the Col1a1-cre transgenic mouse bearing an osteoblast-specific enhancer resulted in a high percentage of OS. These findings suggest that deletion of p53 in mesenchymal cells that give rise to osteoblasts is a powerful initiator of OS. Deletion of Rb does not initiate sarcoma formation in mice, but it accelerates formation of both soft tissue sarcomas and OS.

Risk of local recurrence after deltoid-sparing resection for osteosarcoma of the proximal humerus.

BACKGROUND: The anatomy of the shoulder poses special challenges with regard to limb-sparing surgery. Resection of the deltoid muscle is considered by some surgeons to be necessary to achieve adequate margins for osteosarcoma of the proximal humerus. However, this can compromise the functional results after reconstruction of the shoulder. The goal of the current study was to determine whether deltoid-sparing resection can be safely performed for osteosarcoma of the proximal humerus. METHODS: Between 1978 and 2005, 23 consecutive patients with high-grade nonmetastatic osteosarcoma of the proximal humerus underwent limb-sparing surgery with preservation of the deltoid muscle. All patients received neoadjuvant chemotherapy followed by surgery and postoperative chemotherapy. The mean follow-up was 90 months (range, 7 months-279 months). RESULTS: The overall survival at 5 years was 77%. At the time of last follow-up, 14 (61%) of 23 of patients were alive without evidence of disease. Three (13%) patients developed local recurrence. Two of these patients had poor responses to chemotherapy, with tumor necrosis of 50% and 70%. The third patient had a pathologic fracture of the humerus. Positive surgical margins were associated with local recurrence, and 2 of 4 patients with a positive surgical margin developed local recurrence (P = .01). CONCLUSIONS: Preservation of the deltoid muscle can be performed for carefully selected patients with osteosarcoma of the proximal humerus. Routine use of the procedure is not justified, because it may be associated with an elevated risk of recurrence. The risk of local recurrence appears to be related to positive surgical margins and possibly the percentage of tumor necrosis.

Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment.

BACKGROUND: The current study was performed to evaluate outcomes in patients with osteosarcoma of the head and neck (OHN) who were treated with surgery with or without radiotherapy (RT). METHODS: Between 1960 and 2007, 119 patients with OHN underwent macroscopic total resection with or without RT. The median age of the patients was 33 years (range, 7-77 years). Of these 119 patients 92 (77%) underwent surgery alone whereas 27 (23%) patients were treated with combined modality treatment (CMT) comprised of surgery and RT (median dose, 60 Gray [Gy]; range, 50-66 Gy). RESULTS: The median follow-up was 5.8 years. Overall survival (OS) rates at 5 years and 10 years were 63% and 55%, respectively. Corresponding disease-specific survival (DSS) rates were 67% and 61%, respectively. Stratified analysis by resection margin status demonstrated that CMT compared with surgery alone improved OS (80% vs 31%; P = .02) and DSS (80% vs 35%; P = .02) for patients with positive/uncertain resection margins. Multivariate analysis indicated that CMT for patients with positive/uncertain resection margins improved OS (P < .0001). A total of 44 (37%) patients experienced local disease recurrence (LR) and 25 (21%) developed distant metastases (DM). There was no difference noted with regard to DSS if disease recurrence was isolated (LR vs DM: 26% vs 29%, respectively, at 5 years; P = .48) The use of CMT versus surgery alone improved local control (LC) (75% vs 24%; P = .006) for patients with positive/uncertain resection margins. The rate of surgical complications was 28% at 5 years. The rates of RT-associated complications were 40% and 47% at 5 years and 10 years, respectively. CONCLUSIONS: The results of the current study indicated that RT in addition to surgery improves OS, DSS, and LC for patients with OHN who have positive/uncertain resection margins.

18F-FDG PET/CT as an indicator of progression-free and overall survival in osteosarcoma.

UNLABELLED: The aim of our study was to retrospectively evaluate whether maximum standardized uptake value (SUV(max)), total lesion glycolysis (TLG), or change therein using (18)F-FDG PET/CT performed before and after initial chemotherapy were indicators of patient outcome. METHODS: Thirty-one consecutive patients who underwent (18)F-FDG PET/CT before and after chemotherapy, followed by tumor resection, were retrospectively reviewed. Univariate Cox regression was used to analyze for relationships between covariates of interest (SUV(max) before and after chemotherapy, change in SUV(max), TLG before and after chemotherapy, change in TLG, and tumor necrosis) and progression-free and overall survival. Logistic regression was used to evaluate tumor necrosis. RESULTS: High SUV(max) before and after chemotherapy (P = 0.008 and P = 0.009, respectively) was associated with worse progression-free survival. The cut point for SUV(max) before chemotherapy was greater than 15 g/mL* (P = 0.015), and after chemotherapy it was greater than 5 g/mL* (P = 0.006), as measured at our institution and using lean body mass. Increase in TLG after chemotherapy was associated with worse progression-free survival (P = 0.016). High SUV(max) after chemotherapy was associated with poor overall survival (P = 0.035). The cut point was above the median of 3.3 g/mL* (P = 0.043). High TLG before chemotherapy was associated with poor overall survival (P = 0.021). Good overall and progression-free survival was associated with a tumor necrosis greater than 90% (P = 0.018 and 0.08, respectively). A tumor necrosis greater than 90% was most strongly associated with a decrease in SUV(max) (P = 0.015). CONCLUSION: (18)F-FDG PET/CT can be used as a prognostic indicator for progression-free survival, overall survival, and tumor necrosis in osteosarcoma.

Raymond's Paragraph System: an alternative format for the organization of gross pathology reports and its implementation in an academic teaching hospital.

CONTEXT: Traditionally organized gross pathology reports, which are widely used in pathology resident and pathologists' assistant training programs, may not offer the most efficient method of communicating pertinent information to treating physicians. Instructional materials for teaching gross pathology dictation are limited and the teaching methods used are inconsistent. Raymond's Paragraph System, a gross pathology report formatting system, was developed for use at a cancer center and has been implemented at The Methodist Hospital, Houston, Tex, an academic medical center. Unlike traditionally organized reports in which everything is normally dictated in 1 long paragraph, this system separates the dictation into multiple paragraphs creating an organized and comprehensible report. Recent literature regarding formatting of pathology reports focuses primarily on the organization of specimen diagnoses and overall report layout. However, little literature is available that highlights organization of the specimen gross descriptions. OBJECTIVE: To provide instruction to pathologists, pathology residents and fellows, and pathologists' assistant students about an alternative method of organizing gross pathology reports. DATA SOURCES: Review of pertinent literature relating to preparation of gross pathology reports, report formatting, and pathology laboratory credentialing requirements. CONCLUSIONS: The paragraph system offers a viable alternative to traditionally organized pathology reports. Primarily, it provides a working model for medical professionals-in-training. It helps create user-friendly pathology reports by giving precise and concise information in a standardized format. This article provides an overview of the system and discusses our experience in its implementation.

Use of vascularized periosteum or bone to improve healing of segmental allografts after tumor resection: an ovine rib model.

BACKGROUND: Despite technical advances, nonunion or delayed union remains an important clinical problem when segmental allografts are used to repair diaphyseal defects after bone tumor resection. Using an ovine rib model, the authors studied whether the addition of a vascularized periosteum or bone flap improved healing compared with a segmental allograft alone. METHODS: A 4-cm segment of rib was resected from four consecutive ribs of 15 sheep. Three different reconstructions were compared within the same sheep: allograft alone, allograft and vascularized periosteum, and allograft and vascularized bone. One defect was not reconstructed and served as a control. Five sheep were humanely killed at each of the following time points: 9, 12, and 15 weeks. The host-allograft junctions were analyzed using plain radiographs, micro-computed tomography, and histologic examination. RESULTS: Micro-computed tomographic analysis showed significant improvement with each reconstruction technique over time. Plain radiographs and histologic analyses demonstrated earlier bridging of the host-allograft junction when either vascularized periosteum or vascularized bone was used compared with allograft alone. CONCLUSION: Use of vascularized periosteum or bone may facilitate healing of the host-allograft junction after intercalary allograft reconstruction.

Osteosarcoma multidisciplinary approach to the management from the pathologist's perspective.

Osteosarcoma is a primary malignant tumor of the bone in which proliferating neoplastic cells produce osteoid and/or bone, if only in small amounts. This histological principle defines a tumor that usually affects young males more frequently than females, and disproportionately involves the long bones of the appendicular skeleton. These tumors are generally locally aggressive and tend to produce early, lethal systemic metastases. However, osteosarcoma is not a single disease but a family of neoplasms, sharing the single histological finding of osseous matrix production in association with malignant cells. The majority (i.e., 75%) of cases are relatively stereotypical from the demographic, clinical, radiographic and histologic points of view. These tumors generally occur in the metaphyseal portion of the medullary cavity of the long bone and are referred to as "Conventional Osteosarcoma." The group is sub classified by the form of the dominant matrix present within the tumor, which may be bone, cartilage or fibrous tissue, and it is correspondingly referred to as osteoblastic, chondroblastic and fibroblastic osteosarcoma. The remaining 25% of cases have unique parameters that allow reproducible identification of tumors which are biologically different from conventional osteosarcoma and are referred to as "Variants." The parameters identifying Variants fall into one of three major groups: (1) clinical factors, (2) histologic findings and (3) location of origin--within or on the cortex. Because of their inherent biological difference from Conventional Osteosarcoma, the Variants identify cases which must be excluded from analysis of data pertaining to the treatment of the majority of cases: Conventional Osteosarcoma. The diagnostic parameters of osteosarcoma must be sufficiently inclusive to identify all the members of this potentially lethal tumor. Conversely, criteria for sub classification must be restricted to assure homogenous populations of tumors productively incorporating different biological behavior and the potential for development of unique treatment strategies which are different from those for Conventional Osteosarcoma. This can be designated "Classification Based Therapy" or "Therapy Based Osteosarcoma." With this background, we will discuss the highly disciplined approach to the management of osteosarcoma from the pathologist's perspective. Factors governing the assessment of the response to preoperative chemotherapy will also be reviewed.

Conditions that mimic osteosarcoma.

A variety of conditions may mimic osteosarcoma. The differential diagnosis includes benign and malignant tumors, infection and inflammatory processes arising from the musculoskeletal system. An accurate clinical history, imaging studies, and pathological evaluation are essential to establish the exact diagnosis. This chapter describes many of the conditions which may mimic the diagnosis of osteosarcoma. For convenience, the conditions are divided into several categories.

Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.

PURPOSE: To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily). PATIENTS AND METHODS: Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen. RESULTS: Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm. CONCLUSION: This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.

Aneurysmal bone cysts recur at juxtaphyseal locations in skeletally immature patients.

Aneurysmal bone cysts are associated with a high rate of recurrence. Many aneurysmal bone cysts arise near open physes or articular cartilage in skeletally immature patients. Fear of damaging these structures could cause surgeons to curette the tumors less aggressively. We hypothesized location of an aneurysmal bone cyst in a periarticular or juxtaphyseal location would increase the risk of recurrence. We retrospectively studied 53 patients with aneurysmal bone cysts treated between 1989 and 2004. All patients had primary disease, and all patients underwent curettage of the lesion. Ten patients (18.9%) had local recurrence. Gender, race, and size did not predict recurrence; however 12 years of age or younger was associated with recurrence. Of the 19 juxtaphyseal cysts directly adjacent to an open physis, eight developed recurrence. Of the five periarticular cysts, two developed recurrence. The data suggest the risk of recurrence is highest in pediatric patients with juxtaphyseal or periarticular aneurysmal bone cysts. Meticulous treatment of these cysts is necessary, but we believe an overly aggressive approach that destroys the physis or articular cartilage is not warranted. Preservation of these structures remains a high priority of treatment.

Association of intratumoral vascular endothelial growth factor expression and clinical outcome for patients with gastrointestinal stromal tumors treated with imatinib mesylate.

PURPOSE: Imatinib mesylate (imatinib) has revolutionized clinical outcomes of patients with advanced gastrointestinal stromal tumor (GIST). However, the degree of individual benefit varies, and little is known about prognostic factors for these patients. Importantly, selected patients may be treated with an approach to target both Kit and vascular endothelial growth factor receptor (VEGFR) expression. EXPERIMENTAL DESIGN: Using tissue microarray technology, we analyzed 53 imatinib-naive GISTs for vascular endothelial growth factor (VEGF) expression from patients who then received imatinib. In multivariate analyses, we evaluated overall survival (OS) and progression-free survival (PFS) of these patients based on putative prognostic factors, including VEGF expression. In a separate study, 12 matched pre-imatinib and post-imatinib GIST patient specimens and two human GIST cell lines were assessed for VEGF production in response to imatinib. RESULTS: Independent of kit genotype, patients with GIST expressing high VEGF had inferior median PFS (7.1 months versus 29 months, P = 0.42) and median OS (20 months versus not reached at >50 months; P = 0.02) compared with weak or nonexpressers of VEGF. Non-exon 11 kit mutation predicted inferior PFS but not OS. High mitotic rate was marginally predictive of improved OS. Imatinib resulted in decreased production of VEGF in only a subset of GIST patients (2 of 12) and both cell lines. CONCLUSIONS: We present a study to address the prognostic factors for patients with GIST in the imatinib era. We present a rationale to consider exploration of a front-line therapy of GIST with a regimen targeting both Kit and VEGFR based on the presence of tumor VEGF levels.

Correlation of immunophenotype with progression-free survival in patients with gastrointestinal stromal tumors treated with imatinib mesylate.

BACKGROUND: The therapy for gastrointestinal stromal tumor (GIST) has been revolutionized by imatinib mesylate (IM). It is unknown whether the levels of KIT expression or the presence of CD34, smooth muscle actin (SMA), desmin, or S-100 protein predicts patient outcome from IM therapy. In the current study, the prognostic effects for KIT and other proteins (CD34, SMA, desmin, S-100) were analyzed in a series of GISTs in which protein expression was evaluated by immunohistochemical analysis (IHC). METHODS: The cases of 106 patients with GIST who were uniformly treated with IM at the study institution between December 15, 2000, and January 13, 2002 were evaluated retrospectively. The association between KIT intensity, CD34, desmin, SMA, S-100 protein, and progression-free survival (PFS) was studied. Kaplan-Meier analysis and the Cox proportional hazards regression model were used for statistical analysis. RESULTS: The majority of tumors arose from the stomach (37%), small intestine (35%), and colorectum (14%). KIT expression as determined by IHC was categorized as weak (10%), intermediate (32%), or strong (58%). Patient tumors expressed CD34 (75%), SMA (56%), desmin (1%), and S-100 protein (32%). Patients whose GIST had weak, intermediate, or strong KIT expression were found to have an 18-month PFS rate of 80%, 84%, and 69%, respectively (P = .30). The presence or absence of CD34, SMA, desmin, or S-100 protein did not appear to correlate with PFS after IM. CONCLUSIONS: Patients with the appropriate clinical presentation and KIT-positive GIST tumors appear to benefit from IM independent of the level of KIT or the expression of CD34, SMA, desmin, or S-100 protein by IHC.

Expression of Bcl-2 in gastrointestinal stromal tumors: correlation with progression-free survival in 81 patients treated with imatinib mesylate.

BACKGROUND: The natural history of gastrointestinal stromal tumor (GIST) has been revolutionized by imatinib mesylate (imatinib) therapy. Before imatinib, Bcl-2 expression in GIST was associated with a worse prognosis or added no additional prognostic value. To the authors' knowledge, the current study is the first to evaluate Bcl-2 expression in pre-imatinib GIST tissue samples as a prognostic marker of progression-free survival (PFS) time in patients treated with imatinib. METHODS: The cases of 81 patients with GIST who were evaluated between December 15, 2000 and September 1, 2001 were retrospectively reviewed. Clinicopathologic variables were reviewed. GIST cell morphology and patterns of Bcl-2 expression were described. The methods of Kaplan-Meier and the Cox proportional hazards regression model were used for statistical analysis. RESULTS: Sixty-one (75%) patients had tumors that expressed Bcl-2, and 20 (25%) patients had tumors that were negative for Bcl-2. All epithelioid tumors (n = 12) expressed Bcl-2 and tumors with mixed morphology exhibited Bcl-2 expression in the epithelioid component. A trend toward longer PFS for patients whose tumors expressed Bcl-2 at a greater immunohistochemical intensity was observed (20.6 mos for no Bcl-2 expression; 28.3 mos for 1++Bcl-2 expression; 31.9 mos for 1.5++Bcl-2 expression; 40.8 mos for 2++Bcl-2 expresssion; and 35.9 mos for 3++Bcl-2 expression). CONCLUSIONS: In contrast to studies performed in the preimatinib era, in which Bcl-2 was found to be a negative prognostic indicator, the current study suggests a trend toward better PFS with increasing Bcl-2 expression level in GISTs from patients subsequently treated with imatinib. Larger studies may help elucidate the influence of Bcl-2 expression on PFS after therapy with imatinib.

Postirradiation osteosarcoma of the mandible with heterologous differentiation.

Heterologous differentiation in osteosarcoma is rare, with only 17 cases previously described in the literature. We report a case of a mandibular osteoblastic osteosarcoma with rhabdomyosarcomatous differentiation in a 45-year-old man who had a history of Hodgkin lymphoma that was treated with chemotherapy and radiation. Radiographs showed a destructive osteoblastic tumor of the mandible that was proven by biopsy to be osteosarcoma. After the patient underwent neoadjuvant chemotherapy, the tumor was resected. It contained a high-grade osteosarcoma composed of osteoblastic and chondroblastic elements that had no definitive response to therapy. Within the center of the lesion was a discrete focus of pleomorphic cells with rhabdomyosarcomatous differentiation that was confirmed by immunohistochemical stains for desmin, myogenin, and myogenic differentiation antigen 1. The patient received additional chemotherapy and radiation therapy but developed lung, brain, and spinal metastases and died 7 months after surgery. To our knowledge, this is the first report of osteosarcoma of the mandible with heterologous differentiation.