Breast tumor vascularity identified by contrast enhanced ultrasound and pathology: initial results.

Quantifiable measures of vascularity obtained from contrast enhanced color flow images were correlated with pathologic vascularity measurements in ten female patients with a solid breast mass. Each patient received Levovist Injection (Berlex Laboratories Inc., Montville, NJ). Color flow images pre- and post-contrast were obtained using an HDI 3000 unit (ATL, Bothell, WA) before removing the mass for pathologic vascularity assessments. Image-processing techniques were used to obtain both the ultrasound and pathologic vascularity measurements. Multiple linear regression found significant correlations for ultrasonic vascularity measurements post contrast and pathology (P = 0.02 and 0.06). No correlations were found between pre-contrast ultrasound and pathology. In conclusion, post-contrast ultrasonic flow measures provide a non-invasive measure of breast tumor neovascularity. However, the patient population is small, and until further patients are analyzed, these conclusions are preliminary.

Bone morphogenetic protein 2/4 in early fibromatous lesions of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification in distinct anatomic patterns. Early preosseous lesions in FOP are clinically and histologically indistinguishable from the lesions of aggressive juvenile fibromatosis (AJF). Although the genetic defect in FOP is unknown, bone morphogenetic proteins (BMPs) 2 and 4 are plausible candidates genes. To determine if there is a difference in BMP 2/4 expression in the early fibromatous lesions of the two conditions, we performed immunohistochemical studies with a monoclonal antibody to BMP 2/4 on the earliest detectable fibromatous lesions of FOP and compared them with histologically identical lesions resected from children who had AJF. Fibromatous cells from the early FOP lesions exhibited immunostaining for BMP 2/4, whereas histologically indistinguishable fibromatous cells from AJF lesions showed no evidence of BMP 2/4 immunostaining. It is incumbent on all physicians who treat patients with suspected fibromatosis to examine the toes to rule out FOP and to avoid unnecessary diagnostic biopsies because surgical trauma induces further bone formation in patients who have FOP. However, if diagnostic confusion still exists and a biopsy is performed, immunostaining with BMP 2/4 antibody may resolve the diagnostic dilemma between FOP and AJF before the appearance of heterotopic ossification is observed in the FOP lesions. Our data suggest that the BMP 2/4 subfamily of secreted proteins may be involved in the pathogenesis of the FOP lesions.

Chondromalacia patellae: an in vitro study. Comparison of MR criteria with histologic and macroscopic findings.

OBJECTIVE: To develop MR criteria for grades of chondromalacia patellae and to assess the accuracy of these grades. DESIGN: Fat-suppressed T2-weighted double-echo, fat-suppressed T2-weighted fast spin echo, fat-suppressed T1-weighted, and gradient echo sequences were performed at 1.5 T for the evaluation of chondromalacia. A total of 1000 MR, 200 histologic, and 200 surface locations were graded for chondromalacia and statistically compared. RESULTS: Compared with gross inspection as well as with histology the most accurate sequences were fat-suppressed T2-weighted conventional spin echo and fat suppressed T2-weighted fast spin echo, although the T1-weighted and proton density images also correlated well. The most accurate MR criteria applied to the severe grades of chondromalacia, with less accurate results for lesser grades. CONCLUSIONS: This study demonstrates that fat-suppressed routine T2-weighted and fast spin echo T2-weighted sequences seem to be more accurate than proton density, T1-weighted, and gradient echo sequences in grading chondromalacia. Good histologic and macroscopic correlation was seen in more severe grades of chondromalacia, but problems remain for the early grades in all sequences studied.

Synthesis of a nickel tetracarboranylphenylporphyrin for boron neutron-capture therapy: biodistribution and toxicity in tumor-bearing mice.

Nickel-2,3,7,8,12,13,17,18-octaacetic acid-5,10,15,20-tetra-[3-carboranyl-methoxyphenyl]-porphyrin octamethylester (NiTCP) was given in a Cremophor EL, a polyethoxylated castor oil, and propylene glycol emulsion to BALB/c mice bearing transplanted s.c. KHJJ mammary carcinomas. A total dose of 244 microg NiTCP/gram body weight (gbw) (54 microg B/gbw) was given in 6 i.p. injections over a 32 hr period. Observations of behavior and changes in body weight and chemical and hematological blood tests indicated little or no toxicity from NiTCP over a period of 6-90 hr after injections. Boron concentrations near tumor margins were 160-180 microg B/g at 41-90 hr after the last injection. Tumor:normal brain boron concentration ratios reached approx. 10:1 and tumor:blood ratios reached approx. 250:1 after 4 days. There was no evidence of thrombocytopenia or other potentially important toxicities. Our findings place NiTCP among the leading candidates for pre-clinical experiments aimed toward improvement upon the compounds being tested for boron neutron-capture therapy of glioblastoma multiforme.

Thickness of patellofemoral articular cartilage as measured on MR imaging: sequence comparison of accuracy, reproducibility, and interobserver variation.

OBJECTIVE: Since the thickness of cartilage is an important indicator of the status, progression and response to therapy of articular disorders, assessment of it is desirable. This study was undertaken to assess the accuracy, precision, and reliability of magnetic resonance (MR) measurements of articular cartilage. METHODS: Fifteen cadaveric patellas were imaged in the axial plane at 1.5 T. Gradient echo and fat-suppressed FSE, T2-weighted, proton density, and T1-weighted sequences were performed. We measured each 5-mm section separately at three standardized positions, giving a total of 900 measurements. These findings were correlated with independently performed measurements of the corresponding anatomic sections. A hundred random measurements were also evaluated for reproducibility and interobserver variation. RESULTS: Although all sequences were highly accurate (range r = 0.78-0.82), the T1-weighted images were the most accurate, with a mean difference of 0.25 mm and a correlation coefficient of 0.85. All sequences were also highly reproducible (mean difference between -0.09 and 0.05 mm) with little inter-observer variation (mean difference -0.04 and 0.11 mm). In an attempt to improve the accuracy of the MR measurements further, we retrospectively evaluated all measurements with discrepancies greater than 1 mm from the specimen. All these differences were attributable to focal defects causing exaggeration of the thickness on MR imaging. CONCLUSION: MR imaging is accurate, precise, and reliable as a basis for measuring articular cartilage and may potentially be usable to monitor progression of articular disorders. Care must be taken not to overestimate the thickness of areas with surface defects.

Periarticular hyperostosis and renal disease in six black lemurs of two family groups.

Proliferative periosteal disease was identified in 6 black lemurs (Eulemur macaco macaco) of 2 family groups. Bilaterally symmetric formation of periosteal new bone at the metaphyseal regions of major long bones was first detected at the stifle and tarsal areas and was detected later at the carpal areas. Bony changes were accompanied by progressive renal disease. The syndrome progressed for 6 to 16 months before the lemurs were euthanatized because of debility. Necropsy revealed changes confined to the skeleton and kidneys. Formation of new bone was detected at all affected joints, and chronic renal disease was evident in each lemur. A specific cause was not identified. Although indistinguishable histologically from hypertrophic osteoarthropathy, several important differences were apparent. Distribution of the periosteal new bone was in the metaphyseal rather than diaphyseal areas. Thoracic or gastrointestinal lesions, typically seen with hypertrophic osteoarthropathy, were not detected, and substantial renal disease was evident. A genetic component may be involved in the development of this condition.

Stability of malignant breast microcalcifications.

PURPOSE: To determine the frequency of stability in malignant microcalcifications and its relationship to specific histologic diagnoses. MATERIALS AND METHODS: During a 34-month period, microcalcifications were proved malignant in 182 patients referred for needle-guided biopsy. In 105 patients, the mammograms were compared with one or more than one previous mammogram. These patients were classified on the basis of interval change in two groups: those with stable and those with increasing or new microcalcifications. The histologic diagnoses were reviewed. RESULTS: Microcalcifications were stable for 8-63 months (mean, 25.4 months) in 26 patients (24.8%), only three (12%) of whom had invasive ductal carcinoma, which was found in 29 (37%) of the 79 patients with increasing or new microcalcifications. CONCLUSION: The odds for presence of invasive ductal carcinoma are statistically significantly lower (P < .025) among patients with stable microcalcifications than among those with increasing or new microcalcifications. Stability of indeterminate or suspicious microcalcifications is unreliable for exclusion of a diagnosis of malignancy.

Mammographically detected breast cancer. Nonpalpable is not a synonym for inconsequential.

BACKGROUND: Needle-guided breast biopsy has become a regularly recommended procedure to excise nonpalpable, questionable breast lesions detected by mammography. Whether cancers detected in this manner have a more favorable outcome than those detected by clinical examination is not clearly documented. METHODS: To address questions about the biology of mammographically detected cancer and likelihood of axillary node metastasis, as well as the accuracy of screening mammography, data from 3752 needle-guided breast biopsies and 1175 nonpalpable breast cancers were reviewed. RESULTS: Between 1974 and 1992, 3752 needle-guided biopsies were performed in 3441 women for nonpalpable breast lesions. Benign disease was disclosed in 2575 (68.7%) biopsies and malignancy in 1175 (31.3%). Of 1130 malignancies, 61.8% were invasive carcinomas; 4.8% were microinvasive ductal carcinomas; 28.5% were ductal carcinomas in situ; and 4.8% were lobular carcinomas in situ. Axillary dissection in 558 patients with invasive carcinoma revealed that 27.1% had at least one positive axillary node. Of patients with invasive cancers presenting as nonpalpable calcifications alone, 27.5% had at least one positive axillary node. CONCLUSIONS: More than one fourth of patients with nonpalpable, invasive cancer in this series had axillary node metastasis. Therefore, axillary dissection is an important treatment consideration for all patients with invasive carcinoma, despite technique of detection. Ductal carcinomas in situ detected as limited calcifications do not require axillary dissection. In this study, 31% of biopsies proved the presence of malignancy, an acceptable and appropriate benign-to-malignant ratio.

Clinical applications of serum and tissue markers in malignant disease: breast cancer as the paradigm.

Within the past few years, the measurement of serum and tissue markers, especially the latter, has assumed a more significant role influencing clinical decisions about treatment and follow-up of patients with malignant disease. Breast cancer is a useful paradigm to illustrate the types and importance of these various markers. Tissue markers, including nuclear grade, steroid hormone receptors, DNA index, ploidy, expression of oncogenes or tumor-suppressor genes, epidermal growth factors, cathepsin D, proliferating cell nuclear antigen (PCNA), Ki-67, p32, and others, may influence choices of initial treatment as well as adjuvant chemotherapy and (or) hormone administration. The serial measurement of serum markers, those currently available and those on the horizon, for example, may offer a way to monitor patients at risk for recurrent cancer. Although the current role of these markers may be controversial, as information about them is collected and refined, in the future perhaps a panel of such studies could be incorporated into forthcoming clinical staging systems for carcinoma of the breast and other malignancies to define both treatment and outcome.

The histopathology of fibrodysplasia ossificans progressiva. An endochondral process.

In order to better characterize the biological features of fibrodysplasia ossificans progressiva, we reviewed the histopathological specimens from eleven patients (twelve biopsies) who had a confirmed diagnosis of the disease. All of the biopsies had been performed in children, to exclude the diagnosis of a malignant lesion. In no instance was the diagnosis of fibrodysplasia ossificans progressiva considered before the biopsy. The results of a lesional biopsy in all eleven patients revealed normal endochondral osteogenesis at heterotopic sites. The results of biopsy of an early lesion in six children were misinterpreted as revealing a diagnosis of fibromatosis or sarcoma before the roentgenographic appearance of ossification. Immunohistochemical studies of sections of the earliest lesion demonstrated S-100 antigen positivity before the histological appearance of differentiated osteochondral tissue. The presence of congenital malformation of the great toes and of postnatal heterotopic endochondral osteogenesis strongly suggests that fibrodysplasia ossificans progressiva is a disorder of defective induction of endochondral osteogenesis. This study established the predominant histopathological findings associated with fibrodysplasia ossificans progressiva and can serve as a basis for postulation of a candidate gene in the pathogenesis of the disorder. A lesional biopsy is not needed to make the diagnosis; biopsy uniformly exacerbates the condition and should be avoided.

Subclinical ductal carcinoma in situ of the breast. Treatment by local excision and surveillance alone.

BACKGROUND: Mammography has led to earlier detection of subclinical ductal carcinoma in situ (DCIS) of the breast either as nonpalpable calcifications or as an incidental finding in a biopsy performed for another reason. Many women in whom DCIS was detected early may not be destined to have an invasive carcinoma. How should subclinical DCIS be treated if that is the case? What is the role of excision and surveillance only as an alternative to mastectomy or irradiation? METHODS: All patients with DCIS detected as nonpalpable calcifications or as an incidental finding were eligible for this study. Diagnosis was confirmed, and the histologic subtype was determined. Results of postbiopsy mammography confirmed excision of calcifications; wide local reexcision and assessment of margins was also performed in most patients. The maximum diameter of calcifications considered suitable for this treatment was 25 mm. RESULTS: Between 1978 and 1990, 70 women (72 breasts) were entered into this study (mean follow-up time, 49 months; median follow-up time, 47 months). Of this group, 66% were detected as calcifications and 33% were detected as incidental findings. The recurrence rate was 15.3%. All but one of the patients who experienced a recurrence had the comedo type of DCIS as the initial lesion. Each of the recurrences was of the comedo type. All but one recurrence was at the same site as the primary lesion. None of the patients with DCIS as an incidental finding experienced a recurrence. CONCLUSIONS: Excision and surveillance is a reasonable alternative to mastectomy or irradiation for selected women with DCIS that presents as nonpalpable calcifications or as an incidental finding.

Primary vaginal adenocarcinoma of the intestinal type associated with adenosis.

Primary vaginal adenocarcinoma unrelated to intrauterine hormone exposure is very uncommon. We report a case of a 52-year-old woman who presented with primary vaginal adenocarcinoma that showed intestinal differentiation with prominent papillary formations and numerous papillary and villous features with prominent goblet cells. There was vaginal adenosis in the immediate vicinity of the tumor. To our knowledge, this is the first reported case of a primary vaginal adenocarcinoma of the intestinal type associated with adenosis in a patient unexposed to prenatal diethylstilbesterol.

Uptake of a nido-carboranylporphyrin by human glioma xenografts in athymic nude mice and by syngeneic ovarian carcinomas in immunocompetent mice.

A tetraphenylporphyrin bearing four dicarbollide ([B9C2H11]-) cages linked to the o-phenyl ring positions by anilide bonds, known as boronated tetraphenylporphyrin (BTPP), has been synthesized in excellent yield from tetra-(o-aminophenyl) porphyrin and carborane carbonyl chloride followed by base-assisted cage opening and ion exchange to give the highly water-soluble potassium salt. Preliminary studies showed that BTPP accumulates in liver and in a syngeneic ovarian carcinoma, but not in normal brain parenchyma, of mice infused with BTPP subcutaneously for 6 or 7 days via surgically implanted osmotic minipumps. In this study, the uptake of boron was measured in human gliomas xenografted subcutaneously to athymic nude mice in which BTPP was infused intraperitoneally or subcutaneously or both for 3 or 7 days by using similar minipumps. Immunocompetent mice bearing a syngeneic ovarian carcinoma were similarly infused to provide comparative data. Bulk concentrations of boron up to 18 micrograms/g of glioma and up to 45 micrograms/g of carcinoma were observed when up to 102 micrograms/g of tissue was present in the liver after 7 days of BTPP infusion. Glioma boron concentrations were increased by approximately 80% on the average (up to 33 micrograms/g) when correspondingly greater amounts of BTPP were infused in only 3 days. Cell counts and chemical tests on blood samples from individual mice indicate that BTPP causes moderate hepatotoxicity and thrombocytopenia. This hepatohematic toxicity syndrome should be taken into account if BTPP or a similar agent is used for boron neutron-capture therapy (BNCT) of human malignancies.