A Cathepsin-Targeted Quenched Activity-Based Probe Facilitates Enhanced Detection of Human Tumors during Resection.

PURPOSE: Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity-based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity-based probe (VGT-309) for fluorescence-guided surgery. EXPERIMENTAL DESIGN: We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of lung cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing lung cancer surgery. RESULTS: In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine tumors, we found that the probe selectively labeled tumors and demonstrated high tumor-to-background ratio (TBR; range: 2.15-3.71). In the Phase I human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase II trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs = 2.83 and 7.18) in real time to illustrate its successful clinical translation and potential to improve surgical management. CONCLUSIONS: This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary tumors during resection. These results may be generalizable to other cancers due to cathepsin overexpression in many solid tumors.

Gleason grade accuracy of transperineal and transrectal prostate biopsies in MRI-naïve patients.

PURPOSE: Accurate assessment of Gleason grade is essential to guiding prostate cancer management. Not all healthcare systems have universal access to prostate MRI. We investigated whether transperineal (TP) prostate biopsies provide more accurate Gleason grading than transrectal (TR) biopsies in MRI-naïve patients. METHODS: Consecutive patients undergoing TP and TR systematic prostate needle biopsies from 2011 to 2018 were analysed. Patients who underwent radical prostatectomy (RP) within 180 days of biopsies were included. Patients undergoing MRI prior to biopsies were excluded. Pathological concordance, incidence of Gleason upgrading, and correlation coefficients among biopsies and RP Gleason grade were compared. A sub-analysis for concordance in anterior prostate tumours was conducted. RESULTS: 262 patients were included (112 TP; 150 TR), the median age was 63 years, and median time from biopsy to RP was 68 days. Concordance with RP histology for TP was 65% compared to 49% for TR (p = 0.011). Biopsy technique predicted RP concordance independent of the number of cores. Gleason upgrading occurred following 24% of TP versus 33% of TR biopsies. In anterior and apical tumours, upgrading occurred in 19% of TP biopsies and 38% of TR biopsies (p = 0.027). CONCLUSION: This study suggests TP approach to prostate biopsies result in improved histological grade accuracy in men whom MRI is not available, even after controlling for number of cores. TP approach also resulted in less upgrading for lesions in the anterior and apical prostate compared to TR.

Munchausen syndrome presenting as pulmonary talcosis.

We describe a patient with self-induced inhalational pulmonary talcosis originally diagnosed as asthma. A 35-year-old female respiratory technologist developed severe asthma that was refractory to steroids and methotrexate. An open lung biopsy specimen showed scattered aggregates of refractile golden crystals within membranous and respiratory bronchioles. The particles ranged in size from 30 to 100 microm and were birefringent when viewed with polarized light. Following review of the lung biopsy specimen, the patient admitted to regularly inhaling large amounts of hospital baby powder. Analysis of the lung biopsy specimen and a sample of the hospital baby powder by x-ray energy dispersion showed identical spectroscopic peaks, including elemental peaks for magnesium silicate. Many patients with self-induced illness lack the picturesque symptomatology classically attributed to Munchausen syndrome. Awareness of these more subtle and varied patterns of presentation may aid in earlier recognition.

Erdheim-Chester disease: clinical, radiologic, and histopathologic findings in five patients with interstitial lung disease.

Erdheim-Chester disease is a clinicopathologic entity defined by a characteristic pattern of symmetric osteosclerosis caused by an infiltrate of mononuclear cells that include prominent numbers of foamy histiocytes. About half of patients have extraskeletal manifestations, including involvement of the hypothalamus/posterior pituitary, orbit, retroperitoneum, skin, lung, and heart. Pulmonary involvement is an uncommon but important manifestation of Erdheim-Chester disease because it causes significant morbidity and mortality. A review of the Mayo Clinic files produced four patients with confirmed Erdheim-Chester disease in whom lung biopsy had been performed. One additional patient was included from the University of Pittsburgh. Four patients were women. The mean age was 53.6 years (range 25-70 years). All patients had bilateral and symmetric sclerotic bone lesions characteristic of Erdheim-Chester disease, although in three the skeletal abnormalities were discovered only after lung biopsy. Four patients had dyspnea, and one also had a dry cough. One patient died 17 months after diagnosis. Chest radiographs showed diffuse interstitial infiltrates in all patients, with an upper zone predominance in three. Thoracic computed tomography (CT) scans showed thickening of the visceral pleura and interlobular septa with patchy associated fine reticular and centrilobular opacities and ground glass attenuation. Lung biopsy specimens showed an infiltrate of foamy histiocytes, lymphocytes, and scattered Touton giant cells with associated fibrosis in a striking lymphatic distribution. The infiltrate involved visceral pleura, interlobular septa, and bronchovascular bundles. Immunohistochemical stains were positive for CD68 in all cases and S-100 protein in four cases. Stains for CD1a were consistently negative. Ultrastructural studies in one case showed no Birbeck granules. Although in bone the histologic features of Erdheim-Chester disease may overlap with Langerhans' cell histiocytosis, its expression in the lung is distinct. Lung involvement in Erdheim-Chester disease has emerged as a unique radiographic and histologic entity.

The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study.

BACKGROUND: Women with breast carcinoma diagnosed before age 40 years have a greater prevalence of germline BRCA1 and BRCA2 mutations than women with breast carcinoma diagnosed at older ages. Several recognizable histologic characteristics have been identified in breast carcinoma from studies of BRCA1/2 mutation carriers who belong to multiple-case families. The authors attempted to determine whether breast carcinoma occurring before age 40 years in BRCA1 or BRCA2 mutation carriers who were not selected for family history could be distinguished histologically from one another and from breast carcinoma in women of a similar age without a germline BRCA1 or BRCA2 mutation. METHODS: The study undertook a histologic assessment of breast carcinomas diagnosed before age 40 years identified from a population-based study. RESULTS: Breast carcinoma in BRCA1 mutation carriers was associated with a distinct histologic appearance; these tumors were high grade, and had exceptionally high mean mitotic counts, a syncytial growth pattern, pushing margins, and confluent necrosis. Atypical medullary carcinoma was overrepresented in BRCA1 mutation carriers. All low grade tumors and tumors with low mitotic rates belonged to the group without BRCA1 or BRCA2 mutations. Pleomorphic lobular carcinomas and extensive intraduct carcinomas were more common in BRCA2 mutation carriers. CONCLUSIONS: Breast carcinoma occurring in women with a germline BRCA1 or BRCA2 mutation have recognizable histologic phenotypes, which may be useful in identifying individuals more likely to carry germline mutations. Histologic examination of breast carcinoma should become an important part of the evaluation of women seeking genetic testing for germline mutations in these breast carcinoma susceptibility genes.

Prostatic adenocarcinoma with glomeruloid features.

A wide variety of architectural patterns of adenocarcinoma may be seen in the prostate. We have recently encountered a hitherto-undescribed pattern of growth characterized by intraluminal ball-like clusters of cancer cells reminiscent of renal glomeruli, which we refer to as prostatic adenocarcinoma with glomeruloid features. To define the architectural features, frequency, and distribution of prostatic adenocarcinoma with glomeruloid features, we reviewed 202 totally embedded radical prostatectomy specimens obtained between October 1992 and April 1994 from the files of the Mayo Clinic. This series was supplemented by 100 consecutive needle biopsies with prostatic cancer from January to February 1996. Prostatic adenocarcinoma with glomeruloid features was characterized by round to oval epithelial tufts growing within malignant acini, often supported by a fibrovascular core. The epithelial cells were sometimes arranged in semicircular concentric rows separated by clefted spaces. In the radical prostatectomy specimens, nine cases (4.5%) had glomeruloid features. The glomeruloid pattern constituted 5% to 20% of each cancer (mean, 8.33%) and was usually located at the apex or in the peripheral zone of the prostate. Seven cases were associated with a high Gleason score (7 or 8), one with a score of 6, and one with a score of 5. All cases were associated with high-grade prostatic intraepithelial neoplasia and extensive perineural invasion. Pathological stages included T2c (three cases), T3b (four cases), and T3c (two cases); one of the T3b cases had lymph node metastases (N1). Three (3%) of 100 consecutive routine needle biopsy specimens with cancer showed glomeruloid features, and this pattern constituted 5% to 10% of each cancer (mean, 6.7%). The Gleason score was 6 for two cases and 8 for one case. Two cases were associated with high-grade prostatic intraepithelial neoplasia, and one case had perineural invasion. Glomeruloid features were not observed in any benign or premalignant lesions, including hyperplasia and intraepithelial neoplasia. Glomeruloid structures in the prostate represent an uncommon but distinctive pattern of growth that is specific for malignancy. Glomeruloid features may be a useful diagnostic clue for malignancy, particularly in some challenging needle biopsy specimens. This pattern of growth is usually seen in high-grade adenocarcinoma, often with extraprostatic extension. Further investigations are required to determine its independent predictive value and correlation with stage and Gleason score.

Prediction of extraprostatic extension of prostate cancer based on needle biopsy findings: perineural invasion lacks significance on multivariate analysis.

Extraprostatic extension (EPE) and seminal vesicle invasion (SVI) are adverse prognostic factors in prostate cancer, and their prediction before prostatectomy would be useful. Perineural invasion in needle biopsy has been advocated as a marker of extraprostatic extension, but its independent value as a predictor of stage has not been established. We studied 349 previously untreated men with prostatic adenocarcinoma who underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. All patients were clinically free of metastases and had cancer that was diagnosed on needle biopsy. Five preoperative variables were collected: clinical stage (TNM staging system), serum prostate-specific antigen (PSA), Gleason score on needle biopsy, presence or absence of perineural invasion, and proportion of the biopsy involved by cancer. The subsequent prostatectomy specimens were completely embedded, and whole mount sections were used to evaluate four outcome staging variables: EPE (absent/present), EPE (absent/unilateral/bilateral), seminal vesicle invasion, and pathologic stage (TNM). On univariate analysis, each preoperative variable was significantly associated with each outcome variable except for a lack of association between clinical stage and SVI. Perineural invasion in the biopsy predicted EPE with a sensitivity of 51%, specificity of 70%, positive predictive value of 49%, and negative predictive value of 71%. On multivariate analysis (stepwise logistic regression), only preoperative PSA, proportion of the biopsy involved by cancer, and Gleason score were significant (p < 0.05); perineural invasion and clinical stage had no independent predictive value for any of the outcome variables. We conclude that the finding of perineural invasion in needle biopsy of prostatic carcinoma has no independent predictive value for the presence of extraprostatic extension, seminal vesicle involvement, or pathologic stage in the radical prostatectomy. Accordingly, we no longer routinely evaluate this finding in biopsy specimens.

Prostatic adenocarcinoma with atrophic features: malignancy mimicking a benign process.

Acinar atrophy and postatrophic hyperplasia in the prostate are commonly confused with adenocarcinoma. The converse situation may also present a diagnostic dilemma. We recently encountered a number of cases of adenocarcinoma with features that mimicked atrophy, raising the serious concern for the underdiagnosis of malignancy. To investigate the frequency of prostatic adenocarcinoma with atrophic features and the histologic criteria that allow its distinction from benign processes, we reviewed the histopathologic findings in 202 consecutive totally embedded whole-mount radical prostatectomy specimens with adenocarcinoma, 100 consecutive routine needle biopsy specimens, and five additional selected needle biopsy specimens. None of the patients had received androgen deprivation therapy before specimen acquisition. Prostatic adenocarcinoma with atrophic features was defined as a proliferation of malignant acini that architecturally resembled atrophy or postatrophic hyperplasia but retained the diagnostic cytologic features of cancer. The acini were round, often dilated and distorted, and lined by flattened attenuated epithelium with scant cytoplasm. All cases had cytologic evidence of malignancy, including nuclear enlargement and prominent nucleoli; these findings could not be attributed to inflammation or treatment effect. Atrophic features were identified in cancer in six radical prostatectomy specimens (3%) and two routine needle biopsy specimens (2%). The proportion of cancer with atrophic features comprised a mean of 27% of each tumor in the prostatectomy specimens (range 10-60%) and 24% in the needle biopsies (range 10-90%). In the prostatectomy cases, the Gleason score of the cancers was 7 (in five cases) and 5 (in one case); in the biopsy specimens the Gleason score was 6 (in five cases) and 7 (in two cases). In addition, atrophic cancer in the prostatectomy cases had luminal eosinophilic proteinaceous secretions (six cases), blue mucin (five cases), crystalloids (two cases), apocrine blebs (three cases), collagenous micronodules (one case), and high-grade prostatic intraepithelial neoplasia within two high-power fields (three cases); the histologic features were similar in the needle biopsy specimens. We conclude that prostatic adenocarcinoma with atrophic features is an unusual finding that is easily confused with benign acinar atrophy. It is recognized by a combination of architectural and cytologic findings and usually coexists with typical Gleason score 5-7 acinar adenocarcinoma. This pattern is important to recognize to avoid the underdiagnosis of malignancy.

Transitional (urothelial) cell metaplasia of the uterine cervix: morphological assessment of 31 cases.

Thirty-one cases of transitional cell metaplasia (TCM) of the uterine cervix were studied. The mean age of patients was 62 years (range 30-87); 25 (81%) were postmenopausal and six premenopausal. In 24 of 25 postmenopausal patients, TCM was an incidental finding at operation for a variety of gynecological lesions, and in such patients the distribution of TCM included the endocervical canal, transformation zone, native ectocervix and vagina. In five of six premenopausal patients, TCM was identified in the cervices of women investigated for abnormal Papanicolaou smears. In all six premenopausal patients, as well as in the remaining postmenopausal patient who also presented with an abnormal Papanicolaou smear, TCM was confined to the endocervical canal and transformation zone. TCM was typified by a multilayer epithelium, clearly distinguishable from the atrophic ectocervical epithelium of most postmenopausal patients by its thickness (averaging 12 cells thick). TCM was identified on the surface epithelium or in sequestered endocervical glands resembling Walthard cell nests of the fallopian tube serosa. There was loss of the usual basal "picket fence" layer seen in cervical squamous epithelia; the cells had crowded nuclei oriented vertically and swirling to give a superficial appearance of disorder. Although lack of "differentiation" from the basal to superficial layers was characteristic, in many examples there was an obvious surface umbrella layer. Intraepithelial glandular differentiation and lesions resembling cystitis glandularis of the urinary bladder were occasionally noted on the ectocervix and vagina. Cellular detail included large pale oval nuclei, oriented vertically, with finely stippled chromatin, small inconspicuous nucleoli, and frequently a deep longitudinal groove. Although the nuclear/cytoplasmic ratio was high, cell-to-cell variation was negligible, and mitoses were rare and never atypical, which, with the nuclear details, distinguished TCM from high-grade squamous dysplasias. The nature of the metaplasia and its biological function are unclear. In postmenopausal patients, it presumably arises occasionally as a consequence of the altered hormonal environment of the cervix and vagina and is of interest only for the possibility of misinterpreting it as a high-grade squamous intraepithelial lesion. In premenopausal patients, it may represent a cellular variation of either physiologic or atypical metaplastic squamous epithelium of the cervical transformation zone.

Transitional (urothelial) cell metaplasia of the fallopian tube mucosa: morphological assessment of three cases.

The origin of rarely encountered transitional cell carcinomas of the fallopian tubes has, to date, been ascribed to transitional cell metaplasia of the tubal serosa or subserosal Walthard rests. We report here three examples of transitional cell metaplasia of the mucosa of the fallopian tubes--in each instance an incidental finding--and propose this lesion as a hitherto unreported possible precursor for such tumors.

A survey of allopurinol dosage prescribing.

AIM: To evaluate the appropriateness of allopurinol dosage according to renal function in patients at Dunedin and Wakari hospitals. METHOD: A prospective survey of all patients receiving allopurinol therapy at Dunedin and Wakari hospitals during a four week period in January/February 1994 was performed. Data were collected from medication charts, patient notes and laboratory records. Dosage prescribed was compared with established guidelines. RESULTS: Of 46 patients on allopurinol treatment 18 were prescribed at least 100 mg more than the recommended daily dose. Twenty-nine out of the 46 surveyed patients (median age 77 years) had mild to moderate renal impairment. CONCLUSIONS: A significant proportion of patients were receiving excessive doses. Although information regarding the allopurinol hypersensitivity syndrome and individualised allopurinol dosage is available, it is evident that many practitioners remain unaware of the recommendations.