Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors.

Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation.

Molecular evidence for the independent origin of extra-ovarian papillary serous tumors of low malignant potential.

BACKGROUND: Molecular data suggest that peritoneal tumors in women with advanced-stage ovarian papillary serous adenocarcinoma are monoclonal in origin. Whether the same is true for ovarian tumors of low malignant potential is not known. We compared peritoneal and ovarian tumors from women with advanced-stage ovarian papillary serous tumors of low malignant potential to determine whether the peritoneal tumors arose from the same clone as the ovarian tumors. METHODS: We studied the clonality of 73 peritoneal and ovarian tumors from 18 women with advanced-stage ovarian papillary serous tumors of low malignant potential. Formalin-fixed, paraffin-embedded tumors and representative normal tissues were sectioned and stained with hematoxylin-eosin, representative sections from separate tumors were manually microdissected, genomic DNA was extracted from the microdissected tumors, and the polymerase chain reaction was used to amplify a CAG polymorphic site in the human androgen receptor locus on the X chromosome to determine the inactivation pattern of the X chromosome and the clonality of the tumors. RESULTS: The pattern of X-chromosome inactivation could be determined from the tumors of 13 of 18 patients. Of the 13 patients, seven (54%) had nonrandom inactivation of the X chromosome, and six of the seven had different inactivation patterns in the peritoneal and ovarian tumors. Three of these patients also had different patterns of nonrandom X-chromosome inactivation in tumors from each ovary. The remaining six patients had random patterns of X-chromosome inactivation in the peritoneal and ovarian tumors. CONCLUSIONS: Our data suggest that peritoneal and ovarian tumors of low malignant potential arise independently.

Evidence of independent origin of multiple tumors from patients with prostate cancer.

BACKGROUND: In men with prostate cancer, the gland usually contains two or more widely separate tumors. A critical issue of prostatic carcinogenesis is whether these multiple tumors are independent in origin. Molecular analysis of microsatellite (i.e., highly repeated, short nucleotide sequences) alterations in the DNA from separate tumors in the same prostate can be used to determine whether or not these separate tumors arise independently. METHODS: Four microsatellite polymorphic markers (D8S133, D8S136, and D8S137, for a putative tumor suppressor gene on chromosome 8p, and D17S855, for the BRCA1 gene on chromosome 17q) were used to examine the pattern of allelic loss in prostate cancer from 19 patients who had two or more distantly separate tumors (i.e., located on contralateral sides or separated by at least half the anterior-posterior diameter of the prostate). Forty distantly separate tumors were microdissected, DNA samples were prepared from formalin-fixed, paraffin-embedded wholemount prostate tissue section, and the overall frequencies of loss of heterozygosity at the four loci were determined. RESULTS: The pattern of allelic loss was compatible with independent tumor origin in 15 of 18 informative cases. A random discordant pattern of allelic deletion was observed in distantly separate tumors, whereas the same allele was consistently lost in cells from different regions of the same tumor. For three patients, the results were compatible with either intraglandular dissemination or independent origin of prostate cancer. CONCLUSIONS: Our data suggest that multiple tumors in some patients with prostate cancer have independent origin.

Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: a surgicopathologic study.

PURPOSE: Positron emission tomographic (PET) scanning provides a novel means of imaging malignancies. This prospective study was undertaken to evaluate PET scanning in detecting para-aortic nodal metastasis in patients with locally advanced cervical carcinoma and no evidence of extrapelvic disease before planned surgical staging lymphadenectomy. MATERIALS AND METHODS: After 20 mCi of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) were administered intravenously, the abdomen and pelvis were scanned. Continuous bladder irrigation was used to reduce artifact. Patients were classified by the presence or absence of FDG uptake in the primary tumor and in pelvic or para-aortic nodes. Para-aortic node metastases were classified as present or absent according to a standardized staging procedure. Pelvic node metastases were similarly classified in a subset of patients who underwent pelvic node resection. RESULTS: Thirty-two patients with stage IIB (n = 6), IIIB (n = 24), and IVA (n = 2) tumors were studied. Fluorodeoxyglucose was taken up by 91% of the cervical tumors. Six of eight patients with positive para-aortic node metastasis had PET scan evidence of para-aortic nodal metastasis. One of the two false-negatives had only one microscopic focus of metastatic cancer. In the para-aortic nodes, PET scanning had a sensitivity of 75%, a specificity of 92%, a positive predictive value of 75%, and a negative predictive value of 92%. Fluorodeoxyglucose para-aortic nodal uptake conferred a relative risk of 9.0 (95% confidence interval, 2.3 to 36.0) for para-aortic nodal metastasis. All 10 of 17 patients with metastasis were predicted by PET scanning (P < .001); five of these patients had abnormalities on computed tomographic scans. CONCLUSION: Cervical cancers have a high avidity for FDG. The use of PET-FDG scanning accurately predicts both the presence and absence of pelvic and para-aortic nodal metastatic disease.

Collagen browning and cross-linking are increased in chronic experimental hyperglycemia. Relevance to diabetes and aging.

Diabetes and aging are associated with an increase in collagen-linked fluorescence and cross-linking that can be duplicated by incubating collagen with glucose. We have tested the hypothesis that browning and cross-linking can occur in vivo in rats by feeding them a diet containing 33% galactose. No significant increase in tail tendon browning or cross-linking, measured by tail tendon breaking time in urea, was observed after 3 mo of galactosemia. After 12 mo, however, twofold increases in tendon breaking time and collagen-linked chromophores absorbing greater than 300 nm and fluorophores at 430 nm (excitation 355 nm, P less than .001) analogous to those of diabetic and aging individuals were observed. The observed changes in collagen are attributed to the advanced Maillard (nonenzymatic glycosylation) reaction based on circumstantial evidence. With this premise, our data suggest that chronic galactosemia should be a powerful tool for investigating the role of the advanced Maillard reaction in complications of diabetes and aging.

Angiosarcoma arising in an arteriovenous fistula site in a renal transplant patient: a case report and literature review.

Angiosarcoma in the setting of immunosuppressed renal transplant recipients is exceedingly rare. In this report, we describe the occurrence of angiosarcoma arising at an arteriovenous fistula site of a 39-year-old renal transplant recipient that clinically mimicked a thrombosed aneurysm. These tumors are histologically high-grade and clinically aggressive malignancies. They have a predilection for arteriovenous fistula sites. The literature on this uncommon entity is reviewed and possible histogenesis is discussed.

Paneth cell-like change and small cell carcinoma of the prostate. Two divergent forms of prostatic neuroendocrine differentiation.

Paneth cell-like change of the prostate refers to collections of prostatic cells with eosinophilic cytoplasmic granules that bear a striking histological resemblance to normal intestinal Paneth cells. Paneth cell-like change in malignant prostatic epithelium usually represent neuroendocrine differentiation, with neuroendocrine granules confirmed by immunohistochemical and ultrastructural studies. We report the histopathological, immunohistochemical, and electron microscopic findings in a mixed adenocarcinoma with Paneth cell-like change and small cell undifferentiated carcinoma. This case illustrates two divergent forms of neuroendocrine differentiation occurring in a single prostatic neoplasm. The spectrum of neuroendocrine differentiation in the prostate should be expanded to include tumors with Paneth cell-like change in addition to carcinoid tumors and small cell undifferentiated carcinoma. These three distinct forms of prostatic neuroendocrine neoplasia appear to correlate with three size ranges of neuroendocrine granules seen by electron microscopy.

Clear cell cribriform hyperplasia of prostate. Report of 10 cases.

We report 10 patients with clear cell cribriform hyperplasia of the prostate. Their ages ranged from 62 to 87 years, with a mean of 72 years. The clinical diagnosis in all patients was benign nodular hyperplasia; all the patients are alive and have shown no evidence of recurrent disease. Follow-ups ranged from 1 month to 7 years (median: 12.5 months; mean: 24.6 months). Pathologically, this lesion has a cribriform arrangement of clear cells with a complex papillary growth simulating the cribriform pattern of prostatic carcinoma. In fact, in five of the 10 cases, the referring diagnosis was either carcinoma or possible carcinoma. Cytologically, however, there is no nuclear atypia, mitosis, or prominent nucleoli, and typically there is a double epithelial cell layer at the periphery of the involved acini. In summary, clear cell cribriform hyperplasia is a benign hyperplastic process with a complex papillary-cribriform structure and should not be confused with prostatic carcinoma. The key feature for the diagnosis is the preservation of nodular configuration with a bland cytology and double cell layer lining the involved acini.

Evidence for the neoplastic transformation of Von-Meyenburg complexes.

Von-Meyenburg complexes (VMC) are seen frequently in the liver and are largely considered to be innocuous, with only 11 cases reported in the literature of neoplastic transformation of VMCs. The authors report three cases of cholangiocarcinoma, each occurring in a background of fibrosis and nodularity that was reported initially as micronodular cirrhosis. Although the livers showed cirrhosis, the central veins were often preserved, and regenerative activity was patchy and focal. Histologic examination revealed many VMCs, and a gradual transition from VMCs to hyperplastic or adenomatous lesions and cholangiocarcinoma. The adenomatous lesions consisted of extensive replacement of the parenchyma by tumor-like nodules of ductular proliferations without obvious features of malignancy. All three patients were older than 60 years of age and had portal hypertension. Computed tomographic scans showed multiple, small renal cysts in one patient. Immunohistochemical staining showed positivity for epithelial membrane antigen, carcinoembryonic antigen, and keratins (AE1/AE3 and CAM5.2) in tumor cells, consistent with cholangiocarcinoma. The pattern of fibrosis and nodularity in these cases is not typical of either congenital hepatic fibrosis or usual cirrhosis. The authors propose that these patients represent another aspect in the spectrum of ductal plate malformations that may be modified by other factors such as alcohol, drugs, or infection. To their knowledge, neoplastic transformation of VMCs in the background of such changes has never been reported before.

Paneth cell-like change of the prostate gland. A histological, immunohistochemical, and electron microscopic study.

Paneth cell-like change (PCLC) of the prostatic glandular epithelium was focally observed in one case of normal glandular epithelium, two cases of glandular and stromal hyperplasia, one case of prostatic intraepithelial neoplasia, and four cases of prostatic adenocarcinoma. The distinctive cells were characterized by bright, eosinophilic cytoplasmic granules on routine hematoxylin and eosin-stained material. The cytoplasmic granules in the benign prostatic epithelium were periodate-Schiff's procedure (PAS)-positive and diastase resistant and immunohistochemically negative for lysozyme, neuron-specific enolase, chromogranin, and serotonin. The eosinophilic granules in the prostatic intraepithelial neoplasia and adenocarcinoma cases were immunohistochemically positive for chromogranin, serotonin, and neuron-specific enolase, and negative for lysozyme. By electron microscopy the eosinophilic granules represented exocrine-like or lysosomal-like vesicles in the benign epithelium and neuro-endocrine granules in the malignant epithelium. The lesion represents a prostatic epithelial PCLC rather than a Paneth cell metaplasia. PCLC is the common histological manifestation of two different phenomena: (a) a PAS-positive and diastase-resistant eosinophilic cytoplasmic granular change in benign prostatic epithelium, and (b) endocrine differentiation with neuroendocrine granules in dysplastic and malignant prostatic epithelia. The importance of recognizing PCLC lies in its differentiation from other possible prostatic cytoplasmic inclusions.

Molecular genetic evidence for different clonal origin of components of human renal angiomyolipomas.

Renal angiomyolipoma is a benign neoplasm composed of variable proportions of blood vessels, smooth muscle, and adipose tissue. Smooth muscle, adipose tissue, blood vessels, and adjacent normal kidney tissue were separately microdissected from sections prepared from formalin-fixed, paraffin-processed tissues from angiomyolipomas from 18 women. X chromosome inactivation analysis using the methylation pattern at exon 1 of the human androgen receptor gene on chromosome Xq11-12 was used to study the clonal origin of each component. Nonrandom inactivation of X chromosomes was found in six of the 15 informative tumors. The smooth muscle and adipose tissue showed differing patterns of nonrandom inactivation of X chromosomes in five angiomyolipomas and the same pattern of nonrandom inactivation of X chromosomes in one. Samples from the blood vessels showed random inactivation of X chromosomes in all informative cases. Our data showed that the adipose tissue and smooth muscle cells of renal angiomyolipoma are both monoclonal but may arise independently. The coexistence of tumor subclones with morphologic heterogeneity can lead to the formation of a clinically detectable tumor.

Uterine stromal neoplasms: a clinicopathologic and DNA flow cytometric correlation.

Twenty-five uterine stromal neoplasms (five stromal nodules and 12 low-grade and eight high-grade stromal sarcomas) were studied to determine the correlation between clinicopathologic features, flow cytometric tumor DNA content and proliferative fraction, and patient outcome. Fifteen of the 20 sarcomas (five of them high grade) were confined to the uterus (stages I and II); the other five (two low grade and three high grade) extended outside the uterus (stages III and IV). Stromal nodules and low-grade sarcomas manifested diploid DNA content and low proliferative index. All stromal nodules and the majority of low-grade sarcomas pursued a benign clinical course. Two cases of low-grade sarcoma ran a malignant course; both patients had high-stage disease. Three of the high-grade sarcomas were diploid and five were aneuploid. All eight neoplasms demonstrated high proliferative index and seven ran a malignant course (four of five were stage I and three of three were stage IV). Three high-grade stage I tumors had a low mitotic rate but a high proliferative index and ran an aggressive course. All high-stage sarcomas were clinically aggressive, irrespective of their histologic classification or DNA characteristics. The proliferative index by flow cytometry may offer an objective adjunct in predicting the aggressive potential of a subset in low-stage neoplasms.

Diffuse and localized tenosynovial giant cell tumor and pigmented villonodular synovitis: a clinicopathologic and flow cytometric DNA analysis.

The DNA content and proliferative indexes of seven cases of tenosynovial giant cell tumor of tendon sheath, diffuse type (TGCT-D); 11 cases of tenosynovial giant cell tumor of tendon sheath, localized type (TGCT-L); and seven cases of pigmented villonodular synovitis (PVNS) were analyzed by flow cytometry in an attempt to assess objectively their biologic differences. Three cases of TGCT-D manifested an aneuploid DNA content and four had a diploid DNA pattern. All cases of TGCT-L and PVNS showed a diploid DNA content. The proliferative indexes for TGCT-D were significantly higher than those found in the other two groups. There was no histopathologic feature that correlated with the aneuploid DNA pattern found in two of the three cases of TGCT-D. Only one of the three aneuploid DNA content TGCT-D cases displayed marked cellular pleomorphism with dense fibrous stroma; in that case there was recurrence 4 years after initial excision. Our data further support that TGCT-D, TGCT-L, and PVNS are histopathologically similar but clinically distinct lesions. The high proliferative indexes of TGCT-D may reflect a rapid, uncontrolled growth that may explain its aggressive biologic behavior. The presence of an aneuploid DNA pattern in some cases of TGCT-D in this study, coupled with the reported chromosomal abnormalities and occurrence of malignant transformation in these lesions, clearly supports their neoplastic nature.

Toxic shock syndrome: clinicopathologic findings in a fatal case.

A 15 year old girl presented with a painful desquamative rash, fever, and profound hypotension. Despite antimicrobial therapy and intensive supportive measures, she died 80 hours after admission. The premortem skin biopsy and autopsy findings, which included subepidermal edema and blister formation, subacute vasculitis, and striking interstitial edema involving several organs, are consistent with a toxin mediated process. Current knowledge of the pathogenesis of the toxic shock syndrome and its differential diagnosis are discussed in light of the clinicopathologic findings in this case.

Time course of hemosiderin production and clearance by human pulmonary macrophages.

Tracheal aspirates from four previously healthy infants with acute pulmonary hemorrhage, and small volume bronchial lavages from children undergoing flexible fiberoptic bronchoscopy were examined for pulmonary alveolar macrophages (PAM) containing hemosiderin. Hemosiderin formation was also studied in vitro. Macrophages containing hemosiderin were first seen in tracheal aspirates 50 hours after an acute pulmonary hemorrhage and after 72 hours in cultured macrophages. A small percentage of the PAM recovered by bronchoalveolar lavage from both adults and children contained hemosiderin. Hemosiderin was rapidly cleared from the lungs following an acute pulmonary hemorrhage.

Brown tumor and secondary hyperparathyroidism.

Brown tumor is a focal, bony lesion of hyperparathyroidism that results from parathyroid hormone on bone increasing osteoclastic activity with bone resorption and trabecular fibrosis. This leads to microfractures and hemorrhage and the appearance of brown tumors, which are seen most commonly in primary hyperparathyroidism and less frequently in secondary hyperparathyroidism. Rarely do these tumors involve the orbit. We report the sixth case, to our knowledge, of orbital involvement, in a patient with chronic renal failure (secondary hyperparathyroidism) and review the literature.

Giant cell fibroblastoma: a report of three cases.

Three cases of giant cell fibroblastoma are presented. All three patients were boys younger than four years of age. The neoplasms involved the subcutaneous tissue of the back, perineum, and shoulder, respectively. The tumors were characterized histologically by a mixture of spindle cells and multinucleated giant cells in a myxoid or collagenous background and by the presence of irregular, sinusoidal spaces. All three patients had local recurrence, but all were tumor-free at latest follow-up.

Myf-4 does not mediate AChR receptor subunit mRNA expression in thymic tissues.

We investigated whether a MyoD gene family member plays a role in the expression of AChR or AChR-like proteins in human thymus. We amplified from thymic tissue, mRNA of subunits of the fetal- and adult-type AChR, and Myf-4, a gene product that appears to regulate AChR expression. RNA extracted from paraffin-embedded thymic tissue of five myasthenics and five nonmyasthenics was subjected to reverse transcription followed by polymerase chain reaction using primers specific for these mRNAs. Thymic RNA from eight of ten patients contained transcripts of the alpha- and epsilon-subunits (specific for the adult-type AChR). Presence of these transcripts did not correlate with thymic pathology or clinical presentation. No gamma-subunit (specific for the fetal-type AChR) or Myf-4 transcripts were found. Our results indicate that mRNA for the adult-type AChR is expressed in thymic tissue and is expressed by mechanisms not involving Myf-4. Thymic AChR subunits may be the primary epitope that initiates the immune response in MG against the adult-type AChR.

Cervical intraepithelial neoplasia after conization: a study of 522 consecutive cervical cones.

The relationship between involvement of the cervical cone margins by cervical intraepithelial neoplasia (CIN) and the presence or absence of CIN as determined by subsequent hysterectomy or cytology follow-up was studied in 522 cervical cones. Hysterectomy was performed in 161 patients, 54% of which were done within six weeks after conization. The remaining patients were followed up with cytology. In 136 women, cone margins were involved by CIN. Twelve of these patients were lost to follow-up. Forty of the 73 (54.8%) patients who underwent hysterectomy had CIN in the uterus. One of 51 (1.9%) patients followed up with cytology developed cytologic evidence of CIN. In 60% of the patients with CIN III and involved margins, in whom hysterectomy was delayed for more than six weeks, there was at least one interval of cytology positive for CIN. All these patients had CIN at the time of hysterectomy. In contrast, CIN was not present in patients with negative follow-up cytology. None of the 107 patients with CIN III and free margins had CIN at hysterectomy or during follow-up. However, of the 249 women with CIN I to II and free margins, six had CIN at hysterectomy. In none of the cases was the residual disease worse than CIN. Although it is impossible to predict the presence or absence of residual CIN based on the appearance of the cone margins, it is important to report the status of the margins. Free margins indicate removal of the CIN in a majority of cases, or reassures that invasive cancer is not present.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphometric study of intraepithelial neoplasia of the uterine cervix.

Treatment failure for intraepithelial neoplasia of the uterine cervix following electrocautery, cryosurgery, or carbon dioxide laser therapy is related primarily to incomplete eradication of the lesion. This may be due to the depth of crypt involvement, the linear extent, or the location of the abnormal epithelium. In view of this, the extent (depth and linear extent) and the location of cervical intraepithelial neoplasia (CIN) in 319 cervical cone specimens were analyzed. There is a significant correlation between the severity and the extent of the change. The mean depths of CIN I, II, and III were 0.42 +/- 0.28, 0.93 +/- 0.71, and 1.35 +/- 1.15 mm, respectively. The mean linear extents for CIN I, II, and III were 4.10 +/- 2.84, 5.84 +/- 4.13, and 7.60 +/- 4.32 mm, respectively. To eradicate 99.7% of CIN III lesions, it is necessary to destroy the tissue up to 4.80 mm in depth and of sufficient linear extent. While most lesions (87.2%) involved the transformation zone, 9.7% were higher in the cervical canal and 3.1% were located in the ectocervix. Appropriate cytologic samples, endocervical curettage, and colposcopic examination should be employed in evaluating the CIN, and strict criteria should be followed in selecting the patients for conservative management.