Cystic adenomyosis of the uterus: MRI.

Adenomyosis of the uterus is most often seen as focal or diffuse thickening of the myometrial junctional zone on MRI. We describe the morphologic features and signal characteristics of the rarer cystic form of the disease, as revealed by MRI. We conclude that cystic adenomyosis of the uterus is characterized by a well-circumscribed cystic lesion within the myometrium that demonstrates hemorrhage in differential stages of organization on MR images.

Fibroma and fibrothecoma of the ovary: MR imaging findings.

PURPOSE: To describe the morphologic and signal intensity characteristics on magnetic resonance (MR) images of fibromas and fibrothecomas. MATERIALS AND METHODS: MR images of 11 female patients with histologically proved fibromas or fibrothecomas were reviewed, and morphologic and signal intensity characteristics of the lesions were analyzed. MR imaging findings were correlated with histologic findings. RESULTS: All fibromas and fibrothecomas showed homogeneous low signal intensity on T1-weighted images. On T2-weighted images, the two smallest lesions showed homogeneous low signal intensity, and eight of the other nine lesions showed predominantly low signal intensity. Edema was noted only in larger lesions, and cystic degeneration was noted only in three of the largest lesions. On T2-weighted images, the percentage of low signal intensity in the lesion was not found to be related to lesion size, and the percentage of low signal intensity in fibromas was not significantly different from that in fibrothecomas (P = .55). Many lesions showed heterogeneous signal intensity; the solid component was distributed peripherally, and the cystic component was located centrally or eccentrically. Free intraperitoneal fluid was noted in 10 of 11 lesions and was not significantly correlated with lesion size (r = .52 and P = .10). CONCLUSION: Because of their predominantly low signal intensity on T2-weighted images, fibromas and fibrothecomas display a relatively specific appearance on MR images.

Dose-escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer.

PURPOSE: Based on preclinical data that demonstrated synergy between alkylating agents and topoisomerase (topo) I poisons, we determined the maximum-tolerated dose (MTD) of topotecan, using a 5 day bolus schedule, that could be given in combination with a single, fixed dose of cyclophosphamide. Pharmacodynamics of this combination were explored by analyzing biochemical effects of treatment in peripheral-blood mononuclear cells (PBMCs). PATIENTS AND METHODS: Patients with refractory cancer were treated with cyclophosphamide 600 mg/m2 on day 1, followed by topotecan given as a 30-minute infusion for 5 consecutive days. Cycles were repeated every 3 weeks. Once the MTD was defined, granulocyte colony-stimulating factor (G-CSF) was added to the regimen in an attempt to escalate further the dose of topotecan. Plasma concentrations of topotecan were determined during the first treatment cycle by high-performance liquid chromatography. PBMCs were sampled at baseline and throughout the 5-day treatment period for analysis of topo I protein concentrations and to determine drug-induced DNA fragmentation. RESULTS: Twenty-six patients were treated with topotecan at doses that ranged from 0.5 mg/m2/d to 1.2 mg/ m2/d for a total of 74 cycles. Reversible neutropenia was dose-limiting, with mild to moderate suppression of the other blood-cell elements commonly occurring. Transfusions of RBCs and platelets were required in 24% and 7% of treatment cycles, respectively. The most prominent nonhematologic toxicities were fatigue and weight loss. Compared with previously published data in which topotecan was administered alone, cyclophosphamide did not appear to alter the pharmacokinetics of topotecan. Significant increases in topo I concentration were identified in PBMCs following the administration of cyclophosphamide on day 1 and there was a significant decrease in topo 1 during the 5-day course of treatment (P < .01, sign test). DNA fragmentation as a result of drug treatment was identified in 11 of 15 (73%) cycles analyzed. CONCLUSION: For previously treated patients, the recommended dose of topotecan in this schedule is 0.75 mg/m2/d without growth factor support and 1.0 mg/ m2/d if it is administered with G-CSF. Biochemical changes in cells induced by exposure to camptothecins can be measured in vivo and these effects may have important implication in the design of combination therapies and the optimal scheduling of this class of agents.

Mechanism of technetium 99m sestamibi parathyroid imaging and the possible role of p-glycoprotein.

BACKGROUND: Localization of parathyroid glands is critical in the treatment of recurrent or persistent hyperparathyroidism. Technetium sestamibi imaging may improve localization; however, the mechanism of visualization of parathyroid tissue remains unclear. On the basis of the chemical structure of sestamibi it has been suggested that p-glycoprotein is involved in the transport of sestamibi across cell membranes. This study was designed to examine sestamibi uptake and retention and p-glycoprotein expression in normal and abnormal parathyroid tissue. METHODS: Thirty-two consecutive patients underwent 2-methoxy-isobutyl-isonitrile imaging immediately before parathyroid exploration. Tissue was obtained from normal and abnormal parathyroids and from the thyroid gland. Touch preparations gave rapid confirmation of tissue origin. Specimens were trimmed and weighed, and gamma-emission was counted. Percentage injected dose per gram of tissue was calculated. Immunohistochemistry was obtained with a battery of monoclonal antibodies to identify p-glycoprotein in parathyroid tissue submitted for permanent histologic examination. Slides were graded by a pathologist familiar with immunohistochemistry. RESULTS: Abnormal parathyroid tissue had a higher mean retention of injected dose per gram than did normal thyroid and parathyroid tissue. Immunohistochemistry revealed that abnormal parathyroid tissue expresses less p-glycoprotein. CONCLUSIONS: These results suggest that size is not the single determinant of parathyroid visualization and that p-glycoprotein expression may be involved in the mechanism of parathyroid imaging.

Functional assay for HER-2/neu demonstrates active signalling in a minority of HER-2/neu-overexpressing invasive human breast tumours.

Overexpression of HER-2/neu in human breast carcinomas correlates with poor prognosis, although its strength as a prognostic indicator varies widely in different reports. Variability may be due to active signalling by HER-2/neu in a subset of the tumours in which it is overexpressed. To study this hypothesis, we have developed an activation state-specific anti-HER-2/neu monoclonal antibody. In this report, we use this antibody to analyse the signalling status of HER-2/neu in a large series of invasive breast carcinomas. Overexpression of HER-2/neu was detected in 9% of 223 cases. Of the cases demonstrating overexpression, active signalling by HER-2/neu was detected in only 35%. The clinicopathological characteristics of these cases are described. This functional assay is predicted to improve the utility of HER-2/ neu as a prognostic indicator.

Trifluoperazine as a modulator of multidrug resistance in refractory breast cancer.

Overexpression of P-glycoprotein (P-gp) has been implicated as the mechanism of multidrug resistance (MDR) in a number of human cancers, including carcinoma of the breast. We conducted a clinical trial to determine whether the P-gp inhibitor, trifluoperazine, could sensitize patients with refractory breast cancer to vinblastine chemotherapy. Adult patients with histologically confirmed, refractory, advanced breast cancer were treated with vinblastine at a dose of 1.7 mg/m2 per day by continuous infusion for five consecutive days. Patients who did not respond after two cycles were subsequently treated with vinblastine plus trifluoperazine at a dose of 8 mg twice daily during the five days of chemotherapy. In patients from whom tumor samples were available, the expression of P-gp was determined by immunocytochemistry. Of 35 patients enrolled, 30 were evaluable, 2 of whom (7%) achieved a partial response to vinblastine alone. Among the 16 patients treated with vinblastine plus trifluoperazine there was one response (6%) which lasted 16 weeks. Tumor samples were available from 16 patients, and 14 (87%) were immunoreactive for P-pg. P_pg expression was detected both in the patient who responded to vinblastine plus trifluoperazine and in one of the two patients who responded to vinblastine alone. Continuous-infusion vinblastine demonstrated limited activity in this study. Furthermore, trifluoperazine did not effectively reverse established resistance to vinblastine. This failure may be related the presence of multiple mechanisms of drug resistance in the heavily pretreated population, or because ineffective concentrations of the modulator were achieved in vivo. Future studies should evaluate more effective modulators, and attempt to reverse MDR earlier in the course of treatment, before other forms of resistance can develop.

Histologic spectrum of cutaneous involvement in patients with myelogenous leukemia including the neutrophilic dermatoses.

BACKGROUND: Cutaneous manifestations of myeloid leukemia can be specific or nonspecific. The study was designed to determine the prevalence and histologic appearance of cutaneous lesions in patients with myeloid leukemia and various myeloproliferative disorders. METHODS: The histologic changes of cutaneous lesions in 52 patients with myelodysplastic syndrome, polycythemia vera, and myeloid, myelomonocytic, or monocytic leukemia are presented in this study. RESULTS: Two types of cellular infiltrates were identified. In the first group, the most common pattern was a diffuse involvement by the leukemic cells through the entire dermis with preservation of a "grenz zone" in the superficial dermis. Two cases exhibited a Kaposi's sarcoma-like pattern, with prominent slit-like blood-filled spaces lined by myeloblasts against a fibrocellular stroma. The second group of lesions was characterized by dense, neutrophilic dermal infiltrates resembling acute neutrophilic dermatosis (Sweet's syndrome) or pyoderma gangrenosum. In two of these cases, scattered immature blast cells admixed with the mature neutrophilic elements were identified. CONCLUSIONS: Awareness of these different morphologic features and application of special stains are of value in the evaluation of suspicious cutaneous infiltrates in patients with myeloid leukemia and various myeloproliferative disorders.

Pseudoleukemia after granulocyte colony-stimulating factor therapy.

Therapy with myeloid colony-stimulating factors has been safely and effectively used in a wide variety of situations associated with neutropenia. We present a case of pseudoleukemia occurring in a patient with lymphoma and pancytopenia after 2 days of treatment with granulocyte colony-stimulating factor (G-CSF). Bone marrow aspirate and flow cytometry study results were consistent with acute myelomonocytic leukemia but were normal after G-CSF was discontinued for 4 days. As previous phase I studies of bone marrow morphology after G-CSF use have not described the extreme myeloid immaturity seen in this patient, it seems likely that the action of G-CSF was enhanced by factors associated with the patient's illness. We emphasize the clinical importance of this case in light of the widespread use of G-CSF.

Clinical stage I endometrial carcinoma: pitfalls in preoperative assessment with MR imaging. Work in progress.

PURPOSE: To identify potential pitfalls in using magnetic resonance (MR) imaging to determine the depth of myometrial invasion in patients with clinical stage I endometrial carcinoma. MATERIALS AND METHODS: Forty women with clinical stage I endometrial carcinoma underwent preoperative pelvic MR imaging. Uterine length, tumor signal intensity, appearance of the junctional zone, presence of large polypoid tumors, leiomyomata, and congenital uterine anomalies were analyzed. Univariate logistic-regression analysis was performed to identify associations between incorrect MR staging and these variables. RESULTS: MR staging of IA, IB, and IC disease was 55% accurate (22 of 40 cases); MR differentiation of deep myometrial invasion (stage IC) from superficial disease (stages IA and IB) was 78% accurate (31 of 40 cases). Older age (P = .025), presence of polypoid tumors (P = .025), and difficulty in pathologic staging (P < .005) were significantly associated with incorrect MR assessment. CONCLUSION: When present, large polypoid tumors, leiomyomata, congenital anomalies, small uteri, and indistinct zonal anatomy may make it difficult to assess myometrial invasion at MR imaging.

Leukemic synovitis as the cause of arthritis in myelodysplastic syndrome.

Up to 10% of patients with myelodysplastic syndrome (MDS) may have arthralgias as a feature of their disease. All patients with MDS have the potential to progress into acute leukemia. We describe the case of a 59-year-old male with MDS who presented with synovitis due to leukemic infiltration of the synovium as the first symptom heralding the conversion of MDS into acute leukemia.

Preoperative serum prostate-specific antigen and Gleason grade as predictors of pathologic stage in clinically organ confined prostate cancer: implications for the choice of primary treatment.

PURPOSE: Despite careful preoperative staging, approximately 50% of patients who undergo radical prostatectomy for clinical stage A2 (T1b-c) and B (T2) prostate cancer are found to have pathologic stage C (T3-4) or D (N1) disease. This study investigates whether preoperative serum prostate specific antigen (PSA) and Gleason grade predict pathologic stage among patients with clinically organ confined prostate cancer. METHODS: The records of all 63 patients who underwent attempted pelvic lymphadenectomy and radical prostatectomy for adenocarcinoma of the prostate at our institution in 1990-91 were retrospectively reviewed. RESULTS: Patients with a preoperative serum PSA of 12.5 ng/mL or greater had an 81% incidence of pathologic upstaging to stage C (T3-4) or D (N1) compared with 38% for patients with a PSA less than 12.5 (p = 0.0015). The incidence of various pathologic findings for prostate specific antigen > or = 12.5 vs. prostate specific antigen < 12.5 was as follows: seminal vesicle involvement 29% vs. 5% (p = 0.0186), lymph node metastases 24% vs. 0% (p = 0.0029), capsular penetration 71% vs. 38% (p = 0.0424), and positive margins 47% vs. 36% (p = 0.56). None (0/3) of the patients with Gleason grade 4 or less were pathologically upstaged compared with 49% (24/49) of patients with grade 5-7 tumors (p = 0.15) and 82% (9/11) of patients with grade 8 or higher cancers (p = 0.0474, grade 5-7 vs. 8-10). Within the group of patients with Gleason grade 5-7, a prostate specific antigen of 12.5 ng/mL or greater predicted an 79% rate of upstaging compared with 37% for patients with prostate specific antigen less than 12.5 (p = 0.0098). CONCLUSION: Patients with clinical Stage A2 (T1b-c) or B (T2) prostate cancer who have Gleason grade 8-10 tumors and those patients with Gleason grade 5-7 tumors with a preoperative serum prostate specific antigen of 12.5 ng/mL or higher have a high incidence of pathologic upstaging. These patients should be preferentially treated with external beam radiation in most cases.

Ovarian serous borderline tumors with lymph node involvement. Clinicopathologic and DNA content study of seven cases and review of the literature.

Although several studies have established the excellent prognosis of ovarian serous borderline tumors (OSBTs) in general, the significance of lymph node involvement has not been thoroughly addressed. In this article, we describe seven OSBTs with lymph node involvement and their DNA content and S-phase fraction. Lymph node involvement was identified at presentation in four cases (pelvic, paraaortic, and omental) and after 4, 5, and 7 years in the other three (omental, scalene, and cervical, respectively). In the first group, clusters of cells cytologically similar to those of the OSBT were identified in the nodal sinusoids in all four cases and focally in the lymph node parenchyma in three of them. In contrast, the involved lymph nodes of the three cases with delayed nodal disease showed an almost complete replacement by tumor. In one of them, the tumor in the lymph node was histologically similar to the OSBT, while in the other two cases the tumor was more solid and poorly differentiated, suggesting true metastatic disease. Flow cytometric analysis of nuclear DNA content and S-phase fraction were performed on paraffin-embedded tissue of all of the primary OSBTs and of the involved lymph nodes in six cases; diploid DNA content and low S-phase fraction were seen in all cases. All patients were alive and free of disease 2-9 years after initial diagnosis. While the clinical significance of LN involvement in OSBT is still uncertain, DNA ploidy analysis seems to be unable to identify those cases at risk for tumor progression.

Cardiogenic shock due to progression of cutaneous T-cell lymphoma.

We describe a patient with progressive cutaneous T-cell lymphoma (CTCL) and development of subacute cardiac failure. Symptomatic lymphomatous involvement of the heart may be more common in patients with CTCL than in other lymphomas because the former is more likely to be associated with circulating tumor cells and hematogenous spread to the myocardium. No single symptom or sign is highly predictive of cardiac involvement, but unexplained tachyarrhythmias, conduction disturbances, low voltage on ECG, and unexplained cardiac enlargement should arouse clinical suspicion. Although echocardiography may be helpful in suggesting cardiac involvement, endomyocardial biopsy should be considered in patients with a reasonable chance of responding to chemotherapy or radiation.

Management of ectopic thyroid nodules.

BACKGROUND: Surgical dictum states that the so-called lateral aberrant thyroid represents metastatic thyroid cancer. METHODS AND RESULTS: We present sixteen cases of patients with benign ectopic thyroid tissue. Seven cases were discovered during evaluation and treatment of hyperparathyroidism. The remaining nine cases were discovered during the evaluation and treatment of thyroid disorders or cervical nodules. In fifteen cases there is benign histology on the nodules. One case has been followed for 4 years with scans revealing a normal thyroid gland with an unchanging ectopic thyroid nodule in the superior mediastinum. In eight of our cases there have been thyroid resections searching for occult carcinomas. Histologic examination on these eight thyroid glands revealed either normal thyroid or benign nodules. CONCLUSIONS: Not all lateral aberrant thyroid tissue is malignant. The histologic condition of the nodule combined with intraoperative examination of the ipsilateral thyroid lobe can reliably guide therapy. The old dictum concerning lateral aberrant thyroid representing metastatic cancer should be removed from or modified in review texts and surgical examinations.

Isolated amyloidosis of the penile urethra and corpus spongiosum: a case report.

Localized amyloidosis of the penile urethra and corpus spongiosum is rare. The pathogenesis is obscure and optimal management of such patients has not been defined. We report a case that was treated with transurethral removal of amyloid tissue, which was obstructing the urethral outlet. Previously, the patient had been treated with dilation with temporary relief of the symptoms. He was disease-free 1 1/2 years postoperatively.

Local recurrence versus new primary: clinical analysis of 82 breast relapses and potential applications for genetic fingerprinting.

PURPOSE: The purpose of this study was to perform a detailed clinical pathological analysis of breast relapses in patients treated with conservative surgery and radiation therapy in an effort to classify those relapses as true local recurrences or second primary tumors, and to assess the prognostic and therapeutic implications of such a classification system. METHODS AND MATERIALS: Of 990 patients treated with conservative surgery and radiation therapy at our facilities prior to December 1987, 82 patients have experienced a relapse in the conservatively treated breast as the primary site of failure. Patients were classified as having new primary tumors if they fulfilled any one of the following criteria: a) breast relapse occurring at a site distinctly removed from the original tumor; b) histology of the breast relapse compared with the original tumor consistent with a new primary; or c) DNA flow cytometry converting from an aneuploid primary to a diploid relapse. RESULTS: As of 2/92, with a median follow-up of 5.4 years from the time of breast relapse, the overall 5-year survival rate following breast relapse was 55%. Forty-seven patients were classified as true recurrences and 33 patients were classified as new primaries. Patients classified as true recurrences had a shorter median time to breast relapse than patients classified as new primaries (3.16 years vs. 5.42 years, p < .05) and an inferior post breast recurrence survival rate compared to patients classified as new primaries (36% vs. 89%, p < .05). Residual disease outside of the recurrent tumor bed was also noted to be more frequent in patients classified as true recurrences compared to patients classified as new primaries (48% vs. 16%, p < .05). CONCLUSION: Based on the clinical and pathological criteria outlined, it appears that a significant portion of patients experiencing a relapse in the conservatively treated breast may have new primary tumors as opposed to true local relapses. Distinction between a true recurrence and a new primary tumor may have significant prognostic implications. Uncertainties associated with the clinical and pathological criteria are presented and further investigations with genetic fingerprinting techniques to establish the clonality of breast relapses are presented and discussed.

Benign trichogenic tumours: a report of two cases supporting a simplified nomenclature.

We report two cases of a rare benign tumour of hair germ. Clinically, both were solitary, well-circumscribed, subcutaneous nodules located in the extremities. Histologically, the tumours were characterized by nests and thin cords of basaloid epithelial cells intimately associated with a cellular stroma. The basaloid cells exhibited peripheral palisading, keratinization in the form of keratotic cysts and squamoid transformation, and pilar differentiation. An unusual, but distinctive, cribriform pattern of growth was observed. There was no communication with the overlying epidermis. Abundant primitive hair germinal buds and rare more advanced abortive hair follicles were identified. These histological appearances encompass features of both trichoblastic fibroma and trichogenic trichoblastoma, thus distinguishing these neoplasms from other skin tumours and reinforcing the hypothesis that these tumours are closely related from a histogenetic point of view. The presence of overlapping histological features can be problematic for practising histopathologists who rarely encounter these conditions. With this in mind, the term benign trichogenic tumour may be more appropriate to encompass these two tumours and related neoplasms that appear to lie within the spectrum of hair follicle development.

Gonadotropin-releasing hormone agonist-induced differences in granulosa cell cycle kinetics are associated with alterations in follicular fluid müllerian-inhibiting substance and androgen content.

We have previously shown that the proliferative index (PI), as determined by flow cytometry of luteinized granulosa cells obtained at oocyte retrieval, is greater in ovulation induction regimens which include the GnRH analog (GnRH-a) leuprolide acetate than those using human menopausal gonadotropin (hMG) only. Specific growth factors or intrafollicular hormones may contribute to this leuprolide acetate-induced difference in cell cycle kinetics. We examined whether differences in the PI of these granulosa cells are associated with the alterations of follicular fluid content of Mullerian-inhibiting substance (MIS) and other intrafollicular hormones including FSH, estradiol, progesterone, androstenedione, and testosterone. The control group consisted of follicular fluid obtained from 18 follicles from 4 women receiving hMG alone. The GnRH-a treated group consisted of follicular fluids obtained from 55 follicles aspirated from 18 women receiving GnRH-a in addition to hMG. One-way analysis of variance using log-transformed data and expressed as geometric means with 95% confidence intervals, demonstrated that the follicles from the control group had a significant 14-fold higher concentration of 2.46 ng/mL MIS, 95% CI (1.8-4.8) vs. 0.18 ng/mL, 95% CI (0.13-0.24) P < 0.0005, a 3-fold higher concentration of 17.55 nmol/L androstenedione, 95% CI (14.6-20.9) vs. 5.76 nmol/L, 95% CI (3.1-10.5) P < 0.02, and a 1.5-fold higher concentration of 29.43 nmol/L testosterone 95% CI (22.5-38.14) vs. 19.3 nmol/L, 95% of CI (11.1-33.9) P < 0.01 than GnRH-a treated follicles, although the PI value in controls was half that of the GnRH-a group. These data demonstrate that GnRH-a induced differences in granulosa cell cycle kinetics are associated with alterations of MIS and androgen intrafollicular fluid content and suggest that MIS may be a mitotic inhibitor of human granulosa cells.

Parathyroid carcinoma: the relationship of nuclear DNA content to clinical outcome.

This article reports the use of flow cytometry to determine tumor nuclear DNA content and its correlations with clinical outcome in a series of patients with parathyroid carcinoma. Information concerning nine patients with parathyroid cancer (aged 25 to 88 years) was reviewed. Paraffin-embedded, formalin-fixed archival tissue was used to determine tumor DNA content flow cytometrically. Twenty-five operative procedures were performed in nine patients, including 11 parathyroidectomies, two wide local excisions, six central neck dissections, and four median sternotomies for resection of metastases. With flow cytometry used to determine a tumor DNA index, five patients had evidence of tumor aneuploidy; in two patients two aneuploid peaks were evident. The DNA index ranged from 0.7 (hypodiploid) to 1.92 (mean, 1.31). Follow-up ranged from 1 to 18 years. Four patients died. Five were alive 1 to 13 years after diagnosis of parathyroid disease. Four of the five patients with evidence of tumor aneuploidy had metastatic disease and died, and the fifth has had three local recurrences. The four patients with diploid tumors were alive and free of disease 1, 3, 4, and 8 years after the initial operation. It is concluded that in patients with clinically or pathologically demonstrated parathyroid cancer, flow cytometry may help differentiate those whose cancers are likely to behave indolently (diploid tumors) from those with tumors (aneuploid) more likely to behave aggressively by recurring locally or metastasizing.