Biomedical subjects
Publications and source records attributed to S G Silverberg.
A case of bilateral tubal carcinoma occurring 22 years after tubal sterilization is presented. We believe that this is the first case report of bilateral tubal carcinoma that has arisen in ligated fallopian tubes. The possibility that tubal occlusion is one of the causative factors of tubal carcinoma is discussed.
For many years, it has been assumed that microglandular hyperplasia (MGH) of the cervix occurs almost exclusively in women with endogenous (pregnancy) or exogenous (oral contraceptives) progestational stimulation, but this relationship has never been subjected to rigorous epidemiologic study. All available cases of MGH in our 1990 surgical pathology files were reviewed and clinical histories obtained. For each case of MGH, a control was chosen, consisting of a case in the same time frame of a woman of similar age who had undergone the same procedure (biopsy, conization, hysterectomy) for the same indication. A documented history of current oral contraception or pregnancy within the past 6 months was obtained in 57.9% (22 of 38) of the MGH cases and 47.4% (18 of 38) of the controls. This difference was not statistically significant by McNemar's test for paired data. The histologic features of the MGH lesions (lesion size, cytologic atypia, prominence of inflammation, and presence of solid component and of squamous metaplasia) were evaluated blindly without knowledge of the hormonal history. There were no statistically significant differences by the chi 2 test of association between cases with and without hormonal histories. This study provides no support for considering MGH or any of its constituent features. This study provides no support for considering MGH or any of its constituent features as causally related to oral contraception or other known hormonal perturbations.
The presence or absence of tubal mucosal epithelial proliferation (MEP) and its degree of severity when present were investigated in 191 cases, including 49 ovarian serous tumors of low malignant potential (LMP), 33 nonserous (predominantly mucinous) LMP tumors, various other benign and invasive malignant female genital tract lesions, and 37 cases (73 fallopian tubes) of tubal ligation for sterilization. MEP including all degrees of severity was found to be an almost ubiquitous (83% of all cases) lesion of no clinical significance. On the other hand, MEP of moderate or marked degree was rarely seen (3% of cases) in normal tubes obtained for sterilization, but was identified in from 25% to > 40% of tubes accompanying a wide variety of nonneoplastic and neoplastic lesions. Thus, we recommend that only moderate to marked MEP be considered as a diagnosable lesion in the future. There was no tendency in this material for MEP to show any specific association with ovarian serous LMP tumors, as was previously reported. However, when MEP was present, it was more likely to be widespread and mitotically active when it accompanied an ovarian LMP tumor of any histologic type than when it was found with benign ovarian lesions, invasive gynecologic cancers, uterine leiomyomas, or tubal inflammatory lesions and ectopic pregnancies.
We have reviewed 44 mucinous intestinal (MI) and 10 mucinous mullerian (MM) tumors of low malignant potential (LMP) seen at The George Washington University Medical Center. As previously reported by Rutgers and Scully, MMLMP tumors occurred in younger women, were generally smaller and more frequently bilateral, had a papillary rather than multicystic appearance, and lacked goblet cells. All patients with MMLMP tumors were recurrence-free at last follow-up, including three whose tumors were microinvasive. Patients with MILMP tumors also all did well regardless of tumor grade, with the exception of a single patient with bilateral grade 1 ovarian tumors, an appendiceal villous adenoma, and pseudomyxoma peritonei. Microinvasion was also seen in four of these tumors, none of which recurred. Review of the literature suggests that MILMP tumors without stromal invasion but with either prominent cell stratification or marked nuclear atypia may have a worse prognosis than those lacking these features, but probably largely because of a correlation with higher stage disease. We believe that tumors of this sort should not be diagnosed as "noninvasive carcinomas," but should be sectioned more extensively for evidence of stromal invasion and subjected to careful staging. If the tumor is still noninvasive and in stage I after these procedures, the likelihood of treatment failure appears to be in the range of 1-3%.
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To determine the prognostic significance of signet ring cells in infiltrating lobular carcinomas, the percentage of signet ring cells in 99 infiltrating lobular carcinomas was correlated with the patients' clinical outcomes (mean follow-up interval of 4.8 years). When the carcinomas were divided into those with 0%, 1-9%, and 10% or more signet ring cells, 57% (26/46) of patients with 10% or more signet ring cells had experienced recurrences or metastases compared with 40% (2/5) and 31% (15/48) with 0% and 1-9%, respectively. A similar analysis performed with breakpoints at 20% or 30% failed to yield any statistically significant associations. When patients were stratified by pathologic stage, patients with stage I disease and 10% or more signet ring cells were more likely to have recurrences or metastases than those patients with stage I tumors and fewer than 10% signet ring cells. There was no relationship between signet ring cells and disease progression in stages II, III, and IV. These results indicate that the presence of 10% or more signet ring cells represents a poor individual prognostic factor in stage I infiltrating lobular carcinomas.
In conclusion, the diagnosis of endometrial pathology is changing rapidly as our understanding of the pathogenesis of endometrial lesions expands. Increasingly, recognition of new lesions and further subclassification of well-described entities will become more important in patient care.
To establish prognostically useful pathologic features for infiltrating lobular carcinoma, histologic pattern, nuclear Grade 1 or 2, lymphatic invasion, the presence and extent of lobular carcinoma in situ, estrogen and progesterone receptor status, axillary lymph node status, tumor size, and pathologic stage were assessed as prognostic variables in 92 cases of infiltrating lobular carcinoma. Clinical follow-up was obtained (mean duration, 5.2 yr), and patients were classified as alive with no evidence of disease, alive with disease, or dead of disease. Recurrence (alive with disease and dead of disease) was associated with axillary lymph node metastases (P = 0.04), tumors measuring > 1.0 cm (P = 0.008), and pathologic Stage III/IV disease (P = 0.033). Survival (no evidence of disease and alive with disease) was associated with Stage I/II disease (P = 0.003). Statistically insignificant associations with disease recurrence or survival follow: infiltrative pattern (classical, alveolar, solid, mixed), nuclear grade, lymphatic vessel invasion, presence of lobular carcinoma in situ, extent of lobular carcinoma in situ (< 25% or > or = 25%), and hormone receptor status. Many of the prognostic features used in ductal carcinoma do not appear to be applicable to infiltrating lobular carcinoma. However, tumor size, axillary node status, and pathologic stage are prognostically useful in infiltrating lobular carcinoma.
BACKGROUND: Several studies have suggested that ductal carcinoma in situ (DCIS) of the comedo type (variably defined) is biologically more aggressive than other patterns of DCIS and more likely to progress rapidly to invasive carcinoma. METHODS: Eighty-five pure DCISs were compared histopathologically with 64 carcinomas containing both intraductal and infiltrating ductal components (mixed DCIS/IDC). RESULTS: Solid DCIS with and without necrosis was seen more frequently seen in the mixed DCIS/IDC series, especially in cases with less than 50% DCIS. Periductal stromal inflammation and multifocality also were seen more frequently in mixed DCIS/IDC than in pure DCIS. High nuclear grade and high mitotic activity were also more common in the DCIS component of the mixed cases and were well correlated with the intraductal and infiltrating components of the same tumors in most of the cases. The frequency of axillary lymph node metastases was correlated with the proportions of stromal invasion but not with the DCIS subtypes. When the criteria (solid growth pattern, high nuclear grade, and central necrosis) for the diagnosis of intraductal comedocarcinoma were analyzed separately, the first of these correlated most strongly with mixed DCIS/IDC compared with pure DCIS, the second less strongly, and the third not at all, although central necrosis has been considered the main or only diagnostic criterion for comedocarcinoma in several previous reports. CONCLUSIONS: Solid growth pattern and high nuclear grade are the most important histopathologic features of DCIS used to predict progression to invasive carcinoma. No major changes between the intraductal and invasive elements of the same tumors were noted, but other studies have suggested that markers of aggressiveness either increase or decrease in the progression to invasion. These conflicting data require further investigation.
Abnormalities of p53, a tumor suppressor gene, have been considered to play an important role in tumorigenesis. Clinically, overexpression of p53 has been reported to correlate with poor prognosis in several types of tumors. In this study, we examined 221 cases of endometrioid endometrial carcinoma for overexpression of p53 using immunohistochemistry in patients with a median follow-up of 41 months. Immunohistochemical analysis was performed with monoclonal antibody pAb1801. Overexpression of p53 was detected in 47 of 221 cases (21.3%). There was a statistically significant correlation between p53 overexpression and poor prognosis (P < .0001). In the early stages of cancer (stages 1 and 2), p53 was overexpressed in 11 of 22 patients (50%) who died or had a recurrence during follow-up. In contrast, overexpression was detected in only 14.7% of the 156 disease-free patients during the same period (P < .0001). In advanced stages (stages 3 and 4), tumors from patients with recurrent disease had a higher frequency of overexpression (41.2%; 7 of 17) than those of disease-free patients (23.1% 6 of 26). However, the difference between these frequencies was not statistically significant. In multivariate analysis using the Cox proportional hazard model, p53 overexpression was an independent risk factor when compared with clinical stage, nuclear grade, and patient age. Our results indicate that p53 immunohistochemical evaluation of the most common form of endometrial cancer may be useful in identifying cases of aggressive carcinoma, especially in the early stages.
The pathologic grade of endometrial adenocarcinoma is widely recognized as an important prognostic and therapeutic indicator. However, disagreement persists about the optimal method of determining grade. The pathology committee of the Gynecologic Oncology Group employs a system based on the proportion of tumor in glandular array; this system is both reproducible and predictive of outcome. Others have suggested that grading based on nuclear pleomorphism and the size of nucleoli provides better prognostication. We compared the three-level architectural grading system (AG) with a two-level nuclear grading system (NG) to determine reproducibility and prognostic value in 88 cases of stage 1 endometrial adenocarcinoma. Three pathologists made independent assessments of grade by each method. The division of tumors by architectural arrangement was superior for predicting survival (83%, 73%, and 44%, AG, p = 0.005; vs. 79% and 61%, NG, p = 0.14) and equivalent to nuclear grading for prediction of recurrence. Both systems were moderately reproducible (k = 0.49, AG; k = 0.57, NG). Assessment of NG was more tedious than that of AG. Subdivision of architectural grade based on high nuclear atypia, as recommended in current, International Federation of Gynecology and Obstetrics guidelines, did not improve prognostication. Because grading based on nuclear pleomorphism does not provide prognostic information superior to that resulting from architectural grading, we do not advocate its use in routine surgical pathology practice.
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This study was designed to investigate whether or not the pelvic peritoneum exhibits a metaplastic process into müllerian-type epithelium using a marker for epithelial differentiation (Ber-EP4 antigen) and markers that indicate müllerian differentiation (estrogen receptors and progesterone receptors). The peritoneum and/or ovarian surface epithelium adjacent to endometriotic lesions were obtained from 24 patients with endometriosis at operation, and peritoneum and ovarian surface epithelium without any lesions were also obtained from control patients without endometriosis. The specimens were immunohistochemically analyzed using antibodies for epithelial antigen Ber-EP4, estrogen receptor (ER), and progesterone receptor (PR) on frozen sections. Normal peritoneal mesothelium showed negative staining for Ber-EP4, ER, and PR. The mesothelium of the peritoneum adjacent to the endometriotic lesions showed focal positivity for Ber-EP4, ER, and PR. Several cases of ovarian surface epithelium from normal control ovaries and ovaries adjacent to endometriotic lesions also showed focal positivity for Ber-EP4, ER, and PR. Stromal cells accompanying these foci were sporadically positive for ER and/or PR but negative for Ber-EP4. Focal expression of Ber-EP4, ER, and PR in the mesothelium of the peritoneum and the ovarian surface epithelium adjacent to endometriotic lesions suggests that mesothelium possibly acquires characteristics of epithelial as well as müllerian-type nature. These results support an existence of a metaplastic process of the peritoneal mesothelium in the pathogenesis of endometriosis. The more frequent Ber-EP4 positivity in normal ovarian surface epithelium compared to normal peritoneal mesothelium also suggests a fundamental difference in these tissues that may be related to the greater prevalence of epithelial neoplasms arising in ovarian tissue.
As a quality assurance measure, the usefulness of transmission electron microscopy (EM) and immunohistochemistry (IHC) in our surgical pathology laboratory was compared. The surgical pathology reports from 150 consecutive neoplasms that were examined by both EM and IHC were reviewed. Based on the reported clinical histories, final diagnoses, light microscopy results, and the findings by EM or IHC, the contributions of EM and IHC were classified as "helpful" or "not helpful" for each specimen. Electron microscopy was helpful (92%) more often than was IHC (73%). Electron microscopy was most useful in further classifying poorly differentiated carcinomas, while IHC was particularly useful in classifying poorly differentiated neoplasms. Electron microscopy and IHC were of limited value in identifying the origin of metastatic carcinomas of an uncertain primary. All cases determined to be "not helpful" by either modality were further analyzed to establish a reason for the lack of information provided in each case. This analysis demonstrated a need for improved technical quality and ordering patterns of immunohistochemical stains in our laboratory.
BACKGROUND: A clinicopathologic evaluation of clinical Stage I and II uterine sarcoma was done by the Gynecologic Oncology Group from 1979-1988. METHODS: After all eligibility criteria were met, 453 cases were evaluable and analyzed for prognostic factors. RESULTS: Of the 301 mixed mesodermal tumors (MMT), 167 were homologous (HO), and 134 were heterologous (HE). Fifty-nine tumors were leiomyosarcomas (LM). The remaining 93 sarcomas were predominantly stromal cell and adenosarcomas. For this study, only the MMT or LM tumors were analyzed. The recurrence rate for all MMT was 53% (HO, 44%; HE, 63%). The recurrence rate for LM was 71%. The site of the first recurrence included the pelvis in 21% of MMT and 14% in LM. Factors significantly related to progression-free interval (PFI) by univariate analysis among MMT were adnexal spread, lymph node metastases, tumor size, lymphatic-vascular space involvement, histologic grade, cell type, age, peritoneal cytologic findings, and depth of uterine tumor site of invasion. The prognostic factors based on multivariate analysis were adnexal spread, lymph node metastases, histologic cell type (HO versus HE), and grade of sarcoma. For LM, the mitotic index was the only factor significantly related to PFI.
In an attempt to clarify the histogenesis of carcinosarcoma (malignant mixed müllerian tumor) of the female genital tract, 20 uterine and eight ovarian tumors were studied by light microscopy, transmission electron microscopy, and immunohistochemistry. Cytokeratins (MAK-6 and AE1:AE3) and epithelial membrane antigen were detected in the epithelial component of all tumors and in the stromal component of 15 cases (55%). Vimentin was detected in the stromal component of all cases and was focally positive in the epithelial component of 18 cases (69%). Tumors showing rhabdomyosarcomatous or chondrosarcomatous differentiation were positive for myoglobin and S-100 protein, respectively. At the ultrastructural level epithelial cells were observed in tight clusters (usually surrounded by a basal lamina), in loose aggregates, and singly (sometimes spindle shaped), and were surrounded by cells displaying variable differentiation. The closest examples of "hybrid" epithelial/stromal cells were those with a prominent rough endoplasmic reticulum, cytoplasmic projections, poorly formed intercellular junctions, and an incomplete basal lamina. The observations support the view that carcinosarcomas of the female genital tract could represent examples of biphasic (metaplastic) carcinomas.
We reviewed the clinical and pathological features of 24 cases of well-differentiated villoglandular adenocarcinoma of the uterine cervix. The patients' ages ranged from 27 to 54 years, with an average age of 37. At least 15 patients were taking oral contraceptive prior to diagnosis, compared to five of 18 in a control group of patients with various other histologic types of cervical adenocarcinoma. All of the neoplasms were exophytic polypoid lesions with thick or thin papillae lined by endocervical, endometrial or intestinal-type epithelium showing mild cytologic atypia. Ten were associated with adenocarcinoma in situ, eight with cervical intraepithelial neoplasia, and one with microglandular hyperplasia. All tumors were confined to the cervix. Five patients were treated by excisional biopsy or cone biopsy, four by simple hysterectomy with prior or subsequent radiation therapy, and 15 by radical hysterectomy. All patients are alive and well, with no evidence of recurrent disease. The follow-up ranged from 7 to 77 months, with a mean of 36 months.
Forty patients, originally diagnosed as endometrial hyperplasia, were reviewed histopathologically and evaluated for immunohistochemical staining with antibodies directed against TAG-72 and MSN-1 antigens. All patients had follow-up endometrial biospies or hysterectomies from 1 to 13 years later. The extent of regression to normal of nonhyperplastic endometrium, persistence as any type of endometrial hyperplasia, or progression to endometrial adenocarcinoma was correlated with the histologic hyperplastic subtype and immunohistochemical staining. As expected, cases of complex or atypical hyperplasia more often progressed to carcinoma than cases of simple or no hyperplasia. Interestingly, MSN-1 positivity was more prevalent in cases of higher grades than lower grades of hyperplasia and was associated with the tendency to show persistent hyperplasia or progression to carcinoma. B72.3 positivity was uncommon in the hyperplastic endometrium and was not correlated with clinical regression or progression. Although the tendency for progression of endometrial hyperplasia to endometrial carcinoma is best judged histologically, MSN-1 may add prognostic information in subgroups of hyperplasia.