Pseudorosette-Like Proliferations of the Endometrium.

The endometrium displays a wide spectrum of appearances in both neoplastic and non-neoplastic tissue. Unusual proliferations are not infrequently encountered and may lead to misinterpretation. In this study, we investigated pseudorosette-like proliferations (PLPs) found within the endometrial stroma which, to our knowledge, have not been previously reported. Nineteen endometrial samples with PLPs were identified over a period of 5 yr. Characteristics of the endometrium in which the PLPs were arising as well as patient information were recorded for each case. In addition, residual tissue from 10 of the cases was immunostained for cytokeratin, CD10, smooth muscle actin, S-100, and caldesmon to better characterize the lesions. In all cases the endometrium was in the proliferative phase and none of the patients reported the use of exogenous hormones. In 89% (17 of 19) of the cases, PLPs were present as a single focus; 2 cases showed multiple PLPs. Of the 10 immunostained cases, 90% (9 of 10) showed strong/diffuse staining for smooth muscle actin. Six cases showed negative or weak (1+) staining for CD10, whereas 3 showed moderate (2+) and 1 showed strong (3+) staining. In all cases the PLPs were negative for cytokeratin AE1/AE3, S-100, and caldesmon. These studies suggest that PLPs are benign proliferations with smooth muscle differentiation.

KRAS Mutations in Mucinous Lesions of the Uterus.

OBJECTIVES: The current study examined the KRAS mutation status in a spectrum of mucinous lesions of the uterus, including mucinous metaplasia (MM), atypical mucinous proliferation (AMP), endocervical mucosa, and microglandular hyperplasia (MGH). METHODS: Thirty-nine cases, including 15 AMPs, nine MMs, nine MGHs, and six normal endocervical mucosas, were selected from the departmental archive. All AMP cases with follow-up biopsies or hysterectomies were reviewed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and KRAS codons 12 and 13 sequence analyzed. RESULTS: KRAS codon 12 and 13 mutations were detected in 10 (67%) of the 15 AMP cases. No KRAS mutations were identified in MMs, MGHs, and endocervical mucosas (P = .002, AMP vs MM or MGH, Fisher exact test). Most women with AMP were postmenopausal (13/15 [86.7%]) and presented with dysfunctional uterine bleeding. Among the 10 cases of AMP harboring KRAS mutations, six (60%) cases were subsequently diagnosed with carcinoma, one with atypical complex hyperplasia, and two with AMP within endometrial polyps. CONCLUSIONS: The results suggest a possible association between KRAS mutations and mucinous differentiation in endometrial carcinogenesis. KRAS status can help in assessing benign from precursor or malignant mucinous lesions as well as differentiate endometrial lesions from those of cervical origin.

Increased dermal elastic fibers in the tight skin mouse.

OBJECTIVE: The tight skin (Tsk-1) mouse has been proposed as a model for systemic sclerosis on the basis of increased accumulation of collagen and glycosaminoglycans in the skin, and by the presence of serum autoantibodies. The genetic basis of the mutation has been identified as a genomic duplication within the fibrillin-1 (Fbn-1) gene that results in a larger than normal Fbn-1 transcript, but the mechanism that leads to dermal fibrosis is unclear Fibrillin molecules associate into a polymer that is coated with elastin molecules to form elastic fibers. To further evaluate the Tsk-1 mouse model of scleroderma, we have studied elastic fibers in the skin of these mice. METHODS: Skin sections obtained from C57BL/6-TSK+ (Tsk-1) and C57BL6-pa/+ (control) mice were stained with Masson's trichrome for evaluation of collagen and Gomori's aldehyde fuchsin stain for elastic tissue. Computer assisted image analysis was performed to quantify differences in histologic sections. RESULTS: Tsk-1 mice had a highly significant increase in the percentage of elastic fibers (19.6%) in the dermis compared to control mice (7.9%) [p < 0.001]. This correlates with the findings in the skin of systemic sclerosis patients where increased elastic fibers have been observed. In addition, an increased level of dermal collagen staining was also observed in the Tsk-1 dermis (82.9%) compared with the level in normal sections (73.7%) [p < 0.01]. CONCLUSION: These data support the use of the Tsk-1 mouse as a model for the connective tissue abnormalities of human scleroderma.

ADASP recommendations for processing and reporting of lymph node specimens submitted for evaluation of metastatic disease.

It is well known that different pathologists in different laboratories follow different protocols for the processing and examination of these specimens. There is also extensive literature (some of which is summarized in the references appended to the present report) on the likelihood of identifying metastases of varying sizes with different methods of preparation, as well as on the clinical significance of this identification, which varies not only from site to site but also from report to report on the same site. The Association of Directors of Anatomic and Surgical Pathology (ADASP) has reviewed this literature as well as the personal experience of its own members to present a set of recommendations for lymph node biopsies, lymph node dissections, sentinel node biopsies, lymph node fine needle aspiration (FNA) and core needle biopsies. It should be noted that these recommendations are intended specifically for lymph nodes being studied for metastatic neoplasms, and are not intended to apply to lymph nodes being evaluated for lymphoma, infections, and other disease processes. They are, however, formulated generically enough to apply regardless of whether the primary tumor is a carcinoma of the breast, carcinoma of the prostate, melanoma, or any other malignant, potentially metastasizing tumor. The Association has published numerous documents with recommendations for reporting surgical pathology specimens involving particular organ sites (for example, breast, pancreas, thyroid, etc.) However, the Association has not yet considered the generic question of dealing with lymph node specimens in which the intent is to search for and document the presence of metastatic disease. We are also unaware of guidelines for pathologists published by any other organization on this subject.

Influence of long term silicone implantation on type II collagen induced arthritis in mice.

OBJECTIVES: The use of silicone implants in cosmetic and reconstructive surgery has been implicated in the development of autoimmune connective tissue diseases. Previous investigation of the influence of short-term silicone implantation using an experimental model of rheumatoid arthritis revealed no adverse influence upon disease despite the generation of autoantibodies against silicone bound proteins. This study was designed to examine the influence of long term implantation of different forms of silicone in collagen induced arthritis. METHODS: DBA/1 mice were surgically implanted with silicone elastomers, gel or oil nine months before immunisation with type II collagen emulsified in Freund's incomplete adjuvant. The incidence and severity of arthritis, antibodies to type II collagen, and serum cytokines were assessed and compared with sham implanted mice. Silicone implants were recovered, and autoantibodies to silicone bound proteins evaluated in arthritic and non-arthritic mice. RESULTS: Immunisation with CII/FIA resulted in a 30% arthritis incidence in sham implanted DBA/1 mice. Long term silicone implantation resulted in an increased incidence of arthritis, with a significant increase of 90% arthritis in animals implanted with silicone elastomers. Animals implanted with silicone elastomer also developed foreign body sarcomas during the study. Serum concentrations of interleukin 10 were increased in mice implanted with elastomers and immunised with CII/FIA, while interleukin 5 concentrations were significantly diminished in these mice. The production of autoantibodies to autologous silicone bound proteins, including anti-type I collagen antibody, was also attributed to the implantation of either silicone gel or silicone elastomer in type II collagen immunised animals. CONCLUSIONS: These data suggest that long term silicone implantation results in both the production of autoantibodies to connective tissue antigens and increased susceptibility to an experimental model of autoimmune disease.

Immature teratomas of the genital tract in older women.

We report the clinicopathologic features of three women, 40 years of age or older, with malignant genital tract immature teratomas. All had FIGO stage III, grade II or grade III tumors. One tumor arose from the fallopian tube, the second from the ovary, and the third involved the cortical surfaces of both ovaries with minimal parenchymal involvement. The tumors weighed 1700, 5660, and 330 g and had histologic features similar to those generally seen in younger women. Two of the women died within 1 year of diagnosis. Interval growth of tumor after treatment with chemotherapy was documented in the third patient; she was reexplored and all of the excised tumor was composed of mature tissues. These cases affirm that, although rare, malignant germ cell tumors can occur in older peri- or postmenopausal women.

Ovarian smooth muscle metaplasia: an uncommon and possibly underrecognized entity.

Smooth muscle differentiation in the ovary is rare, and its histopathologic spectrum, including ovarian smooth muscle metaplasia (SMM), has not been well described. The clinicopathologic findings in 48 ovaries with SMM from 40 women are reported. The average age of women with ovarian SMM was 55.6 years (range, 34 to 86 years). Foci of SMM were semiquantitatively characterized as 1+ in 46% (1 to 3 foci), 2+ in 37% (4 to 6 foci), and 3+ in 17% (> 6 foci). SMM was bilateral in 8 (23%) of the 35 patients who had bilateral oophorectomies. SMM was intimately associated with another ovarian process in 28 (58%) cases, including ovarian cysts (11), endometriosis (3), granulosa cell tumors (3), extensive stromal luteinization (1), ovarian fibroma (1), adhesions (1), and folliculogenesis (8). Ovaries with 2+ to 3+ SMM were associated with another ovarian lesion significantly more often than those with 1+ SMM (p < 0.01). Most women with ovarian SMM (86%) also had uterine leiomyomas. Significant endometrial pathology was present in 13 (37%) of 35 simultaneously removed uteri. In conclusion, SMM occurs most often in perimenopausal or postmenopausal women, most of whom also have uterine leiomyomas. Ovarian SMM is usually confined to a few microscopic fields, is bilateral in < 25% of patients, and is often associated with other ovarian lesions.

Ovarian leiomyomas: clinicopathologic features in fifteen cases.

Ovarian leiomyomas are uncommon and have not been systematically studied. The clinical and histopathologic features of 15 ovarian leiomyomas were evaluated, including their clinical presentation, size, cellularity, mitotic index, presence of degeneration, and hyalinization. The mean age of women with ovarian leiomyomas was 45.8 years. The presenting sign was an adnexal mass in 7 (47%), uterine leiomyomas in 4 (26%), contralateral adnexal mass in 2 (13%), and other signs in 2 (13%) women. Thirteen leiomyomas had mitotic indices < 1/10 high-power-fields (HPFs), including one cellular leiomyoma, and 2 had mitotic indices between 1 and 2/10 HPFs. The cellular leiomyoma and those with a mitotic index of > or = 1/10 HPFs had an average size of 3.4 cm. Two leiomyomas exhibited central degeneration, and hyaline change was present in 5 leiomyomas, 4 of which were at least 4 cm in size. The majority of ovarian leiomyomas (78%) were associated with uterine leiomyomas; hyperplastic endometrial polyps were present in 2 cases. Follow-up (mean, 9.6 months) was available in 8 cases, and all had no evidence of recurrence. In conclusion, ovarian leiomyomas exhibit a spectrum of features that are similar to uterine leiomyomas. Although the prognosis is presumed to be good, the short follow-up period of this series precluded definitive evaluation of their natural history.

Extratubal secondary trophoblastic implants: clinicopathologic correlation and review of the literature.

Extratubal secondary trophoblastic implants (ESTI) are a rare complication of conservative laparoscopic procedures for tubal ectopic pregnancies. These implants present with persistent beta-hCG titers postoperatively and are probably the result of disruption of the ectopic pregnancy at salpingostomy or morcellation of the fallopian tube at salpingectomy. We describe the case of a 32-year-old woman who underwent a laparoscopic salpingectomy for a tubal ectopic pregnancy that was complicated postoperatively by peritoneal ESTI including extensive omental implants. Intraoperatively the lesions appeared as 0.3 cm red-black nodules and, microscopically, consisted of degenerating chorionic villi associated with implantation changes in the surrounding tissue. To the pathologist unaware of the clinical entity of ESTI, these lesions may present a diagnostic challenge.

Interinstitutional surgical pathology review in gynecologic oncology: I. Cancer in endometrial curettings and biopsies.

We report our experience with an interinstitutional surgical pathology review of endometrial curettings and biopsies originally diagnosed as cancer. Slides were reviewed from 182 women who were diagnosed with cancer and referred to our institution for further treatment; the slides had been sent for review at the request of the gynecologic oncologist. Review diagnoses were retrospectively compared to original diagnoses made on slides from these specimens, and significant discrepancies were identified in 43 (23.6%) of the 182 cases. For 16 (8.8%) patients, the diagnosis was downgraded from malignant to: 1) a benign non-hyperplastic process in 4 (2.2%); 2) scanty atypical glandular epithelium, not diagnostic for malignancy, in 2 (1.1%); and 3) endometrial hyperplasia in 10 (5.5%), including complex atypical hyperplasia in 8 (4.4%). Other significant differences involved histologic tumor classification in 16 (8.8%), degree of differentiation (two grades) in 2 (1.1%), determination of primary site in 4 (2.2%), and diagnosis of endocervical invasion in 5 (2.7%). Problems in comparison included lack of standardization of terminology and incomplete information from the original diagnoses. The high discrepancy rate between review and original diagnoses underscores the difficulty of interpreting these specimens. Review diagnoses of benign processes prevented an unnecessary operation for several women, and allowed those with cancer to undergo the most appropriate therapy. Review diagnoses in women with endometrial cancer contribute to quality medical care and have a major impact on a significant subset of patients.

Interinstitutional surgical pathology review in gynecologic oncology: II. Endometrial cancer in hysterectomy specimens.

During an 8-year period, 76 post-hysterectomy women with endometrial cancer were referred to our institution for evaluation or treatment, and had slides from the hysterectomy specimen sent for review at the request of the gynecologic oncologist (interinstitutional consultation). The original diagnosis was retrospectively compared to the review diagnosis and discrepancies were recorded. The most frequent discrepancy, identified in 24 (31.6%) of the 76 cases, involved assessment of myometrial invasion; 19 of these 24 had an original diagnosis of inner or middle third myometrial invasion and a review diagnosis of no myometrial invasion. The main reason for this discrepancy was irregularity of the endomyometrial junction, or, less commonly, extension of tumor into superficial adenomyosis. Additional discrepancies noted in 11 (14.4%) of the 76 cases included: 1) histologic tumor classification in 6 (7.9%); 2) assessment of angiolymphatic space invasion in 2 (2.6%); 3) identification of metastatic carcinoma in 1 (1.3%); and 4) change in diagnosis from adenocarcinoma to complex atypical hyperplasia and atypical polypoid adenomyoma in 1 each (2.6%). A significant subgroup of patients in this series had modifications in diagnosis; the most frequent discrepancy involved overdiagnosis of myometrial invasion, underscoring the difficulty sometimes encountered in this determination.

Retained trophoblastic tissue in fallopian tubes: a consequence of unsuspected ectopic pregnancies.

Five patients had retained trophoblastic tissue within the Fallopian tubes, which suggested remote ectopic pregnancies. Four remote ectopic pregnancies were identified in patients after delivery. One patient underwent salpingo-oophorectomy after the identification of a small ovarian mass and 1.0 cm "necrotic area" in the fallopian tube at cesarean section. The other three patients underwent tubal ligation, and one was noted to have a 1.0 cm "calcified" nodule in the distal fallopian tube. The fifth patient underwent laparotomy and was found to have an acute ectopic pregnancy in one fallopian tube and a clinically unsuspected 3.0 cm mass in the other, which proved to be an ectopic pregnancy with ghost outlines of chorionic villi and trophoblast. Histopathologically, all five patients showed foci of viable-appearing intermediate trophoblast and surrounding abundant eosinophilic hyalinized material in the fallopian tubes; four patients also had hyalinized ghost outlines of chorionic villi. None of the mothers had a history of previous ectopic pregnancy. The natural history of clinically unsuspected ectopic tubal pregnancies is not well understood, but these cases illustrate that trophoblast may persist in fallopian tubes and potentially result in clinical confusion as well as tubal pathology.

Glandular lesions of the uterine cervix: prognostic implications of human papillomavirus status.

Endocervical adenocarcinoma in situ (AIS) is believed to be a precursor of invasive disease; however, the biologic behavior of endocervical glandular "atypias" (GAs) is unclear. The purpose of this study was to evaluate the potential role of GA as a precursor of adenocarcinoma by assessment of the human papillomavirus (HPV) status of glandular lesions. We analyzed by polymerase chain reaction (PCR) 69 cases within a spectrum of endocervical glandular lesions encompassing invasive adenocarcinoma (IACA: 20 cases), AIS (21 cases), adenosquamous carcinoma (ASqCA: eight cases) and GA (20 cases) for HPV DNA sequences. Cervical adenocarcinoma is often associated with neoplastic squamous lesions (SL). In this study, after exclusion of AsqCA, 29 (47.5%) of 61 cases of endocervical glandular lesions were associated with an SL. The rate of HPV detection was not statistically different in adenocarcinoma with or without an SL (73.3% vs. 61.5%, respectively). In contrast, 64.3% of GAs with an SL (nine of 14 cases) were HPV positive, while only 16.7% of GAs without an SL (one of six cases) were positive. These findings suggest that HPV was preferentially associated with the concomitant SL rather than the GA. To localize the HPV sequences within the lesions, eight of the nine HPV-positive GAs with an SL were analyzed by in situ hybridization (ISH). Four cases were positive by ISH and showed hybridization of the probe only in the nuclei of squamous epithelial cells; in no lesion did the probe localize to the glandular epithelium. In our study, HPV Infection of the glandular epithelium of GAs unassociated with an SL appeared to be an uncommon event. None of the GAs were associated with low- or intermediate-risk HPV, and only the GA (which was high grade) unassociated with an SL contained a high-risk virus type. The possibility must be considered that pathogenetic mechanisms for squamous intraepithelial lesions may be different from those responsible for intraperitoneal glandular lesions.

Paclitaxel-induced apoptosis in MCF-7 breast-cancer cells.

A study of MCF-7 human breast cancer cells was undertaken to ascertain the degree of apoptosis induction by paclitaxel and if the induction of apoptosis could be enhanced by caffeine. Paclitaxel (0-20 ng/ml) caused concentration-dependent increases in morphologically identifiable apoptotic cells (up to 43% of cell population) and cells with DNA strand breaks (up to 38%), a commonly cited marker of apoptosis. Maximal DNA strand breakage occurred after 16 hr of exposure to paclitaxel and maximal apoptotic-appearing cells occurred after 24 hr. The remaining non-apoptotic paclitaxel-exposed cells were growth arrested in G2. A 4-hr exposure to caffeine concentration-dependently (0-20 mM) increased apoptosis to 88% of the cell population. Our results show induction of apoptosis in breast cancer cells by paclitaxel, and enhancement of this process by caffeine.

Histopathological changes in the testes of prepubertal male rats after chronic administration of cocaine.

PURPOSE: This study was conducted to evaluate histopathologic findings in the testes of prepubertal male rats after long-term cocaine exposure. METHODS: At 25 days of age, male Sprague-Dawley rats were administered cocaine hydrochloride daily (15 mg/kg body weight corresponding to an average single dose for a heavy cocaine user). The treatment was continued for 100 days when all the rats were sacrificed. Morphological analysis of the testes were assessed by qualitative and quantitative histological means. RESULTS: In all the groups, a minimum of 5 to 10 representative seminiferous tubules were examined. The mean diameter of the seminiferous tubules was less in the treated group than in their respective controls (p < 0.05). The thickness of the germinal epithelium was much reduced in the cocaine-treated groups when compared with their controls (p < 0.05). The number of degenerating germ cells was greater in the treated group than in the controls. There was evidence of failure to release the mature spermatids in the treated groups. There was no evidence of sloughed Sertoli cells or germ cells in the tubular lumen or the epididymis. CONCLUSION: There were distinct histopathological changes noted after chronic administration of cocaine. These changes are characteristic of toxic effects on the testes, but the exact mechanism is not clear. Further studies are underway in our laboratory to delineate the exact mechanism of action by cocaine on the testes.

Tumors of the uterine isthmus: clinicopathologic features and immunohistochemical characterization of p53 expression and hormone receptors.

Five (3%) of 161 endometrial cancers treated surgically between 1988 and 1992 were classified as primary isthmic tumors, and their clinicopathologic features, p53 expression, and hormone receptor status were evaluated. Three were endometrioid adenocarcinomas with squamous differentiation, one was a mixed serous and clear cell carcinoma, and one was a malignant müllerian mixed tumor; all five were high grade, invaded the entire thickness of the myometrium, and exhibited lymphatic space invasion. Four of the five patients had extrauterine metastases identified at the time of hysterectomy. All five patients died due to progressive disease with the survival time ranging from 1 to 23 months. Abnormal p53 gene expression was identified immunohistochemically in three of the five isthmic tumors. Weak positivity for estrogen and progesterone receptors was demonstrated in one case, with the remaining four being negative. Tumors arising in and confined to the uterine isthmus are unusual and, in our series, were uniformly aggressive with an unfavorable prognosis. The histopathologic features and biologic behavior of the isthmic tumors appeared similar to those of other high-grade endometrial cancers arising in the uterine corpus.

Intraoperative consultation in ovarian lesions: a comparison between cytology and frozen section.

Little information is available on the relative value of intraoperative cytology (IOC) and frozen section (FS) in evaluation of ovarian lesions. We compared the two methods in 63 histologically proven cases of resected ovaries studied by imprints (40 cases), FNAs (38 cases), and scrapes (5 cases). Diagnoses were: 10 nonneoplastic cysts, 46 neoplasms (benign, 19; borderline, 8; and malignant, 19) and 7 tumors comprised of small blue cells (SBC): granulosa cell (3), lymphoma (1), small cell carcinoma (1), and sarcoma (2). There were no false-positive diagnoses by IOC or FS among the benign and borderline conditions. Five benign lesions, however, had FS deferred because of architectural complexity, this in contrast to only one case reported as atypical by IOC. Borderline tumors were recognized as such in 3 cases examined by FS, but no such diagnosis was possible by IOC due to the inability to assess invasion. The diagnosis in borderline neoplasms of surface epithelial origin was deferred in 4 cases by FS and reported as atypical in 5 cases examined by IOC due to the spectrum of architectural and nuclear atypia in borderline tumors. Of the 19 malignant cases, five were deferred because of uncertainty of invasion by FS, whereas two were called atypical by IOC. Five of 7 SBC tumors were recognized as such by FS and 6 of 7 by IOC, but none could be unequivocally subclassified by either method. Intraoperative FNAs and scrapes were superior to imprints, which tended to be bloodier and thicker. In contrast to FNAs, scrapes were easier to direct and yielded greater cellularity, although both methods were comparable in diagnostic accuracy. Even though the diagnostic yield of IOC was only slightly better than that of FS, it provided much better cytologic detail, and afforded a more representative sampling.