Is quantification of lymphovascular space invasion useful in stage 1B2 cervical carcinomas?

The objective was to determine whether quantification of lymphovascular space invasion (LVSI) by simple techniques adds prognostic information above its mere identification in stage 1B2 cervical cancer. The method was to quantify LVSI by extent, density and distance from the advancing front in 88 consecutive stage 1B2 cervical cancers treated by radical hysterectomy and pelvic lymphadenectomy and to compare them with pelvic lymph node status and local and distant recurrence. The results were that LVSI involved more tumour blocks, was denser and extended a further distance in those with positive nodes. However, effective adjuvant therapy confounded the association between quantification of LVSI and local recurrence. Furthermore, pelvic lymph node status was a stronger predictor of distant recurrence than any degree of LVSI. In conclusion, quantifying LVSI in stage 1B2 cervical cancer is a good predictor of lymph node metastasis, but is not useful where the lymph node status is known.

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro.

Despite a high initial response rate to first-line platinum/paclitaxel chemotherapy, most women with epithelial ovarian cancer relapse with recurrent disease that becomes refractory to further cytotoxic treatment. We have previously shown that the E3 ubiquitin ligase, EDD, a regulator of DNA damage responses, is amplified and overexpressed in serous ovarian carcinoma. Given that DNA damage pathways are linked to platinum resistance, the aim of this study was to determine if EDD expression was associated with disease recurrence and platinum sensitivity in serous ovarian cancer. High nuclear EDD expression, as determined by immunohistochemistry in a cohort of 151 women with serous ovarian carcinoma, was associated with an approximately two-fold increased risk of disease recurrence and death in patients who initially responded to first-line chemotherapy, independently of disease stage and suboptimal debulking. Although EDD expression was not directly correlated with relative cisplatin sensitivity of ovarian cancer cell lines, sensitivity to cisplatin was partially restored in platinum-resistant A2780-cp70 ovarian cancer cells following siRNA-mediated knockdown of EDD expression. These results identify EDD as a new independent prognostic marker for outcome in serous ovarian cancer, and suggest that pathways involving EDD, including DNA damage responses, may represent new therapeutic targets for chemoresistant ovarian cancer.

A distinct molecular profile associated with mucinous epithelial ovarian cancer.

Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT-PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC.

Clinicopathologic review of malignant polyps in stage 1A carcinoma of the endometrium.

OBJECTIVES: The aims of this study were to determine the incidence of malignant polyps in stage 1A endometrial cancer, to define the pathological features of such cancers, and to assess whether clinical outcome differs from similar cancers without a malignant polyp. METHODS: We performed a retrospective pathological review of 107 cases of stage 1A endometrial cancer treated at two centers in New South Wales between January 1988 and July 2003. The presence of a malignant polyp was determined and a pathological description made of the tumor. Clinical data were collected, including prior tamoxifen usage, tumor recurrence and survival. The outcome of the malignant polyp group was compared to the same histological subtype not involving a malignant polyp. RESULTS: The incidence of malignant polyps in our series was 32%. Malignant polyps occurred in all 8 cases involving a serous subtype. Precursor lesions of endometrial cancer were identified within malignant polyps. Three out of the four recurrences occurred in high-grade tumor subtypes and all four had a large primary tumor (size > or = 4 cm). When comparing the same subtype of tumor with and without a malignant polyp, there was no significant difference in clinical outcome. CONCLUSIONS: Approximately one-third of stage 1A endometrial cancers are associated with a malignant polyp. Serous carcinoma commonly arises within an otherwise benign endometrial polyp. Malignant polyps offer an opportunity to identify precursors of endometrial carcinoma. Clinical outcome of stage 1A endometrial carcinoma was related to the histological subtype and the size of the tumor rather than the presence of a malignant polyp.

Endometrial stromal sarcoma resembling adenomyosis and menstrual-phase endometrium.

BACKGROUND: Low-grade endometrial stromal sarcoma (LGESS) and endometriosis are two conditions of different prognostic significance that are usually not difficult to distinguish histologically. CASE: We present the case of a 38-year-old woman who underwent laparotomy after a diagnosis of endometrial stromal neoplasm on uterine curettings. Uterine enlargement and regional and paraaortic lymphadenopathy were found. Pathology showed adenomyotic-like myometrial hypertrophy and menstrual-like shedding of tumor in involved lymph nodes. The finding of large areas of endometrial stromal cells without accompanying glands forming tumorous masses in both sites supported the diagnosis of LGESS. We believe that this is the first time that these phenomena have been reported in LGESS. CONCLUSION: In these cases, adenomyotic myometrial hypertrophy and menstrual shedding have been used to distinguish endometriosis from LGESS, but do not appear to be absolute criteria. Endometriosis and LGESS are undoubtedly separate entities, but occasionally may resemble each other.

Does the density of lymphatic vascular space invasion affect the prognosis of stage Ib and IIA node negative carcinoma of the cervix?

Lymphatic vascular space invasion (LVSI) has been noted as a poor prognostic factor in many tumors. In some studies of carcinoma of the cervix, LVSI has been demonstrated to be independent of other prognostic factors. The aim of this study is to evaluate if, by a simple quantitative technique, the density of lymphatic invasion could be correlated with the risk of recurrence in node negative early stage carcinoma of the cervix. We analyzed the pathology and clinical course of 71 consecutive patients with stage IB and IIA carcinoma of the cervix treated primarily by radical hysterectomy and pelvic lymphadenectomy. All cases had negative nodes and adequate surgical margins. There were 67 patients suitable for evaluation. Tumour type, grade, stage and the dimensions of the tumor were recorded. The density of LVSI was categorized as absent (45%), mild (15%), moderate (33%) or severe (7%) depending on the number of lymphatic vascular spaces involved per high power field in the worst affected slide. The patients were followed for 2-8(1/2) years with a mean follow up of 4 years and 2 months. There were 13 recurrences and 7 deaths. All recurrences occurred in less than 2 years after surgery. The risk of recurrence was 40% for patients with extensive LVSI, 32% for moderate, 30% for mild and 3% if LVSI was absent. Only the presence of LVSI was associated with an increased risk of recurrence. The density of lymphatic invasion as represented by the number of lymphatic spaces occupied on the worst histological slide offered no further clinically useful information.

Genetic aberrations detected by comparative genomic hybridisation in vulvar cancers.

Squamous cell carcinoma of the vulva is a disease of significant clinical importance, which arises in the presence or absence of human papillomavirus. We used comparative genomic hybridisation to document non-random chromosomal gains and losses within human papillomavirus positive and negative vulvar cancers. Gain of 3q was significantly more common in human papillomavirus-positive cancers compared to human papillomavirus-negative cancers. The smallest area of gain was 3q22-25, a chromosome region which is frequently gained in other human papillomavirus-related cancers. Chromosome 8q was more commonly gained in human papillomavirus-negative compared to human papillomavirus-positive cancers. 8q21 was the smallest region of gain, which has been identified in other, non-human papillomavirus-related cancers. Chromosome arms 3p and 11q were lost in both categories of vulvar cancer. This study has demonstrated chromosome locations important in the development of vulvar squamous cell carcinoma. Additionally, taken together with previous studies of human papillomavirus-positive cancers of other anogenital sites, the data indicate that one or more oncogenes important in the development and progression of human papillomavirus-induced carcinomas are located on 3q. The different genetic changes seen in human papillomavirus-positive and negative vulvar squamous cell carcinomas support the clinicopathological data indicating that these are different cancer types.

The accuracy and interobserver reproducibility of endometrial dating.

Although controversial, diagnosis of luteal phase defect (LPD) includes the morphological assessment of endometrial development. This study was conducted to determine if refresher training in the histological criteria could improve the accuracy and interobserver reproducibility of endometrial dating. Seventy-eight endometrial biopsies were dated by a reference panel of two pathologists and then reviewed twice by a study panel of four pathologists. In the first review, usual practice was applied. Prior to the second review, they studied a standard document of histological criteria. Samples were dated as proliferative, secretory (post-ovulatory day, POD), menstrual, and undatable. Accuracy levels based on the reference dating and agreement levels using kappa values were calculated per review and compared. The kappa for overall dating was 0.683 in the first review and 0.696 in the second. The respective first and second review kappa values were 0.736 and 0.771 for proliferative, and 0.794 and 0.764 for secretory. Amongst those dated as secretory in the first and second reviews, respectively, 31 and 28% were assigned the same POD by any two panellists, 68 and 63% were dated to within 1 day, and 77 and 71% were dated to within 2 days. Accuracy levels per panellist for overall dating were very high in both reviews but were low for individual PODs. Accuracy and interobserver reproducibility were unaffected by refresher training, suggesting the limits of histological dating have been reached.

Small atypical leiomyomas: report of two cases.

We describe two small atypical leiomyomas. The first was a 6-mm de novo lesion in a 53-year-old woman. The second was a 3-mm focus in a 12-mm leiomyoma in a 45-year-old woman. Both lesions showed moderate atypia and a mitotic rate of six per 10 high-power fields. Coagulative necrosis was not seen. Neither patient had received exogenous oestrogen or progestogen. There was no evidence of recurrence or metastasis in either patient after 60 months of follow-up. Our report provides evidence that atypical uterine leiomyomas may arise either de novo or within a leiomyoma.

Necrotizing infundibular crystalline folliculitis.

We describe a 22-year-old woman with a background of acne who developed multiple folliculocentric facial papules associated with sharply demarcated waxy, keratotic plugs. Multiple skin biopsies showed umbilicated craters that were filled with dispersed bundles of eosinophilic filaments embedded in a pale amorphous matrix forming a plug. The plugs bulged into the upper dermis. Serial sections showed vacuolar and filamentous destruction of the infundibular and adjacent perifollicular epithelium and a close relationship of the crystalline necrosis to follicles. Electron microscopy revealed that the filamentous bundles were tonofilaments. No fresh material was available for polarization and the paraffin sections failed to polarize. The clinical and pathological findings of the lesions in our patient were identical to those reported as a new perforating disorder with urate-like crystals. Our case indicates that the process may represent crystalline folliculocentric necrosis rather than a primary perforating disorder. The nature and basis of the crystals that have a urate-like appearance remain to be determined.

Classification of ovarian endometriotic cysts.

Current literature describes 3 different pathogenetic types of ovarian endometriotic cysts. Cortical invagination cysts arise when surface ovarian endometriotic deposits adhere to another structure (such as the broad ligament), blocking the egress of menstrual fluid produced by cycling endometriosis, which then collects and causes the ovarian cortex to invaginate. Surface inclusion cyst-related endometriotic cysts develop when endometriotic tissue colonizes preexisting inclusion cysts. Physiological cyst-related endometriotic cysts occur when endometriosis gains access to a follicle, such as at the time of ovulation. To determine whether routine histological examination is of use in the classification of endometriotic cysts, and if so, whether such classification is of clinical relevance, we reviewed the histology of endometriotic cysts of 29 women under 35 years of age. Young women were chosen so that ovarian cortex surrounding the endometriotic lining in invagination cysts could be identified by the finding of oocytes. Ten women (34%) had cortical invagination endometriotic cysts, but no inclusion or physiological cyst-related endometriomas were found. The remaining 19 women (66%) had unclassified endometriotic cysts, of which 14 (48% of total) had a fibrous wall between the endometriotic lining and medulla and 5 had extensive destruction of ovarian tissue. We concluded that cortical invagination cysts were the only common diagnosable sort of the 3 types currently being investigated and that unclassified cysts required further study to determine their pathogenesis. Our study highlights the need for a prospective study using standardized pathological and clinical methods.

Histology of lichen sclerosus varies according to site and proximity to carcinoma.

To investigate why vulvar but not extragenital lichen sclerosus is associated with squamous cell carcinoma, we performed a histologic study of extragenital lichen sclerosus, vulvar lichen sclerosus without carcinoma, and vulvar lichen sclerosus with carcinoma adjacent to and distant from the carcinoma. We compared epidermal thickness, rete ridge length, mitotic activity, atypia, dermal collagen change, dermal inflammation, and presence of other dermatoses in 30 women in each group. Extragenital lichen sclerosus showed thinner epidermis (mean thickness of 0.13 mm versus 0.41 mm; P < 0.0005), shorter rete ridges (P = 0.0001), more dermal edema (P = 0.16), and absence of associated dermatoses of spongiotic dermatitis and lichen planus (P < 0.005) compared with vulvar lichen sclerosus. The epidermal thickening seen in vulvar lichen sclerosus was indistinguishable from lichen simplex chronicus. Vulvar lichen sclerosus without carcinoma was generally similar to that distant from carcinoma. Vulvar lichen sclerosus adjacent to carcinoma showed increased epidermal thickness (0.61 mm versus 0.26 mm; P < 0.005), more dermal fibrosis (P < 0.0005), more inflammation (P < 0.0005), and more simplex (differentiated) vulvar intraepithelial neoplasia (18 cases versus 1 case; P < 0.0005) compared with that distant from carcinoma. We concluded that (1) the classic histologic features of lichen sclerosus are seen in both vulvar and extragenital sites; (2) vulvar lichen sclerosus without associated carcinoma has a mean epidermal thickness more than three times that of extragenital lichen sclerosus; (3) the epidermal thickening is histologically indistinguishable from lichen simplex chronicus; (4) there is a tendency for vulvar lichen sclerosus to have a more sclerotic and inflamed dermis; (5) lichen sclerosus 10 mm from cancer is more similar to vulvar lichen sclerosus without carcinoma than lichen sclerosus 1 mm from carcinoma; and (6) lichen sclerosus adjacent to carcinoma tends to show exaggerated epidermis thickness, basal atypia, and loss of the edematous-hyaline layer.

A prospective evaluation of the pathogenesis of detrusor instability in women, using electron microscopy and immunohistochemistry.

OBJECTIVE: To characterize the types of detrusor smooth muscle junctions in the bladders of women with detrusor instability and in a control group without, and to assess whether there are differences in the cell junctions between these groups. PATIENTS AND METHODS: The study included 13 women with detrusor instability (median age 57 years, range 32-86) and 11 control women (median age 50 years, range 33-62). Bladder biopsies were taken from each participant, processed for electron microscopy and immunohistochemistry (using a labelled antibody to vinculin) and analysed by investigators who were unaware of the patients' diagnoses. RESULTS: Adherens (intermediate) junctions in classic and rudimentary forms were present in all biopsies from patients and controls. Adherens junctions and dense plaques occupied almost the complete cell border in most samples. Complete immunohistochemistry was possible in seven patients and five controls. In almost every detrusor smooth muscle cell studied, there was staining of the entire cell border with labelled antibody to vinculin in all biopsies. CONCLUSIONS: This study provides evidence against an ultrastructural basis for idiopathic detrusor instability based on possible differences in detrusor smooth muscle intercellular junctions. Virtually the entire cell membrane of detrusor smooth muscle fibres is occupied by adherens junctions in classic and rudimentary forms, and with dense plaques present in samples from women with an unstable bladder and from controls. There was no junction detected in those with instability that was not present in the control group. The adherens junctions in the bladder facilitate mechanical coupling between cells.

Progressive genetic aberrations detected by comparative genomic hybridization in squamous cell cervical cancer.

Genetic changes orchestrated by human papillomaviruses are the most important known factors in carcinogenesis of the uterine cervix. However, it is clear that additional genetic events are necessary for tumour progression. We have used comparative genomic hybridization to document non-random chromosomal gains and losses within a subset of 37 cervical carcinomas matched for clinical stage Ib, but with different lymph node status. There were significantly more chromosomal changes in the primary tumours when the lymph nodes were positive for metastases. The most frequent copy number alterations were loss of 3p, 11q, 6q and 10q and gain of 3q. The smallest areas of loss and gain on chromosome 3 were 3p14-22 and 3q24-26. The study identifies progressive DNA copy number changes associated with early-stage invasive cervical cancers with and without lymph node metastases, a factor of potential prognostic and therapeutic value.

Thin layer compared to direct smear in thyroid fine needle aspiration.

The efficacy of preparing thyroid fine needle aspirations (FNAs) by the thin layer as opposed to the direct smear method has not been evaluated sufficiently in a regional laboratory setting. At the Foothills Hospital (Calgary, Canada), the method of processing thyroid FNAs was changed from direct smear to thin layer in January 1996. The results of 327 patients who had direct smear from 1994 to 1995 were compared to 401 who had thin layer between 1996 and 1997. While there were no significant differences across a broad range of quality indicators, thin layer showed a trend towards a higher proportion of true benign diagnoses (31% vs 24%), a lower proportion of inadequate specimens (41% vs 50%) and, most importantly, a lower false negative rate (3% vs 9%). In conclusion, the changeover to thin layer did not compromise the interpretation of thyroid FNAs.

Histologic study of patterns of cervical involvement in FIGO stage II endometrial carcinoma.

The pathology of cervical involvement in endometrial carcinoma has not been fully defined previously. We reviewed the histopathology of 66 hysterectomies of women with stage II endometrial carcinoma. Cervical spread was categorized as macroscopic or microscopic; stage IIA or IIB; direct spread, surface or lymphvascular metastasis; and size, number, and location. The cervical tumor was macroscopically identified in 15 (23%) women and microscopically identified in 51 (77%). Twenty-one patients (32%) were stage IIA and 45 (68%) stage IIB. The method of spread was direct spread in 28 patients, surface metastases in 27, lymphovascular in 3, both direct spread and surface metastases in 7 and both direct spread and lymphovascular in 1. The cervical tumor had a mean horizontal dimension of 3 mm and a median of 2 mm. There were multiple sites of cervical tumor in 31 (47%) patients and single in 35 (53%). The sites of spread, including cases with multiple sites, were the endocervix in 60 women (90%), transformation zone in 24 (37%), and ectocervix in 3 (5%). Most patients had minimal microscopic cervical tumor. Small examples of direct spread may be an artifact of definition depending on the histology of the isthmian-endocervical junction and many surface metastases appear to follow dilatation and curettage. In 7 of 66, 11%, however, the cervical tumor was greater than 5 mm depth of invasion and/or the result of lymphvascular metastasis. Survival studies are required to compare minimal stage II endometrial carcinoma patients and those with larger and/or lymphvascular derived cervical tumor. Patients with minimal stage II and stage I patients should also be compared.

Malignant mesothelioma eight years after a diagnosis of atypical mesothelial hyperplasia.

The separation of mesothelial hyperplasia from early malignant mesothelioma remains one of the most difficult problems in histopathology. Inconclusive cases are termed "atypical mesothelial hyperplasia" and treated expectantly. A 49 year old male pipeline engineer was diagnosed as having atypical mesothelial hyperplasia in appendiceal serosa by the US-Canadian Mesothelioma Panel. Eight years later, he developed overtly malignant peritoneal and pleural mesothelioma. In hindsight, histological similarities between the diffuse malignant mesothelioma and the atypical mesothelial proliferation suggested malignancy from the outset. The most important of these features were the degree of mesothelial proliferation, micronodularity, architectural complexity, superficial invasion, uniform mild cytological atypia, and the absence of a clinical cause for a benign mesothelial proliferation. Ancillary investigations including immunohistochemistry were of no benefit in determining whether the atypical mesothelial hyperplasia was benign or malignant. Careful histological examination remains the mainstay of the diagnosis of early mesothelioma.