Kenneth R. Lee

Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for cervical cancer screening

Objective: To compare the cytologic diagnoses and specimen adequacy of a fluid-based, thin-layer preparation and conventional Papanicolaou tests. Methods: A total of 7360 women from six separate sites—three screening centers and three hospitals—participated in split-sample/matched-pair, double-masked clinical trials. A conventional Papanicolaou test was performed, after which residual material on the sampling device was rinsed into a fluid preservative from which a thin-layer slide (ThinPrep) was prepared using the ThinPrep 2000 automated slide processor (Cytyc Corp., Boxborough, MA). Conventional and ThinPrep slides were read independently. Cytologic diagnoses and specimen adequacy were classified using the Bethesda system. Results: For the three screening centers, 65% more diagnoses of low-grade squamous intraepithelial lesions and higher were made on the ThinPrep slides (P Conclusion: The fluid-based, ThinPrep method of sample preparation resulted in a statistically significant increase in cytologic diagnosis of cervical cancer precursors and in specimen adequacy compared with the conventional Papanicolaou testing method.

Mucinous tumors of the ovary: a clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with 'Pseudomyxoma peritonei'

Mucinous ovarian neoplasms other than cystadenomas and adenofibromas have been classified as either borderline tumors or carcinomas for many years. Borderline tumors have been subdivided more recently into endocervical-like (mullerian) and intestinal forms. Such a distinction is rarely made in the mucinous carcinoma category. We did not encounter a pure endocervical-like carcinoma in the present series. Criteria for distinguishing an intestinal-type mucinous borderline tumor from a mucinous carcinoma have been controversial. In this study of 164 mucinous borderline tumors of intestinal type and 32 mucinous carcinomas, the former were further subdivided into 74 cases with epithelial atypia only and 90 with focal intraepithelial carcinoma. Of the 67 stage I tumors in the borderline (with atypia) category, all 49 with follow-up data were clinically benign; in the seven cases that had been designated stage III, the intraoperative appearance was that of “pseudomyxoma peritonei,” which was fatal in four cases. Most of these tumors, however, were probably metastatic to the ovary rather than truly primary borderline tumors, although failure to examine the appendix in six cases compromised their interpretation. All 90 mucinous borderline tumors that had foci of intraepithelial carcinoma were recorded as stage I, but two of the 69 patients with follow-up data (3%) had fatal recurrences. Both of these tumors were incompletely staged, however, and one had ruptured intraoperatively. Thirty-two invasive carcinomas were subdivided into 12 expansile and 20 infiltrative subtypes; within the latter category seven tumors were only microinvasive. All 12 carcinomas with only expansile invasion were stage I; none of the 10 with follow-up data recurred. All seven microinvasive infiltrative carcinomas were stage I; none of the five with follow-up data recurred. One of five patients with stage I infiltrative carcinomas that were more than microinvasive and were adequately followed had a fatal recurrence, but staging had been incomplete in that case. Seven of the remaining eight infiltrative carcinomas were higher than stage I; five of the six (83%) with follow-up data persisted or recurred and were fatal. Considering all stages, increasing tumor grade in the carcinoma category correlated with an unfavorable outcome. However, grade did not influence prognosis in stage I carcinomas. Among 13 stage I cases in all categories with either preoperative or intraoperative tumor rupture and follow-up data, one recurred, a tumor in the borderline with intraepithelial carcinoma category. “Pseudomyxoma peritonei” is an ill-defined term and should not be used as a pathologic diagnosis. The presence of mucin in the abdominal cavity requires careful histologic evaluation to characterize it for prognostic purposes. Adequate and sometimes extensive sampling of mucinous ovarian tumors, the appendix and the peritoneum in cases of “pseudomyxoma peritonei” is necessary to achieve an accurate diagnosis and prognosis.

The distinction between primary and metastatic mucinous carcinomas of the ovary: Gross and histologic findings in 50 cases

The gross and routine microscopic features of 25 stage I primary mucinous ovarian carcinomas without clinical evidence of recurrence and 25 mucinous carcinomas metastatic to the ovaries were compared. Findings that were frequent in the latter and strongly favored a metastasis were: 1) bilaterality, 2) microscopic surface involvement by epithelial cells (surface implants), and 3) an infiltrative pattern of stromal invasion. Findings that were less frequent but present exclusively or almost exclusively in metastatic carcinomas were: 1) a nodular invasive pattern, 2) ovarian hilar involvement, 3) single cell invasion, 4) signet-ring cells, 5) vascular invasion, and 6) microscopic surface mucin. Findings that were frequent in, and strongly favored, primary ovarian carcinoma were: 1) an “expansile” pattern of invasion and 2) a complex papillary pattern. Findings that were less frequent but also favored a primary tumor were: 1) size >10 cm, 2) a smooth external surface, 3) benign-appearing and borderline-appearing areas, 4) microscopic cystic glands, and 5) necrotic luminal debris. Findings that did not distinguish the tumors were: 1) a cystic gross appearance, 2) gross solid, papillary, necrotic, or hemorrhagic areas, 3) nature of cyst contents (mucinous vs nonmucinous), 4) stromal mucin (pseudomyxoma ovarii), 5) cribriform, villous, or solid growth patterns, 6) focal area resembling typical colonic carcinoma, 7) goblet cells, or 8) tumor grade. Primary and metastatic mucinous ovarian carcinomas can be distinguished from each other in the great majority of cases based solely on their conventional histopathologic findings. Careful gross evaluation is also important with special attention paid to the external surface of the ovarian tumor(s) to detect abnormalities that have the features of surface implants on microscopic evaluation.

Distinction between endometrial and endocervical adenocarcinoma: an immunohistochemical study.

We investigated the possibility of distinguishing between primary endometrial and endocervical adenocarcinomas by using a panel of immunohistochemical stains, which included vimentin (VIM), carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), and cytokeratins 7 and 20 (CK7 and CK20). Twenty-nine endocervical adenocarcinomas (CCAs) and 30 endometrial adenocarcinomas (EMCAs) including cases with overlapping histologic features (CCAs with endometrioid differentiation [15/29] and EMCAs with mucinous differentiation [16/30]) were evaluated. Most EMCAs (29/30, 97%) were VIM positive, whereas only 2/29 (7%) CCAs were VIM positive. The great majority of EMCAs (28/30) and all 29 CCAs were CK7 positive, whereas all 30 EMCAs and 27/29 CCAs were negative for CK20. CEA positivity was more common in CCAs (18/29, 62%) than in EMCAs (8/30, 27%). EMA positivity was present in all 30 EMCAs and in 26 of 29 (90%) CCAs. We conclude that VIM and CEA are useful immunohistochemical markers in distinguishing EMCAs and CCAs, but CK7, CK20, and EMA are not useful in this distinction.

Accuracy of Fine Needle Aspiration in Distinguishing Subtypes of Renal Cell Carcinoma

OBJECTIVE To evaluate the cytologic features of each subtype of renal cell carcinoma (RCC) for separating the various subtypes. STUDY DESIGN Thirty-eight renal fine needle aspiration (FNA) specimens with surgical resection follow-up were retrospectively reviewed and classified without knowledge of the resection specimen diagnosis. These included 18 clear cell RCCs, 8 papillary RCCs, 4 oncocytomas, 2 chromophobe RCCs, 2 sarcomatoid RCCs and 4 metastases to the kidney. RESULTS Seventy-four percent of the primary renal lesions were correctly classified. All 4 oncocytomas and the 2 chromophobe tumors were correctly classified, while both sarcomatoid RCCs and 3 of 8 papillary RCCs were misclassified as clear cell RCC. One clear cell RCC was misclassified as papillary type. Two clear cell and one papillary RCC were nondiagnostic; in each case the tumor had a prominent cystic component. All four metastases were correctly identified. CONCLUSION Subclassification of RCC by FNA is relatively accurate. In this study, the most common error was to misclassify papillary and sarcomatoid RCC as clear cell RCC.

Evaluation of the ThinPrep Processor for Fine Needle Aspiration Specimens

OBJECTIVE To test the ThinPrep Processor for fine needle aspiration. STUDY DESIGN One hundred unfixed, surgically removed specimens were aspirated. One pass was directly smeared, fixed and stained with the Papanicolaou technique. The other pass was rinsed in a proprietary fixative, and a single ThinPrep slide was made. Smears were diagnosed without knowledge of the histologic diagnosis. RESULTS Cellularity and architectural integrity of cell groups were superior on the conventional slides. Preservation and detail of both epithelial and stromal cells were superior with the ThinPrep Processor. Preservation of background material, such as mucus and colloid, was slightly superior on the ThinPrep slides. Diagnostic sensitivity and specificity for malignancy and unsatisfactory rates were all slightly better on the ThinPrep slides. CONCLUSION The ThinPrep Processor offers an alternative to direct smears in situations in which expertise in slide preparation is not available.

Stage IA1 cervical adenocarcinoma: definition and treatment

OBJECTIVE To propose a definition for stage IA1 cervical adenocarcinoma, based on the International Federation of Gynecology and Obstetrics (FIGO) staging system, and to determine if patients meeting criteria might be candidates for conservative surgery. METHODS Two hundred women were diagnosed with early-stage cervical adenocarcinoma from 1982 to 1996. Histopathologic sections were reviewed by a gynecologic pathologist. Medical records were reviewed, and patients included in this study had microscopically identifiable lesions, up to 3 mm invasive depth, up to 7 mm tumor width, and negative margins if cone biopsy was performed. RESULTS Twenty-one patients with microinvasive adenocarcinoma met criteria for FIGO stage IA1 carcinoma of the cervix. The median (range) follow-up was 76 (30-172) months and median (range) patient age was 38 (24-75) years. Definitive treatment included type II or III radical hysterectomy in 16 cases, simple abdominal or vaginal hysterectomy in four cases, and loop electrosurgical excision procedure in one case; one patient received adjuvant pelvic radiation. The histologic subtypes were endocervical adenocarcinoma in 18 cases, adenosquamous carcinoma in two cases, and clear-cell adenocarcinoma in one case. There was no evidence of parametrial invasion or lymph node metastases in any patient who had radical surgery, and there were no disease recurrences. CONCLUSION Patients with microinvasive adenocarcinoma who met criteria for FIGO stage IA1 cervical carcinoma had disease limited to the cervix, and conservative surgery, such as cone biopsy or simple hysterectomy, might offer them definitive treatment.

Atypical Glandular Cells of Undetermined Significance Outcome Predictions Based on Human Papillomavirus Testing

Cases of atypical glandular cells (AGC) diagnosed on liquid-based preparations were culled from a 3-year period. When available, residual cellular material was analyzed for human papillomavirus (HPV) by polymerase chain reaction and correlated with cytologic and histologic (biopsy) outcome. Of 178,994 cytologic cases, 187 (0.1045%) contained AGC compared with 8,740 (4.8828%) atypical squamous cells (ASC) for an AGC/ASC ratio of 0.021. HPV results and follow-up were available for 108 specimens from 106 patients. Depending on the end-point (histologic/cyto-logic), the sensitivity range of HPV testing for significant cervical disease (high-grade squamous intraepithelial lesion [SIL], adenocarcinoma in situ [ACIS], invasive carcinoma) was 83% with a specificity range of 78% to 82%, a positive predictive value of 57% to 61%, and a negative predictive value of 91% to 95%. Fifteen false-positive results included concurrent ASC or low-grade SIL, ASC on follow-up cytology, and previous ACIS with a negative follow-up cone biopsy result. Noncervical glandular neoplasia (including atypical endometrial hyperplasia) was confirmed in 13 cases (1 recurrent), only 2 of which scored positive for HPV. HPV-positive AGC has a substantially higher positive predictive value for significant disease than ASC (61% vs historic 20%) and merits consideration in the triage of patients with atypical endocervical cells not otherwise specified. However, noncervical or other HPV-negative glandular neoplasia must be considered in all patients with AGC, particularly older patients.

k-ras mutation may be an early event in mucinous ovarian tumorigenesis

We explored the possible pathogenetic pathway for mucinous ovarian tumorigenesis by examining the k-ras mutational patterns in ovarian mucinous tumors (OMTs) with benign, borderline, and invasive epithelium in which the different types of mucinous epithelium are in close proximity. Sixteen patients with ovarian mucinous borderline tumors (OMBTs) and 4 patients with grade 1 ovarian mucinous adenocarcinomas (OMCs) were selected for the presence of a single histologic section which contained a clear “transition” zone from benign mucinous epithelium to borderline mucinous epithelium, and in four cases, to invasive epithelium. A PixCell II Laser Capture Microscope was used to microdissect and retrieve benign, borderline, and invasive epithelium separately from the 20 OMTs. Normal ovarian stroma from the same histologic section in each case was also microdissected and retrieved for use as a control. k-ras mutations were detected in these samples by PCR-SSCP analysis followed by direct PCR cycle sequencing. k-ras mutations were found in 8/16 (50%) of the OMBTs and 2/4 (50%) of the grade 1 OMCs. In 6 of these 10 cases (4 in OMBTs, 2 in grade 1 OMCs), the same k-ras mutation was found in both the benign and borderline (and invasive) regions. In 3 cases in which k-ras mutations were identified, the mutation was found in either the benign or borderline tissue samples alone, and in one case, two distinct mutations were found. No k-ras mutations were identified in the normal ovarian stroma. The presence of a k-ras mutation in adjacent benign and borderline regions of a single OMT may suggest a progression in the development of OMTs from benign to borderline and grade 1 OMCs. k-ras mutations, when they occur, are likely early genetic changes but may not alone be sufficient for malignant transformation of ovarian epithelium.

Complex endometrial hyperplasia and carcinoma in adolescents and young women 15 to 20 years of age. A report of 10 cases

The clinical and histologic findings in 10 patients, 15-20 years of age, with complex hyperplasia or well-differentiated adenocarcinoma of the endometrium are presented. The morphologic distinction between the two lesions is discussed, and the frequency of misdiagnosis of this form of hyperplasia as carcinoma in this age group is emphasized. No difference was found in the behavior of the two lesions in this series of cases whether or not a hysterectomy was performed.