Anaplastic large-cell lymphoma associated with breast implants: a unique entity within the spectrum of peri-implant effusions.

Anaplastic large-cell lymphoma (ALCL) is a rare and newly described complication associated with breast implants. Patients often present with a peri-implant effusion, which is amenable to fine-needle aspiration. The laboratory handling of peri-implant effusions for cytology and ancillary studies is as crucial as recognizing the characteristic cytology of ALCL. All cases of peri-implant effusions were retrieved from the PathWest database between January 2003 and May 2013, yielding four cases of breast implant-associated ALCL and six benign samples. The cytological features were evaluated and information from ancillary studies collated. Clinical and follow-up histology was available in all cases. All ALCL cases contained highly atypical lymphoid cells including 'hallmark' cells. In contrast, benign peri-implant effusions showed a mixture of inflammatory cells, being either neutrophil-rich (three cases) or lymphocyte-rich (three cases). A CD30 positive, ALK1 negative immunophenotype was demonstrated in all cases on cell block immunohistochemistry. Flow cytometry and T-cell receptor clonality studies confirmed aberrant T-cell immunophenotype in four of four and clonally rearranged T-cell receptor antigens in three of three cases. ALCL was identified in three of four subsequent capsulectomies. Staging confirmed disease limited to the capsular tissue or peri-implant effusion in all cases. None of the six patients with benign peri-implant effusions developed lymphoma during follow-up. Cases of ALCL accounted for 40% of peri-implant effusions received over a 10-year period, indicating the rarity of these samples and the high likelihood of malignancy. Awareness of this entity and its presentation should allow for appropriate triage of these specimens and definitive diagnosis on effusion specimens.

A diagnosis of malignant pleural mesothelioma can be made by effusion cytology: results of a 20 year audit.

AIMS: Cytological diagnosis of malignant pleural mesothelioma (MPM) is controversial, but has been used in our institution for over 30 years. To assess the role of effusion cytology in mesothelioma diagnosis we conducted an audit of pleural fluid cytology results over a 20 year period (1988-2007). METHODS: Pleural samples were received from 6285 patients; data linkage with Western Australian Cancer and Mesothelioma Registries demonstrated that 815 of these patients had a diagnosis of MPM. Cytological examination of a pleural effusion specimen had been performed in 517 (63%) of these 815 patients. RESULTS: Definitive cytological diagnosis of MPM was made in 377/517 cases, resulting in an 'absolute' sensitivity of 73%. An additional 66 patients were diagnosed as atypical/suspicious, resulting in a 'complete' sensitivity of 86%. If only biopsy/necropsy proven cases are considered, the absolute sensitivity is 68% and the complete sensitivity is 82%. There were no false positive diagnoses of malignancy; two patients with metastatic adenocarcinoma were initially diagnosed as MPM, prior to the availability of specific mesothelial markers, resulting in a positive predictive value of 99%. CONCLUSIONS: Effusion cytology is an inexpensive, minimally invasive procedure which should be included in the diagnostic work-up of cases of suspected MPM.

Mesothelial cell differentiation into osteoblast- and adipocyte-like cells.

Serosal pathologies including malignant mesothelioma (MM) can show features of osseous and/or cartilaginous differentiation although the mechanism for its formation is unknown. Mesothelial cells have the capacity to differentiate into cells with myofibroblast, smooth muscle and endothelial cell characteristics. Whether they can differentiate into other cell types is unclear. This study tests the hypothesis that mesothelial cells can differentiate into cell lineages of the embryonic mesoderm including osteoblasts and adipocytes. To examine this, a functional assay of bone formation and an adipogenic assay were performed in vitro with primary rat and human mesothelial cells maintained in osteogenic or adipogenic medium (AM) for 0-26 days. Mesothelial cells expressed increasing levels of alkaline phosphatase, an early marker of the osteoblast phenotype, and formed mineralized bone-like nodules. Mesothelial cells also accumulated lipid indicative of a mature adipocyte phenotype when cultured in AM. All cells expressed several key osteoblast and adipocyte markers, including osteoblast-specific runt-related transcription factor 2, and demonstrated changes in mRNA expression consistent with epithelial-to-mesenchymal transition. In conclusion, these studies confirm that mesothelial cells have the capacity to differentiate into osteoblast- and adipocyte-like cells, providing definitive evidence of their multipotential nature. These data strongly support mesothelial cell differentiation as the potential source of different tissue types in MM tumours and other serosal pathologies, and add support for the use of mesothelial cells in regenerative therapies.

Experience with standardized thyroid fine-needle aspiration reporting categories: follow-up data from 529 cases with "indeterminate" or "atypical" reports.

BACKGROUND.: A significant number of thyroid fine-needle aspiration cytology (FNAC) cases yield inconclusive results. The recent National Cancer Institute guidelines and those published by other societies are important contributions to standardizing the diagnostic approach. Nevertheless, there are significant issues in the application of guidelines and the evaluation of their clinical efficacy. Data from individual departments can be useful in demonstrating the role of standardized reporting. METHODS.: The authors followed 529 consecutive cases with inconclusive thyroid FNA results that were analyzed in a single laboratory in Western Australia. In that laboratory, standardized reporting in categories has been in place for a decade, and inconclusive cases have been subdivided into indeterminate and atypical groups. Follow-up data was obtained for 341 indeterminate cases (17.2% of total thyroid FNA accessions) and for 188 atypical cases (9.5% of accessions). RESULTS.: In total, 127 nodules with atypical results (67.6%) underwent surgical excision compared with 131 nodules with indeterminate results (38.4%; P < .0001). In 96 excised nodules with atypical results (75.6%), the excised specimens were identified as neoplastic compared with 61 excised nodules with indeterminate results (46.6%; P < .0001). In addition, 31 excised nodules with atypical results (24.4%) had a malignancy proven compared with 17 excised nodules with indeterminate results (13%; P < .05). In addition, 51 of 82 repeat FNAs (62.2%) among patients who had indeterminate results yielded a more specific diagnosis compared with 2 of 9 repeat FNAs (22.2%) among patients who had atypical results (P < .05). CONCLUSIONS.: The routine subcategorization of patients who had inconclusive thyroid FNA reports into indeterminate and atypical groups resulted in statistically significant differences in the likelihood of neoplasia and malignancy. Patients who had indeterminate results were more likely to benefit from repeat FNAC than patients who had atypical results. The current results indicated that patients who fall into these 2 categories are likely to benefit from different clinical management protocols. Cancer Cancer Cytopathol 2010. © 2010 American Cancer Society.

Diagnosis of extramammary malignancy metastatic to the breast by fine needle biopsy.

AIMS: To review and illustrate the findings in fine needle biopsy (FNB) of extramammary malignancies presenting with breast metastases (MMB). METHODS: We reviewed 32 cases of MMB diagnosed on breast FNB. The clinical data, with particular attention to the history of a known primary malignancy, previous systemic metastatic disease in other sites and presentation with extramammary disease in addition to a breast mass were examined. The morphological appearances were reviewed and are illustrated, focusing on those features which allow the pathologist to recognise the possibility of metastatic disease and undertake appropriate steps to investigate this. RESULTS: The 32 cases included metastases from a wide range of sites, including cutaneous melanoma (10), lung (8), non-Hodgkin's lymphoma (5), soft tissue (4), colon (2), endometrium, ovary and bladder. There was a history of extramammary malignancy in 26, while in six patients the breast mass was detected at initial presentation with malignant disease. Of the latter six patients, four had evidence of widespread metastases, while one presented with multiple breast masses. In 16 cases the cytological features allowed the possibility of metastases to be recognised without clinical data, while in the other 16 there was sufficient overlap with primary mammary carcinoma that the possibility of metastases could be missed. Only one case was initially mistaken for a primary tumour, in this case the history of prior malignancy with systemic metastases was not provided to the reporting pathologist. CONCLUSION: The majority (81%) of cases of MMB have a history of primary malignancy, although only a minority have a history of systemic metastases at other sites. Of those patients without known prior malignancy, the majority present with systemic disease or multiple breast lesions. The cytological features allow metastatic disease to be suspected in half of the cases, although in the others, particularly patients with metastatic adenocarcinoma, diagnosis without recourse to immunohistochemistry is difficult or impossible. A combination of complete clinical history, attention to the cytological features and suspicion in cases with metastatic disease beyond the axilla should allow most cases of MMB to be suspected, and suitable material for ancillary confirmatory testing to be obtained.

A comparison of immunohistochemical staining for oestrogen receptor, progesterone receptor and HER-2 in breast core biopsies and subsequent excisions.

AIMS: To compare immunohistochemical staining for oestrogen receptor, progesterone receptor and HER-2 between core biopsy and matched subsequent excisional specimens. METHODS: One hundred consecutive core biopsy cases and subsequent excisional specimens were retrieved and immunohistochemical staining performed. Proportion and intensity of staining for hormone receptors and HercepTest score were recorded for each case in a blinded fashion by the authors. RESULTS: Overall hormone receptor status was concordant between cores and excisions in 96.9% of cases. ER status was concordant between the core and excision in 95.8% of cases. The intensity of staining for ER was similar in both core and excision specimens. PR status was concordant in cores and excisions in 90.3% of cases. There was weaker PR staining in the excisional specimens when compared with the cores. HER-2 status was concordant in cores and excisions in 86.6% of cases. CONCLUSIONS: Hormone receptor staining produced similar results on core and excisional specimens, although a small number of additional hormone receptor positive cases could be detected by performing staining on a previously received core in the case of a negative result on the excisional specimen. HER-2 staining is less reproducible between cores and excisions, but the clinical significance of this observation remains to be tested.

Can HPV DNA testing on FNA material determine anogenital origin in metastatic squamous cell carcinoma?

AIMS: Currently there are no diagnostic techniques that can precisely determine the primary site of a metastatic squamous cell carcinoma (SCC). Anogenital SCC has a high prevalence of high-risk (HR) human papillomavirus (HPV) DNA, particularly in the cervix where the value approaches 100%, whereas non-anogenital SCC generally has a low prevalence. The aim of this study was to examine whether the finding of HR HPV DNA in a fine needle aspiration (FNA) of metastatic SCC could be used to determine a likely anogenital origin. METHODS: Polymerase chain reaction (PCR) and viral sequencing were used to identify HR HPV DNA in cell block and needle rinse material derived from FNA samples in a series of metastatic SCC. RESULTS: HPV DNA was detected in nine of 12 (75%) metastatic anogenital SCC, and type 16 was sequenced in seven. HPV DNA was detected in only one of 18 (5.6%) metastatic SCC from other sites such as lung, oral cavity and skin. The positive control case was an oral cavity tumour and type 33 was sequenced. CONCLUSIONS: Although reservations remain, particularly in relation to the prevalence of HPV DNA in non-anogenital sites, HPV DNA testing by PCR: (1) can be successfully performed on FNA material, and (2) in the correct clinical context, can guide clinicians in assigning a site of origin. HPV DNA detection was the major indicator to the primary site in one occult tumour and several where the previous diagnosis of anogenital cancer was not known at presentation.

Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases.

AIMS: Predicting the clinical behaviour of gastrointestinal stromal tumours (GISTs) is difficult and criteria delineating benign from malignant cases are not firmly established. The aims of this study were to define the clinicopathological and molecular features of 66 GISTs, and to determine whether any specific parameters were associated with patient outcome. METHODS: Archival cases of GIST from two major teaching hospitals in Western Australia were studied. Inclusion criteria for the study were: (1) appropriate morphology, (2) CD117 positivity, (3) adequacy of pathological material for study, and (4) exclusion of other tumour types on the basis of immunophenotypic and/or ultrastructural features. Expression of CD117, CD34, S100 protein, keratin (using broad spectrum MNF116), alpha-smooth muscle actin (SMA) was determined by immunohistochemistry. PCR and single strand conformation polymorphism (PCR-SSCP) analysis were used to screen for mutations in exons 11 and 9 of c-kit. RESULTS: There were equal numbers of males and females with a mean age at diagnosis of 60 years, followed up for a mean of 54 months. Thirteen patients (21%) had died of GIST by the end of the study. Tumours were mostly located in the stomach (67%) and small intestine (SI; 25%). The cell types were pure spindle (68%), pure epithelioid (12%) and mixed epithelioid/spindle (20%). c-kit mutations were found in 69% of GISTs, with the large majority (91%) occurring in exon 11. Size > or = 10 cm, tumour necrosis and pure epithelioid cell morphology each were the only factors significantly associated with adverse survival (p=0.038, and p=0.047 and p=0.028, respectively). Mitotic activity > or = 5/50 HPF showed a definite trend association with adverse survival, but unlike some other studies, did not achieve statistical significance (p=0.067). c-kit mutations were more frequent in small intestinal GISTs (p=0.05) and in those with pure spindle cell morphology (p=0.023) but were not associated with patient outcome. CONCLUSION: In this study, size > or = 10cm, necrosis and/or pure epithelioid cell morphology correlated significantly with adverse survival. Mitotic activity showed a strong association with survival but this did not reach statistical significance. c-kit mutations occurred mainly in GISTs of the SI, and in purely spindle cell tumours. While the mutation status did not associate with patient outcome in this series, this remains a controversial issue, and further studies are needed to assess whether the type of mutation affects response to tyrosine kinase inhibitor therapy in metastatic GISTs. CD117 staining of any mesenchymal lesion of the gastrointestinal tract should be mandatory for accurate classification. PCR-SSCP analysis is a fast, sensitive and relatively inexpensive method of analysing c-kit mutations, which may be important prognostically and also of therapeutic relevance in the assessment of new tyrosine kinase inhibitor therapies.

Adenocarcinoma in situ of the uterine cervix: screening and diagnostic errors in Papanicolaou smears.

BACKGROUND: Little attention has been given to the reasons for failure to detect adenocarcinoma in situ (AIS) of the uterine cervix in Papanicolaou (Pap) smears. In the current study, the authors examined a series of screening or diagnostic errors in cases in which the final histologic diagnosis was either AIS or AIS combined with a high-grade squamous intraepithelial lesion (AIS + HSIL). METHODS: Smears obtained in the 3 years before histologically proven AIS or AIS + HSIL was diagnosed and within a specified 6-year period (1993-1998) were reviewed and reclassified. All were conventional Pap smears. The smears studied were those with a review diagnosis of possible or definite high-grade epithelial abnormality that initially were reported by a cytotechnologist to be negative (screening error) or that were reported by a pathologist to be negative, unsatisfactory, or indicative of a low-grade epithelial abnormality (diagnostic error). A semiquantitative, blinded assessment of the frequency of cytologic criteria for the diagnosis of AIS was made for smears with erroneous diagnoses compared with a series of smears that yielded true-positive findings. RESULTS: Sampling errors, which were defined as cases in which smears did not have sufficient evidence for a diagnosis of possible or definite AIS or HSIL on review, accounted for 35.1% and 36% of all smears from patients with a biopsy diagnosis of AIS and patients with a biopsy diagnosis of AIS + HSIL, respectively. With regard to AIS, there were 3 screening errors and 5 diagnostic errors, accounting for 10.4% of 77 smears. Minimal, poorly preserved material was evident in four smears, including three smears with only one sheet of abnormal glandular cells. In four other smears, there was a moderate amount of adequately preserved glandular material, mainly in large sheets, with varying degrees of crowding and hyperchromasia. With regard to AIS + HSIL, there were 6 screening errors and 6 diagnostic errors, accounting for 13.5% of 89 smears. In those smears, there generally was a moderate amount of abnormal material in the form of crowded groups of suboptimally preserved, hyperchromatic squamous cells. Only two of those smears yielded findings of possible abnormal glandular cells. Only 3 of 20 errors occurred in smears that were examined during the last 3 years of the study. In the semiquantitative assessment, smears with erroneous findings were shown to contain far less abnormal material than true-positive smears and to exhibit a corresponding paucity of diagnostic criteria. CONCLUSIONS: Sampling errors were the main cause of false-negative reports in cases of AIS and AIS + HSIL. The primary factors that contributed to screening or diagnostic errors in AIS were minimal, poorly preserved abnormal material and an overly conservative approach to the assessment of unusual large sheets or aggregates of glandular cells. With regard to AIS + HSIL, most laboratory errors were related to the presence of crowded groups of squamous epithelial cells. There were fewer errors in the last 3 years of the study, raising the possibility of improvement over time.

The value of HPV DNA typing in the distinction between adenocarcinoma of endocervical and endometrial origin.

AIMS: Distinguishing between adenocarcinomas of endocervical and endometrial origin histologically can be difficult, particularly in small biopsies. Most endocervical adenocarcinomas contain human papillomavirus (HPV) deoxyribonucleic acid (DNA) of 'high-risk' (HR) types, whereas this has not been consistently demonstrated in endometrial adenocarcinomas. The aim of this study was to determine whether HPV DNA testing could aid in this differential diagnosis. METHODS: The frequency of HPV DNA in paraffin-embedded tissue samples from 50 endocervical and 50 endometrial adenocarcinomas was investigated using polymerase chain reaction (PCR) amplification techniques involving (i) a screening HPV test followed by HPV DNA sequencing, and (ii) a test designed to detect HR genotypes 16, 18, 31, 33, 35, 45 and 58. Control specimens included cervical intraepithelial neoplasia (CIN) III lesions, squamous cell carcinomas (SCCs) of the cervix and lung, and colonic adenocarcinomas. Measures to minimise cross-contamination were implemented. RESULTS: The screening test followed by HPV DNA sequencing had the highest sensitivity. By this test HR HPV DNA was detected in 11 of 11 (100%) cervical intraepithelial neoplasia (CIN III) lesions, nine of 10 (90%) cervical SCCs, none of 10 (0%) colorectal adenocarcinomas and none of 10 (0%) SCCs of the lung. Thirty-nine (78%) endocervical adenocarcinomas contained HR HPV DNA, compared to one (2.0%) endometrial adenocarcinoma. CONCLUSIONS: The results suggest that HPV DNA testing could be a useful adjunct in distinguishing between endocervical and endometrial adenocarcinomas in curettings or small biopsy specimens.

Predictive value of diagnoses of endocervical glandular abnormalities in cervical smears.

AIMS: To determine the positive predictive value (PPV) of cervical smear diagnoses of 'definite' and 'possible' endocervical adenocarcinoma in situ or invasive adenocarcinoma, and whether diagnostic accuracy can be improved. METHODS: The study examined cervical smears reported as definite or possible high-grade glandular abnormality between 1992 and 1998. PPV was calculated by comparing smear diagnoses with the subsequent histopathology report. All available smears were reviewed without knowledge of follow-up results, and were reclassified by consensus. RESULTS: Thirty-two smears were diagnosed as high-grade glandular lesions, with adequate biopsy follow-up in 31 cases (96.9%). A high-grade epithelial abnormality (HGEA) was detected in 29 cases (PPV, 93.5%), with a high-grade glandular lesion in 24 (PPV, 77.4%). Very few smears were reclassified on review. Seventy-three smears were initially diagnosed in the 'inconclusive' glandular or indeterminate cell-type category. There was adequate biopsy follow up for 54 cases (74.0%). On follow-up, 31 cases had a HGEA (PPV, 57.4%), with 14 cases having a high-grade glandular abnormality (PPV, 25.9%). In the review of 'inconclusive' smears, 12 were reclassified as squamous abnormalities and none of these had a glandular lesion on biopsy. Eight were reclassified as negative; seven contained endometrial stroma and the glandular cells in question were considered to be of lower uterine segment (LUS) origin. No significant lesion was present on follow-up of these cases. CONCLUSIONS: For clinicians using our laboratory, large loop excision of the transformation zone (LLETZ) or cone biopsy should follow a 'definite' cytological diagnosis of a high-grade endocervical glandular lesion. However, cone biopsy may not be the appropriate initial management in the 'possible' high-grade glandular group because of a significantly lower predictive value of the diagnosis. The slide review highlighted the importance of (1) caution in classifying sheets of abnormal cells as glandular, and (2) endometrial stroma as a marker of LUS material.

Adenocarcinoma in situ of the cervix.

BACKGROUND: The current study examines 1) the sensitivity of detection and 2) sampling and screening/diagnostic error in the cytologic diagnosis of adenocarcinoma in situ (AIS) of the cervix. The data were taken from public and private sector screening laboratories reporting 25,000 and 80,000 smears, respectively, each year. METHODS: The study group was comprised of women with a biopsy diagnosis of AIS or AIS combined with a high-grade squamous intraepithelial lesion (HSIL) who were accessioned by the Western Australian Cervical Cytology Registry (WACCR) between 1993-1998. Cervical smears reported by the Western Australia Centre for Pathology and Medical Research (PathCentre) or Western Diagnostic Pathology (WDP) in the 36 months before the index biopsy was obtained were retrieved. A true measure of the sensitivity of detection could not be determined because to the authors' knowledge the exact prevalence of disease is unknown at present. For the current study, sensitivity was defined as the percentage of smears reported as demonstrating a possible or definite high-grade epithelial abnormality (HGEA), either glandular or squamous. Sampling error was defined as the percentage of smears found to have no HGEA on review. Screening/diagnostic error was defined as the percentage of smears in which HGEA was not diagnosed initially but review demonstrated possible or definite HGEA. Sensitivity also was calculated for a randomly selected control group of biopsy proven cases of Grade 3 cervical intraepithelial neoplasia (CIN 3) accessioned at the WACCR in 1999. RESULTS: For biopsy findings of AIS alone, the diagnostic "sensitivity" of a single smear was 47.6% for the PathCentre and 54.3% for WDP. Nearly all the abnormalities were reported as glandular. The sampling and screening/diagnostic errors were 47.6% and 4.8%, respectively, for the PathCentre and 33.3% and 12.3%, respectively, for WDP. The results from the PathCentre were better for AIS plus HSIL than for AIS alone, but the results from WDP were similar for both groups. For the CIN 3 control cases, the "sensitivity" of a single smear was 42.5%. CONCLUSIONS: To the authors' knowledge epidemiologic studies published to date have not demonstrated a benefit from screening for precursors of cervical adenocarcinoma. However, in the study laboratories as in many others, reasonable expertise in diagnosing AIS has been acquired only within the last 10-15 years, which may be too short a period in which to demonstrate a significant effect. The results of the current study provide some encouraging baseline data regarding the sensitivity of the Papanicolaou smear in detecting AIS. Further improvements in sampling and cytodiagnosis may be possible.

Atypical ductal hyperplasia and atypia of uncertain significance in core biopsies from mammographically detected lesions: correlation with excision diagnosis.

AIMS: To assess: (1) the prevalence of reporting of atypical ductal hyperplasia (ADH) and intraductal atypia of uncertain significance (AUS) in a series of core biopsies from mammographically detected lesions, (2) the proportion of cases where excision revealed breast carcinoma, and (3) whether any diagnoses should be revised on review. METHODS: Breast core biopsy reports from the Sir Charles Gairdner Hospital Breast Assessment Centre for the years 1999-2000 were retrieved. Slides from cases reported as ADH or AUS were reviewed as well as slides from the excision biopsies. RESULTS: There were 1048 core biopsies from 911 women. Breast carcinoma was diagnosed in 197 samples (18.8%) including 88 with invasive carcinoma (8.4%), 109 with ductal carcinoma in situ (DCIS) (10.4%). Three biopsies (0.3%) 'suspicious' of invasive carcinoma proved to be so. Of 52 samples (5.0%) with a diagnosis of ADH or AUS, 46 were excised, showing seven invasive carcinomas, 15 DCIS, 11 ADH, two lobular carcinoma in situ (LCIS), nine fibrocystic change (FCC), one mucocoele-like lesion and one fibroadenoma. The 22 malignancies represented 47.8% of the excised lesions. On review, seven of the 52 original core diagnoses were downgraded to benign hyperplasia. Five underwent excision, revealing two FCC, one complex sclerosing lesion, and two incidental lesions unrelated to the mammographic abnormality, including a microscopic tubular carcinoma and a focus of LCIS. In one case reviewed as unsatisfactory, excision showed invasive carcinoma. Lesions of particular interest included a case of high-grade DCIS with local regression in the core biopsy (so-called 'bumt out DCIS'), and one case diagnosed on excision as micropapillary ADH, where the review diagnosis was micropapillary DCIS. CONCLUSIONS: ADH and AUS were reported in 5.0% of biopsies. There was a high rate of carcinoma (47.8%) in subsequent excisions. Very few diagnoses were revised on review. Current protocols for excision of lesions with a 14-gauge core biopsy diagnosis of ADH/AUS appear justified. Literature review suggests that vacuum-assisted core sampling with 11-gauge needles will not remove the need for excision. Further study of local regression of DCIS and micropapillary lesions will be worthwhile.

Adenocarcinoma of the cervix.

BACKGROUND: The current study examines 1) the sensitivity of detection of invasive adenocarcinoma of the cervix in a routine cervical screening service, and 2) the frequency in smears of cytologic criteria previously found to be useful in diagnosis. METHODS: Data on women with diagnoses of adenocarcinoma of the cervix accessioned at the Western Australian Cervical Cytology Registry during the period 1993-1998 were examined, where smears had been reported by Western Diagnostic Pathology within three years of the biopsy diagnosis. Smears and biopsy material were reviewed. RESULTS: Thirty-six smears from 24 women were reviewed. Of those, 58.3% had been reported as a possible or definite high grade epithelial abnormality (HGEA). On review it was thought that this could be improved to 77.8%. The screening or diagnostic error was thus 19.4% and the sampling error 22.2%. The likelihood of an individual woman receiving a report of a possible or definite HGEA in the three years before biopsy was 83.3%. In retrospect this could have been improved to 91.7%. Heavy bloodstaining with abundant abnormal glandular epithelium (14 smears) and small three-dimensional or papillary clusters (16 smears) were the most frequent clues to invasion. Tumor necrosis/diathesis was present in eight smears, but easily seen in only four, while marked nuclear pleomorphism and macronucleoli were seen in three and one smears respectively. In cases with a discrepancy between the initial and the review findings, very small amounts of abnormal material (three smears), a resemblance to endometrial cells (one smear), and an unusual appearance of folded monolayered sheets (three smears) contributed to the difficulty of diagnosis. CONCLUSIONS: There were significant sampling and screening/diagnostic errors (22.2% and 19.4%, respectively). Screening and diagnostic errors could perhaps be reduced by a greater awareness of the range of cytologic changes, but these may be subtle. Heavy bloodstaining with abundant abnormal glandular material may be a useful clue to invasive, rather than in situ, adenocarcinoma, even in the absence of tumor diathesis or fully malignant nuclear criteria.