Differentiated cervical intraepithelial neoplasia-associated invasive cervical squamous cell carcinoma as a source of major cytopathological and surgical pathological discrepancy in Papanicolaou smear screening tests.

INTRODUCTION: Differentiated cervical intraepithelial neoplasia (dCIN) analogous to differentiated squamous intraepithelial neoplasia of the vulva is characterised by the proliferation of atypical cells limited to the basal/parabasal layers. Exfoliative cytology of dCIN has not been investigated. METHODS AND RESULTS: A 46-year-old woman, with a history of normal Papanicolaou (Pap) smear up to 2 years prior to the occurrence of postcoital vaginal bleeding had two consecutive Pap smears, which only revealed atypical squamous cells of unknown significance (ASCUS). The subsequent cervical biopsy revealed dCIN. The cone biopsy showed the invasive cervical squamous cell carcinoma (ICC) that developed from the overlying dCIN. Review of 32 consecutive cases of ICC revealed a second case of dCIN-associated ICC (Group 1) preceded by ASCUS suspicious for high-grade neoplastic cells. In both cases, the ASCUS were keratinised atypical cells without koilocytosis. In addition, there were another seven cases showing focal dCIN associated with extensive usual CIN (Group 2). In comparison with the remaining 24 cases with usual CIN (Group 3), Group 2 lesions occurred in younger patients (mean ages of 36 ± 3 vs 47 ± 9 years) and were associated with shorter intervals after the last normal Pap smears. Pap smears in Group 2 occasionally consisted only of ASCUS cells. CONCLUSIONS: dCIN may occur in the cervix and accounts for a short interval of normal Pap smears and false negative or low-grade Pap smears in ICC.

Progesterone receptor reactivity in renal oncocytoma and chromophobe renal cell carcinoma.

AIMS: To investigate the reactivity for oestrogen and progesterone receptors (ER and PR) in renal oncocytoma (RO) and chromophobe renal cell carcinoma (CHRCC). MATERIALS AND METHODS: Thirty-eight RO, 25 CHRCC, 20 papillary RCC with oncocytic cytoplasm and 10 clear cell RCC with dominant eosinophilic cytoplasm were submitted for immunohistochemistry for ER, PR, CD117 and RCC. RESULTS: All cases of RO and CHRCC displayed moderately positive reactivity for PR. The nuclear reactivity ranged from 60% to 90% in RO and from occasional cells to 70% in CHRCC. In CHRCC, reactivity tended to be more prevalent in areas of tumour cells with eosinophilic cytoplasm. Progesterone reactivity was focal in areas. All RO and most CHRCC were reactive for CD117 and neither RO nor CHRCC was reactive for RCC. CD117 reactivity tended to be more intense in CHRCC than in RO. Negative reactivity for CD117 and positive reactivity for RCC were observed in almost all RCC, as reported in the literature. CONCLUSIONS: PR can be used in combination with CD117 and RCC in the differential diagnosis of RO and eosinophilic variant of CHRCC with other RCC with oncocytic or eosinophilic cytoplasm.

ES1, a new lung carcinoma antibody--an immunohistochemical study.

AIMS: To characterize a single domain antibody (sdAb), AFAI, obtained by panning a naive phage display library of single domain antibodies against the non-small cell lung carcinoma cell line A549. AFAI recognizes a variant form of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6 or CEA6). METHODS AND RESULTS: Various normal tissues and 139 neoplastic lesions from lung and other organs were immunostained with ES1 antibody, a pentameric and highly avid form of AFAI. ES1 was immunoreactive with 34 of 35 non-squamous large cell lung carcinomas with staining intensities ranging from focal to extensive and from moderate to strong. Importantly, ES1 stained poorly differentiated lung adenocarcinomas and many undifferentiated large cell lung carcinomas that typically show negative immunoreactivity with an antibody specific for thyroid transcription factor-1. Non-lung adenocarcinomas showed more focal and weaker immunoreactivity than for lung adenocarcinoma. Other carcinomas showed negative or weak immunoreactivity and normal tissues showed no immunoreactivity. CONCLUSIONS: Compared with other antibodies used in the clinical evaluation of lung adenocarcinomas, ES1 is more lung carcinoma sensitive, more sensitive in immunostaining of poorly differentiated adenocarcinomas that are usually associated with distant metastasis and less immunoreactive with normal tissues.

Endometrioid adenocarcinoma of the uterus with a minimal deviation invasive pattern.

AIMS: Minimal deviation adenocarcinoma of endometrioid type is a rare pathological entity. We describe a variant of typical endometrioid adenocarcinoma associated with minimal deviation adenocarcinoma of endometrioid type. METHODS AND RESULTS: One 'pilot' case of minimal deviation adenocarcinoma of endometrioid type associated with typical endometrioid adenocarcinoma was encountered at our institution in 2001. A second case of same type was received in consultation. We reviewed 168 consecutive hysterectomy specimens diagnosed with 'endometrioid adenocarcinoma' specifically to identify areas of minimal deviation adenocarcinoma of endometrioid type. Immunohistochemistry was done with the following antibodies: MIB1, p53, oestrogen receptor (ER), progesterone receptor (PR), cytokeratin 7 (CK7), cytokeratin 20 (CK20), carcinoembryonic antigen (CEA), and vimentin (VIM). Four additional cases of minimal deviation adenocarcinoma of endometrioid type were identified. All six cases of minimal deviation adenocarcinoma of endometrioid type were associated with superficial endometrioid adenocarcinoma. In two cases with a large amount of minimal deviation adenocarcinoma of endometrioid type, the cervix was involved. The immunoprofile of two representative cases was ER+, PR+, CK7+, CK20-, CEA-, VIM+. MIB1 immunostaining of four cases revealed little proliferative activity of the minimal deviation adenocarcinoma of endometrioid type glandular cells (0-1%) compared with the associated 'typical' endometrioid adenocarcinoma (20-30%). The same four cases showed no p53 immunostaining in minimal deviation adenocarcinoma of endometrioid type compared with a range of positive staining in the associated endometrioid adenocarcinoma. CONCLUSIONS: Minimal deviation adenocarcinoma of endometrioid type more often develops as a result of differentiation from typical endometrioid adenocarcinoma than de novo. Due to its deceptively benign microscopic appearance, minimal deviation adenocarcinoma of endometrioid type may be overlooked and may lead to incorrect assessment of tumour depth and pathological stage. There was a tendency for tumour with a large amount of minimal deviation adenocarcinoma of endometrioid type to invade the cervix.

Pagetoid variant of actinic keratosis with or without squamous cell carcinoma of sun-exposed skin: a lesion simulating extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease usually occurs in anogenital skin. We present five cases of squamous cell carcinoma in situ of sun-exposed skin and non-squamous cell carcinoma in situ actinic keratosis that displayed atypical keratinocytes disposed in intraepithelial cell nests and immunohistochemical staining simulating extramammary Paget's disease. METHODS AND RESULTS: Two pilot cases--one squamous cell carcinoma in situ and one non-squamous cell carcinoma in situ actinic keratosis with formation of intra-epidermal nests of atypical keratinocytes with a pagetoid spread pattern--were encountered at our institution. Fifty-four consecutive cases of squamous cell carcinoma in situ including bowenoid actinic keratosis and 34 cases of non-squamous cell carcinoma in situ actinic keratosis were reviewed to identify pagetoid spread of atypical cells. Representative sections of all cases with pagetoid spread of atypical keratinocytes were submitted for special stains for mucin, and immunostaining for cytokeratin 7 (CK7), cytokeratin 20 (CK20), cytokeratin CAM 5.2 (CAM 5.2), carcinoembryonic antigen (CEA), vimentin and S100 protein. In the group of squamous cell carcinoma in situ, 10 cases displayed pagetoid spread of atypical keratinocytes with cytoplasm ranging from clear to pale and atypical hyperchromatic nuclei. One review squamous cell carcinoma in situ was multicentric with three separate lesions. The atypical keratinocytes tended to form well to poorly defined cell groups extending from the basal cell layer to the corneal layer. No similar cases were identified in the group of non-squamous cell carcinoma in situ actinic keratosis. Two pilot cases and three of 10 review cases with a total of seven separate lesions displayed a moderate to marked immunohistochemical reactivity for CK7 similar to extramammary Paget's disease. CEA immunoreactivity was also detected in two of these cases. In addition, two of 44 squamous cell carcinomas in situ without pagetoid spread of atypical keratinocytes showed a moderate reactivity for CK7 in very occasional atypical keratinocytes. The remaining seven squamous cell carcinomas in situ with pagetoid spread of atypical keratinocytes were not immunoreactive for CEA and CK7. Immunostaining for CK20, vimentin, S100 protein was negative in all atypical cells in all study cases. CONCLUSIONS: Actinic keratosis, particularly squamous cell carcinoma in situ of sun-exposed skin, may have histopathological and immunohistochemical features similar to extramammary Paget's disease and probably represents a variant of actinic keratosis. Awareness of the pagetoid variant of actinic keratosis arising in sun-exposed skin is helpful to avoid the over-diagnosis of extramammary Paget's disease.

Reduced HBME-1 immunoreactivity of papillary thyroid carcinoma and papillary thyroid carcinoma-related neoplastic lesions with Hürthle cell and/or apocrine-like changes.

BACKGROUND: We have recently observed that Hürthle cell tumours and papillary thyroid carcinoma with tumour cells showing decapitation of luminal portion of the cytoplasm (apocrine-like changes) display negative or decreased immunoreactivity for HBME. The purpose of this study is to correlate papillary thyroid carcinoma with positive and negative immunoreactivity for HBME with the histopathological features. METHODS AND RESULTS: Two hundred and five thyroid neoplasms including carcinoma and adenomas were grouped into Hürthle cell tumours, tumours with or without some features of Hürthle cells, tumours with apocrine-like changes and adenomas with or without limited nuclear features of papillary thyroid carcinoma but not diagnostic for papillary thyroid carcinoma. All neoplasms were submitted for immunostaining with cytokeratin 19 (CK19) and HBME. Papillary thyroid carcinoma, follicular carcinoma and follicular adenoma that have areas of limited nuclear features but not diagnostic for papillary thyroid carcinoma showed stronger immunostaining for HBME than their respective counterparts with Hürthle cell changes. All Hürthle cell tumours showed negative to focal reactivity. This decrease of reactivity for HBME was proportional to the levels of Hürthle cell changes. In addition, focal to extensive apocrine-like changes were seen in most Hürthle cell neoplasms and rarely seen in non-Hürthle cell neoplasms. Apocrine-like changes abolished or decreased HBME immunoreactivity of papillary thyroid carcinoma and tumours with limited nuclear features. Immunostaining for cytokeratin AE3 was not affected by Hürthle cell or apocrine-like changes. CONCLUSIONS: All papillary thyroid carcinomas without Hürthle cell or apocrine-like differentiation are reactive for HBME. Hürthle cell tumours and tumours with Hürthle cell or apocrine-like changes show negative or focal reactivity for HBME. Except for this limitation, HBME is a sensitive marker for papillary thyroid carcinoma and tumours with limited nuclear features.

Resection margin status in lumpectomy specimens for duct carcinoma of the breast: correlation with core biopsy and mammographic findings.

BACKGROUND: The strategy for surgical treatment of breast carcinoma proven by biopsy is mainly based on the physical and mammographic examinations. To investigate if the pathological findings in core biopsy are contributory to planning the surgical strategy, we correlated the status of ductal carcinoma in situ (DCIS) in the core needle biopsy of breast, the mammographic changes and the status of resection margins in the subsequent lumpectomy. STUDY DESIGN: Consecutive 130 core needle biopsies with prior mammography and subsequent lumpectomy were reviewed. Biopsies were divided into: group I, DCIS; group II, DCIS and infiltrating carcinoma (IC); and group III, IC. Mammographic findings were categorized into four groups: (a) nonspecific findings; (b) calcification (Ca(++)); Ca(++) and mass, and mass only. The status of margins in correlating lumpectomy specimens was reviewed. Close margin was defined as a free margin at less than 0.1cm from the carcinoma. RESULTS: The rates of positive or close margins in three groups I, II, and III were 13/18, 18/48, and 2/64 (P < 0.001); and in mammography groups of nonspecific finding, Ca(++), Ca(++) mass and mass only were 5/6, 7/15, 8/37, and 13/72 (P < 0.001), respectively. Of the total of 14 cases with positive margins of more than 0.5 cm in length, 8, 4, and 2 cases were from group I, II, and II, respectively. In addition, 13 of 21 cases with nonspecific changes or with only Ca(++) in mammograms belonged to the group I; 10 of these 13 cases were associated with positive margins. Forty-one of 72 cases presenting as a mass only in mammograms belonged to the group III; only 2 of these 41 cases were associated positive margins. CONCLUSIONS: Correlation of the extent of carcinoma with pre-operative histopathological findings was better than with mammography. Core biopsies containing only DCIS, particularly in cases with nonspecific findings or with only Ca(++) in mammograms, represent a group of breast carcinoma that pose the high risk for incomplete resection in lumpectomy. Surgical management of patients having these cores includes wider resection margins than would otherwise be taken. Most core biopsies with only IC were associated with negative margins.

Fine-needle aspiration biopsy of an intra-abdominal inflammatory mass secondary to a penetrating duodenal ulcer mimicking neoplasm.

Peptic ulcers complicated by penetration into the surrounding tissue and presenting as an intra-abdominal mass simulating a malignancy are uncommon. We report on a case of a 56-yr-old physician with a 40-yr history of peptic disease. Due to recent and transitory right flank pain, an ultrasound then a computed tomography scan demonstrated a 4-cm retropancreatic mass. A fine-needle aspiration biopsy (FNAB) of the mass showed an acute and chronic inflammatory exudate. After a course of medical treatment for peptic ulcer disease and 5 mo after the biopsy, the mass remarkably decreased in size. In view of the clinical and FNAB findings, the lesion likely developed as a result of penetration of the duodenal ulcer into the retropancreatic space. Awareness of this uncommon complication of peptic gastroduodenal ulcer disease is helpful in the diagnosis of this benign lesion. A failure in making a firm diagnosis by considering the aspirate material as nonrepresentative may lead to an unnecessary repeat biopsy or an invasive procedure.

A comparative study of metastatic renal cell carcinoma with correlation to subtype and primary tumor.

Clear cell (CRCC), papillary (PRCC) and chromophobe (CHRC) renal cell carcinoma (RCC) are the three most frequent subtypes of RCC. The rate and distribution of their metastatic lesions have not been well documented. We compared metastatic RCC according to subtype and primary tumor characteristics to better understand their behavior and to aid in the diagnosis of metastatic RCC. Pathology reports and clinical charts related to 283 CRCC, 48 PRCC and 13 CHRCC, including their respective sarcomatoid variants, were reviewed. A hundred and thirty-seven CRCC, 5 PRCC and 1 CHRCC with metastases were identified. CRCC and non-CRCC (PRCC and CHRCC) had different patterns of metastasis and primary tumor growth. CRCC metastases were predominantly distributed in lungs, bone, brain, lymph nodes, and adrenal glands. The associated primary CRCC measured 1.5 to 15 cm, were of all grades and stages, and were often associated with invasion of small or large veins. Three PRCC had regional lymph node metastases, 1 PRCC had both regional and mediastinal lymph node metastases. Bone metastasis was present in 1 case each of PRCC and CHRCC. One PRCC with metastasis solely to regional nodes measured 4 cm. The other 4 cases of PRCC with regional lymph node and/or distant metastases as well as the CHRCC with distant metastases were greater than 8 cm in diameter. In metastasizing and non-metastasizing non-CRCC, invasion of small veins was rare and invasion of renal veins was not seen. We cannot comment with any certainty on the metastatic behavior of CHRCC. In our experience, PRCC tend to loco-regional invasion with lymph node spread. They have a low potential for vascular invasion and distant metastases that likely occur only at late stages of the disease. CRCC has a propensity for vascular invasion and may be associated with distant metastasis at an early stage. Therefore, metastatic RCC at a distant location are most likely to be of CRCC origin than PRCC origin.

Fine needle aspiration biopsy of anaplastic thyroid carcinoma developing from a Hürthle cell tumor: a case report.

BACKGROUND: Anaplastic thyroid carcinoma is a highly malignant tumor in elderly people with a long history of multinodular goiter and is usually associated with a rapidly fatal clinical evolution. The tumor often develops as a result of anaplastic transformation of a slowly growing papillary carcinoma or follicular neoplasm. CASE: An 85-year-old woman had a multinodular goiter and had been asymptomatic, with a normal white blood cell count and chest radiograph three months prior to her hospital admission for the treatment. The tumor presented with low grade fever, leukocytosis, multiple metastatic lung nodules and enlargement of the intrathoracic thyroid in a period of three months, causing compression of the esophagus and trachea. Despite a total thyroidectomy, the tumor recurred within one month and caused dysphagia and death. CONCLUSION: FNAB permitted the diagnosis of an anaplastic thyroid carcinoma arising from an intrathoracic Hürthle cell tumor.

Immunostaining for ret oncogene proteins in papillary thyroid carcinoma: a correlation of ret immunoreactivity and potential of lymph node metastasis.

Ret oncogenes, particularly Ret/PTC, have been associated with the potential of local invasion of papillary thyroid carcinoma (PTC). The purpose of this study was to investigate the correlation between the Ret oncogene expression and the potential of lymph node metastasis of PTC. A total of 107 PTC were microscopically reviewed to identify areas of infiltrating carcinoma (IC). IC was defined as tumor cells disposed in a haphazard pattern and in lobules, nests, follicles, or single cells within a desmoplastic or sclerotic stroma. All cases were submitted to immunostaining for Ret oncogene. There were 36 noninfiltrating PTC with lymph node metastasis in 1 case and 71 infiltrating PTC with lymph node metastasis in 40 cases. For non-PTC, the positive immunoreactivity was often weak to moderate and focal. For infiltrating PTC with IC, the IC displayed strong immunoreactivity. The noninfiltrating component of PTC with IC usually showed stronger reactivity than PTC without an infiltrating component. Furthermore, 36 of 40 metastatic PTC in lymph node were immunoreactive. Three follicular adenomas with areas of scar caused by fine-needle aspiration biopsy were not immunoreactive for Ret. In view of the high potential of infiltrating PTC for lymph node metastasis, distinction of this type of carcinoma from its noninfiltrating form is clinically important. Because immunoreactivity for Ret is usually positive in areas of infiltrating PTC and is often negative or focally positive in noninfiltrating PTC, immunostaining for Ret is helpful to identify infiltrating PTC and distinguish it from changes caused by fine-needle aspiration biopsy in benign thyroid lesions.

Ret oncogene protein expression in papillary thyroid carcinoma and related lesions.

BACKGROUND: Activation of Ret oncogenes, particularly Ret/PTC, has been identified in papillary thyroid carcinoma (PTC). The purpose of this study was to investigate the immunostaining pattern of Ret oncogene protein in PTC and nodular non-PTC lesions with a fine chromatin pattern. MATERIALS AND METHODS: Ninety-three PTC and 139 nodular non-PTC lesions were microscopically reviewed to identify the nuclear changes of "limited nuclear features of PTC" (focal nuclear grooves, nuclear inclusions or optically clear nuclei) and areas of infiltrating carcinoma (IC) and were submitted for immunostaining with Ret oncogene protein antiserum. RESULTS: Immunoreactivity for Ret protein ranged from negative in follicular adenoma (FA) with a coarse chromatin pattern, to negative or weak reactivity in FA with a fine chromatin pattern, to strong reactivity in PTC with areas of infiltrating carcinoma (IC). In FA with fine chromatin, FA and follicular carcinoma (FC) containing an admixture of areas of coarse and fine chromatin, areas with nuclear changes with "limited nuclear features of PTC" displayed varying degrees of immunoreactivity. The intensity of immunostaining varied with the degree of nuclear change. The noninvasive component of PTC with IC usually showed more extensive and stronger reactivity than PTC without IC. PTCs with and without IC were associated with a rate of lymph node metastasis of 48% and 3%, respectively. CONCLUSIONS: The expression of Ret oncogenes (Ret/PTC, other unknown variants or wild type) is focally or extensively present in all PTC with IC. The degree of immunoreactivity is likely to be proportional to the potential for lymph node metastasis of PTC. In the context of this study and due to the specificity of Ret oncogenes, it is likely that nodular non-PTC lesions with a fine chromatin pattern and focal positive reactivity for Ret oncogene represent PTC-related lesions.

Follicular adenoma with papillary architecture: a lesion mimicking papillary thyroid carcinoma.

AIMS: The purpose of this study was to investigate the significance of 'benign' encapsulated follicular thyroid nodules with papillary structures. METHODS AND RESULTS: Twenty-one cases of encapsulated neoplastic thyroid nodules with papillary structures and nuclear features not diagnostic of papillary thyroid carcinoma (PTC) were obtained. All cases were reviewed with particular attention to nuclear features (fine chromatin pattern, optical clearing, grooves and inclusions). Representative sections were submitted for measurement of the maximum diameter of 200 round or nearly round nuclei and for immunostaining for MIB1, CK19, HBME and Ret oncogene protein. Nine cases displayed scattered optically clear nuclei or nuclear grooves in less than 30% of total neoplastic cells. They were grouped in the category of thyroid nodules with limited nuclear features of papillary thyroid carcinoma (PTC), but not diagnostic of PTC. The other 12 cases had fine or coarse chromatin, but lacked other features of nuclei in PTC. The diameter of the nuclei ranged from 5.6 to 7.2 microm and were smaller than those of PTC (6.3-10.0 microm). Immunostaining revealed positive reactivity for MIB1 in the papillary structures. Immunostaining for CK19 and HBME varied from negative or focally weak to diffusely moderate reactivity. Ret oncogene protein immunostaining showed focal and weak reactivity in one case and was negative in other cases of the study. Clinical follow-up from 6 months to 15 years revealed no evidence of metastasis. CONCLUSIONS: The papillary structures in the study cases are unlikely to represent degenerative changes due to their proliferative activity. In view of (i) the encapsulation and the uniformity of the constituent cells, (ii) the varying degrees of immunoreactivity for CK19 and HBME and negative immunoreactivity for Ret oncogene protein, and (iii) the absence or insufficiency of nuclear criteria for the diagnosis of PTC and the absence of lymph node metastasis in all study cases, we believe that these lesions represent the papillary variant of follicular adenoma. Recognition of this pathological entity is important to avoid an over-diagnosis of PTC.