Frequency and clinical significance of simultaneous association of lobular neoplasia and columnar cell alterations in breast tissue specimens.

Lobular neoplasia (LN) and columnar cell alterations (CCAs) may share similar genetic abnormalities, but there is no appreciable literature that addresses the simultaneous occurrence of these lesions in breast core biopsy (CNB) specimens or resection specimens. Three groups of breast tissue were examined: group 1, 68 CNB specimens targeted for "suspicious" microcalcifications (Breast Imaging Reporting and Data System [BI-RADS] 4) and diagnosed with LN; group 2, 2,516 CNB reports for a 1-year period; and group 3, 400 consecutive breast carcinoma resection specimens analyzed for LN and CCAs within the vicinity of carcinoma. In group 1, LN was associated with CCAs in 54% of cases (37/68). In group 2, LN was found in association with CCA in 1.3% of cases (32/2,516). In group 3, 13.0% of cases of CCAs (52/400) were associated with LN. Our study suggests the association of these two lesions in breast tissue is nonrandom and that they may have a common progenitor pathway of neoplastic development.

An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects.

We have developed an in vitro muscle preparation suitable for metabolic studies with human muscle tissue and have investigated the effects of obesity and non-insulin-dependent diabetes mellitus (NIDDM) on glucose transport. Transport of 3-O-methylglucose and 2-deoxyglucose was stimulated approximately twofold by insulin in muscle from normal nonobese subjects and stimulation occurred in the normal physiological range of insulin concentrations. In contrast to insulin stimulation of 3-O-methylglucose and 2-deoxyglucose transport in muscle from normal, nonobese subjects, tissue from morbidly obese subjects, with or without NIDDM, were not responsive to insulin. Maximal 3-O-methylglucose transport was lower in muscle of obese than nonobese subjects. Morbidly obese patients, with or without NIDDM, have a severe state of insulin resistance in glucose transport. The novel in vitro human skeletal muscle preparation herein described should be useful in investigating the mechanism of this insulin resistance.

Expression of aromatase protein and messenger ribonucleic acid in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers.

The expression of aromatase by breast cancer cells and the role of locally produced estrogen in the stimulation of tumor growth has been controversial. The present study was performed to determine the site of aromatization in human breast cancers, using both immunocytochemistry and in situ hybridization. The functional significance of locally produced estrogens on growth of the tumor was addressed by measuring aromatase activity and a marker of proliferation (PCNA score). In addition, histocultures of some tumors were carried out to investigate whether testosterone aromatization could stimulate tumor proliferation. Of the 19 tumors investigated, 10 (52.6%) showed significant immunoreactivity to antiaromatase antibody in the cytoplasm of tumor epithelial cells and in surrounding stromal cells. The presence of aromatase mRNA detected by ISH was also located in tumor epithelial cells and stromal cell, and the pattern of expression was the same as with immunocytochemistry. In the ten tumors that showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 +/- 18.6 (SE) fmol estrogen/mg protein.h, whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 +/- 19.3 (SE) fmol estrogen/mg protein-h (P < 0.05). The mean PCNA score was 33.8 +/- 5.1 (SE)% in strongly stained tumors and 20.8 +/- 2.0 (SE)% in weakly stained tumors (P < 0.05). Aromatase activity level and PCNA score were significantly correlated. In histoculture of four tumors, estradiol increased the incorporation of [3H]-thymidine into DNA. In two of these tumors, aromatase activity was high and [3H]-thymidine incorporation into DNA was also stimulated by testosterone. In the other two tumors that had low aromatase activity, no such stimulation occurred with testosterone. The results indicate that aromatase is expressed mainly in tumor epithelial cells and that sufficient amounts of estrogen are synthesized by the tumor to produce a proliferative response. It is concluded that estrogen synthesis by cancer cells could play a important role in promoting growth in a significant proportion of breast tumors.

Glomerular lesions in lymphomas and leukemias.

Renal lesions in lymphoid malignancies are rare, with most lesions observed in association with Hodgkin's disease. In two large series of patients with Hodgkin's disease, only 0.4 percent had minimal-change lesion whereas 0.1 percent had amyloidosis. The non-Hodgkin's lymphomas and leukemias comprise large and heterogeneous groups with equally diverse renal lesions. As in Hodgkin's disease, the most frequent lesion is minimal-change nephrotic syndrome. Also recognized are rare reports of renal disease associated with the atypical lymphoid proliferations of angioimmunoblastic lymphadenopathy, giant lymph node hyperplasia syndrome, and acquired immune deficiency syndrome. Broad generalizations regarding the pathogenesis of renal disease in these syndromes are difficult, partly due to the paucity and sporadic reporting of such cases. Mechanisms proposed to explain the renal pathologic findings include autologous nontumor antigens, tumor antigens, fetal antigen expression, immune complex deposition, viral antigens, and disordered T cell function.

Eosinophilic and lymphoeosinophilic cholecystitis.

Eosinophilic cholecystitis (EC) is an infrequent and poorly understood inflammatory condition of the gallbladder. First described in 1949, EC may be defined as an inflammatory condition of the gallbladder in which the inflammatory infiltrate is composed predominately of eosinophils so that their presence clearly overshadows the presence of any other inflammatory cell component. In the few reports that describe EC, it has been described in association with acalculous cholecystitis, with subacute cholecystitis lasting 2 to 3 weeks and with several forms of drug therapy. This retrospective clinicopathologic study reviewed the histopathologic features of 217 consecutive cholecystectomy specimens with special clinical reference to the timing of gallbladder removal after symptoms, previous drug therapy, systemic infection, and the presence of cholelithiasis. Pathologically, 48 of these cases (22.2%) contained eosinophils to some degree. Eosinophilic cholecystitis was diagnosed in 14 (6.4%) of the specimens, and another 14 (6.4%) specimens demonstrated substantial numbers of eosinophils but also had other types of inflammatory cells in abundance, including neutrophils and lymphocytes. Of the eight patients with acalculous cholecystitis, six had substantial eosinophils in their gallbladders, whereas the other two patients had no eosinophils. In this study, EC was more prevalent than in other reported series, and it did not show any association with the timing of gallbladder removal after initial symptoms, drug therapy, or other preexisting medical conditions. Eosinophilic cholecystitis is more common than previously recognized and probably represents a subgroup of patients with a unique or hypersensitivity type of inflammatory response to altered bile. Large numbers of eosinophils in the inflammatory infiltrate occurred three times more commonly in patients with acalculous cholecystitis than in patients with cholelithiasis.

Intermediate filaments in endometrial and endocervical carcinomas. The diagnostic utility of vimentin patterns.

We examined the distribution of high- and low-molecular-weight cytokeratins, vimentin, and carcinoembryonic antigen (CEA) in normal endometrial glands and endocervical glands (20 cases each) and in endometrial and endocervical adenocarcinomas (29 cases and 15 cases respectively). Low- and high-molecular-weight cytokeratin staining was present in normal endometrial and endocervical epithelium and in carcinomas. Coexpression of vimentin and cytokeratin was universally present in normal proliferative endometrial glands, with marked decrease or absence of vimentin staining in secretory phase patterns. Vimentin staining had a perinuclear distribution within the cells, in contrast to the cytokeratins, which stained diffusely. Vimentin was found in only 65% of endometrial adenocarcinomas. Staining was typically focal as well as regional in portions of the tumors. Vimentin was never observed in normal or neoplastic endocervical epithelium. Ultrastructural studies corroborate the perinuclear vimentin immunostaining pattern we observed in endometrial adenocarcinomas. CEA staining results were similar to those previously reported. These data indicate that the presence of vimentin may readily distinguish endometrial from endocervical carcinoma and is diagnostically useful in the study of metastatic adenocarcinomas.

Localized primary (AL) amyloid tumor of the breast. Cytologic, histologic, immunocytochemical and ultrastructural observations.

Two examples of localized primary amyloid tumor of the breast are presented, including one patient with metachronous bilateral lesions. Our findings and review of the literature indicate that this rare lesion occurs predominantly in elderly females and can be mammographically and clinically confused with carcinoma. Fine-needle aspiration biopsy can be a useful procedure to make a preliminary diagnosis. Congo red staining with prior potassium permanganate incubation confirmed the AL type of amyloid in our two cases; this might be the predominant type in the localized form involving the breast. Immunofluorescence studies demonstrated IgA, with kappa and lambda light-chain deposition within the amyloid foci in one case, and intracytoplasmic IgG with both light chains within plasma cells and amyloid deposits of the second case. Ultrastructural examination of one of the cases showed characteristic findings of straight, nonbranching fibrils of 4-9 nm, diagnostic of amyloid. From our findings and a review of the literature, we conclude that amyloid tumors of the breast can occur in three separate settings: secondary amyloidosis, systemic or multiple myeloma associated amyloidosis, and as a localized primary type having a benign course.

Mammary ductal foam cells: macrophage immunophenotype.

Mammary ductal foam cells are present in normal breast tissue as well as in a number of breast diseases. Such foam cells tend to be in particular abundance with fibrocystic changes of the breast. Foam cells may appear within duct lumens or plastered in cohesive masses along duct walls, simulating an epithelial structure. The nature and origin of these innocuous-appearing cells, based on morphologic studies, remain a controversy, for they appear to be of epithelial derivation. This study was undertaken to determine the nature of intraductal "foam" cells and their origin in the breast. Nine cases of adult fibrocystic disease were examined immunohistochemically with antibodies to cytokeratins (Mak-6, Cam 5.2), leukocyte common antigen, and the following macrophage antibodies: KP-1 (CD68), HAM 56, and MAC 387. The lysozyme and alpha-1-antitrypsin content of foam cells also was studied. The immunohistochemical data in this study confirm the macrophage character of these foam cells, which are positive for CD68, HAM 56, and MAC 387, lysozyme, and alpha-1-antitrypsin and negative for leukocyte-common antigen and cytokeratins.

Ductal carcinoma of breast: nuclear grade as a predictor of S-phase fraction.

Nuclear grade (NG) and S-phase fraction (SPF) are established independent prognostic variables for ductal breast carcinomas. Nuclear grade can be assigned by a pathologist in a simple fashion during histopathologic evaluation of the tumor, while SPF requires flow cytometric evaluation of tumor samples. This prospective study was undertaken to determine whether elevated SPF could be predicted from NG alone and how NG and SPF correlate with c-erbB-2 expression. Eighty-two breast carcinomas of ductal type were assigned an NG of low (grade 1 or grade 2) or high (grade 3). S-phase fraction was recorded initially from fresh-frozen tissue samples and was designated as either low SPF (below the value designated as the cutoff for elevated SPF) or high SPF (a value at or greater than the cutoff value). On fresh tissue the NG predicted the range of SPF (low or high) in 89% of cases. Four percent of the cases that did not correlate could definitely be attributed to sample error. The remaining 7% that did not correlate could have been due to sample error, specimen quality, or tumor heterogeneity, as demonstrated by reversal of SPF range as performed on paraffin blocks of tumor. Eighty-eight percent of the tumors positive for c-erbB-2 were NG 3 and 12% were NG 2. All c-erbB-2 tumors were aneuploid. This study demonstrates the importance of carefully assigning NGs on tissue and indicates the importance of reviewing flow cytometric data side by side with histopathologic parameters to detect discrepancies between these two modalities. Careful nuclear grading assignment can accurately predict the range of SPF.

Renal vascular smooth muscle proliferation in neurofibromatosis.

An unusual vascular lesion was seen in a 14-year-old white boy with renal vascular hypertension and neurofibromatosis. Microscopically, nodular intimal and medial proliferations of spindle-shaped cells involved arteries, arterioles, and veins of all caliber within the renal parenchyma. Immunoperoxidase studies indicated these cells to have characteristics of smooth muscle, and this finding was confirmed by ultrastructural examination. Despite the generalized nature of the process in the biopsy sample, the patient's hypertension responded well to surgical treatment.

The immunohistochemical discrimination of endometrioid adenocarcinomas.

Carcinomas of endometrioid histology frequently arise in the endometrium, ovary, and endocervix and involve the pelvic tissues in women. Adenocarcinomas of psuedoendometrioid morphology developing in the colon also frequently involve the ovary. The authors retrospectively examined 97 adenocarcinomas from the uterus, cervix, ovary, and colon to ascertain whether the site of origin could be determined by using a battery of antibodies with the immunoperoxidase method on formalin-fixed tissue. This study was restricted to tumors with endometrioid morphology. There were 27 endometrial, 16 ovarian, 23 endocervical adenocarcinomas, and 31 psuedoendometrioid colonic adenocarcinomas. The battery of antibodies included vimentin (V), monoclonal carcinoembryonic antigen (mCEA), and monoclonal CEA D-14. V-positive cells were defined by the presence of a crisp paranuclear band of staining, and CEA-positive cells showed irregular or diffuse cytoplasmic staining. V diffusely decorated 22 of 27 (81.4%) of endometrial tumors, 3 of 23 (13%) of endocervical tumors, (rare, focal staining), diffusely stained 5 of 16 (31.3%) of ovarian tumors, and was rare and focal in 2 of 31 (6.4%) of colon tumors. Both CEA antibodies were negative for cytoplasmic staining in both endometrial and ovarian tumors, but decorated from 65.2% (CEA D-14) to 95.6% (monoclonal CEA) of endocervical tumors and from 83.8% (CEA D14) to 90.3% (mCEA) of colonic tumors. The authors conclude that endometrioid adenocarcinomas developing in endometrium and ovary are most often strongly V positive and CEA negative, which greatly aids in distinguishing them from endometrioid or pseudoendometrioid tumors arising in endocervix and colon, which are only rarely, and very focally V and CEA positive. The antibodies do not allow for discrimination between endocervical and colonic tumors. CEA D-14 offered no immunodiagnostic superiority over mCEA. These results support the use of immunohistochemistry is assisting in the distinction of endometrial from endocervical primary sites in curettage specimens and in metastatic sites.

KRAS oncogene mutations suggest a common histogenetic origin for pleomorphic giant cell tumor of the pancreas, osteoclastoma of the pancreas, and pancreatic duct adenocarcinoma.

Giant cell neoplasms of the pancreas are rare tumors of uncertain histogenesis. Mutation of the KRAS oncogene is common in typical pancreatic duct adenocarcinoma. We have analyzed DNA from five pancreatic tumors with giant cells for mutations in the KRAS oncogene and found alterations of the second position of codon 12 in each case (four G > A transitions and one G > C transversion). The common mutation pattern in tumors with giant cells and duct adenocarcinoma suggests a common route to malignant transformation and may indicate a shared histogenesis. We also tested 11 cases of malignant fibrous histiocytoma, a histological mimic of pleomorphic giant cell tumor, for mutations in the KRAS oncogene. The absence of KAS mutations in each of the malignant fibrous histiocytomas (MFHs) and in other histologically similar tumors may provide assistance in the differential diagnosis of pleomorphic pancreatic tumors.

Prognostic information from fine-needle aspiration biopsy of breast carcinoma.

Fine-needle aspiration of the breast is one of the most common procedures performed on patients with a palpable breast mass. The pathologist needs to be aware of the diagnostic and prognostic parameters that must be included in the cytopathology report of breast carcinomas. These fundamental parameters include tumor type, nuclear grade of the carcinoma, and hormone receptor status.

Superficial spreading malignant melanoma with neurosarcomatous metastasis.

Metastatic malignant melanoma often poses a difficult light and ultrastructural diagnostic challenge. A superficial spreading malignant melanoma without desmoplasia displayed neurosarcomatous light and electron microscopic features in metastatic sites. The ultrastructure displayed some Schwann cell features and strong-S-100 immunostaining. Metastatic melanoma with Schwannian differentiation in metastatic sites without lesional desmoplasia is rare and must be included in the differential diagnosis of spindled neoplasms involving lymph nodes. The evolution of this lesion illustrates the spectrum of melanocytic differentiation, i.e., pigment synthesis, adaptive fibroplasia and Schwannian differentiation.

Fine-needle aspiration biopsy of pleomorphic (giant cell) carcinoma of the pancreas. Cytologic, immunocytochemical, and ultrastructural findings.

Four cases of pleomorphic (giant cell) carcinoma (PGC) of the pancreas, diagnosed by fine-needle aspiration biopsy, are presented. Ancillary immunocytochemical studies were also performed on the smears (four cases) and cell blocks (three cases), along with ultrastructural (electron microscopic) examination of the aspirated specimen (two cases). Three of the four patients were elderly (age range: 44-65 years), and all had large pancreatic masses. A spectrum of cytomorphologic features was encountered, including poorly cohesive bizarre mononuclear cells, many multinucleated tumor giant cells, and associated malignant spindle cells. Prominent cellular cannibalism and cytophagocytosis also were seen. Immunoperoxidase studies demonstrated dual staining of the malignant cells for cytokeratin and vimentin in two cases and exclusive staining for vimentin in the remaining two cases. Ultrastructural examination demonstrated epithelial features in both cases studied. One of the cases demonstrated intracytoplasmic whorled bundles of intermediate filaments, corresponding to pale eosinophilic globular material, appreciated both in the Diff-Quik- and Papanicolaou-stained smears and staining with positive results for vimentin. The immunocytochemical studies suggest that the coexpression of vimentin and cytokeratin within the cells is consistent with a pleomorphic malignancy of epithelial origin. It is speculated that the staining of two of the cases exclusively for vimentin can be seen in either epithelial malignancies with sarcomatoid transformation or, less likely, a pure sarcoma of the pancreas.

Terminal subculture of blood cultures using a multipoint inoculator device.

A multipoint inoculation method was used for the terminal subculture of blood cultures. This economical yet reliable technique successfully isolated important human pathogens such as Haemophilus influenzae from macroscopically negative blood cultures.

Bilirubin, ferritin, D-dimers and erythrophages in the cerebrospinal fluid of patients with suspected subarachnoid haemorrhage but negative computed tomography scans.

AIM: To assess the diagnostic value of cerebrospinal fluid (CSF) spectrophotometry, cytology, ferritin, and D-dimer measurements in the investigation of suspected subarachnoid haemorrhage in patients with negative or equivocal computed tomography (CT) scans. METHODS: CSF specimens submitted for assessment of xanthochromia were examined for erythrophages using a cytospin preparation stained with Wright's stain, for ferritin using the Ciba-Corning Magic IRMA assay, D-dimers using the Dimertest 2 latex agglutination slide test, and for bilirubin by scanning spectrophotometry. The patients were divided into three groups for data analysis and the results compared with the existing methods, CT, and angiogram results. Final diagnoses were reviewed by a consultant neurologist. RESULTS: Thirty six patients were recruited. In those patients with confirmed subarachnoid haemorrhage CSF cytology had a low sensitivity and there were false negative results with both the D-dimer and ferritin assays. Eleven patients with a negative or equivocal CT scan underwent angiography, but only one aneurysm and no arterio-venous malformations or bleeding points were identified. In the patient with the aneurysm there was no laboratory evidence of subarachnoid haemorrhage. Six patients had CSF abnormalities detected by the special tests only and in none of these cases was subarachnoid haemorrhage confirmed. All results were normal in four out of five cases of traumatic tap. CONCLUSIONS: This is a small study, but it shows that, depending on the timing of the lumbar puncture, false negative results can occur with both ferritin and D-dimer measurements. It suggests that neither of these tests adds significantly to the information provided by CT, visualisation of CSF, and spectrophotometry and confirms that, despite the use of spectrophotometry, D-dimer and ferritin assays in selecting patients for angiography, the proportion of patients with negative CT scans and colourless CSF with demonstrable vascular lesions remains low.

The surgical pathologist's approach to fine needle aspiration.

The diagnostic process begins with triage of the FNAB, depending on the patient's problem. Portions of the specimen can then be set aside for appropriate immunocytochemistry, hormone receptors analysis, electron microscopy, flow cytometry, or molecular studies. Microscopic evaluation, as in surgical pathology, begins with scanning objective examination of tissue architecture, followed by study of cellular characteristics, and finally the nuclear features. Cytopathology and surgical pathology are no longer distinct entities.

The impact of fine-needle aspiration biopsy on a diagnostic electron microscopy laboratory.

We retrospectively reviewed the number and types of diagnostic electron microscopic specimens from a 4 1/2-year period. During this period, the number of fine-needle aspirate biopsy specimens processed increased in a linear fashion, from a relatively uncommon occurrence to the current level of activity, in which fine-needle aspiration specimens now represent 40% to 50% of the nonrenal diagnostic material examined by electron microscopy. This study documents the increasing importance of fine-needle aspirate-type specimens in the everyday operation of a diagnostic electron microscopy facility.

Immunohistochemical study of uterine stromal sarcoma and rhabdomyosarcoma.

The cytoplasmic filament composition of two pure high-grade endometrial stromal sarcomas and five pure endometrial rhabdomyosarcomas was studied using the immunoperoxidase avidin-biotin method. Ultrastructural correlates were performed on the same tissues. While four of the seven tumors presented as high-grade undifferentiated neoplasms, they were readily categorized on the basis of immunocytochemical findings in which the five rhabdomyosarcomas were positive for muscle-specific actin (HHF 35) and the two stromal sarcomas were positive for vimentin only. Ultrastructure on the HHF 35-positive cases showed the presence of thick filaments and Z-band material, whereas the other tumors showed no cytoplasmic differentiation. Muscle-type actin differs stromal cells, and is useful when used in conjunction with a panel of antibodies in the categorization of undifferentiated endometrial sarcomas.