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BACKGROUND A prospective two-yr study was undertaken to assess the heterogentity of thyroid nodules using the fine-needle aspiration (FNA) technique of systematic regional sampling. In addition, we determined the number of regions to be sampled to minimize non-diagnostic results, and to optimally characterize thyroid nodules. DESIGN: FNA was performed on 74 nodules ≥ 1.5 cm. in diameter in five distinct regions in sequence (center, then four quadrants starting at 12:00, clockwise). Slides from each region were coded, randomized, subjected to blind review, and categorized as non-diagnostic (ND), benign (B), indeterminate (ID), suspicious/neoplastic (S/N), or malignant (M). Final cytologic diagnosis (CD) was made from all slides of each nodule. RESULTS The ND rate for center FNAs alone was 16%, but addition of the 12:00 region decreased it to 5.3%. With 3, 4, or 5 sequential sites the nondiagnostic rates were 4, 2.6, and 2.6%. The center region diagnosis was identical to the final CD in 71% of the cases. Addition of the 12:00 region increased the concordance to 88%. Three sequential regions equaled the CD in 93% of cases, and 4 regions equaled the CD in 99% of cases. All nodules characterized as M or S/N were resected as were 76% of the ID nodules. Of the 43 nodules characterized as B, 3 were resected, 24 involuted, 6 were unchanged, and 10 were lost to follow-up. All 3 M nodules proved malignant by histology, as did 7/10 S/N, 0/17 ID, and 0/43 B nodules; 3/10 S/N, 1/17 ID and 1/43 B were adenomas. Likelihood ratios for diagnosing neoplasia were ND:0, B:0.10, ID:0.21, S/N:∞, M:∞. CONCLUSIONS Sampling of at least four distinct regions accurately assesses thyroid nodules while minimizing ND results. Regional sampling also addresses intranodular heterogeneity. Diagn. Cytopathol. 1998;18:76–80. © 1998 Wiley-Liss, Inc.

The presence of prostatic glandular tissue in female pseudohermaphrodites has previously been documented. However, prostatic neoplasia in this clinical setting has not been reported. A karyotypic female with congenital adrenal hyperplasia due to 21-hydroxylase deficiency developed a prostatic adenocarcinoma associated with elevated serum prostatic specific antigen levels and osteoblastic skeletal metastases. This demonstrates that this tissue in pseudohermaphrodites can become malignant. In addition, the patient subsequently developed clear cell carcinoma of the endometrium, possibly related to radiation therapy for the prostatic adenocarcinoma. This demonstrates that female pseudohermaphrodites may be at risk not only for malignancies seen in genotypic females but also prostate cancer.

Objectives. To determine whether a very small focus of prostate cancer in a needle biopsy specimen correlates with organ-confined disease or with favorable disease parameters. Methods. Of 598 needle biopsies of the prostate performed from January 1990 through June 1994, 49 specimens (8.2%) contained a microscopic focus (less than 2 mm in length of the entire biopsy core specimen) of adenocarcinoma. For these 49 patients, the clinical and pathologic features were correlated. Results. Of these 49 patients, 27 (55.1%) underwent either radical prostatectomy, with or without pelvic lymph node dissection (26), or pelvic lymph node dissection alone (1). Seven of these 27 patients (25.9%) had extraprostatic disease: lymph node involvement (1), positive surgical margins (5), or seminal vesicle invasion (1). Ten of the 49 patients (20.4%) underwent radiotherapy, and 12 (24.5%) chose hormonal therapy. The pathologic stage for these 22 patients could not be ascertained. However, despite the limited amount of disease in the biopsy specimen, 2 patients treated with radiotherapy suffered a relapse (mean interval to recurrence, 11.5 months), and 3 patients treated with hormonal therapy (early or delayed) had bony metastasis at the time of diagnosis. Overall, 12 of the 49 patients (24.5%) had unfavorable disease (as defined by extraprostatic disease on pathologic specimen, relapse after radiotherapy, or bony metastasis at the time of diagnosis). Conclusions. These findings suggest that a microscopic focus of prostatic adenocarcinoma in a needle biopsy specimen, per se, does not predict the pathologic stage or the biologic behavior of a tumor.

Background. Leuprolide, an agonist of luteinizing hormone-releasing hormone (LH-RH), and flutamide, an antiandrogen, increasingly are being used in the treatment of clinically localized prostate cancer. Only two small series (of 23 and 12 patients) have been published on the distinctive pathologic changes induced in the prostate by androgen deprivation therapy with discrepancies on the presence of squamous metaplasia, necrosis, and possible tumor destruction by combined androgen deprivation therapy. Methods. One hundred and thirteen radical prostatectomy specimens obtained after at least 3 months of leuprolide-flutamide androgen inhibition therapy and 60 nonhormonally treated prostates in randomly selected clinical Stage T2 prostate adenocarcinoma patients were entirely sectioned. Distinctive histologic findings were tabulated and their statistical value determined. Results. Resection margins of excision were involved by tumor in 43% of untreated and in 19% of androgen-deprived patients. Characteristic changes in androgen-inhibited nontumor glands included atrophy, basal cell prominence, vacuolated luminal cell layer, and squamous and transitional cell metaplasia. Prostatic intraepithelial neoplasia (PIN) was observed in 35% of treated patients. The presence of small tumor glands separated by stroma was the most frequently noted effect of androgen deprivation on prostate adenocarcinoma; pyknosis and branching empty spaces were less frequent. Large clear tumor cells within an inflammatory response was a third histologic pattern. Apparently unaltered tumor areas were observed in 43% of prostates exposed to androgen deprivation therapy. Conclusions. Androgen deprivation therapy result in histologically distinctive changes that can be recognized in both nonneoplastic and neoplastic prostate tissue. Residual tumor was present in all 113 treated radical prostatectomy specimens. In addition to glandular shrinkage, therapy was associated with statistically significant reductions in the frequency of high grade PIN and extension of cancer to prostate specimen margins of excisions. Cancer 1995;75:1634-41.

Background. Thirty percent of patients with clinically localized prostate cancer and a negative bone scan will experience relapse with recurrent disease despite treatment of the primary tumor. This may be due to the presence of metastatic prostate cancer cells at the time of treatment undetected by conventional methods, radionu-cleotide bone scan, and serum prostatic specific antigen blood test. Methods. The authors used polymerase chain reaction (PCR) amplification of the prostate-specific antigen (PSA) mRNA sequence reverse-transcriptase PCR (RTPCR) and immunohistochemistry using a PSA antibody to identify metastatic prostate cancer cells in the bone marrow of patients with prostate cancer. Results. Micrometastases were found in the bone marrow of 29 of the 55 patients (51%) with prostate cancer and in 0 of the 5 patients with benign prostatic hyperplasia. Samples from five of the seven patients with lymph node metastases and from all five patients with bony metastases contained micrometastases. Of the samples taken from 43 patients undergoing radical prostatectomy and with no evidence of metastatic disease, 19(44%) had micrometastases. Four of the 20 samples (20%) from patients with pathologically localized disease and 15 of the 23 samples (65%) from patients with extraprostatic disease had micrometastases (P = 0.003). Bone marrow slides were available on 24 of the 29 patients who were positive for micrometastases by RTPCR. Immunohisto-chemistry using the PSA antibody identified metastatic cells in 19 of these 24 patients. Conclusions. Reverse-transcriptase polymerase chain reaction of bone marrow samples from patients with clinically localized prostate cancer may improve the accuracy of prostate cancer staging and identify patients at high risk for metastatic disease.

Criteria for assessing adequacy of cervicovaginal smears according to the Bethesda System include cellular composition and quantity, specimen preservation, fixation, and absence of obscuring elements. The reproducibility of adequacy assessment using these parameters was the focus of this study. Specimens were chosen to include a wide spectrum of clinical history and adequacy interpretations, but excluded cases with epithelial abnormalities and those judged "limited" because of insufficient transformation zone component. The 114 specimens were independently evaluated twice by five reviewers, with interceding randomization. Full interobserver concordance was obtained in 50.4% of cases, with consensus reached by three or more observers in 97.4% of cases. Of 2280 paired interpretations, 74% (1692) concurred. Pairwise kappa values for interobserver agreement ranged from .71 to .54 (very good to fair), with overall kappa = .61. Interobserver agreement for each category was near excellent for "satisfactory" (kappa = .73), good for "unsatisfactory" (kappa = .63), and only fair for "satisfactory but limited" (kappa = .48). Paired intraobserver reproducibility (agreement for two separate readings by the same observer) ranged from 69% to 77% (average, 74%), with good to fair kappa values (.66-.51). These findings indicate that the specimen adequacy guidelines of the Bethesda System provide good inter- and intraobserver reproducibility. The "satisfactory but limited" category appears to show the lowest concordance. Problem areas include evaluation of adequate minimum cellularity and estimation of number of cells obscured.

Cytologic evaluation of body cavity fluids is useful to detect malignancy within the pleural and peritoneal spaces. A definitive diagnosis cannot always be made on cytologic evaluation alone. As malignant processes may show abnormal DNA content, DNA analysis of effusions may be useful. Therefore, we determined the DNA content of 37 effusions by flow cytometry (FC) and image analysis (IA) using the CAS 200. Of the 37 fluids evaluated, 18 were cytologically malignant, 15 benign, and four atypical. Overall, 22 fluids (60%) showed concordance between FC and IA. None of the benign fluids were aneuploid. All showed diploid histograms or diploidy with increased proliferating cells. Three of four atypical fluids had increased proliferating cells by either FC or IA, whereas one was diploid by both methods. Aneuploidy was detected in 13 malignant fluids: five were aneuploid by both methods and eight by only one method. IA identified aneuploidy in five of those eight cases, while three were identified by FC. Three of the cytologically malignant fluids were diploid by both methods, and two showed increased proliferating cells by IA and diploidy by FC. The specificity of both methods was 100%. However, the sensitivity of identifying a malignant fluid by aneuploidy is low, 44% for FC and 55% for IA. IA appears to identify small aneuploid populations more frequently than FC. The detection of aneuploidy in effusions is highly suggestive of malignancy, and the combination of both techniques gives the highest detection rate (72%). However, neither are as sensitive as traditional cytologic evaluation with the occasional use of additional histochemical stains. © 1994 Wiley-Liss, Inc.

Histologic grading of breast carcinomas is an important prognostic indicator of survival. An increasing number of patients, however, receive definitive therapy based on a fine-needle aspiration cytologic (FNA) diagnosis. This may limit standard grading techniques. Nuclear grade and DNA image cytometry in 35 FNA specimens taken from 34 patients were compared to DNA flow cytometry and histologic grade of the excised carcinoma using the Bloom system, as modified by Elston. Seven histologic grade I, 14 grade II, and 14 grade III infiltrating ductal carcinomas were studied. All histologic grade I carcinomas were diploid on the FNA specimen, and six showed nuclear grade 1. Twenty-seven of 28 histologic grade II and III cancers had nuclear grades of 2 or 3. Twenty-five showed aneuploidy (19 cancers) or tetraploidy (6 cancers). The other three showed diploidy with increased S/G2M (17-20%). Most of the tetraploid tumors were histologic grade II. Interobserver variability was greatest for nuclear grade (31%). Concordance between DNA studies by image analysis on the FNA and flow cytometry on the excised specimen was 80%. Both nuclear grade and DNA cytometry on FNAs can be used to distinguish most histologic grade I carcinomas from grade II and III cancers. DNA cytometry is more time-intensive but is less influenced by interobserver variation, and usually correlates with DNA flow cytometry on the excised specimen.

Histologic material from 42 patients with endometrioid carcinomas of the ovary was reviewed. Ovarian endometriosis was present in 11 cases (26%) and 8 of these patients were postmenopausal. The exact site of transition from benign to malignant epithelium was observed in 4 cases. The clinical characteristics of patients with associated endometriosis were not significantly different from those without this finding except that endometriosis was present only in patients with Grade 1 or Grade 2 carcinomas. These data suggest that ovarian endometriosis in the postmenopausal patient has the potential to undergo malignant transformation and, when detected, should be removed surgically.

A female child with Weaver syndrome is described. She did not show the excessive growth characteristic of this syndrome until after adequate caloric intake was achieved by feeding through a gastric feeding tube. Her inadequate nutrition was a result of feeding difficulties during infancy. In addition, she had recurrent pulmonary infections, apneic spells, and severe developmental delay. She died at 16 months of sepsis, congestive heart failure, and respiratory arrest. The autopsy revealed marked atrophy of the brain and cardiac ventricular hypertrophy. Most of the brain changes were thought to be from hypoxia.

Cutaneous squamous carcinoma with true glandular differentiation has only rarely been documented. Ten patients with such tumors are presented. There were six men and four women, aged 48 to 87 years. The tumors were located on the central face (eight), scalp (one), and hand (one) and consisted of minimally elevated, indurated, keratotic plaques, up to 6 cm in size. Microscopically, the neoplasms exhibited multifocal origin from the epidermis; deep, dispersed, infiltrative growth; perineural invasion; and stromal desmoplasia. Squamous differentiation was most marked superficially. Glandular differentiation was more obvious in deeper areas. Lumens typically developed within squamous nests and were often lined by cells with cytoplasmic vacuoles, some of which contained mucin. The neoplastic cells had obvious cytologic atypia and easily identified mitotic figures. Immunohistochemically, nine neoplasms studied contained carcinoembryonic antigen in glandular foci. Each patient had one or more surgical resections, and six also received radiation and/or chemotherapy. Five patients died with uncontrolled local recurrence, and two are alive with extensive disease and clinical evidence of regional lymph node involvement. Two individuals with small, superficial neoplasms that could be completely removed are disease free. One patient died of unrelated causes shortly after diagnosis. Cutaneous adenosquamous carcinoma is more aggressive than the usual carcinoma of the skin. It must be distinguished from the cytologically bland, microcystic adnexal (sclerosing sweat duct) carcinoma which is capable of recurring but rarely, if ever, proves fatal. The question of whether adenosquamous carcinoma is an epidermally derived squamous tumor with divergent differentiation or should be viewed as a newly recognized adnexal carcinoma remains to be resolved.

Intravascular menstrual endometrium, a rare finding in hysterectomy specimens, can pose clinically critical differential diagnostic problems. We describe a 28-year-old female with cervical dysplasia and numerous foci of menstrual endometrium in the parametrial blood vessels of her subsequent hysterectomy specimen. Histologically, the intravascular tissue consisted of small spindled stromal cells, larger cuboidal epithelial cells, or both components in close association. Immunohistochemically, the small spindled cells were vimentin positive and the larger cuboidal cells stained with epithelial markers. Distinction of intravascular menstrual endometrium from intravascular malignancies such as carcinoma, sarcoma, or lymphoma may be difficult, especially at the time of frozen-section diagnosis. Awareness of this process, attention to its cytologically bland, usually biphasic appearance, knowledge of the menstrual status, and application of appropriate immunohistochemical markers will allow distinction from neoplasia.

Adenomatoid tumors are well-recognized neoplasms generally considered to be of mesothelial derivation. We describe an unusual vascular neoplasm that arose in the testis of a 29-year-old and resembled an adenomatoid tumor by light microscopy. An orchiectomy was performed, and the patient is alive and disease-free 3 years later. The 2-cm tumor was composed of small tubules lined by mesothelial-like cells with uniform, vesicular nuclei. However, some lumina contained erythrocytes, and immunohistochemically, the luminal cells reacted with antibodies to vimentin, Factor VIII-related antigen, and Ulex europaeus I lectin but not cytokeratin or epithelial membrane antigen. A cuff of muscle-specific actin-positive cells surrounded the luminal cell layer. This adenomatoid-like vascular neoplasm is more properly interpreted as a histiocytoid (epithelioid) hemangioma. Although some authors have considered microscopically similar lesions to represent a vascular variant of adenomatoid tumor, we prefer to reserve the term "adenomatoid tumor" for microscopically appropriate proliferations that have mesothelial features.

Cytokeratin (CK) positivity has been considered a specific marker for epithelial differentiation in cytologic specimens. After observing CK reactivity in fine-needle aspirate (FNA) specimens of melanoma and sarcoma, a retrospective study of melanomas and sarcomas was undertaken to investigate the frequency of anomalous CK staining in these neoplasms. Cell block sections and/or restained smears from 36 melanomas and sarcomas were retrospectively stained for CK. An appropriate internal positive control (HMB-45, S100 protein, or vimentin) was also used to insure antigen preservation. of the smears from 19 melanomas, five revealed focal strong CK positivity of neoplastic cells, two cases showed faint or equivocal staining, 11 cases were negative for CK, and one could not be interpreted due to inadequate controls. of the smears from 14 sarcomas, two showed positivity for CK (one fibrosarcoma and one condrosarcoma), 11 were negative, and one had inadequate controls. the number of CK positive cells was less than that observed with the appropriate internal positive control antibodies. Destained Papanicolaou smears were superior to Diff-Quik smears for retrospective immunocytochemical stains. Cell block sections from four of the melanomas and one sarcoma demonstrated no aberrant staining. Since Cytokeratin positivity occasionally is seen in nonepithelial neoplasms, its presence alone cannot be used to make a definitive diagnosis of carcinoma. Therefore, a panel of immunocytochemical stains should be utilized in diagnosis of FNA specimens. © Wiley-Liss, Inc.

Objective. The utility of an antibody to proliferating cell nuclear antigen (PCNA), a growth-specific nuclear protein, was assessed as a prognostic variable for prostatic adenocarcinoma. Its expression was correlated with established prognostic indicators, including tumor grade, stage, prostattc-specific antigen (PSA), and percent of tumor in the gland at excision. Methods. Forty archival needle biopsies containing a minimum of four hundred tumor cells were analyzed. Immunoperoxidase staining of paraffin sections was performed for PCNA (PC 10) after pretreatment in antigen retrieval solution. A proliferative index (PI) for each case was derived using image analysis with measurement of at least four hundred twenty-five nuclei. Results. PI values ranged from 2.4 to 31.3 percent. Mean PI values varied significantly (ANOVA, p = 0.005) among cases with dominant Gleason grade (DGG) of 3 (mean PI = 9.3%), 4 (mean PI = 13.7%), and 5 (mean PI = 18.8%). By t test, significant differences were noted for PI in cases with DGG 2 and 3 versus those with DGG 4 and 5 ( p = 0.0065). PI for cases with DGG 3 versus 5 showed significant difference (p = 0.0017). Tumors of Gleason scores 5 to 7 differed significantly from those with scores 8 to 10 (p = 0.014). A statistical relationship for PI and PSA, clinical stage, and percent tumor at resection could not be established by linear regression. Conclusions. These findings suggest that additional study of the PI, as determined by PCNA immunohistochemistry and image analysis, may be warranted to determine its usefulness as an adjunctive parameter in prostate adenocarcinoma. This technique may be particularly useful in needle biopsies where limited tumor may render assessment of grade difficult.

Basaloid squamous cell carcinoma (BSCC) of the head and neck is a recently described high-grade variant of squamous cell carcinoma. It is a biologically virulent neoplasm with a propensity for nodal, as well as systemic, metastases. Because of the limited number of published reports, we reviewed data from patients of the University of Virginia Health Sciences Center and identified 16 cases of BSCC. The intent of this study was to determine the role of radiotherapy in the treatment of BSCC and better define the clinical features of this entity. Radiotherapy alone, or in combination with surgery, resulted in excellent local control rates. Distant metastases, chiefly pulmonary, occurred in more than half of the patients.

In this study of 40 cases of basaloid squamous cell carcinoma, 83% arose in the pyriform sinus, base of tongue, tonsil, and larynx. The 35 men and five women ranged in age from 27 to 88 years (median 62). In patients for whom social habits were recorded, 24 of 26 patients were smokers and 22 of 25 drank ethanol. Most presented with stage III or IV disease. Twenty-seven patients had regional metastases at the time of presentation and 15 developed distant metastases. Seventeen patients died with disease (median survival 18 months). The tumors were composed of moderately pleomorphic basaloid cells forming nests, cords, and frequent cribriform patterns. Squamous dysplasia of surface mucosa, focal squamous differentiation within invasive basaloid squamous cell carcinoma, or foci of conventional squamous cell carcinoma were present, alone or in combination. All studied neoplasms were immunohistochemically positive for keratins with the 34 beta E12 antibody. Approximately 80% were immunoreactive using AE1/AE3 or CAM 5.2. Epithelial membrane antigen, carcinoembryonic antigen, and S100 protein were found in 83%, 53%, and 39%, respectively, of the cases. Diffuse, weak immunoreactivity for neuron-specific enolase was seen in 75% of tumors. Synaptophysin, chromogranin, muscle-specific actin, and glial fibrillary acidic protein were absent. Basaloid squamous cell carcinoma has been confused with adenoid cystic carcinoma and small cell undifferentiated carcinoma, but is usually distinguishable in routine hematoxylin and eosin-stained sections, or, in rare problematic cases, with the aid of immunohistochemical studies. Distinction is warranted because the biologic behavior of basaloid squamous cell carcinoma differs from that of both of these lesions.

Hodgkin's disease (HD) is increasingly being evaluated by fine-needle aspiration (FNA); however, criteria to subclassify HD into its four subtypes--nodular sclerosis (NS), mixed-cellularity (MC), lymphocyte-depleted (LD), and lymphocyte-predominant (LP)--has not been established. In order to evaluate criteria for subclassification, all FNA cases of HD obtained over a 5-yr period at Indiana University Medical Center that had confirmatory surgical biopsies were reviewed. The number of Reed-Sternberg (RS) cells was quantitated in each cytologic case and statistically analyzed by subgroup, using analysis of variance (ANOVA). LD had the highest mean (means) number of RS cells (means = 51) with NS and MC having similar means (means = 7 and 6, respectively). Only one case of LP was identified and therefore could not be analyzed statistically. Fibrosis and the presence of RS variants were qualitatively assessed and were not helpful in distinguishing the subtypes of HD. Although the quantitation of RS cells may be used to identify LD types of Hodgkin's disease, MC and NS cannot be separated reliably on this criterion alone. Although FNA can be used to diagnose HD, stage a patient, or assess efficacy of chemotherapy, subtyping of HD should still be done on histologic sections of excised lymph nodes.