Progression of prostate cancer to neuroendocrine cell tumor.

BACKGROUND: The progression to endocrine therapy-resistant prostate cancer is partly due to clonal change to neuroendocrine cell tumor. To elucidate this pathologic process, the clinical courses of four cases of neuroendocrine cell tumor that were found at autopsy are reported. METHODS: Between 1995 and 1999, autopsies were performed for 20 cases of prostate cancer. Lesions predominantly composed of a neuroendocrine cell tumor (small cell carcinoma) were found in four men. The clinical courses of these cases were compared to 16 other non-neuroendocrine cell tumors (adenocarcinomas). RESULTS: The outstanding features of the neuroendocrine cell tumors were: (i) survival was brief after relapse, although the duration of control by employing endocrine therapy varied; (ii) the prostate-specific antigen level did not increase after relapse; and (iii) the sites of metastasis were similar to those of common adenocarcinomas. CONCLUSION: The progression to a neuroendocrine cell tumor indicated a poor prognosis and slight (if any) changes in the serum prostate-specific antigen level. This tumor might not appear to respond to any therapeutic attempt.

Carcinoma of the urinary bladder with a lymphomatous appearance.

We present the first report of bladder carcinoma that demonstrates a mixture of two distinct histological patterns resembling malignant lymphoma. The patient was a 79-year-old man. One of the histological patterns was a diffuse growth of monomorphic carcinoma cells, and the other was a dense lymphoplasmacytic infiltrate, obscuring the carcinoma. The tumor cells showing both patterns expressed cytokeratin and epithelial membrane antigen, but not lymphoid markers. Careful immunohistochemical evaluation should be done when diagnosing urinary bladder carcinomas resembling lymphomas (other than primary lymphomas).

The impact of a 4 cm. cutoff point for stratification of T1N0M0 renal cell carcinoma after radical nephrectomy.

PURPOSE: The 1997 TNM classification defines T1 tumors as those smaller than 7 cm. Recently, a cutoff point of 4 cm. has been proposed to create a subclass of T1 tumors. We evaluated the validity of this cutoff point by assessing the pathological findings and prognoses of patients with T1N0M0 renal cell carcinoma following radical nephrectomy. MATERIALS AND METHODS: We reviewed the hospital charts of 333 patients with T1N0M0 tumors, followed as long as 282 months (median 63) after radical nephrectomy. The validity of tumor size cutoff point for predicting survival outcome was tested in relation to other prognostic factors, including patient age, tumor position, nuclear grade, tumor histopathology and degree of microscopic venous invasion. RESULTS: During followup 32 patients (9.6%) had tumor recurrence and 21 (6.3%) died of renal cell carcinoma. A 5 cm. cutoff point maximized the differences in cancer specific survival rates and a 4 cm. cutoff point maximized the differences in disease-free survival rates. Tumor size was directly related to microscopic venous invasion and nuclear grade, which are significant prognostic factors, and a 4 cm. cutoff point enhanced these relationships. CONCLUSIONS: Tumor size is an important prognostic factor for patients with T1N0M0 renal cell carcinoma. A cutoff point of 4 cm. is practical for dividing the T1N0M0 classification into T1a and T1b subclasses.

Intraductal papillary tumors of the major salivary glands: case reports of benign and malignant variants.

Intraductal papilloma is an extremely rare benign salivary gland tumor that occurs most commonly in the minor salivary glands. To our knowledge, a malignant counterpart of intraductal papilloma has not been described previously. We report one case each of benign and malignant intraductal papillary tumors. The benign tumor occurred in the sublingual gland and was a typical example of intraductal papilloma, with the exception that we found no previously published reports of this type of tumor in this location. The other patient had a left parotid gland tumor that was architecturally similar to the intraductal papilloma, with the addition of cytologic atypia, intraductal extension, microinvasion, and lymph node metastases. This tumor was diagnosed as intraductal papillary adenocarcinoma with an invasive component. Both patients were alive and well without evidence of recurrence 2 years and 6 months (case 1) and 6 years (case 2) after surgery. Immunohistochemical examination revealed that the tumor cells resembled duct luminal cells in both cases. The 2 tumors had different immunoreactivities for carcinoembryonic antigen, p53, and Ki-67. The malignant counterpart of intraductal papilloma should be considered in the differential diagnosis of salivary gland tumors with a predominantly papillary structure, even though this tumor is extremely rare.

Myocardial Depolarizing Response to Glutamate in the Myogenic Heart of the Branchiopod Crustacean Triops longicaudatus.

Fine structure of the heart and the effects on the heartbeat of some transmitter candidates in crustacean cardioregulatory system were examined in the myogenic heart of the branchiopod crustacean Triops longicaudatus. Electron microscopy revealed that, in each myocardial cell, myofibrils are confined in the part facing the epicardium and intercalated disks are present between the myofibrillar regions of adjacent myocardial cells. No neural elements were found in the heart, suggesting lack of extrinsic cardioregulatory nerves from the central nervous system. Gamma aminobutyric acid and acetylcholine produced no detect-able changes in the myogenic activity of the heart at concentrations up to 10(-3) M, respectively. Glutamate induced a depolarizing membrane response in the cardiac muscle with a threshold concentration of approximately 1x10(-5) M. The amplitude of the depolarizing response was concetration-dependent and saturated at approximately 1x10(-4) M. The myogenic activity of the heart increased in frequency with glutamate of less than approximately 3x10(-5) M. With higher dose of glutamate, action potential adaptation occurred in the cardiac muscle and the heart exhibited a systolic arrest.

Localization of the olfactory cyclic nucleotide-gated channel subunit 1 in normal, embryonic and regenerating olfactory epithelium.

The spatial and temporal expression of subunit 1 of the olfactory cyclic nucleotide-gated channel was investigated using affinity-purified anti-fusion protein antibodies. Immunoreactivity was most prominent in the ciliary layer of the olfactory epithelium, but high protein expression was also seen along the entire length of olfactory receptor neuronal axons to the level of the glomeruli. Electron microscopy showed that the long, thin distal compartments of olfactory cilia labeled more prominently than their thicker proximal segments. This was true as soon as these distal parts began to develop. Using light microscopy, developmental expression of olfactory cyclic nucleotide-gated channel subunit 1 could be detected in discrete populations of olfactory receptor neurons by embryonic day 14. Other signaling molecules are expressed either later (Golf) or only at the level of the epithelial surface and not in axons (adenylyl cyclase type III). Following unilateral lesions of the olfactory bulb, olfactory cyclic nucleotide-gated channel subunit 1 immunoreactivity was present early and throughout developing olfactory receptor neurons; adenylyl cyclase type III immunoreactivity, in contrast, was detectable only later, and again present only in the cilial layer. These results support the hypothesis that this subunit of the olfactory cyclic nucleotide-gated channel may be involved in olfactory axon guidance, in addition to its well-described role in olfactory signal transduction.

Transformation of fibrolamellar carcinoma to common hepatocellular carcinoma in the recurrent lesions of the rectum and the residual liver: a case report.

A 21-year-old man had undergone central bisegmentectomy of the liver due to fibrolamellar carcinoma (FLC). Twice, 24 and 30 months after the first operation, lymph node metastases were removed. We have reported this case previously and this is the second report of the same case. Forty-two months after the second operation to remove lymph node metastases, a recurrence occurred in the rectum and was excised. However, the tumor also recurred in the residual liver. The patient underwent hepatectomy for a palliative purpose but died 16 months after the last operation. Histopathologically, the primary tumor was diagnosed as pure FLC, but the lymph node metastases had foci of the common hepatocellular carcinoma (HCC) mixed with FLC. In contrast, the recurrent tumors in the rectum and the residual liver showed the histopathological features of common HCC. Thus, during repeated recurrences, histopathological features changed from pure FLC to common HCC.

Prognostic factors relating to survival in uterine endometrioid carcinoma.

OBJECTIVE: Epidemiologic and clinicohistopathologic prognostic factors of uterine endometrioid carcinomas were analyzed. The association of estrogen related factors, focused on adenomyosis in the prognosis of endometrioid carcinomas was also examined. METHODS: Risk factors of surgically treated 286 patients with endometrioid carcinoma (Stage I-III) were statistically analyzed. RESULTS: Overall a recurrence-free 5-year survival rate was 81% (Stage I, 94%, Stage II, 71% and Stage III, 40%). Significant prognostic factors were lymph node metastases (P = 0.0035) and serosal/parametrial invasion (P = 0.014) by multivariate analysis. Endometrioid carcinomas with co-existing adenomyosis tend to be associated with endometrial hyperplasia (P = 0.04, Fisher's exact test), diagnosed in less invasive status (myometrial invasion, P = 0.004 and serosal/parametrial invasion, P = 0.006) and therefore have a favorable prognosis (P = 0.01, log rank test). CONCLUSIONS: A favorable prognosis of endometrioid carcinomas with co-existing estrogen related factors (adenomyosis and endometrial hyperplasia) was suggested.

[Penile carcinoma with humoral hypercalcemia of malignancy (HHM): a case report].

A 57-year-old male, with 1.5 cm tumor in his prepuce, was admitted to our institute in Feb. 1990. Circumcision and inguinal lymph node dissection was performed under the diagnosis of T1 disease of penile carcinoma. Pathological evaluation revealed well-differentiated squamous cell carcinoma (SCC). In April 1996, the patient revealed recurrence of the disease in the right inguinal lymph nodes and the lower abdomen, that was diagnosed to be poorly differentiated SCC. Laboratory findings showed elevation of serum calcium, parathyroid hormone-related protein (PTHrP) levels. Immunohistochemical staining confirmed production of PTHrP in the tumor tissue. This is the first case report of penile carcinoma that caused humoral hypercalcemia of malignancy in Japan.

Cystic partially differentiated nephroblastoma in an adult: an immunohistochemical, lectin histochemical and ultrastructural study.

AIMS: Cystic partially differentiated nephroblastoma (CPDN) is an uncommon renal multicystic tumour, usually affecting early infants. To our knowledge, this report describes the first case of CPDN occurring in an adult. METHODS AND RESULTS: A 45-year-old man was found incidentally to have a left renal cystic tumour, measuring 20 mm in diameter, at the lower pole far from the pelvis. The tumour was composed of multilocular cystic spaces of variable size and intervening septa without solid nodular areas. The cysts were lined by a single layer of flattened, hobnail, or columnar epithelium. The septa were made of mesenchymal cells, which were admixed with small numbers of loosely aggregated blastemal cells, occasional tubular structures in various stages of development, and a few glomeruloid structures. The tumour cells had no anaplasia, and mitoses were rare. Immunohistochemical and lectin histochemical studies revealed that the cyst lining epithelium and the tubular structures in the septa expressed predominantly the markers for distal tubules and collecting ducts. Ultrastructurally, the cyst lining cells closely resembled collecting duct cells while some tubular structures showed an immature nephrogenic morphology. The patient was alive and well without evidence of recurrence 11 months after surgery. CONCLUSIONS: CPDN does occur in adults, as experienced in Wilms' tumour, though its incidence is extremely low. This study suggests that CPDN may show maturation intermediate between cystic nephroma and Wilms' tumour, even in adult cases.

[Cyclophosphamide-induced bladder cancer in a patient with Wegener granuromatosis].

Cyclophosphamide (CPM) has been considered to be a factor of bladder carcinogen. A 60-years old woman had been received a total dose of 370 g of CPM for the treatment of Wegener's granulomatosis since August, 1977. She was consulted to our department with chief complaint of macrohematuria in August, 1986. Hemorrhage cystitis was diagnosed and cystoscopy and urine cytology were performed as follow-up schedule in every year. In 1996, urine cytology showed class IV and cystoscopy revealed multiple nonpapillary tumors. Abdominal computerized tomography demonstrated a low density mass on the posterior wall of the bladder. A transurethral cold cup biopsy showed G3 transitional cell carcinoma (TCC). Radical cystectomy and tubeless cutaneous ureterostomy was performed on December 6, 1996 and histopathological diagnosis was TCC, G 3, pT3 bNXM0. She died of liver failure due to metastatic bladder cancer after seven months postoperatively.

[Bilateral pheochromocytomas with von Hippel-Lindau's disease: a case report].

A case of bilateral pheochromocytomas with von Hippel-Lindau's disease (VHL) is reported. A 46-year-old woman who had hyperglycemia was admitted to our hospital because of abdominal tumors. Her elder sister and niece had been diagnosed as VHL. Ultrasonography, CT, and MRI revealed bilateral adrenal tumors. Noradrenaline levels in serum and urine were elevated and 131I-MIBG scintigraphy showed accumulation in bilateral adrenal glands. Moreover, she had bilateral renal cysts and cerebellar hemangioblastoma. Bilateral adrenalectomies were performed and pathological diagnosis was pheochromocytoma. This is the seventh case of bilateral pheochromocytomas with VHL reported in Japan.

Salivary gland malignant myoepithelioma: a clinicopathologic and immunohistochemical study of ten cases.

BACKGROUND: Malignant myoepithelioma (MME) of the salivary gland, also known as myoepithelial carcinoma, is rare and its biologic behavior has not been clarified fully. METHODS: Ten cases of MME were analyzed for their clinicopathologic features and immunohistochemical characteristics, focusing on prognostic factors and tumor differentiation. In addition, six cases of benign myoepithelioma (BME) also were examined for comparison. RESULTS: The ten patients with MME (3 men and 7 women) ranged in age from 48-81 years (mean, 61.9 years). Seven cases of MME arose in the parotid salivary gland, two in the submandibular salivary gland, and one in minor salivary glands of the soft palate. In the current series, the incidence of MME was 0.45% among 1945 cases of major salivary gland tumors. Seven cases of MME developed from a benign preexisting tumor (six in pleomorphic adenoma and one in BME). Four of nine patients with MME died of the disease and two patients developed a recurrence. It was shown that MMEs were comprised of one cell type or a combination of two cell populations; these included, in order of incidence, epithelioid, spindle, and plasmacytoid cells. Patients with MME with marked cellular pleomorphism and perineural invasion had a poor prognosis. Immunohistochemically, putative myoepithelial markers such as muscle actins, cytokeratin 14, vimentin, and calponin, and S-100 protein were expressed highly in MME. High and low molecular weight cytokeratins and epithelial membrane antigen also frequently were positive in MME. p53 expression was observed in five MME cases, four of which either recurred or were fatal. Cellular proliferative activity assessed by mitotic count and the Ki-67 labeling index was significantly higher in MME cases than in BME cases. In limited cases, such cellular proliferative activity was shown to have prognostic value. Ultrastructurally, the tumor cells displayed certain myoepithelial characteristics. CONCLUSIONS: MME is a rare salivary gland tumor showing clinicopathologic diversity and presenting with various stages of myoepithelial differentiation. Histologic aggressiveness, marked cellular pleomorphism, p53 expression, and high cell proliferative activity were found to be correlated with a poor clinical outcome.

Etiological analysis of focal nodular hyperplasia of the liver, with emphasis on similar abnormal vasculatures to nodular regenerative hyperplasia and idiopathic portal hypertension.

Pathological studies were performed on 23 cases of focal nodular hyperplasia (FNH) under the hypothesis that FNH is a hyperplastic lesion caused by abnormal vasculatures of portal tracts within the nodule. For a comparison of the histological features of portal tracts, nodular regenerative hyperplasia (NRH), idiopathic portal hypertension (IPH), chronic hepatitis and so-called normal liver were used as control tissues. Extranodular areas of FNH nodules were also examined. Clinical data were briefly summarized. Most of the portal tracts within FNH nodules showed various abnormal findings, such as dilatation and/or stenosis of portal vein, muscular thickening of arterial wall with dilated or stenotic lumina, lymphocyte infiltration, and bile ductule proliferation. However, portal vein thrombi were not found. These findings were not thought to represent compensatory reaction to portal vein thrombosis. Similar abnormal features were also observed in extranodular areas of FNH although to a milder degree. These abnormal features resembled those of NRH and IPH. Moreover, the characteristic scar-like tissues within FNH nodules were proved to be abnormally large portal tracts including large feeding arteries, portal veins and bile ducts. It has been believed that septa and scar-like tissue within FNH nodules are not portal tracts and that arterial malformation independent of portal tracts are related to the development of FNH. In addition, venous structures within FNH modules have until now not been considered to be portal veins. However, this study revealed that severe anomaly of portal tracts including portal veins and hepatic arterial branches existed in FNH nodules. Moreover, portal tracts in extranodular areas were also abnormal. Clinically, only one patient had a history of oral contraceptives. Based on these findings, congenital anomaly of the portal tracts histologically resembling the abnormal portal tracts of NRH and IPH may be related to the pathogenesis of FNH.

Basal cell adenocarcinoma of the salivary glands: comparison with basal cell adenoma through assessment of cell proliferation, apoptosis, and expression of p53 and bcl-2.

BACKGROUND: Basal cell adenocarcinoma (BCAC) of the salivary gland is a rare tumor and recently described entity. Eleven cases of BCAC are presented here and compared with basal cell adenoma (BCA) through assessment of cell proliferative activity, apoptosis, and expression of p53, bcl-2, and epidermal growth factor receptor (EGFR) because these two tumors show close similarity in some cytologic and architectural characteristics. METHODS: Formalin fixed, paraffin embedded sections of 11 cases of BCAC and 9 cases of BCA, selected from the authors' files of 1851 primary tumors of the major salivary gland, were examined using immunostaining for Ki-67 (MIB-1), p53, bcl-2, and EGFR. In addition, apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling. RESULTS: The incidence of BCAC was 0.6% among patients with major salivary gland tumors in the current series. Nine cases of BCAC arose in the parotid gland and two were of submandibular gland origin. Approximately 50% of the patients had recurrences, but no patient developed metastases or died of disease. Vascular involvement (75%), perineural invasion (36%), and necrosis (45%) were common features. Cell proliferative activity, including mitotic count, Ki-67 labeling index (LI), and apoptotic index were significantly higher in BCAC than BCA. More than four mitotic figures per ten high-power fields or a Ki-67 LI > 5% appeared to be limited to cases of BCAC. Considering those cases expressing p53 or EGFR in > 10% of tumor cells as positive, 6 of the 11 BCAC cases were positive for p53 and 3 were positive for EGFR. In contrast, all BCA cases were negative for p53 and EGFR. Although all cases of BCA were strongly positive for bcl-2 (> 50% of tumor cells), 3 of 11 cases of BCAC were completely negative. CONCLUSIONS: BCAC is a rare salivary gland tumor with a relatively high recurrence rate. Examination of cell proliferation, apoptosis, and expression of p53, bcl-2, and EGFR were found to be useful in distinguishing malignant basal cell tumors from their benign counterparts arising in the salivary gland.

Cell display library for gene cloning of variable regions of human antibodies to hepatitis B surface antigen.

A novel cell display system was developed for cloning the variable region (V) genes of antigen-specific human antibodies. The system is based on an antibody library displayed on the surface of COS cells, using a plasmid vector designed to direct expression of membrane-bound antibodies. COS cells expressing antigen-specific antibodies were separated using a flow cytometer for their binding to a fluorescent dye-labeled antigen. To test the performance of this system. We cloned V genes of 4 antibodies directed against hepatitis B surface antigen (HBsAg) from a library prepared from peripheral blood lymphocytes of a vaccinated donor. These membrane-bound anti-HBsAg antibodies were easily converted to soluble forms, all of which showed a size similar to human serum IgG in SDS-PAGE and the same specific binding to HBsAg as membrane-bound forms in ELISA. All VH and VK gene segments of the 4 clones isolated in this study belonged to VHIII and VKI subgroups, respectively. These findings demonstrate the potential and selection capabilities of our cell display system for cloning the V genes of antigen-specific human antibodies.

Carcinoma in basal cell adenoma of the parotid gland.

Malignant transformation of basal cell adenoma (BCA) of the parotid gland is rarely reported, and when occurred, may principally become manifest as a malignant basaloid tumor, i.e. basal cell adenocarcinoma or adenoid cystic carcinoma. We describe herein three cases of non-basaloid carcinoma arising in BCA. The incidence of this malignant tumor was 0.2% of all parotid gland tumors and 4.3% of BCAs in our series. One case was salivary duct carcinoma showing histologic evidence of transition between malignant and benign elements. The remaining two cases were well-encapsulated parotid gland tumors, which were composed of BCA and scattered foci of malignant transformation. Malignant components were adenocarcinoma, not otherwise specified (NOS), and sometimes intermixed with neoplastic myoepithelial cells included BCA cells. These two cases were regarded to be intracapsular carcinoma in BCA. BCA components showed solid, tubular and trabecular arrangements. The patients' prognosis was quite variable among these three cases; the first case died of disease after 27 months, whereas the latter two cases are alive and well for 4 and 10 years after surgery. Ki-67 labeling index indicated that cell proliferative activity was at least five times higher in carcinomas than BCAs. Non-basaloid carcinomas such as salivary duct carcinoma or adenocarcinoma, NOS, do develop in BCAs as in the case of a pleomorphic adenoma with malignant transformation, though the incidence may be extremely rare.

Increased expression of S100A4, a metastasis-associated gene, in human colorectal adenocarcinomas.

The S100A4 gene (also known as pEL98/mts1/p9Ka/18A2/42A/calvasculin /FSP1/CAPL) encoding an S100-related calcium-binding protein is implied to be involved in the invasion and metastasis of murine tumor cells. In the present study, the expression of S100A4 in human colorectal adenocarcinoma cell lines (SW837, LoVo, DLD-1, HT-29, SW480, SW620, WiDr, and Colo201) and surgically resected neoplastic tissues was examined to investigate whether S100A4 plays a role in the invasion and metastasis of human tumor cells. Northern blot analysis using total RNA isolated from the adenocarcinoma cell lines revealed that five of the eight cell lines expressed substantial amounts of S100A4 mRNA. Normal colon fibroblasts (CCD-18Co) expressed little of the RNA. Using surgically resected specimens, it seemed that the amount of S100A4 mRNA in adenomas was nearly equal to that in normal colonic mucosa, whereas adenocarcinomas expressed a significantly higher amount of the RNA than did the adjacent normal colonic mucosa. Immunohistochemical analysis using formalin-fixed paraffin-embedded surgical specimens and monoclonal anti-S100A4 antibody demonstrated that none of 12 adenoma specimens were immunopositive, whereas 8 of 18 (44%) focal carcinomas in carcinoma in adenoma specimens and 50 of 53 (94%) adenocarcinoma specimens were immunopositive. Interestingly, the incidence of immunopositive cells increased according to the depth of invasion, and nearly all of the carcinoma cells in 14 metastases in the liver were positive. These results suggest that S100A4 may be involved in the progression and the metastatic process of human colorectal neoplastic cells.