Atypical Glandular Proliferations Research Articles

Prostate Type Malignancies Arising in Ovarian Teratomas - A Report of Two Patients.

The identification of benign prostatic tissue within ovarian and testicular mature teratomas is an unusual occurrence. While a few documented reports exist in the literature regarding the emergence of benign prostatic tissue within teratomas, the occurrence of prostatic-type adenocarcinoma in a mature ovarian teratoma is an exceptionally rare phenomenon. To date, only two prior reports have documented such instances, and no tumors have been previously reported with prostate-type tissue with morphologically two different malignancies. We outline our experience with two tumors involving prostatic-type carcinoma, both arising in ovarian mature teratomas. Microscopic examination of the first tumor revealed small areas of infiltrative atypical glandular proliferation within the mature teratoma. In the second tumor, prostate-type tissue exhibited a low-grade basal cell carcinoma. Additionally, adjacent minute foci of adenocarcinoma of the prostate (Gleason score 3 + 4 = 7, <5% pattern 4) were identified. Goblet cell adenocarcinoma of appendiceal type was also evident in the latter tumor. In both tumors, immunostains (NKX3.1, PSA) were performed to establish the prostatic origin of these atypical glands and PIN4 was performed to document the absence of basal cell in the atypical glands. On clinical follow-up, both patients have no signs of recurrence at 14 and 11 months after the surgery. Further reports on such neoplasms would contribute to a better understanding of the prognosis and management of such occurrences.

Early TP53 Alterations Shape Gastric and Esophageal Cancer Development.

Simple SummaryRecent evidence establishes that gastric and esophageal (GE) adenocarcinomas are similar cancers at cellular, genomic, and epigenomic levels. Human GE adenocarcinomas develop TP53 mutations at early stages of malignant progression. This contrasts with other gastrointestinal adenocarcinomas, including sporadic colorectal and pancreatic adenocarcinomas, where TP53 alterations occur late. Exposure of the esophagus and stomach to environmental risk factors contributes to the selection of early TP53 mutations and subsequent chromosomal instability, which then lead to activation of mitogen and cell cycle pathways in GE adenocarcinomas by way of focal amplifications rather than mutations. While early TP53 mutations enable GE adenocarcinoma development, they also expose therapeutic vulnerabilities that should be prime for targeted therapy directed against the DNA damage response.Gastric and esophageal (GE) adenocarcinomas are the third and sixth most common causes of cancer-related mortality worldwide, accounting for greater than 1.25 million annual deaths. Despite the advancements in the multi-disciplinary treatment approaches, the prognosis for patients with GE adenocarcinomas remains poor, with a 5-year survival of 32% and 19%, respectively, mainly due to the late-stage diagnosis and aggressive nature of these cancers. Premalignant lesions characterized by atypical glandular proliferation, with neoplastic cells confined to the basement membrane, often precede malignant disease. We now appreciate that premalignant lesions also carry cancer-associated mutations, enabling disease progression in the right environmental context. A better understanding of the premalignant-to-malignant transition can help us diagnose, prevent, and treat GE adenocarcinoma. Here, we discuss the evidence suggesting that alterations in TP53 occur early in GE adenocarcinoma evolution, are selected for under environmental stressors, are responsible for shaping the genomic mechanisms for pathway dysregulation in cancer progression, and lead to potential vulnerabilities that can be exploited by a specific class of targeted therapy.

S3595 "Cutting Edge Honjo Masamune Saving Lives" ESD Preferred and Popular for Early Gastric Cancer

INTRODUCTION: Gastric cancer (GC) is the second leading cause of cancer-related mortality worldwide and complete resection is the only curative treatment. Historically, total or subtotal gastrectomy was the only curative option. However, with the advances in therapeutic endoscopy, endoscopic submucosal dissection (ESD) has emerged as a minimally invasive treatment option for precancerous lesions and early stage gastric cancer. Here we present a case of large gastric mass that was able to be fully resected using ESD, which was found to be rare GC. CASE DESCRIPTION/METHODS: A 50-year-old female with multiple comorbidities who presented to our Gastrointestinal (GI) clinic for further evaluation of iron deficiency anemia. Her initial endoscopic gastroduodenoscopy (EGD) revealed a 5–6 cm large gastric mass in the greater curvature of the stomach. The mass was hyperechoic, heterogeneous, and extended to the deep mucosal layer on endoscopic ultrasound (EUS). No adjacent lymphadenopathy was noted. Endoscopic biopsies of the mass revealed atypical glandular proliferation with extensive acute inflammation. Resection of the lesion by ESD was planned. After the lesion and its borders were carefully evaluated, the entire circumference of the lesion was marked with the Dual Knife (Olympus, Tokyo, Japan). A submucosal cushion was created using ORISE gel (Boston Scientific) expanding the submucosa and lifting the lesion away from the muscularis propria layer. The Dual Knife was then used to perform incision at the oral aspect of the lesion. Following this, the submucosa was partially dissected using swift coagulation. The submucosa was then further injected with ORISE gel to expand the submucosal space. Further dissection was performed until the lesion was completely separated from the surrounding gastric mucosa. The lesion was removed en bloc from the patient via Roth net. The resected mass measured 5 × 8 cm. Final histopathology revealed Epstein-Barr virus (EBV)-associated gastric adenocarcinoma with lymphoid stroma with negative margins. Metastatic workup was negative, and the tumor was staged as stage 1. No complications were reported. The patient was referred to the Medical and Surgical Oncology clinic and underwent subtotal gastrectomy and lymphadenectomy despite negative margins and against GI recommendation. Notably, all of the surgically resected tissue was negative for malignancy. DISCUSSION: ESD is an effective minimally invasive treatment for premalignant and early stage gastric cancer.

SUN-482 A Very Rare Case of Thyroid Cancer

Background: Cribriform-Morular variant of Papillary Thyroid Cancer (PTC-CMV) is an exceedingly rare subtype of thyroid cancer that predominantly affects younger females. As the name implies, it is a papillary thyroid carcinoma with predominantly cribriform and morular pattern of carcinoma cells on cytopathology. While completion thyroidectomy is usually recommended for larger and higher-risk Papillary Thyroid Cancer (PTC), surveillance may be acceptable with PTC-CMV, which tends to be a less aggressive malignancy. Clinical Case: A 46-year-old Guyanese woman presented with a three week history of an enlarging right-sided neck mass associated with a globus sensation while swallowing food. She denied any history of radiation exposure. Her exam findings were positive for a tender, right-sided neck mass. CT neck without contrast revealed a 4.1 x 4.0 x 5.9cm heterogeneous mass within the right thyroid lobe causing mild tracheal deviation to the left. Ultrasound of thyroid gland showed a solid heterogeneous hypoechoic 4.22 x 2.39 x 2.46cm right lobe nodule with no microcalcifications, border irregularity or taller-than-wider morphology. Fine Needle Aspiration of the nodule came back as Atypia of Undetermined Significance. The patient then underwent a core needle biopsy. The resultant pathology was negative for thyroid carcinoma or medullary thyroid carcinoma but was suggestive of a bronchial cleft cyst versus bronchogenic cyst with atypical glandular proliferation. She subsequently underwent a right hemithyroidectomy which revealed a final pathological diagnosis of a 3.5cm PTC-CMV. Such pathology warranted the patient to undergo a colonoscopy which was negative for Familial Adenomatous Polyposis (FAP). Given her negative GI workup and non-contributory family history for colonic polyposis or carcinoma the decision was made to continue surveillance rather than performing completion thyroidectomy as the disease was presumed to be sporadic. Discussion: PTC-CMV accounts for 0.2% of all PTC. It is associated with FAP in more than 50% of cases but can also occur sporadically. This subtype of PTC generally follows a less aggressive course. Review of current literature revealed several case series of CMV-PTC patients. In the largest one, 32 cases were observed over a 19 year period and only two out of twelve patients with FAP-associated PTC-CMV initially treated with hemithyroidectomy developed recurrence to the contralateral lobe. Interestingly, none of the remaining patients with the sporadic type developed recurrence suggesting that completion thyroidectomy may not be mandatory in this group. It is, therefore, critical to identify these patients and screen them with a colonoscopy to avoid the potentially unnecessary resection of the contralateral lobe and the consequent need for thyroid hormone replacement.

Foamy Gland Variant of Prostatic Adenocarcinoma (FGVPA), diagnostic pitfalls: A case report and literature review

A transurethral resection of prostate (TURP) specimen was received from a 72-year-old male who presented with a recent history of urinary tract infection and increased serum prostate specific antigen (PSA) of 15 ng/mL. There was an atypical glandular proliferation of which a predominant population demonstrated abundant pale xanthomatous cytoplasm with small hyperchromatic nuclei and inconspicuous nucleoli. A minor component of conventional prostatic acinar adenocarcinoma was identified focally in the background. Immunohistochemistry was used to confirm the diagnosis of adenocarcinoma. FGVPA is a rare variant, with foamy cytoplasm due to intracytoplasmic vesicles not lipid or neutral mucin, and usually with small pyknotic nuclei with minimal atypia. Gleason scoring is performed by the underlying architectural pattern. Immunohistochemistry of basal cell markers and AMACR are often used to confirm a diagnosis of prostatic adenocarcinoma; however, it is to be noted that variants of prostate cancer including FGVPA are labelled with AMACR in only 60–70% of cases. It is important for the pathologist to be aware of FGVPA as in its pure form can easily be missed especially on needle core biopsy. The differential diagnoses of benign mimics with clear cytoplasm include xanthoma, Cowper’s glands, clear cell cribriform hyperplasia and mucinous metaplasia.

EPITHELIAL-MIOEPITELIAL CARCINOMA IN THE SOFT PALATE: CASE REPORT

Epithelial-myoepithelial carcinoma is a rare low-malignant neoplasm consisting of 1% of all tumors in the salivary glands. A 53-year-old black female patient complained of pain in the palate. Past medical history included an incisional biopsy whose histologic slices stained in hematoxylin and eosin (H&E) showed atypical glandular proliferation compatible with myoepithelial carcinoma, low-grade polymorphous adenocarcinoma, and adenoid cystic carcinoma. A reddish area of 1 cm was observed in the soft palate, with no symptoms. Faced with the lack of diagnostic definition, excisional biopsy was chosen where the anatomopathologic analysis corroborated previous findings, but immunohistochemistry showed positivity for Ki67, P63, cytokeratin 7, cytokeratin 8/18, and calponin, leading to the definitive diagnosis of epithelial-myoepithelial carcinoma. Because of the free margins observed in H&E, we chose to follow-up, who after oral rehabilitation continues without signs of local recurrence in a 2-year follow-up.

P40 as a Basal Cell Marker in the Diagnosis of Prostate Glandular Proliferations: A Comparative Immunohistochemical Study with 34betaE12.

Immunohistochemistry is important for the accurate diagnosis of basal cells in atypical glandular proliferations of the prostate. p40, an isoform of p63, may be an adjunct to a marker panel in this setting. Biopsies of 68 patients were analyzed by immunohistochemistry using antibodies to 34betaE12 and p40. Basal cell staining was classified as negative, partial (<60%), or diffuse (≥60%); irregular staining was defined as discordant staining patterns. In acinar proliferations (N = 41), partial staining for both markers was seen in 42%, and diffuse staining in 46% of reactive cases. An irregular reactivity was noted in one case only (2%). Finally, these lesions were signed out as benign. Acinar proliferations negative for both markers and limited amount of glands (≤4) were termed atypical small acinar proliferations (ASAP). Out of six PIN lesions two cases showed partial, three cases showed diffuse reactivity for both markers, and one case was stained irregular. All cases diagnosed as prostate carcinomas (N = 20) had no evidence of basal cell staining for neither of the markers. p40 expression is closely correlated to 34betaE12 with respect to demonstration of basal cells of prostate glands and may provide further information on the dignity of glandular proliferations of the prostate.

Utility of seriated sections in prostate biopsies

IntroductionWith the routine use of prostate specific antigen, focal carcinomas and atypical small acini proliferation (ASAP) are currently detected more frequently. The number of sections per cylinder needed to detect most of them is still unknown. MethodsWe reviewed 250 sextant prostate biopsies in the 2008–2011 period. The average number of cylinders per biopsy was 14. In each case, in addition to the original sections with three histological levels, three more sections were performed with three levels (total: 12 levels). Biopsies with focal lesion were analyzed immunohistochemically. The frequency of focal lesions was compared to a previous study of 1000 biopsies in which a single section was made with three histological levels. The main clinical and laboratory data were recorded. ResultsThere were 16 focal lesions (6.4%). Seven (2.8%) corresponded to focal carcinomas and nine (3.6%) to atypical proliferation. In the previous study, thirteen (1.3%) focal carcinomas and 29 (2.9%) cases with atypical proliferation were found. ConclusionsThere was an increase of 4.2–6.4% of focal lesions carcinomas increased from 1.3% to 2.8%. Making additional sections in all biopsies may have practical drawbacks. However, they could be performed in patients with high clinical suspicion of carcinoma (especially in young patients), or when there is a history of atypical glandular proliferations consistent with carcinoma in previous biopsies.

Utilidad de cortes seriados en biopsias prostáticas

IntroductionWith the routine use of prostate specific antigen, focal carcinomas and atypical small acini proliferation (ASAP) are currently detected more frequently. The number of sections per cylinder needed to detect most of them is still unknown. MethodsWe reviewed 250 sextant prostate biopsies in the 2008-2011 period. The average number of cylinders per biopsy was 14. In each case, in addition to the original sections with three histological levels, three more sections were performed with three levels (total: 12 levels). Biopsies with focal lesion were analyzed immunohistochemically. The frequency of focal lesions was compared to a previous study of 1000 biopsies in which a single section was made with three histological levels. The main clinical and laboratory data were recorded. ResultsThere were 16 focal lesions (6.4%). Seven (2.8%) corresponded to focal carcinomas and nine (3.6%) to atypical proliferation. In the previous study, thirteen (1.3%) focal carcinomas and 29 (2.9%) cases with atypical proliferation were found. ConclusionsThere was an increase of 4.2% to 6.4% of focal lesions carcinomas increased from 1.3% to 2.8%. Making additional sections in all biopsies may have practical drawbacks. However, they could be performed in patients with high clinical suspicion of carcinoma (especially in young patients), or when there is a history of atypical glandular proliferations consistent with carcinoma in previous biopsies.

Atypical Small Acinar Proliferation: Utility of Additional Sections and Immunohistochemical Analysis of Prostatic Needle Biopsies

BackgroundIn surgical pathology, atypical small acinar proliferation is commonly detected in prostate biopsies. Most studies on atypical small acinar proliferation have examined morphological characteristics and the utility of immunohistochemical studies. However, these resources are not available to many pathology departments. We have found that examining additional sections is a simple and inexpensive method that allows better evaluation of focal prostatic glandular atypia.ObjectivesThe present report compares the diagnostic utility of immunohistochemical techniques versus examining additional sections in prostate biopsies with focal glandular atypia.Patients and MethodsThirty recently studied prostate biopsies with focal glandular atypia were selected. In each case, 3 additional levels were examined. An immunohistochemical study was performed on one level using an antibody against high-molecular-weight keratin (34BetaE12). Two additional sections were stained with hematoxylin and eosin.ResultsThe diagnosis of focal carcinoma was established with only additional sections in 4 cases (13.3%). In 2 of these biopsies, additional areas of carcinoma were found that were not identified in the original sections. In 4 other cases, immunohistochemical analysis was the only useful method for diagnosing cancer. In 9 cases (30%), both methods were useful for classifying focal glandular atypia as carcinoma. In the remaining 13 cases,neither immunohistochemical analysis nor additional sections were useful in changing the diagnosis of focal glandular atypia.ConclusionsFocal glandular atypia in prostatic needle biopsies should be routinely examined with additional sections, particularly when immunohistochemical analysis is not possible. Some biopsies with atypical glandular proliferation may show focal carcinoma in additional sections, even if the immunohistochemical analysis did not provide a diagnosis of malignancy. Additional sections can also reveal areas of carcinoma that were not apparent in the original sections.

The Case of the Disappearing Solitary Liver Lesion

Purpose: Purpose: To report an interesting case where a lesion in liver seen on CT disappeared. Methods: 61yo male with past medical history of poorly controlled diabetes, hypertension, Hepatitis C genotype 1 never treated, and prior history of alcohol abuse is followed in GI clinic. During an annual screening in 2009 he had a CT scan which showed an ill-defined lesion in the right lobe of the liver described as an area of decreased attenuation. It was suspicious for heptocellular carcinoma (HCC). The remainder of the liver appeared cirrhotic on the CT scan. He was referred for liver biopsy. The biopsy was referred to the Armed Forces Institute of Pathology (AFIP). The biopsy was read as “large areas of scarring with ductular reaction and foci of atypical glandular proliferation raising the question of adenocarcinoma, however, a definite diagnosis cannot be established…” The patient was sent for EGD, Colonoscopy, PET scan, and consultation to oncology. The PET scan and endoscopies were unremarkable. The Alpha Fetal Protein (AFP) was 5.51 and raised to 7. Oncology was concerned, and referred the patient to general surgery. After a discussion between GI Hepatology and pathology, the patient was referred for repeat liver biopsy. The second biopsy showed “micronodular cirrhosis (stage IV fibrosis) associated with chronic hepatitis and grade 2 necroinflamatory changes and moderate steatosis.” Surgery was deferred, and the patient has followed over 2 years now with no evidence of hepatocellular carcinoma. He has had 2 repeat CT scans, and close clinical follow-up. Additionally an emphasis was made on weight loss and improved glycemic control. He remained asymptomatic. He had good weight loss, and better control of his blood sugar. His AFP remained in the 5-6 range. The 2 subsequent scans showed a decrease, and then complete a disappearance of his liver lesion. He continues to do well. Results: This case demonstrates the workup of an ill-defined liver lesion in the setting of a cirrhotic patient which in this patient was focal accumulation of fat mimicking neoplasm. Our patient had multiple factors contributing to his liver disease: a history of alcohol use, obesity, diabetes, and hepatitis C. While cancer is of concern, steatosis, nodular regeneration, and even focal nodular degeneration must be considered. With noninvasive treatment focusing on weight loss, glycemic control, and close follow-up our patient's liver lesion completely resolved and he continues to do well. Conclusion: Focal accumulation of fat can mimick HCC and with weight loss, better control of diabetes can disappear.

Endometrioid adenocarcinoma of the vagina with a microglandular pattern arising from endometriosis after hysterectomy

Primary endometrioid adenocarcinoma rarely occurs in the vagina. Occasionally, endometrioid adenocarcinoma has a microglandular pattern. Herein, a case of primary endometrioid adenocarcinoma of the vagina with a microglandular pattern arising from pre-existing endometriosis long after a hysterectomy, is described. A 57-year-old postmenopausal woman developed a vaginal discharge over one decade after undergoing a hysterectomy. Microscopic examination of the vaginal smear and a biopsy specimen demonstrated an atypical glandular proliferation composed of columnar cells with occasional intracytoplasmic mucin and bland nuclear morphology, showing microcysts and numerous neutrophils within and around cysts. Immunohistochemically, the neoplastic cells were diffusely positive for CK7, MUC1, ER, and PR, and focally positive for vimentin, CEA, CK5/6, p63, p16(INK4a), and p53. A portion of residual endometrioid adenocarcinoma was identified adjacent to foci of endometriosis in the vaginectomy specimen. The patient has done well without evidence of recurrent disease for 1 year after surgery. Pathologists are encouraged to be aware of the occurrence of endometrioid adenocarcinoma associated with endometriosis in the vaginal stump after hysterectomy, and microglandular morphology which might be a source of misinterpretation.

Adenosquamous gastric carcinoma in Caucasian patient

In a 56-year-old Caucasian woman an ulcerated malignant mass was found at the gastric antrum in a endoscopicalstudy due to chronic anemia. The microscopical study exhibited a malignant tumor composed of two different epithelialcell types (Fig. 1), with an infiltrating growth pattern, and wide necrotic and hemorrhage areas. Nearly 60% of the tumorwas an atypical polygonal cell proliferation with intercellular bridges, keratin, and presence of pearl corns (Fig. 2), whichwas a squamous carcinoma. The rest of the tumor (40%) was an atypical glandular proliferation with back-to-back pheno-menon corresponding to an adenocarcinoma. The mitotic rate was high in both components. The tumor was perforated, sothe patient had a secondary sepsis and died a few days after surgery.Adenosquamous gastric carcinoma represents about 1% of all gastric tumors (1), with most of them occurring in Asianpatients. Only a few cases have been published in our country, and most of them in Asian patients too (2,3); thus, the inte-rest of this case is that it happened in a Caucasian patient. The origin of these tumors is controversial; the squamous com-ponent may develop from previous foci of squamous metaplasia or from the dedifferentiation of primitive cells. Electronicmicroscopical studies done in these types of tumors demonstrate that some individual cells contain both specific ultras-tructural components such as tonofibrils and mucous vacuoles (2,4).The differential diagnosis includes poor differentiated adenocarcinoma, collision tumors, pure squamous gastric carci-noma, mucoepidermoid carcinoma, and metastatic tumors. Finally, adenosquamous gastric carcinoma has a worse prog-nosis and more aggressive behavior

Usefulness of Basal Cell Cocktail (34βE12 + p63) in the Diagnosis of Atypical Prostate Glandular Proliferations

We evaluated the diagnostic usefulness of the 34βE12-p63 cocktail, compared with 34βE12 and p63 used alone, in 34 prostate needle biopsy (NBXs) and 3 transurethral resection specimens containing atypical glandular proliferations and in 18 NBXs containing unequivocal prostate carcinoma (PCa). Staining intensity; percentage of basal cells staining in benign, atypical, and malignant glands; number of benign glands lacking basal cell staining; and staining variance were analyzed. All NBXs with unequivocal PCa were negative with all 3 markers. Diagnoses were as follows for the atypical cases after staining for the 3 markers: PCa, 9; postatrophic hyperplasia, 12; high-grade prostatic intraepithelial neoplasia (HGPIN), 5; atypical adenomatous hyperplasia, 6; benign atypical proliferations, 4; and HGPIN with adjacent small atypical acinar proliferation suggestive of PCa, 1. The cocktail demonstrated consistently strong staining intensity and improved basal cell staining in morphologically benign and benign atypical glands compared with p63 and 34βE12 alone; it had the smallest staining variance compared with 34βE12 (F < 0.0001) and p63 (F = 0.31), although its advantage for resolving individual atypical cases was limited compared with 34βE12 and p63 alone. Of 37 atypical cases, 1 (3%) additionally was resolved as benign using the cocktail and p63. Because the diagnosis of PCa is supported by lack of basal cell staining, the immunohistochemical analysis with highest possible sensitivity and lowest possible variability is critical to ensure that a negative reaction is true. The cocktail provides a simple, cost-effective improvement in basal cell immunohistochemical analysis of difficult prostate lesions.

Usefulness of basal cell cocktail (34betaE12 + p63) in the diagnosis of atypical prostate glandular proliferations.

We evaluated the diagnostic usefulness of the 34betaE12-p63 cocktail, compared with 34betaE12 and p63 used alone, in 34 prostate needle biopsy (NBXs) and 3 transurethral resection specimens containing atypical glandular proliferations and in 18 NBXs containing unequivocal prostate carcinoma (PCa). Staining intensity; percentage of basal cells staining in benign, atypical, and malignant glands; number of benign glands lacking basal cell staining; and staining variance were analyzed. All NBXs with unequivocal PCa were negative with all 3 markers. Diagnoses were as follows for the atypical cases after staining for the 3 markers: PCa, 9; postatrophic hyperplasia, 12; high-grade prostatic intraepithelial neoplasia (HGPIN), 5; atypical adenomatous hyperplasia, 6; benign atypical proliferations, 4; and HGPIN with adjacent small atypical acinar proliferation suggestive of PCa, 1. The cocktail demonstrated consistently strong staining intensity and improved basal cell staining in morphologically benign and benign atypical glands compared with p63 and 34betaE12 alone; it had the smallest staining variance compared with 34betaE12 (F < 0.0001) and p63 (F = 0.31), although its advantage for resolving individual atypical cases was limited compared with 34betaE12 and p63 alone. Of 37 atypical cases, 1 (3%) additionally was resolved as benign using the cocktail and p63. Because the diagnosis of PCa is supported by lack of basal cell staining, the immunohistochemical analysis with highest possible sensitivity and lowest possible variability is critical to ensure that a negative reaction is true. The cocktail provides a simple, cost-effective improvement in basal cell immunohistochemical analysis of difficult prostate lesions.

Proliferating cell nuclear antigen expression in peribiliary glands of stone-containing intrahepatic bile ducts.

All cases of hepatolithiasis showed features of chronic proliferative cholangitis, and it has been speculated that the atypical glandular proliferation might be a precursor to overt cholangiocarcinoma. Proliferative cell nuclear antigen (PCNA) is a nuclear protein synthesized in the G1/S phase of the cell cycle and therefore is related to cell proliferative activity. In an attempt to assess the activity of cell proliferation of stone-containing intrahepatic bile ducts, we conducted a study using immunohistochemical staining with monoclonal antibody to score PCNA in intrahepatic bile ducts. Thirty patients (10 men, 20 women; mean age 52.4 years) having hepatolithiasis surgically resected were studied. Ten stone-free patients served as controls. All 40 specimens were immunostained for PCNA using PC 10 monoclonal antibody. PCNA of both stone-containing and stone-free intrahepatic bile ducts were assessed by counting positive staining nuclei per 500 cells and expressed as labeling index (LI), ie, percentage of positive nuclei to the total number of nuclei. The PCNA LI in stone-free intrahepatic bile ducts was generally low: 10.0+/-13.2%, 10.4+/-10.7% and 7.9+/-9.6% for extramural glands, intramural glands, and epithelial lining, respectively. In contrast, the PCNA LI for stone-containing intrahepatic bile ducts were significantly higher than those of controls (P < 0.001): 49.4+/-8.3%, 40.6+/-7.0% and 34.1+/-6.8% for extramural glands, intramural glands, and epithelial lining, respectively. The extramural glands had a significantly higher PCNA LI (P < 0.001) than the intramural glands and controls. Hyperplasia was found in all specimens, while dysplasia was found in six of 30 cases with hepatolithiasis. The dysplastic cells also had a higher PCNA LI (P < 0.001) than the hyperplastic cells and normal epithelium. Our findings showed that there is marked increase of activity of cell proliferation in stone-containing intrahepatic bile ducts. It is well known that genetic mutations are facilitated in proliferating cells. Therefore, our results suggest that the high epithelial turnover in dysplastic cells and extramural glands had higher potential for proliferation and neoplastic transformation in long-standing untreated hepatolithiasis.

Nucleolar and AgNOR-analysis of Prostatic Intraepithelial Neoplasia (PIN), Atypical Adenomatous Hyperplasia (AAH) and Prostatic Carcinoma

Atypical glandular proliferations of the prostate are found in combination with prostate carcinomas but also with benign prostatic hyperplasia (BPH). These atypical glandular lesions that mimic glandular carcinoma within the anterocentral part of the prostate (transition zone) are named "atypical adenomatous hyperplasia (AAH)." The term for atypical ductal and acinar mainly papillary and/or cribriform proliferations in the peripheral zone is "prostatic intraepithelial neoplasia (PIN)." In this study the significance of the status of nucleoli and the number of silver-stained nucleolar organizing regions (AgNOR) as a method for measuring proliferative activity was investigated in biopsies of AAH, PIN and carcinomas of different grades of malignancy. The aim was to prove whether there are relationships of AAH to low grade carcinomas on the one hand and of PIN to high grade carcinomas on the other hand. The frequency of nuclei with small nucleoli was low in BPH (0.6%). The values increased to 8.3% in AAH, and 28.7% in PIN. The frequency of nuclei with prominent nucleoli in low grade carcinomas was 41.7% and in high grade carcinomas 81.1%. Usually, one single nucleolus was found per nucleus. Multiple prominent nucleoli were found in high grade carcinomas and in some cases of high grade PIN only. The result of AgNOR-analysis was similar: low numbers in BPH, low to moderate values in AAH, moderate values in low grade carcinomas and high values in PIN, as well as high grade carcinomas. Besides correlation between topography, histology and cytology, the similarities of nucleolar and AgNOR-analysis between PIN and high grade carcinomas support the idea that PIN is the precursor of the peripheral prostatic carcinoma. The histological, cytological and cell kinetical features of AAH are intermediate between BPH and low grade carcinoma of the prostate. Therefore, the findings to date are inconclusive and further follow up studies are necessary to prove if AAH may be a precursor of transition zone carcinoma of the prostate.

Is microglandular adenosis a precancerous disease? A study of carcinoma arising therein.

Microglandular adenosis (MGA) is a recently described and little appreciated proliferative glandular lesion of the breast that may mimic carcinoma both clinically and histologically. Several recent publications indicate that this lesion, while capable of recurrence if incompletely excised, is itself benign. In an earlier report from this institution we suggested that MGA might serve as the substrate for the development of mammary carcinoma. This report presents the pathologic findings in seven patients who developed carcinoma of the breast in association with MGA. The patients, aged 39-72, presented with firm masses that raised the clinical suspicion of carcinoma. The lesions reported here are linked not only by the presence of benign MGA associated with mammary carcinoma, but by a spectrum of atypical glandular proliferations ("atypical" MGA) that suggest transitions from MGA to infiltrating carcinoma. These carcinomas shared unusual histologic features which strengthen our impression that they are derived from MGA. On the basis of the experience presented in this study, it appears that MGA may on occasion serve as the substrate for the development of mammary carcinoma. For patients with uncomplicated MGA, complete excision of the lesion with clinical follow-up is recommended. When atypical hyperplasia is present in MGA, the lesion should be widely excised and the same caution exercised in following the patient as with other atypical hyperplasias. The treatment of carcinoma arising in MGA will depend on the stage of the disease. Presently we do not know whether these carcinomas have unusual clinical or biological characteristics.

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The effects of gastrin on the histopathology of the glandular stomach and on the incidence of gastric carcinoma induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in inbred Wistar (W) rats. Prolonged administration of gastrin after treatment with MNNG significantly reduced the incidence of adenocarcinomas of the glandular stomach. In addition, atypical glandular proliferations were significantly less frequent and were smaller, and the incidence of marked mucosal atrophy was significantly reduced in both the antral and oxyntic gland mucosae. Both atypical glandular hyperplasia and mucosal atrophy are precursors of gastric cancers; prolonged administration of gastrin to rats after treatment with MNNG suppressed development of precursors of gastric cancer and so prevented development of gastric cancers.

Histology of the prostate in elderly men. A study in an autopsy series.

As part of a comprehensive study of the testes, the pituitary gland and the adrenal glands in relation to abnormal growth of the prostate, the occurrence of benign nodular hyperplasia (BNH), carcinoma (C), diffuse atrophy (DA) and normal histology (N) of the prostate was studied in a consecutive series of 206 men over 40 years of age submitted to necropsy. Atypical glands without obvious invasive properties were recorded separately and termed atypical glandular proliferation (AGP). The occurrence of BNH and C were both strongly related to age. BNH was the most frequent histological pattern encountered (80.1 per cent), and after the age of 70 years, BNH was observed in practically all cases. C was observed in 70 patients (34 per cent) and was an incidental finding at autopsy in all but four cases. After the age of 80 years, 52 per cent carried C. The great majority of carcinomas were small and were located predominantly in the peripheral zone of the prostate. The frequency of C in patients previously operated upon for BNH was similar to that in non‐operated patients. The frequency of BNH in prostates with C was not different from that to be expected as a purely coincidental occurrence. The location of AGP resembled that observed for C. However, the simultaneous occurrence of AGP and BNH was more frequent than that to be expected as pure coincidence. Whether AGP represents benign or potentially malignant lesions remains obscure. The classification of AGP as a benign lesion or carcinoma may markedly influence the prevalence ratios of latent prostatic carcinoma in autopsy series. In patients dying from cardiovascular disease, BNH occurred more frequently, and C less frequently, than what would be expected.