Precursors to pulmonary neoplasia

Squamous dysplasia in the bronchi has been long recognized as a precursor of lung carcinoma, particularly squamous carcinoma. Atypical adenomatous hyperplasia (AAH) has been recently implicated as a precursor to adenocarcinoma. Bronchiolar neuroendocrine cell hyperplasia has also been suggested as a precursor to some pulmonary carcinoid tumors. The atypical adenomatous hyperplasia-adenocarcinoma sequence has been likened to the adenoma-carcinoma sequence in the large intestine. AAH is commonly multifocal, and may explain multicentricity that is observed with some adenocarcinomas. AAH has been shown to have immunohistochemical, morphometric, flow cytometric and genetic abnormalities overlapping with adenocarcinoma. Bronchiolar neuroendocrine cell hyperplasia (carcinoid tumorlets) is classically associated with inflammatory lesions in the airways, but may also be multifocal and bilateral. In the latter setting, lesions may attain a size greater than 0.5 cm and be (arbitrarily) classified as carcinoid tumors.     

Desmoplastic response in biopsy specimens of early colorectal carcinoma is predictive of deep submucosal invasion

PURPOSE: The aim of this study was to evaluate the role of histopathology of biopsy specimens in predicting depth of infiltration in early colorectal carcinomas before treatment. METHODS: Early colorectal carcinomas that had been resected surgically or endoscopically between 1984 and 1995 were analyzed. Histopathologic findings, including differentiation of adenocarcinoma and a desmoplastic response were investigated. RESULTS: One hundred nine early colorectal carcinomas consisted of 73 lesions of carcinoma in situ, 13 submucosal carcinomas with minimum invasion, 8 lesions with moderate invasion, and 15 lesions with deep invasion. Of 73 carcinoma in situ lesions, 72 (approximately 99 percent) showed well-differentiated adenocarcinomas and no desmoplastic response. Twelve (92 percent) of 13 submucosal carcinomas with minimum invasion also revealed well-differentiated adenocarcinoma without a desmoplastic response. Sixty-three percent (5/8) of lesions with moderate invasion revealed well-differentiated adenocarcinoma. None of the lesions had a desmoplastic response. Among lesions with deep invasion, 73 percent (11/15) demonstrated moderately differentiated adenocarcinoma, and 11 lesions had a prominent desmoplastic response (73 percent; P < 0.01). CONCLUSIONS: These results suggest that if histopathologic findings of biopsy specimens taken from them before treatment demonstrated adenocarcinoma associated with a desmoplastic response, the lesions had at least deep invasion carcinomas. These lesions should be resected surgically. Submucosal carcinomas with minimum invasion, which have no desmoplastic response, could be treated endoscopically.     

Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression

Pancreatic adenocarcinoma develops from histologically identifiable intraductal lesions that undergo a series of architectural, cytological, and genetic changes. Limited genetic evidence recently suggested that the p16 gene plays a role in the progression of these "duct lesions." Duct lesions were identified in pancreata from 33 pancreaticoduodenectomies performed for infiltrating adenocarcinoma. All of these infiltrating adenocarcinomas were previously shown to contain alterations in the p16 gene or its promoter. Monoclonal and polyclonal anti-p16 antibodies were used for histological immunodetection. One hundred twenty-six duct lesions were identified. Nine (30%) of 30 flat, 4 (27%) of 15 papillary, 37 (55%) of 67 papillary with atypia, and 10 (71%) of 14 carcinoma in situ duct lesions showed loss of p16 expression. These included 30% of the flat lesions versus 53% of the nonflat lesions and 29% of the nonatypical lesions versus 58% of the atypical lesions. For both comparisons, the differences were statistically significant (P = 0.036 and P = 0.003, respectively). Loss of p16 expression occurs more frequently, but not exclusively, in higher-grade duct lesions. These data support the hypothesis that pancreatic duct lesions are neoplastic and that they represent the precursors of infiltrating adenocarcinoma. Immunohistochemical detection of p16 provides a new technology to study the genetic alterations in and stages of progression of large numbers of morphologically defined pancreatic duct lesions.     

Fluorine-18-FDG PET imaging is negative in bronchioloalveolar lung carcinoma

The goals of our study were to establish PET accuracy with 18F-fluorodeoxyglucose (FDG) in finding localized formations of bronchioloalveolar lung carcinoma (BAC) and to investigate the correlation between FDG uptake and the degree of cell differentiation in adenocarcinoma of the lung. MATERIALS: Twenty-nine patients with 30 adenocarcinomas of the lung (7 bronchioloalveolar lung carcinomas, 9 well differentiated, 2 well-moderately differentiated, 11 moderately differentiated and 1 poorly differentiated) were studied. All patients underwent thoracotomies within 4 wk after the FDG PET study. For qualitative analysis, the degree of FDG activity in the tumors was visually scored using a five-point grading system: 0 = same to background activity, 1 = less than mediastinal blood-pool activity, 2 = same to mediastinal blood-pool activity, 3 = slightly greater than mediastinal blood-pool activity and 4 = substantially greater than mediastinal blood-pool activity. Foci of activity with Grades 2-4 were considered tumors. For semiquantitative analysis, standardized uptake values (SUV) were calculated. RESULTS: In 7 BACs, 4 lesions (57%) showed negative results on FDG PET, while in 23 non-BACs, only 1 lesion (4%), which was a well-differentiated adenocarcinoma showed a negative result. BACs' mean visual score (1.43 +/- 1.27) was significantly lower than that of non-BACs (3.17 +/- 1.03) (p = 0.001). The BACs' mean SUV (1.36 +/- 0.821) was significantly lower than that of well-differentiated adenocarcinomas (2.92 +/- 1.28) (p = 0.014); the mean SUV of well-differentiated adenocarcinomas was significantly lower than that of moderately differentiated adenocarcinomas (4.63 +/- 1.86) (p = 0.031). No significant differences were apparent in average size among these three histologic types. CONCLUSION: A correlation was observed between FDG uptake and the degree of cell differentiation in adenocarcinoma of the lung. FDG PET may show negative results for BAC.     

Differential expression of CD44v6 in adenocarcinoma of the pancreas: an immunohistochemical study

Alternative splicing gives rise to numerous CD44 isoforms, some of which seem to have a role in tumour metastasis. Specifically, a variant form of CD44 with sequences encoded by exon v6 (CD44v6) confers metastatic potential when transfected into a nonmetastasizing cell line of rat pancreatic adenocarcinoma. This study has investigated standard CD44 (CD44s) and CD44v6 expression immunohistochemically in 6 samples of normal pancreatic tissue, 4 of tissue affected by chronic pancreatitis, and 24 of tissue from metastasizing and nonmetastasizing pancreatic adenocarcinomas. In addition, 18 samples from lymph node or visceral metastases were included in the study. CD44s was expressed in nonneoplastic tissue and in tissue from pancreatic adenocarcinomas. In contrast, CD44v6 was not detected in any of the normal tissue or chronic pancreatitis specimens, whereas 54% of pancreatic adenocarcinomas and 55% of metastases expressed this variant exon. Although it is not clear whether CD44 isoforms containing exon v6 play a part in malignant progression in the human exocrine pancreas, it seems plausible that the expression of multiple isoforms containing this and other variant exon confers a selective advantage on pancreatic adenocarcinoma.     

Tooth autotransplantation into the bone-grafted alveolar cleft: report of two cases with histologic findings

Because of histological similarities between nephrogenic adenomas and clear cell adenocarcinomas of the urinary tract, there is the potential for diagnostic confusion between these two entities. The histopathologic features of 13 nephrogenic adenomas and five clear cell adenocarcinomas of the urethra and urinary bladder are compared in this report, and detailed immunohistochemical staining profiles are provided for these tumors. Only 2 of the 13 nephrogenic adenomas contained clear cells, and these constituted less than 10% of the lesions. In contrast, four of the five clear cell adenocarcinomas contained prominent areas with clear cells. Nephrogenic adenomas generally showed only mild cytologic atypia, whereas four of the five clear cell adenocarcinomas showed severe atypia. A single mitotic figure was identified in only two of the nephrogenic adenomas, whereas the mitotic rate in the clear cell adenocarcinomas ranged from 2 to 14 per 10 high-power fields. None of the nephrogenic adenomas showed evidence of necrosis, but focal necrosis was noted in four of the five clear cell adenocarcinomas. In general, the nephrogenic adenomas and clear cell adenocarcinomas showed negative to weak staining with CK903 but strong staining with AE1, AE3, and Cam 5.2. Variable staining was observed with Brst-3 and antibodies to S-100, CEA (monoclonal and polyclonal), LeuM-1, and CA19.9. Nephrogenic adenomas and clear cell adenocarcinomas were all negative for prostate-specific acid phosphatase (PSAP), prostate-specific antigen (PSA), and estrogen and progesterone receptors (except for two nephrogenic adenomas, which showed only focal weak staining for estrogen receptor). Neither bcl-2 nor c-erbB-2 staining was able to discriminate between the tumors. However, strong staining for p53 was noted in each clear cell adenocarcinoma and in none of the nephrogenic adenomas. MIB-1 positivity in nephrogenic adenomas ranged from 0 to 13 (average of 5.5) per 200 cells, whereas the positive range for clear cell adenocarcinomas was 33 to 70 (average of 47) per 200 cells. In summary, histopathologic features that favor clear cell adenocarcinoma over nephrogenic adenoma include a predominance of clear cells, severe cytological atypia, high mitotic rate, necrosis, high MIB-1 positivity, and strong staining for p53.     

Primary nonampullary/periampullary adenocarcinoma of the duodenum

Primary duodenal adenocarcinoma not involving the ampullary region is rare. Our aim was to review the outcome of these patients and determine the factors that affect survival. We performed a retrospective review of all patients with primary, nonampullary duodenal adenocarcinoma at the Cleveland Clinic Foundation from January 1986 through December 1996. Twenty-six patients with primary, nonampullary duodenal malignancies were identified. There were 16 adenocarcinomas, 3 gastrinomas, 3 stromal tumors, 3 leiomyosarcomas, and 1 carcinoid tumor. Patients with adenocarcinoma had symptoms present an average of 6.1 months. Tumors were identified by upper gastrointestinal contrast study and esophagogastroduodenoscopy in 90 per cent and 87 per cent of patients, respectively. Twelve of 13 (93%) cancers found in the third or fourth portion of the duodenum were adenocarcinomas. Seven of the 16 adenocarcinomas were resectable on exploration. Those that were contained within the serosa have not recurred (mean, 6 years); one of the two patients with locally invasive adenocarcinoma remains disease free. The average survival for patients with unresectable disease was 6.7 months. The 5-year survival rates were: all adenocarcinoma, 38 per cent; resectable, 86 per cent; and unresectable, 0 per cent. All patients presenting with weight loss or obstructive symptoms died of disease; those with melena survived long term. Patients with tumors other than adenocarcinoma had a 90 per cent 5-year survival. We conclude that patients typically present with a long history of symptoms. Distal duodenal malignancies are most frequently adenocarcinomas. Upper gastrointestinal contrast study or endoscopy is often diagnostic. Patients with weight loss and/or obstructive symptoms had invasive disease and a morbid prognosis. Aggressive surgery is warranted, and most with resectable disease (86%) had long-term survival.     

Cytochrome P4502E1 is present in rat pancreas and is induced by chronic ethanol administration

OBJECTIVE: To determine if the monoclonal antibody 7E12H12, which reacts with a 40 kDa protein in normal human enterocytes and has been shown to be a marker for intestinal metaplasia and adenocarcinoma arising in the bladder, could assist in distinguishing prostatic, urachal and vesical adenocarcinoma, using a sensitive immunohistochemical assay. MATERIALS AND METHODS: Fifteen primary prostatic adenocarcinomas and five adenocarcinomas of the urinary bladder were selected for a retrospective evaluation. The monoclonal antibody 7E12H12 (IgM isotype) was used in an immunoperoxidase assay to survey formalin-fixed, paraffin-embedded archival tissue specimens. RESULTS: All vesical adenocarcinomas reacted positively with the antibody, regardless of grade; none of the 15 prostatic specimens reacted positively in either the benign or malignant glandular epithelium. CONCLUSION: The monoclonal antibody 7E12H12 can differentiate primary adenocarcinoma of the bladder from secondary adenocarcinoma arising in the prostate and may be a useful tool in diagnostic pathology.     

Primary neoplasms of the duodenum

The records of 12 patients with primary malignant neoplasms of the duodenum, excluding ampullary lesions, have been studied. There were eight adenocarcinomas and four leiomyosarcomas. The second portion of the duodenum was the most common site for these neoplasms. Common symptoms were epigastric pain; obstructive symptoms, such as nausea and vomiting; obstructive jaundice, and hematemesis. Hematemesis is the most common symptom in leiomyosarcoma of the duodenum. The mean duration of symptoms was six months for leiomyosarcoma and 3.2 months for adenocarcinoma. In five patients, excision of the tumor was carried out more frequently for those in the distal portion of the duodenum. More radical procedures, such as pancreaticoduodenectomy, are the treatment of choice in neoplasms of the second portion of the duodenum. A bypass procedure is done for palliation of intestinal obstruction. Three patients with leiomyosarcomas that were resected had a mean survival time of 51 months. On the other hand, patients with adenocarcinomas that were resected had a mean survival time of nine months, while patients with unresectable tumors had a mean survival time of 2.3 months.     

Bilateral renal carcinoma in von Hippel-Lindau Disease

Von Hippel-Lindau disease, one of the phakomatoses, is believed to be a disorder of mesodermal differentiation. Renal lesions, usually cysts or adenocarcinomas with an occasional hemangioblastoma, occur in approximately two thirds of all patients. The renal neoplasms previously reported have been multiple, bilateral, and usually beyond resection. A thirty-eight-year-old white male with a cerebellar hemangioblastoma and bilateral renal adenocarcinoma underwent suboccipital craniotomy, right heminephrectomy, and left radical nephrectomy. No evidence of recurrent disease can be identified ten months postoperatively. An aggressive approach in this systemic disease appears to be warranted.     

Anti-MOC-31: a potential addition to the pulmonary adenocarcinoma versus mesothelioma immunohistochemistry panel

MOC-31 expression has recently been advocated as an immunohistochemical marker for distinguishing mesothelioma from adenocarcinoma in tissue sections. We studied formalin-fixed, paraffin-embedded tissue from 23 pleural mesotheliomas and 23 primary pulmonary adenocarcinomas for immunoreactivity with anti-MOC-31, a human epithelial-related antigen. All of the 23 adenocarcinomas strongly expressed the marker, whereas only one of the mesotheliomas showed weak reactivity. These results demonstrate the usefulness of anti-MOC-31 in differentiating pulmonary adenocarcinoma from mesothelioma.     

The presence of K-12 ras mutations in duodenal adenocarcinomas and the absence of ras mutations in other small bowel adenocarcinomas and carcinoid tumors

BACKGROUND: Adenocarcinomas and carcinoid tumors are the most common malignant tumors of the small intestine. K-ras oncogene mutations at codon 12 are common in gastric, pancreatic, and colon carcinomas, with an incidence of 35-88%. K-ras mutations have not been extensively studied in either adenocarcinomas or carcinoid tumors of the small bowel. The purpose of this study was to determine whether ras mutations play an important role in the formation of these tumors. METHODS: Archival tissues from 28 adenocarcinomas and 22 carcinoid tumors of the small bowel were studied, along with archival tissues from 32 adenocarcinomas of the large bowel, which were used as controls. DNA from the small intestine tumors was analyzed for K-ras, H-ras, and N-ras oncogene mutations at codons 12, 13, and 61, using polymerase chain reaction and sequence specific oligonucleotide hybridization techniques. Large bowel adenocarcinomas were analyzed for K-ras mutations at codons 12 and 13. RESULTS: A point mutation of K-ras at codon 12 was detected in 4 of 28 (14.3%) of the small bowel adenocarcinomas, in 12 of 32 (37.5%) of the large bowel adenocarcinomas, and in 0 of 22 small intestine carcinoid tumors. No other K-ras, H-ras, or N-ras mutations were detected in any of the small bowel tumors. Each small intestine K-ras mutation was found in a duodenal adenocarcinoma (4 of 12 cases, 33%), whereas none occurred in 16 other jejunal or ileal adenocarcinomas. CONCLUSIONS: K-ras mutations appear to play a significant role in the pathogenesis of duodenal adenocarcinomas, but they do not appear to be important in the development of jejunal or ileal adenocarcinomas or of carcinoid tumors of the small intestine.     

Computed tomography analysis of resected small adenocarcinomas of the lung less than 15 mm in diameter--correlation of radiologic and histologic characteristics

To analyze the radiographic characteristics of small adenocarcinomas of the lung that can be detected by computed tomography (CT), 46 resected small peripheral adenocarcinomas measuring less than 15 mm in diameter were retrospectively reviewed, and the marginal and internal findings and surrounding vessels of the tumors as shown on thin-section CT images were correlated with six histologic classifications (types A-F) as defined by Noguchi et al. The adenocarcinoma CT images were classified into two patterns: a solid-density type (n = 21) and an air-containing type (n = 25). The lesions of the air-containing type were further divided into two different growth patterns: a complete air-containing type (n = 12) and an incomplete air-containing type (n = 13). The solid-density adenocarcinomas shown in the CT images fell mainly into the C, D, F and Noguchi classifications. Although one sample in the complete air-containing category was type C, the rest were type A. The incomplete air-containing category included 4 type As and 9 type Bs. The CT findings for the 24 adenocarcinomas in the air-containing category (96%) showed an opaque ground-glass internal texture. Plural vascular involvement was observed in all 46 adenocarcinomas examined. Our results suggest that thin-section CT findings can play an important role in differentiating lung cancer and increasing our knowledge of the radiologic and pathologic correlations.     

Carcinoma of the stomach with hepatocyte differentiation (hepatoid adenocarcinoma)

A case of hepatoid adenocarcinoma of the stomach is reported, and the literature is reviewed. The stomach is one of the most common sites in which hepatoid adenocarcinomas have been detected. Of the 59 cases reviewed from the literature (including the current case), a 2:1 male predominance was noted, and the serum alpha-fetoprotein level was almost always increased. All patients were adults, and most had evidence of metastases at the time of resection. Prognosis seems less favorable than that associated with the more common intestinal type of adenocarcinoma of the stomach. Hepatoid adenocarcinomas typically show periodic acid-Schiff-positive, diastase-resistant intracytoplasmic globules, which are demonstrated to be positive with antibodies to alpha-fetoprotein. The tumor cells resemble liver cells, and rare cases, including our own, have evidence of bile production. In our case, messenger RNA for albumin, unique to liver cells, was demonstrated by in situ hybridization of the tumor cells.     

p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas

Loss of heterozygosity (LOH) of 9p21, which contains the p16INK4a tumor suppressor gene locus, is one of the most frequent genetic abnormalities in human neoplasia, including esophageal adenocarcinomas. Only a minority of Barrett's adenocarcinomas with 9p21 LOH have a somatic mutation in the remaining p16 allele, and none have been found to have homozygous deletions. To determine whether p16 promoter hypermethylation may be an alternative mechanism for p16 inactivation in esophageal adenocarcinomas, we examined the methylation status of the p16 promoter in flow-sorted aneuploid cell populations from 21 patients with premalignant Barrett's epithelium or esophageal adenocarcinoma. Using bisulfite modification, primer-extension preamplification, and methylation-specific PCR, we demonstrate that the methylation assay can be performed on 2 ng of DNA (approximately 275 cells). Eight of 21 patients (38%) had p16 promoter hypermethylation and 9p21 LOH, including 3 patients who had only premalignant Barrett's epithelium. Our data suggest that promoter hypermethylation with LOH is a common mechanism for inactivation of p16 in the pathogenesis of esophageal adenocarcinomas.     

The value of antibodies 44-3A6, SM3, HBME-1, and thrombomodulin in differentiating epithelial pleural mesothelioma from lung adenocarcinoma: a comparative study with other commonly used antibodies

The distinction between pleural mesothelioma and peripheral pulmonary adenocarcinoma involving the pleura continues to be a diagnostic problem in surgical pathology. In recent years, the use of various immunohistochemical markers to facilitate this differential diagnosis has become common. In this study, the value of monoclonal antibodies 44-3A6, SM3, HBME-1, and thrombomodulin is compared in the differentiation of these conditions. Fifteen (68.2%) of 22, and 10 (52.6%) of 19 mesotheliomas stained positively with 44-3A6 and SM3, respectively, whereas all 23 (100%) adenocarcinomas reacted with both antibodies. Sixteen (80%) of 20 mesotheliomas and 14 (63.6%) of 22 lung adenocarcinomas reacted with HBME-1, whereas 16 (80%) of 20 mesotheliomas and only three (11.1%) of 27 adenocarcinomas were positive for thrombomodulin. Because thrombomodulin was expressed in most mesotheliomas but in only a few lung adenocarcinomas, this marker may have some diagnostic value when it is included in the standard immunohistochemical panel of markers used in the evaluation of mesotheliomas, especially when a positive marker for mesothelioma is needed. Antibodies 44-3A6, SM3, and HBME-1 have no practical value in discriminating epithelial pleural mesothelioma from lung adenocarcinoma.     

The jet-wash-technique (author's transl)

For the early detection of the endometrial adenocarcinoma the Gravlee-Jet-wash-technique was used in 600 cases. The procedure is simple and requires only 2 to 3 minutes to the gynecologist. An anesthesia is not necessary. In women with stenosed os externum and in anxious patients we use an analgesia of the paracervix (PCB). The technique allows a cytologic and/or cytohistologic investigation. In 600 examined cases we found 37 endometrial adenocarcinomas. We obtained a 100 per cent accuracy in the detection of the 37 malignant lesions. Our experience up to now with the Jet-wash-technique should stimulate its wider use also for outpatients with a high risk for the endometrial adenocarcinoma.     

Primary adenocarcinoma of the renal pelvis with special reference to histochemical observations

A case of adenocarcinoma of the renal pelvis is presented. The patient was an 84-year-old man suffering from long-standing right-sided nephrolithiasis. Surgical resection of the right kidney revealed adenocarcinoma with slight stromal invasion. A tubulovillous adenoma, which was morphologically similar to an adenoma of the large intestine, was also found adjacent to the adenocarcinoma. The pelvic epithelium neighboring the lesion revealed intestinal metaplasia. Histochemical studies revealed that the tumor in the patient and adenocarcinomas or adenomas of the large intestine have similar properties of cytoplasmic mucin. These findings suggest that the epithelium with intestinal metaplasia may have developed into the adenoma and finally transformed into the adenocarcinoma. In addition, only tumor cells with severe atypia, most of which morphologically corresponded to adenocarcinoma, demonstrated positive nuclear staining for anti-p53. This suggests that p53 may play an important role in the malignant transformation of adenomas into adenocarcinomas, as is the case in the large intestine.     

Luno-triquetral angle and dislocation of the wrist

BACKGROUND: In the United States, pulmonary adenocarcinomas have recently replaced squamous cell carcinomas as the most frequent type of lung cancer encountered. The incidence of pulmonary adenocarcinoma continued to increase worldwide. METHOD: To determine the roles of the transforming growth factor-beta 1 (TGF-beta 1), and TGF-beta type I receptor (T beta R-I), and the TGF-beta type II receptor (T beta R-II) in the progression of a pulmonary adenocarcinoma, their respective expressions have been immunohistologically studied in specimens from 120 pulmonary adenocarcinoma patients. RESULT: The overall prognosis was significantly poorer for patients showing positive TGF-beta 1, T beta R-I, T beta R-II expressions than for patients who were negative to all three immunostainings (P < 0.01). Our multivariate analysis also revealed that a positive TGF-beta 1 response significantly affect prognosis (P < 0.05). CONCLUSIONS: TGF-beta 1, T beta R-I, and T beta R-II play important roles in tumor progression, and a positive TGF-beta 1 expression can serve as a pulmonary adenocarcinoma marker. T beta R-I and T beta R-II expressions are necessary for TGF-beta signal transduction.