Non-metastatic Cases Research Articles

Retinoblastoma: from bench to bedside.

Retinoblastoma (Rb) is the most common primary ocular malignancy of children and is caused by a mutation in the gene RB1. Approximately 40% of cases are associated with one or more constitutional mutations, and are therefore heritable, whereas the other 60% are sporadic. Rb is exclusively found in young children. In some cases, Rb tumours metastasise to extraocular organs including bone, lung and brain. Although there is no effective treatment for metastatic disease, non-metastatic cases can be cured by removal of the eye(enucleation). Newer treatment strategies emphasise salvaging the affected eye whenever possible. Animal models of Rb have been developed with xenograft and transgenic techniques. Each model has both strengths and weaknesses for exploring the mechanisms of disease development and progression and the efficacy of new treatment strategies.

Oral squamous cell carcinoma: electron microscopic and immunohistochemical characteristics.

Oral squamous cell carcinoma is the most common oral malignancy, and we performed electron microscopic and immunohistochemical investigation of the tumor. In patients with cervical metastasis, microvilli were developed and a small number of desmosomes were found, regardless of the width of the intercellular spaces. In patients without the metastasis, few microvilli were found in relatively wide intercellular spaces, or numerous microvilli were found in narrow intercellular spaces, and a large number of desmosomes were shown. However, these findings were different from those of tumors that had received radiotherapy, in which numerous microvilli and a small number of desmosomes were found in the nonmetastatic cases. Transferrin receptor, which is a marker of cell proliferation, was localized on the cell membrane, especially in microvilli. Ultrastructural similarity between the primary tumor and the metastatic tumor was recognized, however, the features of microvilli, desmosomes, and the intercellular spaces differed between them in most cases. It is suggested that microvilli might be related to the metastasis of oral squamous cell carcinoma cells. Immunohistochemically, the protein expression of p53 and pRb2/p130 was related to the clinical course of the patients with oral squamous cell carcinoma; the mechanism of the synthesis of these proteins should be investigated in order to understand the biological behavior of the tumor.

Expression of CD44v3 splice variant is associated with the visceral metastatic phenotype of human melanoma.

We analyzed the immunohistochemical expression of the metastasis-associated protein, CD44v3, in 46 primary human malignant melanomas (MMs). This is the first time that the v3 splice variant of CD44 was found to be expressed in human melanomas (15 of 46), ranging from 3% to 35% of the cell population in the positive tumors. The expression of CD44v3 was observed in tumors thicker than 1.0 mm, and one-third of these tumors proved to be positive irrespective of the thickness. Patients were followed for a minimum of 61 months. The onset of lymph node or organ metastases occurred not later than 58 months and 60 months, respectively. Of the 15 CD44v3 positive tumors, 14 were observed in the organ metastatic tumor group, comprising the majority of those cases (14 of 21), and this association proved to be statistically significant compared with the non-metastatic (P<0.05) and lymph-node metastatic cases (P<0.01). CD44v3 expression in melanoma was also confirmed at the protein and messenger (mRNA) level in several human melanoma cell lines using flow cytometry and reverse transcriptase polymerase chain reaction analysis. In parallel to CD44v3, MMP-2 expression (determined using immunohistochemistry) was significantly elevated (P<0.05) but only in the organ metastatic group of MM. The 5-year survival of patients having thicker tumors than 1.0 mm (where v3 expression occurred) who had CD44v3+ tumors was significantly lower than those of the negative ones (35.7% versus 68.2%, respectively; P=0.025). Finally, we observed that the CD44v3-expressing tumors were characterized by significantly higher MMP-2 expression than the CD44v3-negative tumors (P<0.001), indicating a possible correlation between CD44v3- and MMP-2-positive phenotype and the organ metastatic potential of MM.

Microvilli and desmosomes of squamous cell carcinoma cells in tongue carcinoma related to regional lymph node metastasis: ultrastructural and immunohistochemical studies with transferrin receptor.

Squamous cell carcinomas of the tongue (n = 49), consisting of 21 cases with cervical lymph node metastasis and 28 nonmetastatic cases, were examined by electron microscopy with special emphasis on tumor cell attachment. No difference of tumor size (T classification) or pathological findings between the metastatic group and the nonmetastatic group was found. The metastatic cases had numerous microvilli and a small number of desmosomes regardless of the width of the intercellular spaces. The nonmetastatic cases had few microvilli in relatively wide intercellular spaces, or, in the cases in which numerous microvilli were present in the narrow intercellular spaces, the tumor cells were connected by a large number of desmosomes. Transferrin receptor, which is a marker of cell proliferation, was localized in the cell membrane by immunohistochemistry and especially in microvilli by immunoelectron microscopy. It is suggested that microvilli might be related to the proliferation and the metastasis of squamous cell carcinoma cells.

The spectrum of neuroendocrine differentiation among gastrointestinal carcinoids: importance of histologic grading, MIB-1, p53, and bcl-2 immunoreactivity.

The advent of panneuroendocrine markers has helped to better depict the heterogeneity of gastrointestinal carcinoids. Consequently, it has been proposed that these tumors constitute a histologic spectrum that includes well-, moderately, and poorly differentiated carcinoids. However, the reproducibility of this grading system and its prognostic importance have sometimes been called into question. To investigate the potential utility of cell proliferation and oncoprotein markers in augmenting the histologic classification. Retrospective study; tertiary care teaching hospital. Fifty-eight patients with 41 well-differentiated, 12 moderately differentiated and 5 poorly differentiated carcinoids from various topographic sites of the gastrointestinal tract were selected and immunostained for panneuroendocrine markers, MIB-1, p53, and bcl-2. Degree of association between histologic grading, MIB-1, p53, and bcl-2 immunoreactivity and carcinoid metastatic behavior. The group comprised 30 males and 28 females whose mean age was 52.7 years (range, 14-81). Mean follow-up time was 85.8 months. All 58 patients tested positive for chromogranin A and/or synaptophysin. The group was divided into nonmetastatic (42/58, or 72.4%) and metastatic (16/58, or 27.6%) cases. Histologic grading tended to be associated with metastatic spread, but this occurrence of metastases did not attain statistical significance (P =.08). Positivity for MIB-1 (P =.004) and p53 (P =.04) was significantly associated with metastatic behavior, whereas bcl-2 was not (P = 0. 63). Although an organoid pattern and neuroendocrine immunophenotype help to define the spectrum of gastrotestinal carcinoids, this study suggests that the histologic grading of these tumors has some limitations with respect to predicting metastatic behavior. However, MIB-1 and p53 can compliment histologic grading as prognostic indicators in this regard while bcl-2 appears to be less useful.

The roles of chemotherapy and surgery in gastric carcinoma and the influence of prognostic factors on survival.

In this study, we present the results of surgery and chemotherapy and the impact of various prognostic factors on survival in patients with gastric carcinoma with a follow-up of 6 years. All of the 328 cases were adenocarcinoma histologically and had a median age of 55 years. Median survival was 11 months, and the 5-year survival rate was 18%. Nonmetastatic cases were associated with improved survival as compared with the cases with metastatic disease (p<0.001). Patients with gastrectomy had improved survival (p<0.001). Subtotal gastrectomized patients had better survival rates in comparison to the total gastrectomized patients (p = 0.03). Addition of splenectomy to total gastrectomy and adjuvant chemotherapy did not influence survival rates (p>0.05). In metastatic patients, we determined beneficial effects of gastrectomy and chemotherapy on survival. The benefit was most predominant in chemoresponsive patients (p<0.001). Higher serum CA 19.9 levels in patients without metastases, higher serum lactate dehydrogenase and carcinoembryonic antigen levels in patients with metastases, and lower serum albumin levels in both stages were determined as significant predictors of poor survival. On multivariate analysis, only higher serum CA 19.9 level was the independent unfavorable prognostic factor of survival time in nonmetastatic patients (p = 0.008). In metastatic disease, older age (p = 0.03) and male gender (p = 0.05) were associated with poorer survival. In conclusion, gastric cancer is a great health problem, especially in developing countries, and we need more optimal approaches and treatment modalities for gastric cancer.

Strong intracellular and negative peripheral expression of fibronectin in tumor cells contribute to invasion and metastasis in papillary thyroid carcinoma

The intracellular and stromal expression of fibronectin (FN) in invading and central parts of papillary thyroid carcinomas with/without lymph node (LN) metastasis (54 metastasizing cases, 52 non-metastasizing cases) were examined immunohistochemically. The intracellular expression of FN in tumor cells in invading parts was stronger than that in central parts in most cases (79/106 cases, 74.5%). In invading parts, negative stromal FN was frequently found at the periphery of the tumor in cases with extracapsular soft tissue invasion (26/37 cases). Tumor cells in invading parts in metastatic cases were significantly more likely to be negative for stromal FN at the periphery of the tumor than those in non-metastatic cases ( P<0.0001). The strong intracellular and negative stromal FN at the periphery of the tumor in invading parts were associated with invasion and metastasis in papillary thyroid carcinoma. These results suggest that these distinctive characteristics of FN may be useful for understanding invasion and metastasis in vivo.

Gelatinolytic activity of matrix metalloproteinase in tumor tissues correlates with the invasiveness of oral cancer.

We examined whether or not the gelatinolytic activity in tumor tissue was associated with the invasion and metastasis of oral squamous cell carcinoma (OSCC). Tissue homogenates were prepared from 57 biopsy specimens of OSCC. The gelatinolytic activities in the homogenates were measured by gelatin zymography and its densitometric analysis. The Immnunoblot findings revealed the major gelatinolytic activities to be due to matrix metalloproteinase (MMP)-2 and -9. The zymography-detected gelatinolytic activities of MMP-2 and MMP-9 in the tissue specimens significantly correlated with the degree of immunohistochemical staining detected in frozen sections of the same biopsy specimens. According to a histopathological analysis of the mode of invasion, highly invasive cases showed the increased gelatinolytic activities of MMP-2 as well as MMP-9 in the tissue specimens. Although no significant differences were observed in the gelatinase activities between the metastatic cases and the non-metastatic cases, the levels of tissue inhibitor of MMP (TIMP)-1 in the tumor tissue specimens were higher in the non-metastatic cases than in the metastatic cases. The cases with the high levels of MMPs and low levels of TIMP-1 thus seemed to have a high potential to metastasize. As a result, the zymographic measurement of the gelatinolytic activity in biopsy tissue specimens may therefore be useful in predicting the behavior and prognosis of OSCC.

An immunohistochemical study of the extracellular matrix in oral squamous cell carcinoma and its association with invasive and metastatic potential.

The expression of extracellular matrices (ECMs) laminin (LN), type IV collagen (IV C), heparan-sulphate proteoglycan (HS-PG), fibronectin (FN), tenascin (TN), decorin and vitronectin (VN) was examined immunohistochemically in 112 primary tumours and 29 metastatic cervical lymph nodes in oral squamous cell carcinoma (OSCC). In highly invasive primary tumours, the expression of LN, IV C and HS-PG in the basement membrane along the tumour-stroma borderline and the expression of decorin and VN in the tumour stroma at the invasive site were all significantly decreased. The expression of FN and TN in the tumour stroma at the same site was markedly increased. In peritumour stroma in metastatic lymph nodes, LN, IV C, HS-PG, decorin and VN were weakly expressed, while FN and TN were strongly expressed. Thus, the staining pattern of the ECMs in the metastatic lymph nodes was similar to that in highly invasive primary tumours. Furthermore, in primary tumours of metastatic cases, the expression of LN, IV C, HS-PG, decorin and VN obviously decreased, while the expression of FN and TN increased when compared with those of the non-metastatic cases. The investigation of ECMs in OSCC was valuable in predicting tumour behaviour.

Proliferation Characteristics of Cutaneous Squamous Cell Carcinomas Developing in Organ Graft Recipients

Cutaneous squamous cell carcinomas (SCCs) are a frequent complication in organ graft recipients (OGRs). The clinical evolution of these lesions has been a matter of controversy. We studied, by the technique of counting argyrophilic proteins associated with nucleolar organizing regions, the proliferative profile of 11 SCCs developing in six OGRs and compared it with the profile in a group of 18 nonimmunocompromised patients with SCCs. The density of the inflammatory cellular peritumoral infiltrate was also assessed semiquantitatively. The SCCs in OGRs and controls contained similar numbers of argyrophilic proteins associated with nucleolar organizing regions; however, the density of the inflammatory cellular peritumoral infiltrate was much lower in OGRs than in controls (2.00 +/- 0.77 vs 3.17 +/- 0.79). The proliferative potential of SCCs developing in the setting of iatrogenic immunosuppression does not seem to be different from that of SCC in nonimmunocompromised hosts; however, since metastatic SCCs are known to have a reduced density of the inflammatory cellular peritumoral infiltrate as compared with nonmetastatic cases, SCCs in OGRs could have a higher metastatic potential than similar lesions developing in a control population.

Immunohistochemical detection of desmosomes in oral squamous cell carcinomas: Correlation with differentiation, mode of invasion, and metastatic potential

An expression of desmosomal glycoprotein 1 (DG 1) was immunohistochemically examined in 77 biopsies and 21 metastatic cervical lymph nodes of oral squamous cell carcinomas (SCC). In the primary tumors the DG 1 expression was significantly reduced at the invasive site of poorly differentiated and highly invasive tumors. In cases of metastases in cervical lymph nodes, the DG 1 staining at the invasive site of the primary tumor was significantly less than that of nonmetastatic cases. The DG 1 expression in the metastatic lymph nodes was as weak as that in the primary tumor. Thus, we suggest that immunohistochemical investigation of DG 1 expression in oral SCC is valuable in predicting tumor behavior.

Prostate Tumour Markers and Differentiation Grade in Prostatic Cancer

Serum acid phosphatase activity, prostate specific phosphatase and prostate specific antigen were measured in 100 patients with prostatic cancer. The patients were divided according to the differentiation grade into 3 groups: G1 (well), G2 (moderately) and G3 (poorly differentiated) carcinoma. Bone metastases were identified by scintigraphy. Among the 76 M0 patients the mean levels of all 3 markers were slightly higher in patients with moderately differentiated prostatic carcinoma. Among the 24 M1 patients the primary tumour was either G2 (18 patients) or G3 (6 patients); none had G1 lesions. Significantly higher serum ACP and PAP levels were found in patients with G2 tumours than in those with G3 lesions. It was concluded that the histological differentiation grade of prostatic carcinoma did affect serum levels of prostatic tumour markers; the tendency towards higher levels in the G2 group was noticeable in both non-metastatic and metastatic cases despite the limited number of patients in the latter category. In clinical practice this information may be an important additional tool in staging prostatic cancer.

Spontaneous osteogenic sarcoma in the rat

A spontaneous osteogenic sarcoma of the spinal column (tail, sacrum and lumbar regions) with metastases to the lungs, kidneys and right ovary were found in a 15-month-old BHE rat. The literature on spontaneous osteogenic sarcoma in rats indicates that this tumour is rare (0·22 per cent), occurs in several strains and has no sex, age or site predilections; non-metastatic cases are more common than metastatic ones.

PROGNOSTIC SIGNIFICANCE OF REGIONAL LYMPH NODE HISTOLOGY IN UTERINE CERVICAL CANCER

Histologic material from 75 cases of uterine cervical cancer was studied with particular emphasis on the morphology of the regional lymph nodes. Sixty-seven cases were squamous cell and eight were adenocarcinomas. Sixteen were metastatic and 59 non-metastatic. Five-year survival data were available in 42 cases. We found that lymph nodes could be classified in four distinct histologic patterns which we designated “lymphocyte predominance,” “germinal center predominance,” “lymphocyte depletion,” and “unstimulated.” Correlation of the histologic pattern with the presence or absence of metastasis and the survival data demonstrated that lymphocyte predominance was common in non-metastatic cases and in cases with high survival rate. The “lymphocyte depletion” pattern was common in metastatic cases and in cases with low survival rate. The “germinal center predominance” pattern was associated with an intermediate survival rate. The possible relationship of these patterns to host cell-mediated and humoral immune responses is discussed.

Prognostic significance of regional lymph node histology in uterine cervical cancer.

Histologic material from 75 cases of uterine cervical cancer was studied with particular emphasis on the morphology of the regional lymph nodes. Sixty-seven cases were squamous cell and eight were adenocarcinomas. Sixteen were metastatic and 59 non-metastatic. Five-year survival data were available in 42 cases. We found that lymph nodes could be classified in four distinct histologic patterns which we designated “lymphocyte predominance,” “germinal center predominance,” “lymphocyte depletion,” and “unstimulated.” Correlation of the histologic pattern with the presence or absence of metastasis and the survival data demonstrated that lymphocyte predominance was common in non-metastatic cases and in cases with high survival rate. The “lymphocyte depletion” pattern was common in metastatic cases and in cases with low survival rate. The “germinal center predominance” pattern was associated with an intermediate survival rate. The possible relationship of these patterns to host cell-mediated and humoral immune responses is discussed.

BRONCHOGENIC CARCINOMA SIMULATING HYPERPARATHYROIDISM.

METASTATIC malignant disease to bone is known to cause hypercalcemia. 1-5 In nonmetastatic cases, the occasional findings of associated serum and urinary phosphorus abnormalities and the disappearance of the hypercalcemia with the removal of the tumor suggest a relationship to a hyperparathyroid state. 3-27 The following case report of nonmetastatic bronchogenic carcinoma demonstrates the typical features of hyperparathyroidism and their reversal by surgical removal of the tumor. Report of Case A 66-year-old Caucasian man was hospitalized for evaluation of an intrapulmonary mass on June 18, 1963. He had been in excellent health all his life until three months prior to admission when he noted the onset of cough, anorexia, dysphagia and a 20 lb (9.1 kg) weight loss. There were no other pulmonary, cardiac, renal, or metabolic symptoms. The patient's past history revealed that he had smoked 1½ packs of cigarettes a day for 40 years. Physical examination revealed a