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The most important discriminant in staging carcinoma of the breast is the presence of positive axillary lymph nodes. In this study, we determined if 45 female breast cancer patients originally classified as lymph node-negative by standard light microscopy (SLM) could be more accurately classified by immunohistochemical (IH) examination of their lymph nodes with an anticytokeratin monoclonal antibody cocktail. Identical sections of lymph nodes were sequentially examined by SLM and IH. Eight nodes (1%) in a total of five patients (11%) were positive by SLM. In comparison, 12 nodes (1.5%) in a total of nine patients (20%) were positive by IH. Five nodes were positive by IH and negative by SLM. There was no correlation between IH-detected metastases and tumor size or patient age. The survival curve for patients with IH-detected metastases was significantly worse than that of patients without IH-detected metastases. IH detection methods may be an important adjunct in staging breast cancer patients.

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A new dosage form of anticancer agent, mitomycin C adsorbed to activated charcoal (MMC-AC), was evaluated in the rabbit model of hepatic hilar bile duct cancer. The model was produced by inoculation of VX2 cells into the wall of the hepatic hilar bile duct. Histologic examination revealed that the mode of spreading of VX2 cells in the model closely resembles that of human bile duct cancer. On the other hand, selective accumulation of MMC-AC into the lymphatic vessels around the intrahepatic bile duct was observed after its injection into the hepatic hilum in rabbits. To assess the anticancer effect, 1 ml of MMC-AC was injected into the bile duct wall near the VX2 tumor. The numbers of lymphatic vessels where necrosis of VX2 cells was observed in one-third or more were 34 of 103 vessels 0.5 cm away from the tumor, 23 of 80 vessels 1.5 cm away, and 9 of 67 vessels 2.5 cm away. We believe that the injection of MMC-AC into the hepatic hilum can be effective adjuvant therapy for hepatic hilar bile duct cancer.

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In the preceding paper the authors demonstrated that the lectin staining patterns of normal colonic epithelium obtained from colitis and carcinoma-prone cotton top tamarins (CTTs), Saguinus oedipus, a New World primate, differs from colitis- and carcinoma-resistant primate species. In this study they determined the usefulness of cytochemical features in inflamed epithelium as indicators for malignant change. They compared the lectin staining pattern in inflamed mucosa and adjacent mucosa with colonic carcinoma from 8 CTTs with that of 9 clinically healthy CTTs with no histologic evidence of colitis. Deparaffinized sections were labeled with ten biotinylated lectins and stained by the avidin-biotin peroxidase complex method. Numerous significant differences were demonstrated in the lectin staining pattern between normal epithelium and colonic carcinoma; fewer between normal and chronic inflamed epithelium. However, between chronic inflamed epithelium and colonic carcinoma significant staining differences were observed with only two lectins, peanut agglutinin (PNA) and Ulex europaeus agglutinin-I (UEA-I). These findings suggest that there is a progression in alteration of lectin staining pattern from normal epithelium, via chronic colitis, to colonic carcinoma. Furthermore, the differences between chronic colitis and colonic carcinoma are expressed only with those lectins that are associated with malignant transformation of human colonic epithelium.

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Oxygen distribution was measured in 31 fixed lymph node metastases (mean diameter 4.4 cm +/- 0.8 cm) from squamous cell carcinoma of the head and neck by passing a needle electrode through each tumor under CT guidance. Thirteen tumors had uniform oxygen distribution with all measurements under 10 mm Hg. Six tumors had uniform oxygen distribution with all measurements above 10 mm Hg, and twelve tumors had variable oxygen distribution with measurements higher in the periphery than in the center. Response to radiation therapy was judged by changes in tumor volume 90 days following completion of therapy compared to pre-therapy volume. Eighteen tumors were considered complete responders (CR); eleven, non-responders (NR); two, partial responders (PR). No statistically significant difference in radiation dose or tumor size was seen in the PR and CR groups. Mean pO2 was 20.6 (+/- 4.4) mm Hg in the CR group and 4.7 (+/- 3.0) mm Hg in the NR group (p less than 0.001). Normalized pO2 content defined as the total tumor oxygen content normalized by dividing by the volume was 37.4 (+/- 8.2) mm Hg in the CR group and 8.2 (+/- 5.1) mm Hg in the NR group (p less than 0.001). The volume and oxygen levels of each tumor were tabulated and analyzed. Twelve tumors had greater than 26% of their volume containing a pO2 less than 8 mm Hg. Eleven of these were NR and one PR. Nineteen tumors had less than 26% of their volume containing a pO2 less than 8 mm Hg. Eighteen were CR and one PR (p less than 0.001). These data suggest that oxygen plays a significant role in human tumor response to radiation therapy. Oxygen measurements appear to allow separation of subgroups of patients with a poor prognosis who would most benefit from maneuvers to circumvent the hypoxic effect.

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Epidermal growth factor (EGF) seems to play an important role in regulating the proliferation of human breast cancer. Fifty-five primary breast tumors and 7 lymph node metastases were simultaneously assayed for the presence of EGF receptors (EGFR), estrogen receptors (ER), and progesterone receptors (PR). Overall, 42% (23/55) of the tumors were EGFR positive. EGFR were more frequently present in ER- and PR-negative than in ER- and PR-positive tumors. In particular, a negative correlation between EGFR and PR (chi 2 = 6.8; p greater than 0.01) was observed. All metastatic tumors were EGFR negative, and in all cases but 1 the levels of EGFR were higher in metastatic than in primary tumors. Our results suggest the presence of a subclass of breast tumors, the growth of which is primarily regulated by EGF or EGF-like substances rather than by steroid hormones. In this group, not amenable to endocrine therapy, EGF receptors should represent a target for therapeutic intervention.

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Activities of several steroid metabolizing enzymes (steroid sulfate-sulfatase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, and 3 alpha beta-hydroxysteroid dehydrogenase) as well as total tissue content and subcellular distribution (nuclear-extranuclear) of several androgen precursors, active androgens, and androgen deactivation products (DHEA sulfate, DHEA, 5-androstenediol, 4-androstenedione, testosterone, DHT, and 3 alpha-androstanediol) were quantified in primary tumors and lymph node metastases of human prostatic cancer obtained from patients without previous endocrine manipulation. Primary tumors were compared to benign parts of the same prostates, and the metastases were compared to their primary tumors. All enzymes and steroids found in benign prostatic tissues could also be detected in the malignant tissues. Even the capacity to accumulate active androgens in the nuclei was found to be unchanged in nearly all of the samples. Lower activities of hormone-dependent enzymes were observed in the cancers, suggesting a less efficient utilization of hormonal stimuli. Most striking changes found in the malignant tissues were a subtotal loss of 5 alpha-reductase activity and a metabolic shift to testosterone, which was more pronounced in samples from metastatic disease as compared to samples from non-metastatic disease. In conclusion, primary tumors and metastases of prostatic cancers not treated by endocrine manipulations retain their androgen receptor system and possess the same capacity to metabolize adrenal androgen precursors along the pathway to DHT as benign prostatic tissue. Consequently, they should be able to use at least androstenedione for production of active androgens directly in the target tissue.

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Specimens of primary lung carcinomas and lymph node metastases from the same 18 patients were investigated by means of flow cytometry. The number of DNA stemlines, DNA indices, the proportion of diploid cells in the tumors and the distribution of the cell cycle phases were compared. In 10 patients DNA stemlines and DNA indices were identical in primary tumors and metastases. In two cases the DNA indices were doubled in metastases. In 6 cases the primary tumors contained two abnormal DNA stemlines and their metastases contained only one aneuploid stemline. Gross differences between primary tumors and lymph node metastases with regard to the proportion of cell cycle phases could not be found. The large variation between primary tumors and lymph node metastases with regard to DNA stemlines indicates that flow cytometric analysis of lymph nodes gives only limited information about the primary tumors.

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We report the history, laboratory and histological findings in a man who presented with Cushing's disease. Despite removal of the primary pituitary tumour, his disease progressed and after bilateral adrenalectomy, he became pigmented and plasma ACTH levels remained elevated. He had further pituitary surgery and radiotherapy, to relieve compression of the optic chiasma. Plasma ACTH levels remained elevated. He developed liver, bone and lymph gland metastases and after an acute paraparesis due to spinal metastases he died. Immunoperoxidase staining techniques demonstrated ACTH in the pituitary recurrence and metastases. The combination of bone, liver and lymph node metastases has not previously been reported, nor has ACTH been reported before in metastases from a primary intrasellar tumour.

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Lymphopoiesis stimulating drugs were injected into the blood of rabbits bearing Brown-Pearce transplantable tumor. It was found that treatment with mannitol targeted on osmoregulation mechanisms and terrilytin--on blood and lymph coagulation intensified the lymphogenic migration of tumor cells. When used in an experimental series involving endolymphic transplantation of tumor cells, the said drugs promoted tumor cell passage from lymph to blood, which resulted in an increased number of metastasis-bearing animals. It was also found that the promoting effect may be counteracted by preliminary endolymphic injection of a fat-soluble antitumor preparation. Lymphopoiesis and lymph flow stimulation in conjunction with thoracic duct draining may be used for removal of tumor cells from the lymphatics.

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Nevus cell aggregates occurring in association with axillary lymph nodes can be difficult to recognize and differentiate from a metastatic breast carcinoma. We believe S100-protein immunoreactivity, along with negative staining for keratin and epithelial membrane antigen, and typical geographic distribution of nevus cell aggregates in lymph nodes are helpful in providing an accurate diagnosis.

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Androgen binding (cytosol and nucleus) was measured in tissue obtained from 223 untreated patients with proven prostate cancer (199 primary tumor, 24 malignant lymph nodes), 19 patients with hormone refractory cancer, and 46 patients with benign prostatic hyperplasia (BPH). The mean binding in both the cytosol and nucleus was significantly higher for patients with cancer than for those with BPH. Binding appeared to correlate with tumor stage. Androgen binding in malignant nodes can differ from that in the primary tissue and can vary from node to node in the same patient. Results obtained from an assay using a single saturating concentration of R1881 correlated well with those calculated from a full six-point Scatchard analysis when an adequate amount (500 mg) of tissue was available. However, binding results obtained from a single-point analysis performed on needle biopsy specimens (about 50 mg) obtained before complete surgical removal of the prostate correlated poorly with those derived from a full six-point analysis performed on tissue (500-1000 mg) removed from the center of the malignancy. Androgen binding in nuclear extracts of histologically benign tissue adjacent to the malignancy was significantly higher than in nuclear extracts of BPH tissue. Cytosolic androgen binding in tissue removed from patients who were refractory to hormonal therapy was higher than in tissue from untreated cancer patients. The binding of estradiol by extracts of benign and malignant prostate tissue was low or absent and, thus, did not appear to be a significant phenomenon.

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The binding of peroxidase-labelled wheat germ agglutinin (WGA) to a series of 125 human breast carcinomas has been studied. Routine fixation and processing has been shown to have no deleterious effect on reactivity. In contrast to the homogeneous binding of WGA to normal and hyperplastic human breast previously reported, the binding of WGA to breast carcinomas exhibits heterogeneity. This is of two forms: (1) in relation to cell reactivity, which is significantly correlated to tumour differentiation, with fewer cells reacting in those carcinomas showing loss of histological differentiation; (2) with regard to the interaction between WGA and specific saccharides of cellular glycan-components, binding to sialic acid appearing to be of significance to varying degrees in some carcinomas but not in others nor, as previously reported, in normal breast. The alteration in WGA-saccharide interaction is an indicator of the heterogeneity of the carbohydrate chains of glycoproteins within neoplastic cells of the same tumour and between carcinomas. The other finding of note has been that of the significant association between heterogeneity of cellular reactivity to WGA and the presence of axillary lymph node metastasis, but a lack of correlation between virtual absence of reactivity and nodal metastasis.

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Tissue sections from 80 human breast carcinomas have been examined for evidence of binding of the two fucose-specific lectins, Lotus tetragonolobus and Ulex europeus I, with enzymes utilized as an indicator system. Both single-staining and double-staining methods (Lotus tetragonolobus-peroxidase and Ulex europeus I-alkaline phosphatase) have been employed. In contrast to normal breast in which there is consistent reactivity of all epithelium with Lotus tetragonologus a variable loss of binding has been found within carcinomas. Surprisingly, this bears no relationship to tumour differentiation; nor does it correlate with local lymph node metastasis. Ulex europeus I has a variable reactivity with carcinomas, as it does with normal breast epithelium, and this likewise has no correlation with differentiation. However, a relationship has been found between specific patterns of binding and axillary lymph node status. The value of using two lectins with the same major sugar specificity but having different binding affinities is illustrated in this study, in which differences in behavioural characteristics have been identified between fucose-containing glyco-conjugates having minor structural variations.

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The synchronous relationship between oestrogen (ER) and progesterone (PgR) receptor status in primary tumours and their nodal metastases has been analysed in 26 patients. All patients with ER-negative primary tumours were found to have ER-negative axillary nodes but of those with ER-positive tumours only 65% had, correspondingly, all nodes ER-positive. The concentration of ER in the nodes was found to be significantly lower (P less than 0.001) than that in the primary tumour. PgR information was unobtainable in 3 patients. Of the remainder, 75% of those having PgR-negative tumours had all nodes PgR-negative but only 36% of those with PgR-positive tumours had all nodes PgR-positive. PgR levels were found to be generally lower in the axillary nodes but this did not reach statistical significance. The clinical relevance of these findings is discussed.

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The possible relationship between ganglioside levels and ganglioside profiles in malignant tumors and the formation of metastasis was investigated by the analysis of gangliosides in metastasizing SMT-2A and nonmetastasizing MT-W9a mammary carcinomas as well as in metastases formed from SMT-2A tumors. The extracted lipid of SMT-2A tumors contained 3.3-fold more lipid-bound sialic acid than did that of MT-W9a tumors. THe differences were also substantial in the ganglioside profiles in these 2 tumors. Plasma membranes isolated from SMT-2A tumors also contained 1.8-fold more lipid-bound sialic acid than did plasma membranes from MT-W9a tumors. Ganglioside profiles in two types of SMT-2A secondary tumors were investigated. The lipid-bound sialic acid content was 1.5-fold higher in tumor nodules in the lung and 1.9-fold higher in axillary lymph node tumors than it was in primary SMT-2A tumors. The ganglioside pattern in these 2 secondary tumors generally reflected that found in SMT-2A: high levels of gangliosides containing three or four sialic acid molecules. The lung nodule retained its specificity with respect to lipid-bound sialic acid content and ganglioside pattern after the lung nodule was sequentially transplanted three times to the site of the original SMT-2A tumor growth.

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Axillary lymphoscintigraphy using 99Tcm antimony sulphide colloid has been carried out in 29 patients with suspected breast cancer and was correlated with histology. Of the 23 with proved tumour, axillary node metastases were found in 19 and, although 10 did have diminished uptake on the side of the lesion, 5 had an equal uptake in both sides and 4 had an increased uptake on the side of the lesion. Further, some of the nodes in which the high uptake had occurred were those heavily infiltrated by tumour. It is concluded that: a, lymphoscintigraphy with antimony sulphide colloid is not a reliable technique for the detection of metastatic disease in the regional nodes; b, any lymphoscintigraphy with this or any other agent requires more meticulous histological correlation than hitherto before it can be assumed to have any proved clinical value.

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To characterize the relationship of the TSH receptor-adenylate cyclase system to differentiation in human thyroid cancers, adenylate cyclase and TSH binding were studied in membranes from primary and metastatis thyroid carcinomas of varying histological types (n = 33) and normal thyroids (n = 12). Membranes from differentiated carcinomas (n = 23) exhibit wide patient to patient variability; some membranes show entirely normal adenylate cyclase and TSH-binding characteristics, and other membranes exhibit decreased TSH stimulation of adenylate cyclase which is accompanied by either a normal or decrease TSH-binding site concentration. With respect to the TSH-binding site concentration and TSH stimulation of the adenylat cyclase, the well differentiated carcinomas are not significantly different from normal thyroids, whereas the moderately differentiated and the papillary carcinomas are significantly different (P < 0.001 and P < 0.001, respectively). Membranes from undifferentiated carcinomas (n = 5) and those from medullary carcinomas (n = 5) are characterized by an absence of both TSH binding and TSH stimulation of the adenylate cyclase. In conclusion, while a general relationship exists between the impairment of TSH responsiveness and the dedifferentiation process, no pattern of membrane alteration is specific for any histological type.

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Glycosaminoglycans of human chordoma and a metastasis were studied. The glycosaminoglycans were derived from the extracellular matrix and consisted of chondroitin 4- and 6-sulphate, keratan sulphate and hyaluronate. The ratio of chondroitin sulphate to keratan sulphate was much lower in the metastasis than in the primary. Proteoglycan extracted with 4M guanidinium chloride and purified by associative density-gradient centrifugation was assessed on Sepharose 2B before and after reduction and alkylation. The result of this experiment suggested that only a small proportion of the proteoglycans were aggregated.

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