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PubMed2004

A case of invasive lobular carcinoma of the breast first manifesting with duodenal obstruction.

Lobular carcinoma of the breast presents with various clinical manifestations. Lobular carcinoma comprises about one fifth of cases of ductal carcinoma. Intestinal metastasis is dominant in cases of lobular carcinoma. Without a prior diagnosis of lobular carcinoma of the breast, the diagnosis of intestinal metastasis from breast cancer is difficult. A 52-year-old women underwent duodenogastrectomy for duodenal cancer. About 18 months later, she underwent mastectomy for lobular carcinoma of the breast. The duodenal cancer consisted mainly of malignant cells invading the submucosa that were identical to those in the breast. Immunohistochemical assays for estrogen receptor also confirmed breast cancer metastasis. Duodenal obstruction was the first sign of isolated metastatic lobular carcinoma of the breast in this case. The characteristic metastatic pattern of lobular carcinoma, which differs from that of ductal carcinoma, should be kept in mind to ensue proper diagnosis. Preceding breast surgery for lobular carcinoma should prompt investigation based on the typical metastatic pattern.

Breast Neoplasms↗
PubMed1977

Metastatic and histologic presentations in unknown primary cancer.

The patient with metastatic adeno- or undifferentiated carcinoma who presents with a cryptic primary is subjected to an extensive diagnostic search. These efforts apparently stem from the following assumptions: 1). The ultimately proven primary sites in such patients will occur with the same frequency as the most commonly occurring carcinomas (i.e., lung, breast, colon, prostate, etc.); and 2). Metastatic patterns and histologies seen at diagnosis are the same as for patients presenting with these more common tumors. Our data contradict these assumptions. For example, the most commonly occurring unknown primary was pancreas. Rarely occurring primaries included breast and prostate. Lung cancer was observed frequently, but the presentation was atypical because of the large proportion of female patients. In addition, the metastatic patterns at diagnosis were unusual for many of the ultimately proven primary sites. In an attempt to deal with these contradictions, a method to search for new relationships between primary site and metastatic-histologic presentations was employed. This method succeeded in placing the location of the primary cancer to above or below the diaphragm in 80% of the patients studied retrospectively. Tested prospectively in a small group of patients, the method appears to be clincally useful. Finally, in this study we have made the diagnosis, antemortem, of the primary cancer site (PCS) in only 30 of 264 patients. The failure to find the primary site, dispite extensive radiologic work-up, was disappointing to the authors, and emphasizes the difficulty of finding PCS antemortem. In our study pancreas and lung appear to be most common cryptic primary sites.

Abdomen↗
PubMed1990

Advanced colon cancer: staging and prognosis by CEA test.

The carcinoembryonic antigen (CEA) test was studied in 54 patients with advanced stages of colon cancer which was treated with high doses of folinic acid + fluorouracil. The CEA test correlates evaluated included: prognostic value, performance status, metastatic pattern, histologic grading, predictive value for response to chemotherapy, and value differences in cases with partial response to therapy. CEA levels less than 5 ng/ml corresponded to a greater survival time than did levels greater than 5 ng/ml. A correlation of CEA with performance status and with metastatic pattern was demonstrated. A progressive increase in average CEA values corresponded to increases in neoplastic mass. Although CEA levels were not found to be an index for predicting the response to chemotherapy, there was a significant different between pre- and posttreatment levels for partial response. The results suggest that CEA offers an additional criterion for evaluating the response of colon cancer to chemotherapy and it also has a role in the staging of advanced disease.

Adult↗
PubMed1991

The role of NK cells in the regulation of experimental metastasis in a murine lymphoma system.

This report describes the role of natural killer (NK) cells in regulating the localization of two closely related murine lymphomas (ASL1 and ASL1w) to various organ sites. These tumors are phenotypically similar yet differ in their overall malignancy and experimental metastatic pattern. Both tumors show similar patterns of migration in kinetic studies, however, they vary in their NK susceptibility. Cold target inhibition analysis and assessment of susceptibility to cytotoxic T lymphocytes (CTL) suggested that the NK resistance of ASL1 was due to the lack of expression of a relevant target structure(s) required for NK recognition. The role of NK cells in regulating the growth of the tumors in vivo was studied by altering NK cell levels in recipient mice prior to tumor injection. Neither NK cell depletion nor augmentation affected the growth of the NK resistant ASL1 tumor but NK depletion significantly shortened the mean survival time (MST) of recipients of the NK sensitive ASL1w tumor as well as changed its metastatic pattern; conversely, NK augmentation significantly increased the MST of ASL1w recipients. These data suggest that NK cells play a critical role in determining the metastatic characteristics of the ASL1w lymphoma.

Animals↗
PubMed2002

Oncologic mathematics: evolution of a new specialty.

HYPOTHESIS: Mathematical methods and their derivatives have practical applications to oncology. They can be used to describe fundamental aspects of tumor behavior, such as loss of genetic stability, tumor growth, immunologic identity, genesis of diversity, and methods of prognosticating cancer. DATA SOURCES: Descriptive models and published literature in the fields of oncology and applied mathematics. DATA SYNTHESIS: Cancer does not conform to simple mathematical principles. Its irregular mode of carcinogenesis, erratic tumor growth, variable response to tumoricidal agents, and poorly understood metastatic patterns constitute highly variable clinical behavior. Defining this process requires an accurate understanding of the interactions between tumor cells and host tissues and ultimately determines prognosis. Applying time-tested and evolving mathematical methods to oncology may provide new tools with inherent advantages for the description of tumor behavior, selection of therapeutic modes, prediction of metastatic patterns, and providing an inclusive basis for prognostication. We term this combined field of research "oncologic mathematics." As surgeons, we have the unique opportunity to be active participants and assume leadership in research that affects selection of the optimal anticancer treatment for our patients. Mathematicians describe equations that define tumor growth and behavior, whereas surgeons actively deal with biological processes. Oncologic mathematics applies these principles to clinical settings. CONCLUSION: Experimentally testable, oncologic mathematics may provide a framework to determine clinical outcome on a patient-specific basis and increase the growing awareness that mathematical models help simplify seemingly complex and random tumor behavior.

Disease Progression↗
PubMed2003

Radical cystectomy for bladder cancer today--a homogeneous series without neoadjuvant therapy.

PURPOSE: To investigate the effect of pelvic lymph node dissection and radical cystectomy for transitional cell cancer of the bladder on recurrence-free and overall survival, pelvic recurrences, and metastatic patterns in a homogeneous group. PATIENTS AND METHODS: A consecutive series of patients undergoing pelvic lymphadenectomy and radical cystectomy between 1985 and 2000 was analyzed. All patients were staged N0, M0 preoperatively, and no patient received neoadjuvant radio/chemotherapy. Pathologic characteristics based on the 1997 tumor-node-metastasis system, recurrence-free/overall survival, and metastatic patterns were determined. RESULTS: Five hundred seven patients (age 66 +/- 12 years) with a mean follow-up time of 45 months (range, 0.1 to 176 months) were analyzed. Five-year recurrence-free and overall survival were, respectively, 73% and 62% for patients with organ-confined, lymph node-negative tumors (n = 217; < or = pT2, pN0) and 56% and 49% for non-organ-confined, lymph node-negative tumors (n = 166; > pT2, pN0). Positive lymph nodes were found in 124 (24%) patients who had a 5-year recurrence-free (33%) or overall (26%) survival. Isolated local recurrences were observed in 3% of patients with organ-confined tumors (< or = pT2, pN0), 11% with non-organ-confined tumors (> pT2, pN0), and 13% with positive lymph nodes (any pT, pN+). Distant metastases developed in 25% of patients with organ-confined tumors, 37% with non-organ-confined tumors, and 51% with positive lymph nodes. CONCLUSION: Despite negative preoperative staging, pelvic lymphadenectomy and cystectomy for bladder cancer reveal a high percentage of unsuspected nodal metastases (24%) that have a 25% chance for long-term survival. This procedure also ensures a low pelvic recurrence rate even in lymph node-positive patients, and patients with locally advanced cancer have a 56% probability of 5-year recurrence-free survival.

Adult↗
PubMed2006

Mouse models in oncogenesis and cancer therapy.

Animal models have been critical in the study of the molecular mechanisms of cancer and in the development of new antitumor agents; nevertheless, there is still much room for improvement. The relevance of each particular model depends on how close it replicates the histology, physiological effects, biochemical pathways and metastatic pattern observed in the same human tumor type. Metastases are especially important because they are the main determinants of the clinical course of the disease and patient survival, and are the target of systemic therapy. The generation of clinically relevant models using the mouse requires their humanization, since differences exist in transformation and oncogenesis between human and mouse. Although genetically modified (GM) mice have been instrumental in understanding the molecular mechanisms involved in tumor initiation, they have been less successful in replicating advanced cancer. Moreover, a particular genetic alteration frequently leads to different tumor types in human and mouse and to lower metastastatic rates in GM mice than in humans. These findings question the capacity of current GM mouse carcinoma models to predict clinical response to therapy. On the other hand, orthotopic (ORT) xenografts of human tumors, or tumor cell lines, in nude mice reproduce the histology and metastatic pattern of most human tumors at advanced stage. Using ex vivo genetic manipulation of human tumor cells, ORT models can be used to molecularly dissect the metastatic process and to evaluate in vivo tumor response to therapy, using non-invasive procedures. Nevertheless, this approach is not useful in the study of the initial stages of tumorigenesis or the contribution of the immune system in this process. Despite ORT models are more promising than the most commonly used subcutaneous xenografts in preclinical drug development, their capacity to predict clinical response to antitumor agents remains to be studied. Humanizing mouse models of cancer will most likely require the combined use of currently available methodologies.

Animals↗
PubMed2001

Involvement of chemokine receptors in breast cancer metastasis.

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

Actins↗
PubMed1982

'Seed and soil' revisited: mechanisms of site-specific metastasis.

Clinical studies have shown that malignant tumors frequently show definite metastatic patterns. This tendency for neoplasms of a particular histologic type to metastasize to a specific organ is also a characteristic of experimental animal tumor systems. Mechanical entrapment, arrest determined by specific recognition between neoplastic cells and capillaries and organ-determined modulation of tumor growth have all been suggested as mechanisms that regulate this specificity. Experimental evidence for the role that each of these mechanisms plays in the regulation of metastatic patterns of transplantable rodent tumors is discussed in this review.

Animals↗
PubMed1988

Extrapulmonary, tissue-specific metastasis formation in nude mice injected with FEMX-I human melanoma cells.

FEMX-I human malignant melanoma cells, originating from a lymph node metastasis in a patient, uniquely and selectively produced extrapulmonary metastases after i.v. injection of cells prepared from xenografts into adult, nude mice. After a lag time of approximately 50 days, metastases were observed in s.c. sites at the back and front of the neck, and in axilla and inguinal regions. Tumor colony formation in lungs were never detected. The interscapular tumors showed a close relationship to brown fat, partly infiltrating this tissue, whereas the other s.c. tumors seemed to be localized to lymph nodes. Mesenterial and mediastinal lymph node metastases were frequently found, together with retroperitoneal tumors along the spine. The normal cells of the adrenal medulla were often replaced by melanoma cells, whereas the cortical tissue was not affected. The conclusion that FEMX-I cells possess an inherent ability for tissue-specific metastasis formation is supported by the metastatic pattern seen after i.p. and intrasplenic injection, as well as after inoculation of the cells in the footpads of the mice. The relatively slowly growing FEMX-I tumors showed the same differentiated morphology as the patient's tumor, independent of the site of growth and the number of passages in the animals. The FEMX-I tumor was easily established as a cell line in vitro. Such cells showed a strongly reduced metastatic capacity, indicating that the in vitro growth conditions had induced alterations in the FEMX-I cells influencing their ability to form site-specific metastases, changes that were shown to be reversible. It is suggested that structures on the surface of the tumor cells, as well as growth factors in the host tissues, may be of importance for the observed tissue specificity. The FEMX-I melanoma, which, as a human tumor in nude mice, has a unique metastatic pattern, offers possibilities for investigating mechanisms involved in site-specific metastasis formation, as well as for testing effects of antimetastatic, chemotherapeutic, and immunotherapeutic agents against human extrapulmonary micro- and macrometastases.

Animals↗
PubMed1993

Neoplasms of unknown primary site: a clinicopathological study of autopsied patients.

BACKGROUND: Malignant neoplasms of an unknown primary site (NUPS) remain a diagnostic and therapeutic challenge in clinical practice. With this in mind, we have reviewed all autopsies performed in patients with NUPS in a single institution. PATIENTS AND METHODS: By reviewing 1656 autopsies performed on adults in our institution (1974-1990), 43 cases of NUPS were found. (NUPS was defined as histologically proven malignant tumor for which a primary site could not be found after anamnesis, complete physical examination, chest X-ray and routine chemistries.) RESULTS: There were 24 men (56%) and 19 women. Mean age was 62 years (76% of patients were aged 40-75). Clinical presentation included general deterioration (73%), digestive symptoms (58%), liver enlargement (58%) abdominal pain (56%), respiratory symptoms (45%), ascites (26%) and node enlargement (16%). Abnormalities in analysis and image tests were frequent but nonspecific. Median time from admission to death was 42 days (range, 4-135). Pathologic diagnoses at autopsy were: 23 adenocarcinomas (53%), arising from pancreas (6), biliary tree (6), lung (3), prostate (2), stomach (1), kidney (1) and unknown (4); 3 squamous carcinomas (5%) (1 renal pelvis, 1 biliary tree, 1 stomach); 5 undifferentiated carcinomas (1 lung, 4 unknown); and 12 miscellaneous tumors (including 3 lymphomas, 3 neuroendocrine tumors, 3 hepatocarcinomas, 2 mesotheliomas and 1 melanoma). There was a tendency towards a metastatic pattern different from that expected from the primary tumor. Image tests were of little usefulness in the search for the primary tumor. CONCLUSIONS: 1) Adenocarcinomas were the most frequent tumor presenting as NUPS, especially from the pancreas and biliary tree. 2) In this series, at least 11% of patients were amenable to standard systemic therapies (3 lymphomas and 2 prostatic adenocarcinomas) if a correct pathologic diagnosis could have been established when alive. 3) Presenting symptoms and metastatic pattern differed from those expected for the primary neoplasm eventually found. 4) Image tests were often misleading as regards the primary site, although they were useful to quantify the dissemination of the tumor.

Adult↗
PubMed1980

Unusually high creatine kinase BB isoenzyme and study of lactate dehydrogenase pattern in metastatic adenocarcinoma of the prostate.

We report a case of metastatic adenocarcinoma of the prostate with widespread bony and hepatic involvement having extremely high BB isoenzyme of creatine kinase in serum (2405 U/liter). The serum LD5/LD1 ratio is greater than one, with total LD activity more than twenty-five fold the normal value. The homogenate of prostate gland of the patient shows an extra band with electrophoretic mobility between MM and MB isoenzymes of creatine kinase and highly elevated LD5 fraction compared to LD1 (33% vs. 9%), a remarkable LD isoenzyme pattern of malignant prostate tissue.

Adenocarcinoma↗
PubMed1976

"Early" and "late" breast cancer: a unified concept for treatment.

Most women with "early" breast cancer have distant metastases by the time the primary growth comes to diagnosis. This observation is based upon the fact that these frequently appear despite successful removal of the primary growth, and given that they originate from the now no longer present tumour, the inescapable conclusion is that dissemination must have taken place prior to initial treatment. Failure to appreciate this rather obvious point results from shortcomings in available diagnostic technology, and inadequate usage of that which is available. Whether detected early or late, treatment of this disseminated cancer poses a common problem, and the various systemic methods are reviewed. Androgens, oestrogens, progestogens and single drug chemotherapy can, from time to time, produce useful results. By careful selection of patients with appropriate metastatic patterns, these methods may yield improved response rates up to 50% but, by and large, experience remains disappointing with across the board representative figures of perhaps 25% response being commonplace. Additionally, these methods are not without their side effects which can be distressing, and indeed on occasion life-threatening. Their short-comings have led to the development of cyclical combination chemotherapy as here reported. Cyclophosphamide, vincristine, 5-fluorouracil and methotrexate are administered for five consecutive days per month. The results obtained in 100 patients treated with this technique are compared with the authors' previous experience with norethisterone acetate and hypophysectomy. Whether the results are considered in total or broken down into prognostic categories such as predominant metastatic pattern, disease-free interval, or age, combination chemotherapy has a clear advantage over other techniques. Whilst this experience does not constitute a randomised trial, it is considered that the results are so superior to previous treatment techniques as to render such a study unnecessary or even unethical. It is proposed that combination chemotherapy should constitute the first line of treatment for overt advanced breast cancer. It is further proposed that its role should be explored at an earlier stage in the treatment of breast cancer. Before this can take place however, treatment must be made less demanding and less toxic. Further research is underway with these aims in mind.

Breast Neoplasms↗
PubMed2005

In vivo echographic evidence of tumoral vascularization and microenvironment interactions in metastatic orthotopic human neuroblastoma xenografts.

Human neuroblastoma (NB) is the second most frequent solid tumor of childhood and represents a highly heterogeneous disease at clinical and biologic levels. Little progress has been made to improve the poor prognosis of patients with high-stage NB. Tumor progression and metastatic dissemination still represent major obstacles to the successful treatment of advanced stage disease. In order to develop and evaluate new, targeted, therapeutic strategies, fully defined and biologically relevant in vivo models of NB are strongly needed. We have developed an orthotopic model of metastatic human NB in the nude mouse, using 2 well-characterized NB cell lines. Tumor growth, vascular properties and metastatic patterns were investigated using a sensitive and newly developed in vivo echographic technology in addition to immunohistochemistry and PCR analyses. Results show that implantation of low numbers of NB cells directly into the adrenal gland of nude mice resulted in rapid and homogeneous tumor growth without tumor morbidity. Nude mice were shown to rapidly develop highly vascularized adrenal tumors that selectively metastasized to the liver and bone marrow. In addition, the newly formed mouse vessels in orthotopic but not in heterotopic tumors, were found to express the highly angiogenic alphavbeta3 integrin marker, indicating the development of a truly malignant neovasculature in orthotopic conditions only. This observation confirms the impact of the regional microenvironment on tumor biology and suggests the existence of cross-talk with the tumor cells. In conclusion, such model faithfully reproduces the growth, vascular and metastatic patterns as observed in patients. It therefore represents a powerful and biologically relevant tool to improve our understanding of the biology of NB and to develop and assess new antiangiogenic and metastasis-targeted therapies.

Animals↗
PubMed1995

Virchow's node revisited. Analysis with clinicopathologic correlation of 152 fine-needle aspiration biopsies of supraclavicular lymph nodes.

OBJECTIVE: The left supraclavicular lymph node (Virchow's node) may be involved by metastatic malignancies, including those of abdominal or pelvic origin. Almost all previous studies have been based on examination of surgically sampled tissue or postmortem examination. To our knowledge, there has not been a study for nearly 40 years addressing the metastatic pattern to the left supraclavicular lymph node. Furthermore, there has been no study comparing left with right supraclavicular lymph node metastasis or the utilization of fine-needle aspiration biopsy to samples these sites. DESIGN: A retrospective review of 152 fine-needle aspiration biopsies of supraclavicular lymph nodes was performed, and the neoplasms were grouped into six diagnostic categories from five primary regions. RESULTS: The patients ranged in age from 2 years to 94 years (average, 55 years) and consisted of 66 males and 83 females. Three patients were biopsied twice. Of the 152 fine-needle aspirations, 87 (57.2%) were of the left supraclavicular lymph node and 65 (42.8%) of the right supraclavicular lymph node. Of the 96 biopsies positive for malignancy, 58 (60.4%) were biopsies of the left and 38 (39.6%) were of the right supraclavicular lymph nodes. Sixteen of 19 pelvic tumors and all six primary abdominal malignancies metastasized to the left supraclavicular lymph node. Thorax, breast, and head and neck malignancies showed no differences in metastatic patterns to the right and left supraclavicular lymph nodes. Ten patients (10.4% of positive nodes) had a diagnosis of non-Hodgkin's lymphoma, leukemia, or Hodgkin's disease. Six patients (7.1% of positive nodes) had a metastasis of unknown primary site, and 19 cases (19.8%) had acute or chronic inflammation; seven of the latter cases demonstrated acid-fast bacilli in the aspirated smears. CONCLUSIONS: Fine-needle aspiration biopsy is an excellent initial procedure in the workup of an enlarged supraclavicular lymph node. Our study confirmed that malignancies originating in the pelvis or abdomen were significantly more likely to metastasize to the left supraclavicular lymph node and that the primary site and types of malignancies that involved the left supraclavicular lymph node were different from those involving the right supraclavicular lymph node.

Abdominal Neoplasms↗
PubMed1994

Uterine papillary serous carcinoma: patterns of metastatic spread.

Uterine papillary serous carcinoma (UPSC) is a distinct histologic type of endometrial cancer which is associated with a high relapse rate and poor prognosis. Between 1983 and 1993, 50 patients with UPSC of the endometrium were surgically staged. Thirty-three patients had pure UPSC and 17 had UPSC admixed with other histologies. Extrauterine disease was found in 36 women (72%). Lymph node metastases were present in 36% of women without myometrial invasion, 50% with inner one-half invasion, and 40% with outer one-half invasion. Similarly, the presence of intraperitoneal disease or positive washings did not correlate with increasing myometrial invasion. Grade and histology (mixed vs pure) were also not predictive of extrauterine disease. Patients with lymphatic/vascular space invasion (LVSI) were more likely to have extrauterine disease (85%); however, even without LVSI the incidence of extrauterine disease was 58% (P = 0.05). Unlike endometrioid adenocarcinomas, grade and depth of myometrial invasion were not significant predictors for extrauterine disease. This study reinforces the need for complete surgical staging in all patients with UPSC regardless of depth of invasion.

Aged↗