Occurrence Of Multiple Tumors Research Articles

Warthin's tumour: a study of 78 cases with emphasis on bilaterality, multifocality and association with other malignancies.

The authors reviewed the clinical records and the histopathological preparations of 78 cases of Warthin's tumours (WTs), treated at the Department of Dental Sciences, Centre for the Study of Oral Tumours, of the University of Bari. All the surgical specimens had been fixed in neutral buffered formalin, sampled according to the step-serial, whole-specimen sectioning technique, embedded in paraffin and stained with haematoxylin-eosin, periodic acid Schiff and Gomori's reticulin. The results showed that Warthin's tumours characteristically affect the parotid gland, and most frequently arise in adults (mean age=57 years) and in males (95%). Multiple tumours were detected in 16 cases (20.5%), and five of these were bilateral (6.5%). One of the multifocal tumours involved an intra-parotideal lymph node and the laryngeal piriform sinus. In addition, 13 cases (16.6%) were associated with other malignancies. These data indicate that multiple (synchronous or metachronous) WTs may occur more frequently than previously reported. The high rate of multiple WTs detected in the current study may result from extensive and accurate sampling of these neoplasms for histopathological evaluation. Consequently, complete preoperative work-up of patients harbouring parotideal tumours consistent with or suspicious for WT is necessary. The work-up should include CT scans and/or magnetic resonance imaging of both parotid glands, to exclude the occurrence of multiple tumours, which may be clinically undetectable. Also, fine needle aspiration biopsy may be an accurate tool for excluding malignant neoplasms and for better planning subsequent surgical procedures. These usually consist in (bilateral) superficial parotidectomy and should be followed by long term follow up of the patients, in view of possible metachronous WTs, even after prolonged time intervals.

The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association

The neurofibromatosis 2 protein product merlin, named for its relatedness to the ezrin, radixin and moesin (ERM) family of proteins, is a tumour suppressor whose absence results in the occurrence of multiple tumours of the nervous system, particularly schwannomas and meningiomas. Merlin's similarity to ERMs suggests that it might share functions, acting as a link between cytoskeletal components and the cell membrane. The N-terminus of merlin has strong sequence identity to the N-terminal actin-binding region of ezrin; here we describe in detail the merlin–actin interaction. Employing standard actin co-sedimentation assays, we have determined that merlin isoform 2 binds F-actin with an apparent binding constant of 3.6μM and a stoichiometry of 1mol of merlin per 11.5mol of actin in filaments at saturation. Further, solid-phase binding assays reveal that merlin isoforms 1 and 2 bind actin filaments differentially, suggesting that the intramolecular interactions in isoform 1 might hinder its ability to bind actin. However, merlin does not bind G-actin. Studies of actin filament dynamics show that merlin slows filament disassembly with no influence on the assembly rate, indicating that merlin binds along actin filament lengths. This conclusion is supported by electron microscopy, which demonstrates that merlin binds periodically along cytoskeletal actin filaments. Comparison of these findings with those reported for ERM proteins reveal a distinct role for merlin in actin filament dynamics.

The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association.

The neurofibromatosis 2 protein product merlin, named for its relatedness to the ezrin, radixin and moesin (ERM) family of proteins, is a tumour suppressor whose absence results in the occurrence of multiple tumours of the nervous system, particularly schwannomas and meningiomas. Merlin's similarity to ERMs suggests that it might share functions, acting as a link between cytoskeletal components and the cell membrane. The N-terminus of merlin has strong sequence identity to the N-terminal actin-binding region of ezrin; here we describe in detail the merlin-actin interaction. Employing standard actin co-sedimentation assays, we have determined that merlin isoform 2 binds F-actin with an apparent binding constant of 3.6 microM and a stoichiometry of 1 mol of merlin per 11.5 mol of actin in filaments at saturation. Further, solid-phase binding assays reveal that merlin isoforms 1 and 2 bind actin filaments differentially, suggesting that the intramolecular interactions in isoform 1 might hinder its ability to bind actin. However, merlin does not bind G-actin. Studies of actin filament dynamics show that merlin slows filament disassembly with no influence on the assembly rate, indicating that merlin binds along actin filament lengths. This conclusion is supported by electron microscopy, which demonstrates that merlin binds periodically along cytoskeletal actin filaments. Comparison of these findings with those reported for ERM proteins reveal a distinct role for merlin in actin filament dynamics.

Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses.

The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.

Coexistence of two different intraspinal tumors

The occurrence of multiple neoplasms in the central nervous system is well documented. In von Recklinghausen's disease, patients frequently present with multiple neurofibromas and/or meningiomas at different sites within the spinal axis. However, the presence of multiple, histologically different spinal tumors in the absence of von Recklinghausen's disease is extremely rare. The authors describe a patient with progressive paraparesis in whom an extradural, malignant lesion and a separate benign, intradural tumor of the thoracic spine were found. The histological diagnosis of the intradural tumor was a pigmented schwannoma. On review of the literature, the authors found nine additional cases of coexisting, histologically different tumors of the spine. The majority of these tumors occurred in the thoracic spine and, not unexpectedly, intradural meningiomas and schwannomas prevailed. Except for the presumed same mesenchymal cell origin of neurinomas and meningiomas, no explanation for the coexisting, different spinal tumors could be determined.

Solitary, multiple, and familial oxyphil tumours of the thyroid gland.

A study of 169 oxyphil tumours of the thyroid, correlating histological features with age, sex, thyroiditis, and available clinical history, has shown two significant findings relevant to pathogenesis, diagnosis, and treatment. Oxyphil tumours with a papillary architecture can be divided into papillary carcinomas with secondary oxyphilia and true oxyphil tumours. The tumours of the former group are typically unencapsulated, invasive, show nuclei characteristic of papillary carcinoma generally, are associated with thyroiditis, and frequently show psammoma bodies. The tumours of the latter group are typically encapsulated, with nuclei similar to those found in other oxyphil tumours; usually lack psammoma bodies; and some show capsular and vascular invasion. Papillary architecture alone is not thought to justify a diagnosis of malignancy in this group of tumours, and further study with follow-up is needed to determine the appropriate treatment. It is suggested that oxyphilia in the first group is secondary to the accompanying thyroiditis, comparable to the oxyphilia in follicular cells in Hashimoto's thyroiditis, while the oxyphilia in the latter group, as in other oxyphil tumours, is due to a somatic mutation leading to an increase in mitochondrial number. About 20 per cent of all cases showed multiple oxyphil tumours. These were more frequently female, more often associated with thyroiditis, younger, and less often malignant than solitary tumours. The occurrence of multiple tumours of the same uncommon histological type in these patients is compatible with a germline mutation conferring a liability to oxyphil follicular cell tumours. This is supported by the occurrence of oxyphil tumours in families; the present series of cases included two mother-daughter pairs and similar examples have been reported, including multiple oxyphil tumours in identical twins. Further studies are needed to identify the gene involved and any co-operating genes. Oxyphil carcinoma in patients with multiple oxyphil tumours occurred at a mean age 10 years greater than that for multiple adenomas, suggesting that the carcinomas arose by progression from adenomas. It is important to complete thyroidectomy in a case with multiple oxyphil tumours if there is evidence of the presence of lesions in both lobes. It is necessary to consider the differences between primary and secondary oxyphilia, and between sporadic and multiple or familial oxyphil tumours in future studies of these lesions.

Solitary, multiple, and familial oxyphil tumours of the thyroid gland

A study of 169 oxyphil tumours of the thyroid, correlating histological features with age, sex, thyroiditis, and available clinical history, has shown two significant findings relevant to pathogenesis, diagnosis, and treatment. Oxyphil tumours with a papillary architecture can be divided into papillary carcinomas with secondary oxyphilia and true oxyphil tumours. The tumours of the former group are typically unencapsulated, invasive, show nuclei characteristic of papillary carcinoma generally, are associated with thyroiditis, and frequently show psammoma bodies. The tumours of the latter group are typically encapsulated, with nuclei similar to those found in other oxyphil tumours; usually lack psammoma bodies; and some show capsular and vascular invasion. Papillary architecture alone is not thought to justify a diagnosis of malignancy in this group of tumours, and further study with follow-up is needed to determine the appropriate treatment. It is suggested that oxyphilia in the first group is secondary to the accompanying thyroiditis, comparable to the oxyphilia in follicular cells in Hashimoto's thyroiditis, while the oxyphilia in the latter group, as in other oxyphil tumours, is due to a somatic mutation leading to an increase in mitochondrial number. About 20 per cent of all cases showed multiple oxyphil tumours. These were more frequently female, more often associated with thyroiditis, younger, and less often malignant than solitary tumours. The occurrence of multiple tumours of the same uncommon histological type in these patients is compatible with a germline mutation conferring a liability to oxyphil follicular cell tumours. This is supported by the occurrence of oxyphil tumours in families; the present series of cases included two mother–daughter pairs and similar examples have been reported, including multiple oxyphil tumours in identical twins. Further studies are needed to identify the gene involved and any co-operating genes. Oxyphil carcinoma in patients with multiple oxyphil tumours occurred at a mean age 10 years greater than that for multiple adenomas, suggesting that the carcinomas arose by progression from adenomas. It is important to complete thyroidectomy in a case with multiple oxyphil tumours if there is evidence of the presence of lesions in both lobes. It is necessary to consider the differences between primary and secondary oxyphilia, and between sporadic and multiple or familial oxyphil tumours in future studies of these lesions.Copyright © 1998 John Wiley & Sons, Ltd.

Benign schwannoma and parathyroid adenoma occurring in the nonradiated neck: Report of two cases

The late occurrence of multiple neoplasms in the previously radiated neck is a well-known association. However, multiple tumours in the nonradiated neck remain a rare finding. This paper presents two cases of the infrequently seen schwannoma occurring with a parathyroid adenoma without antecedent history of radiation or neurofibromatosis.

MULTIPLE PRIMARY MALIGNANT TUMORS OF THE BREAST ASSOCIATED WITH OTHER ORGANS

During the past 20 years, we have treated 570 female primary breast cancers. Of these, 17 breast cancers (3.0%) were primary multiple malignant tumors with malignancies of other organs. The definition of primary multiple malignant tumors was based on the report by Warren & Gates. When multiple tumors were detected within one year, the tumors were considered as synchronous; otherwise, tumors detected at an interval period of over one year were metachronous. In 17 primary multiple tumors of the breast and other organs, 4 were synchronous. In the remaining 13 metachronous tumors, the breast cancers preceded in 6, and other organ tumors preceded in 7. The organs where other tumors occurred included the uterus in 35.3%, the stomach in 23.5%, and the rectum in 11.8%. As of the interval period for detection, 4 metachronous second tumors were found more than 10 years following identification of the first tumors. The relation with postoperative adjuvant therapy indicated that 5.7% of total breast cancers which were treated with chemotherapy and radiation therapy were associated with occurrence of multiple tumors. Prognosis of these multiple malignant tumors was dependent on the organs involved and the staging of the tumors. The present study suggests that careful postoperative follow-up for more than 10 years is needed after treatment of the first developed malignant tumors.

Radiation-induced thyroid and other head and neck tumors: occurrence of multiple tumors and analysis of risk factors.

In 2561 patients who received conventional external radiation treatment before age 15 yr for benign conditions of the head, neck, and upper thoracic area, we found an increase in the number of salivary gland tumors and benign neural tumors of the head and neck area. To determine whether patients who developed these relatively uncommon tumors were more susceptible to the long term effects of radiation, we analyzed how frequently these patients also developed benign and malignant thyroid neoplasms. Compared to the remainder of the irradiated population, the patients with salivary and neural tumors had an increased frequency of thyroid disease (19.4% vs. 11.2% for thyroid cancer and 52.4% vs. 39.9% for all thyroid nodules). Various risk factors were studied to determine whether they were related to the eventual occurrence of thyroid disease. Higher doses, being female, and lower ages at time of treatment were associated with increased risk. However, these factors did not fully explain the differences in the frequency of coexisting tumors, suggesting that additional factors, such as radiation sensitivity, may account for the increased risk.

Canine Mammary Gland Tumors

An understanding of the known biologic facts of this disease and methodical evaluation of the individual patient are necessary prerequisites for outlining rational courses of therapy for dogs afflicted with mammary tumors. Because of the common occurrence of multiple tumors arising at various stages of development simultaneously and the heterogeneity of histology of the complex (mixed tissue types) tumors, presurgical biopsy is recommended only in cases in which mast cell tumor or anaplastic carcinoma is suspected. Although investigative work is being performed regarding the efficacy of chemotherapy, radiation therapy, and immunotherapy, surgery still remains the mainstay in treatment of this condition. No one surgical procedure fits the needs of all patients, although it seems logical to remove as much breast tissue as is reasonable in each circumstance owing to the multicentric nature of the disease. Ovariohysterectomy has not been demonstrated to be of value in treatment of dogs with mammary tumors, but it is a markedly effective method of preventing mammary tumors if it is performed before puberty; it is moderately effective if performed before the dog is 21/2 years of age.

Predicting breast cancer recurrence.

The prognostic value of 435 cytochemical, cytometrical, morphological, epidemiological, and clinical variables was analyzed in a prospective study of 179 breast cancer patients followed for five years after mastectomy. A variable reduction was obtained by first selecting variables correlated with recurrence rate in direct (Student's t test) or correlation analysis with consideration of the type of variable analyzed (nominal, interval, ordinal). The 20 variables most strongly correlated with recurrence were analyzed by logistic stepwise regression analysis in order to find out what combination of variables had most discriminatory power in predicting recurrence. It was found that axillary metastization as such was correlated with a combination of variables describing mitotic frequency, size of primary tumor and differentiation of the primary tumor (average cluster size in fine-needle biopsies). It was also found that there was a strong time dependency in the predictive power of the variables, so that different variable combinations predicted the recurrence rate during the first 2.5 year period (size of axillary metastases and primary tumor, number of lymphocytes around the tumor, mitotic frequency, and degree of differentiation) compared with the second 2.5 year period (variance of DNA content among tumor cell nuclei, number of lymphocytes around the tumor, occurrence of multiple tumors in the operated breast and occurrence of breast cancer among relatives). While other factors previously shown to be correlated with risk of recurrence were also found to be positively correlated here, they were neither as highly predictive as, nor did they increase the predictive value of the above mentioned combined variables. The current study strongly emphasizes that, at the present time, studies of recurrence prediction in human breast cancer should be based on an optimal combination of a number of variables which, independently, influence the prognosis. Further, the current study indicates that prerequisite methods for predicting breast cancer recurrence exist today.

Pancreatic vein catheterization with gastrin assay in normal patients and in patients with the Zollinger-Ellison syndrome

Simultaneous catheterization of the aorta and the caval, portal, and pancreatic veins with blood sampling for gastrin radioimmunoassay was performed in three patients with the Zollinger-Ellison syndrome and in five control patients without peptic ulcer disease. In the controls the gastrin concentrations in the pancreatic veins ranged from 15 to 148 pg/ml (mean, 65; median, 67). Pre- and postoperative catheterizations were performed in two of the Zollinger-Ellison patients, and very high gastrin concentrations in several pancreatic veins indicated the occurrence of multiple tumors, whereas angiography was able to reveal only one tumor in one of the patients. Twelve months after extirpation of the tumors and total gastrectomy, gastrin concentrations in peripheral as well as pancreatic venous blood were lower but still pathologically high. The third patient was catheterized twice, two and twelve months after tumor extirpation and total gastrectomy. The gastrin values from this patient were within the range of the reference group except for one pancreatic vein with slightly increased concentrations. The gastrin concentration did not increase in the interval between the two catheterizations. No complications were noted. The triple catheterization technic with blood sampling for hormone assay is advocated as a diagnostic tool and as a localization procedure in patients with suspected or proved Zollinger-Ellison syndrome.

The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases.

T UE morphologic and histogenetic criteria distinguishing congenital from neoplastic vascular lesions of the brain have been alternately assailed and upheld. Cushing and BaileS ,s designated hemangioblastomas of the brain as true neoplasms, for they were composed of mature and immature vascular elements which enlarged by proliferation and supposedly contained no glial cells. Thereafter Bailey and Ford 1 demonstrated the presence of astrocytes in such a tumor which infiltrated the cerebellum. Hemangioblastomas of the brain occur most commonly in the cerebellum. 5,15,1s,19,~1 They are usually characterized grossly by a cyst of variable size, filled with clear or xanthochromic fluid, in which a mural nubbin of tumor is found. Microscopically, these mural tumors are composed of variable proportions of adult and immature vascular elements. In some cases the solid mass is composed almost exclusively of adult capillary or cavernous structures and in other instances primarily of vasoformative tissue. In other cysts, careful search is necessary to identify minute buried or sclerosed nodules of tumor. The characteristic cystic development is caused by an inherent line of differentiation of the immature cellular elements of the solid mural nodule. 13 The cyst is the result of the process of differentiation of blood vessels and the formation of primitive plasma from masses of angioblasts. This line of vascular differentiation gives even solid tumors a grossly spongy appearance. When hemangioblastomas of the brain are associated with tumors of the eye, skin, spinal cord or viscera, 2-4, 9-11 the patient may present a distinct clinical syndrome with a familial history. Unfortunately, many clinical variants or anatomical associations of lesions have been dignified by proper names. This cumbersome, although flattering, nomenclature, through sharp selection of cases, tends to obscure the underlying interrelationship of the variants. The occurrence of multiple tumors in a patient with a known hereditary predisposition suggests an arrest or defect in maturation of one or more tissues at a particular time in embryological development. Thus, morphologic variations of vascular tumors may merely reflect a level of maturation of primitive vascular mesenchyme.

Incidence of Multiple Primary Tumors and the Problem of Acquired Cancer Immunity

While multiple tumors of identical type are frequently encountered in the same person, as for instance in all cases of multicentric skin lesions and of metastasis, we are justified in speaking of multiple primary tumors only when we are reasonably sure that such tumors have developed independently and have no ascertainable direct or indirect connection with each other. This lack of connection is obvious in the case of combinations of tumor types entirely dissimilar morphologically and clinically, as for example tumors arising from embryologically different layers, as connective tissue and epithelium, and in the case of manifestly benign tumors and definitely malignant neoplasms. On the other hand, the differential diagnosis may become extremely difficult or even impossible if we are confronted with a combination of morphologically or clinically similar tumors. To exclude metastases, Billroth formulated the following postulates, which he believed should be fulfilled before a diagnosis of multiple primary tumors can be given: 1. That the tumors have a different anatomical structure. 2. That each tumor be histogenetically derived from the tissues of the organ in which it is primarily found. 3. That each malignant growth have its own metastases. These requirements appear too strict. It is impossible to insist on metastasis as a diagnostic sine qua non in every case of malignant neoplasm. In addition, it is well possible that, because of a variety of factors, a tumor may be modified in structure and character to such a degree as almost completely to lose its original type and identity. Etiologically, tumor multiplicity may be explained as the effect of multiple cell implantation, of multiple stimuli, or of multiple primordial cell nests (Geschwulst-Anlagen). Lubarsch interprets the occurrence of multiple tumors as evidence of a general tumor diathesis, while Walter thinks that in the majority of cases it signifies nothing more than a coincidence. Among 3,700 consecutive autopsies performed by the Department of Pathology of the University of Colorado Medical School from 1925 to 1940, 42 examples of multiple primary tumors were recorded. An analysis of these cases shows that in 38 instances two tumors were found in the same person, while in 4 cases the patient harbored three tumors. A combination of benign tumors only was seen but twice. The most frequent combination was that of a benign and a malignant tumor. This combination was seen in 27 patients. The combination of two benign tumors and one malignant tumor occurred in 3 cases. In 9 cases, two independent malignant tumors were observed simultaneously, while in still another case two primary malignant tumors were seen together with a benign tumor.

The production of cancer by pure hydrocarbons. V

Tests for carcinogenic activity have been carried out with about seventy compounds, mostly new substances specially synthesized for the purpose and related to known carcinogenic compounds. The results support the view that there is a definite association between molecular structure and carcinogenic action; thus in the 3:4-benzphenanthrene series, which has not hitherto been investigated extensively, positions 1 and 2 seem to be the favourable points for substitution. The capacity to produce epithelioma does not always run parallel with the capacity to produce sarcoma. Some preliminary observations are given upon the occurrence of multiple tumours in animals receiving some classes of these compounds; this subject requires much further investigation with animals in which the spontaneous incidence of such tumours is known.

MULTIPLE MYELOMAS OF CHILDREN

The occurrence of multiple tumors of the skeleton has been recognized for many years, especially in adults. The frequency of multiple myeloma is either increasing, or the clinical diagnosis and reports of cases are being made more frequently. Previous to 1916, Martini1collected only 204 cases of this type of multiple bone tumor reported in the literature. All of the cases reported were in adults, the youngest patient being 24 years of age. As two cases of multiple myelomas of children have come under my observation, I feel that they should be recorded in the literature. Harbitz2reported two cases of multiple bone tumors involving the cranial bones, ribs, sternum and vertebrae, which were associated with enlargement of the liver and spleen. He suggested the name, myeloerythroblastoma for these tumors because of their microscopic structure. The term multiple myelomas was first applied in 1876 by Rustizky to a