Additional Primary Tumors Research Articles

Second primary epithelial malignancy of nasopharynx and nasal cavity after successful curative radiation therapy of nasopharyngeal carcinoma

Patients with head and neck cancer are at high risk of developing additional second primary tumors in the aerodigestive tract as a result of the field cancerization phenomenon. In this context, the appearance of a new neoplasm often poses a problem in differential diagnosis between recurrence and new primary tumor. Twelve patients with nasopharyngeal carcinoma (NPC) who received radiation therapy for the primary tumor and developed a second epithelial malignancy in the nasal cavity or nasopharynx during the follow-up period are presented in this report. The differentiation between the 2 entities based on the spatiotemporal relations, histological features, and the status of Epstein-Barr virus in tumor lesions are also presented. Our study showed that the epithelial malignancy after NPC having late-onset or prolonged interval (range, 5 to 18 years), different histological patterns (keratinizing squamous cell carcinoma, neuroendocrine carcinoma, or small cell carcinoma) distinct from the primary NPC (differentiated or undifferentiated nonkeratinizing carcinoma), and absence of Epstein-Barr virus, indicate a newly developed tumor rather than recurrent NPC. Our observations showed for the first time that second primary epithelial malignancy developed in the nasal cavity or nasopharynx years after curative therapy for NPC with a prevalence of 0.4% (12/2,794). Wild-type p53 protein was expressed more often in the original NPC (9 of 12) than in the second tumors (4 of 10), but the significance was not statistically significant (P = .2048). Genomic analysis for p53 mutation and in situ hybridization for human papillomavirus showed negative results, indicating that both important molecular events in NPC or head and neck cancer play a small role in this particular type of newly developed second malignant tumor. More studies are warranted for further clarification for the development of second epithelial malignancies in treated NPC patients.

Chemoprevention in head and neck cancer: Basic science and clinical application

The concept of field cancerization and the multistep carcinogenesis theory are the premises on which the development of chemoprevention efforts has been based. The first concept underlies the fact that patients who have been cured of a cancer in the aerodigestive tract are still at risk of developing additional primary tumors in the same field, and the multistep carcinogenesis theory implies that the conceivable arrest of one of the steps by chemoprevention might be enough to impede the development of cancer. There is ongoing research for development of new candidate-chemopreventive substances in most areas of oncology. Most of the clinical experience in chemoprevention of head and neck cancer is based on the use of retinoids. Retinoids in high doses have demonstrated activity in treating oral premalignant lesions (OPLs) but with frequent side effects and early relapse after cessation of therapy. Subsequent trials showed better tolerability of retinoids in lower doses. Ongoing trials are currently evaluating whether chemoprevention over 3 years might have longer-lasting effect both on OPLs and in the prevention of second primary tumors.

Breakpoints of 19q13 translocations of benign thyroid tumors map within a 400 kilobase region

Structural rearrangements involving the long arm of chromosome 19 characterize a cytogenetic subgroup of benign thyroid tumors. To localize the breakpoint of the 19q13 aberrations, we have established three cell lines derived from benign thyroid tumors showing translocations in this region. We have used these cell lines and four additional primary tumors with 19q13 abnormalities for fluorescence in situ hybridization (FISH) mapping studies with ten cosmid clones located between the molecular markers POLD1 and TNNT1. The breakpoints of all chromosome 19 abnormalities mapped within a 400 kb region.

Breakpoints of 19q13 translocations of benign thyroid tumors map within a 400 kilobase region

Structural rearrangements involving the long arm of chromosome 19 characterize a cytogenetic subgroup of benign thyroid tumors. To localize the breakpoint of the 19q13 aberrations, we have established three cell lines derived from benign thyroid tumors showing translocations in this region. We have used these cell lines and four additional primary tumors with 19q13 abnormalities for fluorescence in situ hybridization (FISH) mapping studies with ten cosmid clones located between the molecular markers POLD1 and TNNT1. The breakpoints of all chromosome 19 abnormalities mapped within a 400 kb region. Genes Chromosomes Cancer 20:201–203, 1997. © 1997 Wiley-Liss, Inc.

Factors affecting smoking cessation in patients with head and neck cancer.

The role of tobacco in the etiology of upper aerodigestive tract carcinomas is well established. Smoking decreases the effectiveness of cancer therapy and increases the risk of all treatment modalities. Smoking adversely affects the general health of the cancer survivor and places the patient at risk of developing additional primary tumors. The smoking habits of head and neck cancer patients were evaluated using a questionnaire administered at two tertiary head and neck cancer centers. Demographic factors, level of exposure, tumor stage and location, treatment modalities, concomitant alcohol use, and cessation methods were examined. Results demonstrate a high rate of smoking cessation at the time of cancer diagnosis. Significant demographic factors were not identified. Physical barriers to continued smoking because of cancer treatment as well as counseling at the time of tumor diagnosis were the most effective deterrents to continued tobacco use. Heavy alcohol use was a negative predictor of smoking cessation. Pharmacologic aids alone were found to be of no value. This study demonstrates the difficulties with smoking cessation in head and neck cancer patients, and emphasizes the importance of intervention by the otolaryngologist-head and neck surgeon.

A retrospective study of pancreatic tumors in slaughter cattle.

Sixteen primary pancreatic tumors were found in a retrospective study of bovine pancreatic lesions detected in slaughtered cattle. Eleven islet cell tumors and three pancreatic exocrine carcinomas were identified based on light microscopy and immunohistochemistry. Nine of 11 islet cell tumors were classified as malignant. Metastatic sites included iliac, mediastinal, hepatic, and mesenteric lymph nodes, peritoneum, mesentery, and liver. Six cows with multiple islet cell tumors also had pheochromocytomas. All 11 islet cell tumors had positive immunoreactivity to insulin and somatostatin. Three tumors also contained cells immunoreactive for glucagon and two tumors contained pancreatic polypeptide immunoreactive cells. Immunoreactivity of tumor cells in metastatic sites was similar to their respective primary tumors. All exocrine pancreatic carcinomas metastasized widely and were immunonegative for insulin, somatostatin, glucagon, and pancreatic polypeptide. No mixed endocrine-exocrine tumors were identified. None of the endocrine or exocrine tumors contained amyloid. Additional primary tumors of the bovine pancreas included one neurofibroma and one neurofibrosarcoma. Additional cases with lesions of the bovine pancreas included nodular hyperplasia in 15 cows, exocrine acinar atrophy and fibrosis in four cows (two of which also had pancreatic lithiasis), pancreatitis in one cow, peripancreatic fibrosis in two cows, pancreatic steatosis in one animal, and pancreatic hemorrhages in one cow.

Recurrences and second primary tumours in the head and neck region: Differentiation by p53 mutation analysis

Patients with head and neck cancer are at high risk of developing additional primary tumours in the aerodigestive tract as a result of field cancerization phenomena. In this context, the appearance of a new neoplasm often poses a problem of differential diagnosis between recurrence and new primary tumour. The differentiation between the two entities in essentially clinical and conventionally based on the histological and spatio-temporal relations between the two lesions; however, the validity of these criteria has still to be assessed. To evaluate whether field cancerization phenomena may affect the clinical diagnosis of relapse/metastasis in the head and neck region, p53 mutation pattern was analysed in a series of primary tumours and corresponding recurrences/metastases. The rationale was that, since p53 mutations are a very early and polymorphic phenomenon, a recurrence/metastasis must retain the same mutation as the the primary tumour, whereas independent tumours are likely to display a different p53 gene status. Molecular analysis provided conclusive results in 9 of 12 cases analysed. The clinical diagnosis of recurrence was confirmed by molecular analysis in 4 of these cases. In contrast, a differential p53 mutation pattern supported an independent origin for 3 presumed local recurrences and 2 lung lesions. The use of p53 mutation analysis as a clonality marker allowed us to ascertain the inadequacy of the current diagnostic criteria for the differentiation between a new independent tumour and recurrence/metastasis. These findings substantiate the relevance of field cancerization phenomena in the head and neck region and prompt the use of p53 mutation analysis as a fundamental tool to improve the diagnosis and management of head and neck cancers.

Multiple primary tumours in a population-based series of patients with histopathologically peer-reviewed sarcomas.

Multiple primary tumours occurring in a three-year population-based series of patients with histopathologically peer-reviewed sarcomas from North West England were ascertained in order to look at the patterns of neoplasms seen. A total of 30 out of the 310 patients entered in the study had additional primary tumours. Very few patients were aged under 60 years at diagnosis of both their malignancies. The youngest was a known case of neurofibromatosis and, although seven patients were diagnosed with a sarcoma and carcinoma of the breast--a combination of cancers characteristic of the Li-Fraumeni cancer family syndrome--no other patients could directly be identified as suffering from any other cancer predisposition syndrome.

Meningiomas are not significantly associated with breast cancer.

We studied 283 meningiomas seen at the University of Kansas, Kansas City, from 1948 through 1984, identifying all additional nonmeningeal malignancies and primary brain tumors in these patients and calculating the expected number of additional tumors by the use of a person-year method from age and sex-matched cancer incidence data. We determined expected numbers of total neoplasms in our meningioma population as well as the expected numbers in each major organ system for the sexes independently and together. We then calculated standard morbidity ratios and 95% confidence intervals for each tumor type. The number of breast cancers did not reach statistical significance. We found a significantly increased number of second primary brain tumors in women (standard morbidity ratio, 8.0; 95% confidence interval, 2.2 to 20.4) and an increased number of thyroid cancers in both sexes (standard morbidity ratio, 7.5; 95% confidence interval, 1.5 to 21.9).

Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors.

Hepatitis B virus (HBV) DNA integration has been shown to occur frequently in human hepatocellular carcinomas. We have investigated whether common cellular DNA domains might be rearranged, possibly by HBV integration, in human primary liver tumors. Unique cellular DNA sequences adjacent to an HBV integration site were isolated from a patient with hepatitis B surface antigen-positive hepatocellular carcinoma. These probes detected rearrangement of this cellular region of chromosomal DNA in 3 of 50 additional primary liver tumors studied. Of these three tumor samples, two contained HBV DNA, without an apparent link between the viral DNA and the rearranged allele; HBV DNA sequences were not detected in the third tumor sample. By use of a panel of somatic cell hybrids, these unique cellular DNA sequences were shown to be located on chromosome 4. Therefore, this region of chromosomal DNA might be implicated in the formation of different tumors at one step of liver cell transformation, possibly related to HBV integration.

Development of Additional Primary Tumors After 62 Years in the First Patient with Retinoblastoma Cured by Radiation Therapy

In the first well-documented case of bilateral retinoblastoma to be cured by X-irradiation of the nonenucleated eye, a basal cell carcinoma and then a squamous cell carcinoma of the eyelids developed 60 years after the original treatment. The patient, a 66-year-old man, had been treated by Verhoeff between 1917 and 1919. These new tumors may have been examples of second primary tumors, found in about 0.5% to 2.5% of patients with bilateral retinoblastoma, or they may have been coincidental. Because of the 60-year period between the patient's original treatment and the development of these tumors, it seems unlikely that they were the result of the irradiation.

Lymphocyte cytotoxicity of patients developing multiple primary melanomas.

A study of cellular immunity was conducted, with particular attention to natural killer cell mediated in vitro cytotoxicity in 6 patients who had two or three primary melanomas (2 patients presenting synchronously with multiple primaries and additional melanomas subsequently developing in 4). All 6 patients were reactive to one or other recall skin test antigens (PPD, streptokinase streptodornase (SK-SD), monilia, mumps) and DNCB skin testing. All exhibited natural killing against melanoma and nomelanoma tumor target cells when examined in the 3H proline microcytotoxicity test with unfractionated as well as natural killer cell enriched (Fc receptor positive cells recovered as Fc receptor rosettes) lymphocyte fractions. None of the 4 patients who subsequently had additional primary tumors was found to lack in mature T or natural killer cell mediated cytotoxicity at the time of the development of additional primaries. Two melanoma cell lines were established from two separate primary tumors in 1 patient and in vitro cytotoxicity assays were performed with that patient's lymphocytes (unfractionated, T enriched, and natural killer cell enriched fractions) against these two lines. While the first melanoma cell line was consistently sensitive to lysis by all three lymphocyte fractions, the other cell line showed no sensitivity either for natural killing or for T enriched lymphocyte mediated lysis at any effector to target ratio. These results suggested that in vitro natural cytotoxicity was not translated into any substantive immunoprotective role in the development of multiple primary tumors and that the two separate melanoma cell lines from the same patient were antigenically hererogenous. Antigenic heterogeneity between different primary tumors may explain the lack of immunity against such development of multiple tumors of the same histology.

Cellular immunity in patients with laryngeal cancer developing additional primary malignant tumors.

Eleven patients with laryngeal cancer associated with additional primary tumors underwent cutaneous delayed hypersensitivity tests and lymphocyte stimulation studies with phytohemagglutinin for evaluation of their cellular immunity. Five of the 11 patients were anergic or hypoergic as shown by skin tests to recall antigens and seven of nine patients had impaired lymphocyte transformation. Depressed immunity was more often observed in patients with an active malignancy. The level of serum immunoglobulins was elevated in two of eight studied patients, and in the remaining patients was within the normal range. All patients had a history of excessive smoking. Most frequently, second tumors were found in the lung, urinary tract and skin. The prognosis seemed to be determined by the additional tumor rather than by the laryngeal cancer.

Ethnical and clinical aspects of chronic lymphocytic leukemia in Israel: a survey on 288 patients.

The ethnic distribution of 288 patients with chronic lymphocytic leukemia (CLL) from five medical centers in Israel during the decade 1960--1970 was investigated as well as other features of the disease. 80.5% of the patients were of East European descent, 14.5% originated from Asia and Africa and 5% were born in Israel. Based on the ethnic distribution of the elderly population of Israel during the above period, it is suggested that CLL occurs more frequently in European-born Jews than in Asian and African Jews. A low occurrence of Coombs positive hemolytic anemia was revealed, amounting to 7.2% of the patients. Of 68 patients who underwent serum immunoglobulin studies, up to 74% exhibited deficiency of at least one type of immunoglobulin. Low levels of IgA were encountered in 61.2%, IgM in 51.5% and IgG in 29.5% of the patients. 26 of 206 patients with CLL (12.5%), all of East European origin, had an additional primary malignant tumor, cancer of the skin and breast being the most frequent associated malignancies. In 6 patients of the 26, two additional neoplasms were diagnosed. Hypogammaglobulinemia was more frequent in patients with additional primary malignant tumors and in patients with advanced disease. The possible causes for the ethnic distribution of CLL in Israil as well as of other tumors are discussed.

Laryngeal Carcinoma Associated With Multiple Additional Primary Tumors

Four malignant tumors and one benign in a 76-year-old man appeared. Three of the neoplasms were in the respiratory system, and one was a bladder carcinoma; all were linked to heavy smoking habits. The patient underwent immunologic investigations consisting of in vivo testing for cutaneous reactivity, in vitro lymphocyte blastogenesis studies, T- and B-cell level studies, and serum immunoglobulin level studies. The studies have demonstrated anergy to recall antigens, decreased lymphocyte responses to phytohemagglutinin, and low levels of peripheral T-lymphocytes. The serum immunoglobulins were at the upper limit of the normal. The relationship between the patient's immunologic status and the occurrence of multiple primary neoplasms is discussed.

Squamous carcinoma of the lower lip in patients under 40 years of age.

In a series of 1,308 squamous carcinomas of the lower lip, 97 (7%) occurred in patients under 40. Among the 56 followed up for at least five years, there were 12 deaths due to disease for a determinate mortality of 21%. In five of these patients (41%) the tumor persisted more than three years from the time of initial treatment and in four others (33%), for more than five years. Of all 97 patients, 15 (15%) developed additional primary tumors. Most second lesions were squamous or basal cell carcinomas of the skin; however, four patients developed second primary lesions with considerable malignant potential (one melanoma and three visceral cancers). Three of these patients died of their second tumors, raising the overall mortality to 26%. Squamous carcinoma of the lower lip appears to have a worse prognosis in younger patients. A significant fraction of these patients succumb to their disease more than five years after initial treatment. This, coupled with a tendency to develop significant second primaries, suggests that a protracted period of close clinical follow-up is essential.

Neoplasms of the small bowel.

Small bowel tumors are unusual lesions exhibiting nonspecific clinical features often diagnosed at an advanced stage. In the cases studied at the Hospital of the University of Pennsylvania nearly all the 32 patients with malignancies were symptomatic whereas in the 34 patients with benign lesions the condition was discovered as an incidental finding in about half of the patients. Weight loss, palpable mass or anemia usually indicated malignancy. Small bowel radiography was the most useful diagnostic aid in the present series. While the etiology of these lesions is unknown, villous adenomas probably bear a relationship to carcinoma. The association between chronic regional enteritis and small bowel tumors is unestablished but suggestive. An analysis of reported series reveals a disproportionate incidence of additional primary tumors in patients with small bowel neoplasms. Surgical extirpation is indicated for curative treatment. In the present series, resection in hope of cure was carried out in 25 of 32 malignant tumors resulting in eight five-year survivals. One of these latter lived nine years with disseminated malignant carcinoid reflecting the occasional indolent course of this tumor.