Occurrence Of Multiple Primary Tumors Research Articles

Abstract 771: Mechanisms of genetic predisposition to multifocal lung cancer

Abstract Detection of multiple primary lung cancers is increasing in frequency, with up to 15% of all non-small cell lung cancer (NSCLC) patients presenting with two or more anatomically separate tumor nodules on CT scans. Increased detection is in part due to expanded lung cancer screening criteria in an aging population. Distinguishing multiple primary tumors from intrapulmonary metastases can be challenging, yet is critical for determining clinical management. Current models predict development of multiple primary tumors out of a cancerized field, such as occurs due to smoking. The occurrence of multiple primary tumors is unexplained in patients with EGFR-mutant lung cancer (~15% of all NSCLC), lacking environmental exposures. We identified patients with non-small cell lung cancer (NSCLC) who presented with multiple primary EGFR-mutant tumors, in the absence of family history of lung cancer or heavy smoking. We subjected the macrodissected tumors and surrounding normal tissues to whole exome sequencing as well as to analysis of hypermutable poly-guanine (poly-G) repeats, which are two orthogonal methods of lineage tracing. An additional familial case with a germline EGFR-T790M mutation was used to establish parameters for timing of somatic mutations, and functional properties of novel germline variants were modeled in vitro. Of eleven non-familial NSCLC cases with two or more geographically distinct EGFR-mutant lung cancers, two patients harbored a germline EGFR variant allele, which confers moderately enhanced signaling in vitro, followed by a somatically acquired EGFR mutation. In an additional four cases, both whole exome sequencing and poly-G repeat analyses indicate a distant shared somatic cell-of-origin, consistent with embryonic mosaicism. Three cases revealed clinically unappreciated metastasis and two cases remain unexplained. Together, our data suggest that multiple primary lung cancers with somatic EGFR driver mutations may result from genetic susceptibility, attributable either to attenuated EGFR germline variants or to embryonic mosaicism resulting in geographically disparate patches of predisposed lung tissue. Such predisposed cases should be surveilled for early detection of future tumors, and surgical resection in these cases should consider the life-long risk of additional cancers. Citation Format: Risa Burr, Ignaty Leshchiner, Christina L. Costantino, Martin Blohmer, Tilak Sundaresan, Justin Cha, Karsen Seeger, Sara Guay, Brian P. Danysh, Ira Gore, Raquel A. Jacobs, Kara Slowik, Filippo Utro, Kahn Rhrissorrakrai, Chaya Levovitz, Jaimie L. Barth, Taronish Dubash, Brian Chirn, Laxmi Parida, Lecia V. Sequist, Mari Mino-Kenudson, Kamila Naxerova, Shyamala Maheswaran, Gad Getz, Daniel A. Haber. Mechanisms of genetic predisposition to multifocal lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 771.

Multiple primary tumors: a\xa0case report and review of the literature

BackgroundMultiple primary tumors, especially quadruple primary neoplasms is extremely rare. Fibrous dysplasia (FD), osteosarcoma (OS), and giant cell tumor of bone (GCTB) are three bone tumors with low incidence while primary pulmonary meningioma is a rare disease. In this case report, we present a unique synchronous occurrence of these four separate pathological conditions.Case presentationA 53-year-old male previously underwent resection of OS of fifth rib and FD of eighth rib 1 year ago. Recently, a discontinuous pain at right knee developed. Serial X-ray films showed a progressively pure osteolytic lesion of proximal tibia which extended gradually. The incisional biopsy revealed that this tumor was confirmed as GCTB, and the tumor was successfully managed by extensive curettage and bone cement filling. The diagnosis of GCTB was re-confirmed by the postoperative histopathologic examinations. High-throughput sequencing from the GCTB exhibited a somatic mutation of H3.3A (G35W exon2). Germline testing revealed a germ-cell variant in gene of BRCA2 (exon 8 V220Ifs*4).ConclusionsThis is a unique case with quadruple primary tumors. Germline mutation in gene of BRCA2 may be associated with the occurrence of multiple primary tumors in this patient.

MIR605 rs2043556 is associated with the occurrence of multiple primary tumors in TP53 p.(Arg337His) mutation carriers

Li-Fraumeni and Li-Fraumeni-like (LFS/LFL) Syndrome are cancer predisposition syndromes caused by germline pathogenic variants in TP53 and are associated with an increased risk of multiple early-onset cancers. In Southern and Southeastern Brazil, a germline founder variant with partial penetrance located in the oligomerization domain of TP53, c.1010G>A p.(Arg337His, commonly known as R337H), has been detected in 0.3% of the general population. Recently, the functional MIR605 variant rs2043556 (A>G) has been identified as a novel LFS phenotype modifier in families with germline TP53 DNA binding variants. In this study, our goal was to verify MIR605 rs2043556 allele frequencies and further explore its possible effects on the phenotype of 238 Brazilian individuals carrying TP53 p.(Arg337His). The MIR605 rs2043556 G allele was detected in 136 (57.1%) individuals, including 25 homozygotes (10.5%), and although it had been previously associated with an earlier mean age of tumor onset, this effect was not observed in this study (p = 0.8). However, in p.(Arg337His) mutation carriers, the GG genotype was significantly associated with the occurrence of multiple primary tumors (p = 0.005). We provide further evidence of MIR605 rs2043556 G allele's effect as a phenotype modulator in carriers of germline TP53 pathogenic variants.

Impact of a complex nutraceutical supplement on primary tumour formation and metastasis in Trp53+/– cancer-prone mice

A complex dietary supplement designed to impact multiple mechanisms associated with aging and cancer reduced overall tumorigenesis in cancer-prone heterozygous Trp53+/- mice by ~30% (P < 0.018). Carcinomas were reduced by 67% (P < 0.006). Remarkably, metastasis (a leading cause of cancer mortality) was undetectable in treated animals (P < 0.004), and the occurrence of multiple primary tumours was reduced by 74% (P < 0.012). Reduction of pulmonary adenocarcinoma by 62% (P < 0.021) was of particular note given that lung cancer is the second leading cause of death in humans. Tumours showed pronounced age-related expression in untreated animals older than 600 days. Benefits of treatment only emerged in these later ages, suggesting that the supplement acted on mechanisms common to aging and cancer. The supplement was administered daily on bagel bits that were usually eaten within minutes by the mice. Although longevity was not statistically different between treatments, longevity was strongly related to the compliance of mice in eating the supplement. Linear regression revealed a strong positive relationship between the proportion of supplement eaten and the longevity of mice within the treatment group (P < 0.0001).

Uncommon Lesions in the Internal Auditory Canal (IAC): Review of the Literature and Case Report

Despite the relatively frequent occurrence of multiple primary tumors, namely, 10% of intracranial tumors, metastasis is a rare occurrence within the internal auditory canal (IAC) and cerebellopontine angle (CPA). Intracanalicular metastases of adenocarcinoma are documented, but a primary adenocarcinoma remains unreported. We provide a review of uncommon lesions in the IAC and describe to our knowledge the first instance of a primary adenocarcinoma. A 60-year-old man presented with nausea and vomiting. Cranial computed tomography scan revealed bilateral nonspecific periventricular and subcortical vascular lesions. He presented 8 months later with left-sided tinnitus, progressive hearing loss, and attacks of vertigo. Magnetic resonance imaging (MRI) showed an extra-axial mass most likely representing a left-sided vestibular schwannoma with characteristic contrast enhancement in the IAC. The follow-up MRI showed an unchanged pattern of contrast enhancement. Due to progressive headaches and dizziness, the patient underwent a left transtemporal craniotomy with subtotal tumor resection. Histological examination revealed blennogenic cylindrical adenocarcinoma. The investigations for the primary tumor site were all negative. The patient's condition deteriorated gradually. MRI showed an increase of the residual tumor and meningeosis carcinomatosa, and cerebrospinal fluid (CSF) examination was positive for tumor cells. The patient was treated with intrathecal chemotherapy. He died of multiple organ failure. The discussion focuses on the incidence of extra-axial CPA and IAC lesions with their clinical presentations and their radiological findings. We address the issue of a possible regulation of CPA lesion laterality by asymmetrically expressed genes. In view of the sparse literature on treatment of single intracanalicular metastases, the review is broadened to the current treatment recommendations of single brain metastases. The differentiation between benign and malign lesions in the CPA and IAC is important, as it requires diverse treatment protocols. For the physician this differentiation represents a clinical and radiological challenge. For the developmental research the left-right asymmetry might be a field of research.

CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women

BackgroundMutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women...

Double primary tumor of the stomach and the prostate managed robotically simultaneously.

The occurrence of multiple primary tumors is rare. Here we present a case of a 65-year-old male with a longstanding cardiac condition who presented with synchronous adenocarinoma of the stomach and prostate. Both cancers were managed simultaneously using robot-assisted laparoscopy techniques. Subtotal gastrectomy with gastro-jejunostomy and nerve-sparing radical prostatectomy were performed successfully. Post-operative course was likewise uneventful. Operative and oncologic outcomes were excellent with the patient cancer-free after one year of follow up. We believe the robotic system enabled us to manage this case simultaneously with excellent results.

Multiple Primary Tumors in Differentiated Thyroid Carcinoma and Relationship to Thyroid Cancer Outcome

Patients with differentiated thyroid carcinoma (DTC) have long-life expectancy and are at risk for developing a second primary cancer. Aim of this study was to assess the occurrence of DTC in conjunction with other primary neoplasms. It was also aimed to explore the possibility of synchronous or metachronous other malignancies having an impact on clinical course of thyroid carcinoma. Clinical records of 1680 DTC patients treated and followed in our institution over last twenty years were reviewed. Forty-five second primary tumors were found in 42 patients. These patients were classified into 3 groups as antecedent (group I), synchronous (group II) or subsequent (group III) according to the timing of occurrence of non-thyroidal malignancy. The initial characteristics of thyroid neoplasm were compared between patients with DTC plus another tumor and DTC only. Kaplan-Meier Survival Analysis was used to estimate the survival probability for patients with DTC alone and DTC plus another primary tumor. There were 15 synchronous and 30 metachronous tumors in 42 patients. Three of them had triple tumors. The most common second primary was lympho-haematological and upper aero digestive system tumors in group I and II respectively, whereas a variety of tumors were noted in group III. Despite the more common occurrence of unfavourable prognostic factors in patients with multiple cancers than thyroid cancer alone, complete response to radioiodine therapy and recurrence free survival rate was similar in both groups (p>0.05). The results of the current series imply that the occurrence of multiple primary tumors is not uncommon in patients with DTC. Close medical surveillance and the use of advanced screening modalities might lead to the detection of second primary tumors in DTC. However, the presence of second primary seems not to affect the clinical course of DTC.

MDM2 Promoter Polymorphism Is Associated With Both an Increased Susceptibility to Gastric Carcinoma and Poor Prognosis

Recently, a single-nucleotide polymorphism in the MDM2 promoter (SNP309) has been found to lower the age of onset of tumors and increase the occurrence of multiple primary tumors in Li-Fraumeni syndrome, and accelerate the development of sporadic adult soft tissue sarcoma. The aim of this study was to determine whether SNP309 is associated with susceptibility to gastric carcinoma and its prognosis. In a case-control study including 438 controls and 410 patients with sporadic gastric carcinoma, MDM2 SNP309 was genotyped. Serum pepsinogens (PGs) I and II were measured in 438 control subjects and 253 cases selected from 410 patients. Tumor tissue was immunostained with p53 and examined for mutations in exons 5 to 8 of p53 using polymerase chain reaction-based single strand conformational polymorphism analysis and direct sequencing. The risk of overall gastric carcinoma for SNP309 (G/G) was significantly increased when compared with T carriers (P = .039), especially carcinomas with extragastric tumors (P = .005), carcinoma with severe atrophic gastritis positive for PG assay (PG I level < 70 ng/mL and PG I/II < 3.0; P = .005), antral carcinoma (P = .020), intestinal-type carcinoma (P = .023), p53-immunopositive carcinoma (P = .007), and carcinoma with p53 mutations (P = .007). No significant difference in age at diagnosis was observed among genotypes. SNP309 (G/G) was an independent marker of poor overall survival in advanced carcinoma (hazard ratio, 3.16; 95% CI, 1.22 to 8.20; P = .018). This study provides evidence supporting the association of SNP309 with gastric carcinogenesis via p53 tumor suppressor pathway, extragastric tumorigenesis, and poor prognosis.

Squamous cell carcinoma of the esophagus and multiple primary tumors of the upper aerodigestive tract.

Squamous cell carcinoma of the esophagus is frequently associated with other, synchronous or metachronous tumors, in the upper aerodigestive tract. All 264 patients with squamous cell carcinoma of the esophagus, treated in the Gastrointestinal Surgery, Esophagus section, of the "Hospital das Clínicas" (São Paulo University Medical School, Brazil), between 1979 and 1989 were analyzed retrospectively with regards to the occurrence of multiple primary tumors in the upper aerodigestive tract. Multiple primary tumors were encountered in 10 (3.8%) patients. All patients were male and the mean age at the time of the first primary was 52.2 years. Tobacco smoke and alcohol were the principal carcinogens in these patients (n = 10). The sites of the tumors were: larynx (n = 4), tongue (n = 4), lung (n = 2), and oral cavity (n = 1). Two simultaneous, three synchronous and five metachronous multiple primary carcinomas were detected. The esophagus was the second primary tumor in nine patients. The mean overall survival after the diagnosis of the second primary was 2.8 months (SD = 0.89). Inquiry regarding other malignancies, associated with panendoscopy should be carry out prior to the treatment of the first primary to diagnose simultaneous or synchronous primary tumors, and careful follow-up should be performed after treatment of the first primary to detect new tumors in these high-risk patients.

Retinoid chemoprevention studies in upper aerodigestive tract and lung carcinogenesis : Lippman SM, Benner SE. Waun Ki Hong Thoracic/Head/Neck Med. Oncol. Dept., Texas Univ. M. D. Anderson Can. Ctr., Box 80, 1515 Holcombe Boulevard, Houston, TX 77030. Cancer Res 1994; 54: Suppl 2025s-8s

Chemoprevention is a clinical strategy to block or reverse carcinogenesis before the development of invasive cancer. Studies of chemoprevention in the lungs and upper aerodigestive tract have relied on the field carcinogenesis hypothesis, which predicts that diffuse epithelial injury will result from exposure of that epithelium to carcinogens. This hypothesis is supported by the frequent occurrence of multiple primary tumors within the exposed field. In addition, the understanding of carcinogenesis as a multistep process supports the use of interventions in damaged epithelium before the development of clinically invasive cancer. Current efforts are focused on applying to chemoprevention studies the increasing knowledge of the molecular events in carcinogenesis. In our program, clinical trials in lung and head and neck chemoprevention have focused on individuals with evidence of field carcinogenesis, i.e., a history of previous epithelial cancer or the presence of premalignant lesions. These trials include studies to develop clinically applicable intermediate markers of carcinogenesis and large Phase III trials to evaluate the efficacy of the retinoid isotretinoin in preventing second primary tumors following head and neck or lung cancers.

Flow cytometric DNA-ploidy analysis of synchronously occurring multiple malignant tumors of the female genital tract

In this study the authors applied flow cytometric DNA-ploidy analysis to multiple female genital tract malignant tumors in 43 patients, most of whom (n = 37) had bilateral ovarian cancer. An algorithm was developed for calculation of the likelihood ratio of the probabilities that measured DNA index differences between multiple tumor localizations within the same patient could be attributed to measurement variation or to true biologic DNA content differences. The results of this statistical analysis show that in 72% of the cases (31 of 43) this probability ratio exceeded 1. Because the probability that two independent tumors will have a near-identical aneuploid DNA content is very low, this finding supports a metastatic process rather than the occurrence of multiple primary tumors in these patients. Thus, flow cytometric DNA-ploidy analysis can be helpful in the identification of metastatic disease in patients with multiple female genital tract malignant tumors.

Multiple primary tumors in patients with laryngeal squamous cell hyperplasia.

We analyzed retrospectively the case histories of 204 patients with squamous cell hyperplasia of the larynx for the occurrence of multiple primary tumors. All patients were grouped according to Kleinsasser's 1963 classification of laryngeal pathology. Patients with simple hyperplasia (class I) had a low risk for developing a coincidental primary tumor. The rist was 7% in patients with hyperplasia with atypia (class II) and was 15% in patients with carcinoma in situ (class III). This frequency is similar to that of our patients with glottic cancer (13%). Although no coincidental tumors were found in our female patients, the small number of females in our series made the differences in frequency between males and females not significant. This is still of interest to us because our previous study of patients with proven glottic cancers also showed that no second tumors occurred in our female patients. This difference was statistically significant. In our present study, all second tumors occurred metachronously. Our findings indicate that all patients with class III laryngeal disease (carcinoma in situ) should undergo the same aggressive search for second primary tumors, as do patients with invasive glottic cancers. This means that panendoscopy or bronchoscopy should be done at the initial work-up and also at periodic intervals during the follow-up period. We have also found that patients lacking immunoglobulin allotype Km(1) have to be followed aggressively, since these patients are at high risk of developing multiple tumors. A possible exception can be made for female patients.

Metastases of cancer to primary intracranial tumor.

Introduction The occurrence of multiple primary tumors in one patient has been noted frequently and is no longer considered remarkable. However, metastasis of cancer to another primary tumor is distinctly uncommon. Only five previous instances of metastasis to primary intracranial tumors have been reported. Osterberg 1 found three cases of metastatic carcinoma in meningioma; in two the metastasis originated from a primary site in the breast, and in one, from the bronchus. He added two cases. One patient was a 51-year-old white man with symptoms of a brain tumor. At craniotomy a meningioma was removed, which on microscopic examination contained large clear cells. The diagnosis was renalcell carcinoma metastatic to a meningioma; this could not be confirmed by further clinical study, and autopsy was not permitted. The second patient was a 71-year-old white man who died of bronchogenic carcinoma with widespread metastases. At autopsy an incidental parasagittal meningioma was found