Deciphering clonal dynamics and metastatic routines in a rare patient of synchronous triple-primary tumors and multiple metastases with MPTevol.

Multiple primary tumor (MPT) is a special and rare cancer type, defined as more than two primary tumors presenting at the diagnosis in a single patient. The molecular characteristics and tumorigenesis of MPT remain unclear due to insufficient approaches. Here, we present MPTevol, a practical computational framework for comprehensively exploring the MPT from multiregion sequencing (MRS) experiments. To verify the utility of MPTevol, we performed whole-exome MRS for 33 samples of a rare patient with triple-primary tumors and three metastatic sites and systematically investigated clonal dynamics and metastatic routines. MPTevol assists in comparing genomic profiles across samples, detecting clonal evolutionary history and metastatic routines and quantifying the metastatic history. All triple-primary tumors were independent origins and their genomic characteristics were consistent with corresponding sporadic tumors, strongly supporting their independent tumorigenesis. We further showed two independent early monoclonal seeding events for the metastases in the ovary and uterus. We revealed that two ovarian metastases were disseminated from the same subclone of the primary tumor through undergoing whole-genome doubling processes, suggesting metastases-to-metastases seeding occurred when tumors had similar microenvironments. Surprisingly, according to the metastasis timing model of MPTevol, we found that primary tumors of about 0.058-0.124 cm diameter have been disseminating to distant organs, which is much earlier than conventional clinical views. We developed MPT-specialized analysis framework MPTevol and demonstrated its utility in explicitly resolving clonal evolutionary history and metastatic seeding routines with a rare MPT case. MPTevol is implemented in R and is available at https://github.com/qingjian1991/MPTevol under the GPL v3 license.

Germline mutation and aberrant transcripts of WWOX in a syndrome with multiple primary tumors.

Multiple primary tumors are defined by the presence of two or more independent primary tumors in the same or different organs of an individual patient. However, the underlying genetic cause for the development of multiple primary tumors is largely unknown. In the study, we report a rare case with four synchronous distinct histological cancer types in a 26 years old Chinese female. In the patient, whole-exome sequencing identified a homozygous germline insertion mutation in WWOX which encodes the DNA repair-related enzyme, WW domain containing oxidoreductase. The mutation was found in a heterozygous state in her parents and brother without any cancer phenotype thus far. Surprisingly, we found multiple novel aberrant WWOX transcripts in the patient's normal colon tissue. The patient's colon metastasis from clear cell adenocarcinoma of the ovary showed a nonhypermutated profile enriched for C-T transition, and harbored somatic pathogenic mutations of HRAS, BRCA2, SMAD4, CHEK2, and AKT1 genes. To our knowledge, this is the first study reporting WWOX gene aberrations in a young patient with the early occurrence of multiple primary tumors. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Management and survival trends for adult patients with malignant gliomas in the setting of multiple primary tumors: a population based analysis.

INTRODUCTION: The impact of multiple primary tumors, in the setting of malignant glioma (MG), has not been heavily explored. METHODS: We extracted demographics and clinical data from the SEER-18 registry for adult patients with MGs. The cases were separated based on the sequence of MG diagnosis relative to the other primary tumors: Group (A) One primary only or first primary of multiple primaries and Group (B) second primary or subsequent primary tumor. Incidences, frequencies, and glioma-related survivals were analyzed. RESULTS: Group B constituted 12.8% of new MG. The incidences of group B, relative to those of all new MG, range from 0.14 to 0.18. Compared to group A, group B exhibited an older age. Moreover, group B exhibited a higher proportion of females, Caucasians, smaller tumors, non-operative cases, and those receiving radiation (p < 0.05); the proportion with GTR remained comparable. Multiple groupings (oral cavity, digestive system, respiratory system, skin, breast, genital systems, urinary system, lymphoma) exhibited lower glioma-related observed survival (p < 0.05) compared to Group A. An active diagnosis of "leukemia" appears to confer longer glioma-related survival while a history of "breast" or "digestive system" malignancies portends a shorter glioma-related survival. CONCLUSION: For newly diagnosed MG, a high proportion does have history of extra-CNS primary tumors. Generally, these patients appear to have worse glioma-related observed survival compare to those with malignant glioma as the only primary or the first of multiple primary tumors. Knowledge regarding epidemiology, clinical factors, and observed survival can help guide clinical management/consultation for this subset of patients.

EGFR copy number alterations in primary tumors, metastatic lymph nodes, and recurrent and multiple primary tumors in oral cavity squamous cell carcinoma.

BACKGROUND: The EGFR and downstream signaling pathways play an important role in tumorigenesis in oral squamous cell carcinoma (OSCC). Gene copy number alteration is one mechanism for overexpressing the EGFR protein and was also demonstrated to be related to lymph node metastasis, tumor invasiveness and perineural invasion. Therefore, we hypothesized that EGFR gene copy number alteration in the primary tumor could predict amplification in recurrent tumors, lymph node metastatic foci or secondary primary tumors. METHODS: We recruited a group of newly diagnosed OSCC patients (n = 170) between Mar 1997 and Jul 2004. Metastatic lymph nodes were identified from neck dissection specimens (n = 57). During follow-up, recurrent lesions (n = 41) and secondary primary tumors (SPTs, n = 17) were identified and biopsied. The EGFR gene amplifications were evaluated by fluorescence in situ hybridization (FISH) assay in primary tumors, metastatic lymph nodes, recurrences and SPTs. RESULTS: Of the 170 primary OSCCs, FISH showed low EGFR amplification/polysomy in 19 (11.4%) patients and amplification in 33 (19.8%) patients. EGFR gene amplification was related to lymph node metastasis (χ2 trend test: p = 0.018). Of 57 metastatic lymph nodes, nine (15.8%) had EGFR polysomy and 14 (24.6%) had EGFR gene amplification. The concordance rate of EGFR gene copy number in primary tumors and lymph node metastasis was 68.4% (McNemar test: p = 0.389). Of 41 recurrent tumors, five (12.2%) had EGFR polysomy and five (12.2%) had gene amplification. The concordance rate of EGFR gene copy number between primary tumors and recurring tumors was 65.9% (McNemar test: p = 0.510). The concordance rate between primary tumors and SPTs was 70.6%. EGFR amplification in either primary tumors, metastatic lymph nodes or recurrent tumors had no influence on patient survival. CONCLUSION: We can predict two-thirds of the EGFR gene copy number alterations in lymph node metastasis or recurrent tumors from the analysis of primary tumors. For OSCC patients who are unable to provide lymph node or recurrent tumor samples for EGFR gene copy number analysis, examining primary tumors could provide EGFR clonal information in metastatic, recurrent or SPT lesions.

Concomitant Heart, Ovaries, and Renal Neoplasms: Atypical Findings During Hypertension Evaluation.

Multiple primary tumors is defined as the occurrence of two or more primary lesions, benign or malignant, where each tumor occur in separate sites and is neither an extension, recurrence, nor metastasis [1]. The occurrence of multiple primary tumors is extremely rare with an incidence of less than 4 % [2] of the total tumor cases. We present a case of synchronous heart, ovaries, and kidney tumors in a 63-year-old Caucasian female patient whom primarily attended our institution for a hypertension evaluation. The case we report relates to diagnosis and treatment of the three synchronous lesions unveiled during the work-up.

Trichoblastoma and breast carcinoma as metachronous primary tumors: Case report.

INTRODUCTION AND IMPORTANCE: The occurrence of more than one tumor originating from the same or different organs is the definition of multiple primary tumors. According to the time of diagnosis, these tumors are classified into two types: metachronous and synchronous tumors. Trichoblastoma is a rare benign skin tumor that is rarely involved in multiple primary tumors, especially in patients with breast cancer. CASE PRESENTATION: A 60-year-old male with left breast and lateral chest wall masses. Lastly, he has been diagnosed with invasive ductal carcinoma of the left breast and chest wall trichoblastoma as metachronous primary tumors with no significant genetic background. CLINICAL DISCUSSION: With the development in the medical field, such tumors are being encountered more. Some authors suggest a relationship between these tumors and genetic mutations. Although rare trichoblastomas can be transformed into malignant tumors and get metastasized. CONCLUSION: The diagnosis and management of primary tumors can be challenging in some cases. Researchers should focus on further exploration of the genetic bases and risk factors of such tumors.

Exploring the Susceptibility to Multiple Primary Tumors in Patients with Differentiated Thyroid Cancer.

PURPOSE: It was demonstrated that differentiated thyroid cancer (DTC) patients may develop multiple primary tumors (MPT) during follow-up. Many studies showed an association between reduced telomere length and cancer phenotype; in particular, the short telomeres were associated with the development of a primary tumor. However, the role of altered telomere length in MPT development has not yet been demonstrated. The aim of this study was to evaluate the possible correlation between a short telomere length in blood leukocytes and the risk of developing MPT in DTC patients. PATIENTS AND METHODS: We retrospectively evaluated 167 DTC patients followed up for a median of 13.6 years. Our control group was represented by 105 healthy subjects without any thyroid disease or present or past history of tumors. Our study groups, age-matched, were evaluated for the relative telomere length measured in leukocytes of peripheral venous blood. RESULTS: The relative telomere length (RTL) was significantly different in healthy subjects compared to the total group of differentiated thyroid cancer patients [p < 0.0001]. Shorter telomeres length was observed in DTC patients with (n = 32) and without (n = 135) MPT compared to healthy subjects (p < 0.0001 and p = 0.0002, respectively). At multivariate analysis, the parameters independently associated with the presence of MPT were RTL [OR: 0.466 (0.226-0.817), p = 0.018] and the familial DTC [OR: 2.949 (1.142-8.466), p = 0.032]. CONCLUSIONS: The results of this study suggest a role of the relative telomere length in predicting MPT development in DTC patients. Our results contribute to increasing the knowledge of the genetic mechanisms underlying MPT development in DTC patients, considering relative telomere length as a possible prognostic marker.

Primary coexisting adenocarcinoma of the colon and neuroendocrine tumor of the duodenum: A case report and review of the literature.

BACKGROUND: Neuroendocrine tumors (NETs) arise from the body's diffuse endocrine system. Coexisting primary adenocarcinoma of the colon and NETs of the duodenum (D-NETs) is a rare occurrence in clinical practice. The classification and treatment criteria for D-NETs combined with a second primary cancer have not yet been determined. CASE SUMMARY: We report the details of a case involving female patient with coexisting primary adenocarcinoma of the colon and a D-NET diagnosed by imaging and surgical specimens. The tumors were treated by surgery and four courses of chemotherapy. The patient achieved a favorable clinical prognosis. CONCLUSION: Coexisting primary adenocarcinoma of the colon and D-NET were diagnosed by imaging, laboratory indicators, and surgical specimens. Surgical resection combined with chemotherapy was a safe, clinically effective, and cost-effective treatment.

Quadruple primary tumors in a lynch syndrome patient surviving more than 26 years with genetic analysis: a case report and literature review.

The incidence of multiple primary tumors(MPTs) is on the rise in recent years, but patients having four or more primary tumors is still rare. Lynch syndrome (LS) patients have a high risk of developing MPTs. NGS sequencing could identify the genetic alterations in different tumors to make a definite diagnosis of uncommon cases in clinical practice. Here, we report the case of a 66-year-old female patient who develops four MPTS between the ages of 41 and 66, that is sigmoid colon cancer, acute non-lymphocytic leukemia, urothelial carcinoma and ascending colon cancer. She has survived for more than 26 years since the first discovery of tumor. Targeted sequencing indicates that she has a pathogenic germline mutation in the exon 13 of MSH2, and her 2020 ureteral cancer sample and 2023 colon cancer sample have completely different mutation profiles. To the best of our knowledge, this is the first case of multiple primary tumors with an acute non-lymphocytic leukemia in LS patients.

Multiple Warthin Tumors With Epithelial-Myoepithelial Carcinoma of the Ipsilateral Parotid Gland: A Case Report.

Multiple primary tumors of the parotid gland refer to the occurrence of 2 or more primary tumors in the ipsilateral or bilateral parotid gland metachronously or synchronously, which do not originate from postoperative recurrence or metastasis. Multiple primary tumors of the parotid gland, especially synchronous benign and malignant tumors, are extremely uncommon. A rare case of multiple Warthin tumors with epithelial-myoepithelial carcinoma of the ipsilateral parotid gland is reported as follows.

Germline whole genome sequencing in adults with multiple primary tumors.

Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored. Here, we report our germline sequencing results from WGS in 9 patients with MPTs who had non-informative multigene panel testing. Following germline WGS, sequence (agnostic or 735 selected genes) and copy number variant (CNV) analysis was performed according to the American College of Medical Genetics (ACMG) standards and guidelines for interpreting sequence variants and reporting CNVs. In this cohort, WGS, as a second-tier test, did not identify additional pathogenic or likely pathogenic variants in cancer predisposition genes. Although we identified a CHEK2 likely pathogenic variant and a MUTYH pathogenic variant, both were previously identified in the multigene panels and were not explanatory for the presented type of tumors. CNV analysis also failed to identify any pathogenic or likely pathogenic variants in cancer predisposition genes. In summary, after multigene panel testing, WGS did not reveal any additional pathogenic variants in patients with MPTs. Our study, based on a small cohort of patients with MPT, suggests that germline gene panel testing may be sufficient to investigate these cases. Future studies with larger sample sizes may further elucidate the additional utility of WGS in MPTs.

A rare case of double primary lung adenocarcinomas with uncommon complex EGFR G719X and S768I mutations and pleomorphic carcinoma.

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-targeted therapy has emerged as a viable treatment for patients with advanced non-small cell lung cancer with common EGFR mutations. The uncommon G719X and S768I mutations can co-occur as complex mutations in the same tumor. Here we report a case of a 72-year-old male patient with double lung carcinoma, with G719X and S768I complex mutations detected in the right upper lung lobe along with brain metastases. Osimertinib (80 mg/day) was administered as the first-line treatment, and a reduction in the right lobe tumor and brain lesions was achieved. However, the left upper lung lobe mass remained unchanged; histopathological examination via a lobectomy revealed pleomorphic carcinoma. Thus, the patient was diagnosed with multiple primary lung cancers. In conclusion, osimertinib is a viable treatment option for lung cancer with rare EGFR G719X and S768I complex mutations.

Clinical characteristics and survival of glioblastoma complicated with non-central nervous system tumors.

BACKGROUND: Diagnosis and treatment of patients with glioblastoma (GBM) who are also diagnosed with primary non-central nervous system (CNS) tumors remain a challenge, yet little is known about the clinical characteristics and prognosis of these patients. The data presented here compared the clinical and pathological features between glioblastoma patients with or without primary non-CNS tumors, trying to further explore this complex situation. METHODS: Statistical analysis was based on the clinical and pathological data of 45 patients who were diagnosed with isocitrate dehydrogenase (IDH) wild-type glioblastoma accompanied by non-CNS tumors between January 2019 and February 2022 in Beijing Tiantan Hospital. Univariate COX proportional hazard regression model was used to determine risk factors for overall survival. RESULTS: It turned out to be no significant difference in the overall survival (OS) of the 45 patients with IDH-wild-type GBM plus non-CNS tumors, compared with the 112 patients who were only diagnosed with IDH-wild-type GBM. However, there was a significant difference in OS of GBM patients with benign tumors compared to those with malignant tumors. CONCLUSIONS: Implications for the non-central nervous system tumors on survival of glioblastomas were not found in this research. However, glioblastomas complicated with other malignant tumors still showed worse clinical outcomes.

Multiple primary malignant neoplasm: Case report and comprehensive literature review.

Multiple primary tumors, especially quadruple primary tumors, are extremely rare clinically, and there is no standard protocol for clinical management. We described a case in which a bone tumor, a malignant bladder tumor, a malignant melanoma, and an intrahepatic cholangiocarcinoma were all original malignancies. The patient is a 79-year-old woman who underwent surgery for a left middle finger bone tumor 45 years ago, as well as surgery for bladder malignancy and postoperative adjuvant chemotherapy 15 years ago, and the precise pathological results and treatment are unclear. One year ago, she underwent amputation of the toe due to a black mass of the right toe and was diagnosed pathologically as a freckled malignant melanoma of the extremity. Prior to postoperative adjuvant systemic medication, PET/CT revealed malignancy in the lateral segment of the left lobe of the liver, and multiple lymphadenopathies in the left parotid gland, hilar hepatic, and retroperitoneal region. Intrahepatic cholangiocarcinoma was found in the liver puncture biopsy's pathology report. The serum sample's next-generation sequencing (NGS) revealed a missense mutation, designated P.G12V, in exon 2 of the KRAS gene. Based on patients with malignant melanoma and intrahepatic cholangiocarcinoma, she received 6 cycles of GP (gemcitabine/cisplatin) combined with Camrelizumab systemic therapy, and followed by 3 cycles of Camrelizumab maintenance therapy, the efficacy was evaluated as stable disease (SD) during treatment. When the 4th cycle of Camrelizumab was suggested for maintenance therapy, the efficacy evaluation revealed that the tumor had greatly advanced. The patient refused to continue anti-tumor therapy and passed away from septic shock and multiple organ failure 3 months later. The patient had satisfactory efficacy and lived for a year after being diagnosed with two primary cancers. Despite the rarity of quadruple primary tumors and the lack of a conventional clinical management strategy, we postulate that germline mutations in the KRAS gene may be closely associated with the formation and development of multiple primary tumors. NGS testing is necessary for clinical management, and systemic treatment based on concurrent multiple main tumors is the key to improving prognosis.

The Common Thread: A Case of Synchronous Lung Cancers and a Germline CHEK2 Mutation.

Patients with one form of cancer are at increased risk for another, and this is true for lung cancer, where synchronous primary lung cancers are an increasing multifaceted challenge.1,2 Here, we present the case of a middle age woman who was found to have bilateral lung masses. Biopsy and subsequent testing revealed unique synchronous lung adenocarcinomas, each with unique genetic signatures. Despite having two unique tumors, she was found to have CHEK2 mutations in both tumors and in germline testing. Because of this extensive testing that showed unique tumors, she was ultimately diagnosed with stage IIIb and IA2 lung cancers, and this changed her treatment options. Consideration of unique primary tumors leads to thorough diagnostics, which changed this patient's diagnosis, prognosis, and treatment. We hope this case raises awareness for multiple primary tumors, as well as CHEK2 as an important oncogene.

A Female With Synchronous Multiple Primary Malignant Tumors in the Esophagogastric Junction, Duodenum and Pancreas: Case Report and Review of the Literature.

The incidence of multiple primary carcinomas (MPCs), which are defined as two or more malignancies detected in an individual person, is gradually increasing around the world. According to the timing of diagnosis for each constituent tumor, MPCs are classified into 2 categories: synchronous MPCs if constituent tumors emerge simultaneously or within 6 months or metachronous MPCs otherwise. In this report, we describe our recent observation and treatment of a female patient with synchronous primary esophagogastric junction adenocarcinoma, duodenal adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). To the best of our knowledge, this combination has not yet been reported in the literature. A crucial aspect is the decision regarding which tumor to treat initially and how to schedule further treatments according to individual tumor hazards. Our multidisciplinary team devised an individualized treatment regimen for this patient. The patient ultimately achieved an overall survival time of 18 months, which was much longer than the median survival time (6~11 months) of patients with locally advanced pancreatic cancer. Moreover, treating this rare combination raised a series of diagnostic, etiological and therapeutic questions, motivating us to carry out a critical review of the literature. In summary, an individualized treatment strategy with input from a dedicated multidisciplinary team and consideration of all options at different points along the disease trajectory is essential to optimize outcomes for patients with MPC.

Synchronous Diagnosis of Squamous Cell Carcinoma of the Lung and Mixed Cellularity Hodgkin Lymphoma of the Nasopharynx.

Hodgkin lymphoma (HL) is a highly curable B cell lymphoproliferative neoplasm with a bimodal age distribution. Lung cancer is the leading cause of cancer-related deaths in both sexes. We present a rare case of synchronous squamous cell carcinoma (SCC) of the lung and mixed cellularity HL of the nasopharynx. A gentleman in his 70s presented with right-sided chest pain and shortness of breath. CT of the chest showed a peripheral lung mass, and a biopsy confirmed SCC of the lung. The patient underwent a positron emission tomography/computed tomography (PET/CT) for staging that revealed an 18F-fluorodeoxyglucose (FDG)-avid mass in the nasopharynx. Flexible nasal endoscopy and biopsy of the nasopharyngeal mass revealed mixed cellularity classical HL. The patient was started on chemoimmunotherapy for lung cancer. Unfortunately, two months after initiation of treatment, the patient died from COVID-19 pneumonia and multiorgan failure.

Long-Term Survival of a Lynch Syndrome Patient With Eight Primary Tumors: A Case Report.

With the modern technological developments in the diagnosis and treatment of cancer, the survival rate of cancer patients has increased. On the other hand, the incidence of multiple primary tumors is increasing annually. Lynch syndrome (LS), an autosomal dominant disorder with germline mutations in DNA mismatch repair genes, increases the risk of cancer in patients carrying those mutations. In this report, we present an extremely rare case of an 81-year-old male patient with eight primary malignancies and LS. The patient is still alive having survived for more than 41 years since the initial discovery of the first tumor. The eighth and most recently diagnosed primary cancer was a malignant peripheral nerve sheath tumor. Although there have been numerous reports of malignancies in LS, malignant peripheral nerve sheath tumors have not been reported previously with LS. Here, we report, to the best of our knowledge, the first case of a malignant peripheral nerve sheath tumor with LS.

Warthin's Tumor Unexpectedly Detected in Submandibular Gland After Neck Dissection in Carcinoma of Floor of Mouth: A Case Report.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the world, and it is extremely rare that HNSCC occurs with salivary gland tumor(s). Here, we presented a rare case that squamous cell carcinoma of floor of mouth occurred simultaneously with Warthin's tumor in the submandibular gland. CASE PRESENTATION: A 65-year-old Chinese male presented with a 6-month history of an ulcer on the floor of the mouth and preoperative biopsy pathological examination demonstrated it was squamous cell carcinoma. Postoperative microscopic examination unexpectedly found the carcinoma occurred simultaneously with two Warthin's tumors in the right submandibular gland. CONCLUSION: This case serves as a reminder to oral surgeons that in head and neck carcinomas, enlarged lump may be caused by inflammation or secondary primary focus rather than lymph node metastasis. Recognition and implication of the unexpected pathologic findings in patients with head and neck cancer are thus worth of studying.