[Multiple primary tumors in children: a clinicopathological analysis of four cases].

Objective: To investigate the clinicopathological features of children with metachronous or synchronous primary tumors and to identify related genetic tumor syndromes. Methods: The clinicopathological data of 4 children with multiple primary tumors diagnosed in the Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China from 2011 to 2023 were collected. The histological, immunophenotypic and molecular characteristics were examined using H&E staining, immunohistochemical staining, PCR, Sanger sequencing and next-generation sequencing (NGS). The patients were followed up. Results: Case 1 was an 8-year-old boy with the adrenal cortical carcinoma, and 5 years later a poorly differentiated gastric adenocarcinoma was detected. Case 2 was a 2-year-old boy, presented with a left ventricular choroid plexus carcinoma, and a hepatoblastoma was detected 8 months later. Case 3 was a 9-month-old girl, diagnosed with renal rhabdoid tumor first and intracranial atypical teratoid/rhabdoid tumor (AT/RT) 3 months later. Case 4 was a 7-year-old boy and had a sigmoid colon adenocarcinoma 3 years after the diagnosis of a glioblastoma. The morphology and immunohistochemical features of the metachronous or synchronous primary tumors in the 4 cases were similar to the corresponding symptom-presenting/first-diagnosed tumors. No characteristic germ line mutations were detected in cases 1 and 2 by relevant molecular detection, and the rhabdoid tumor predisposition syndrome was confirmed in case 3 using NGS. Case 4 was clearly related to constitutional mismatch repair deficiency as shown by the molecular testing and clinical features. Conclusions: Childhood multiple primary tumors are a rare disease with histological morphology and immunophenotype similar to the symptom-presenting tumors. They are either sporadic or associated with a genetic (tumor) syndrome. The development of both tumors can occur simultaneously (synchronously) or at different times (metachronously). Early identification of the children associated with genetic tumor syndromes can facilitate routine tumor screening and early treatment.

When Lightning Strikes Twice: Routes to Second Malignancies in Young Patients.

SUMMARY: Given the rarity of cancer in childhood, it should be even more uncommon for pediatric cancer survivors to develop a second, independent malignancy, yet they incur a greatly elevated risk after initial remission. In this issue of Cancer Discovery, Sánchez-Guixé and colleagues unpick the origins of second tumours in four children, and the potential role platinum-based chemotherapy may play in subsequent tumorigenesis. See related article by Sánchez-Guixé et al., p. 953 (8).

Risk factors for secondary thyroid cancer in patients with breast cancer: a propensity­matched SEER analysis.

With the rapid development of imaging technology and comprehensive treatment in modern medicine, the early diagnosis rate of breast cancer is constantly improving, and the prognosis is also improving; As breast cancer patients survive longer, the risk of developing second primary cancers increases. Since both breast and thyroid are Hormone receptor sensitive organs, which are regulated by hypothalamus pituitary target gland endocrine axis, changes in body endocrine status may lead to the occurrence of these two diseases in succession or simultaneously. This study extracted clinical data and survival outcomes of breast cancer patients registered in the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2019. After matching the case and controls with propensity scores, the selected patients were randomly split into training and test datasets at a ratio of 7:3. Univariate and multivariate COX proportional regression analysis is used to determine independent risk factors for secondary thyroid cancer and construct a column chart prediction model. Age, ethnicity, whether radiotherapy, tumor primary location, N stage, M stage were identified by Cox regression as independent factors affecting secondary thyroid cancer in patients with breast cancer patients, and a risk factor nomogram was established to predict patients' 3 and 5 year survival probabilities. The AUC values for 3 and 5 years in the training set were 0.713, 0.707, and the c-index was 0.693 (95% CI 0.67144, 0.71456), and the AUC values for 3 and 5 years in the validation set were 0.681, 0.681, and the c-index was 0.673 (95% CI 0.64164, 0.70436), respectively.

Risk and prognosis of secondary lung cancer after radiation therapy for thoracic malignancies.

OBJECTIVE: Radiation therapy (RT) may increase the risk of second cancer. This study aimed to determine the association between exposure to radiotherapy for the treatment of thoracic cancer (TC) and subsequent secondary lung cancer (SLC). MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (from 1975 to 2015) was queried for TC. Univariate Cox regression analyses and multiple primary standardized incidence ratios (SIRs) were used to assess the risk of SLC. Subgroup analyses of patients stratified by latency time since TC diagnosis, age at TC diagnosis, and calendar year of TC diagnosis stage were also performed. Overall survival and SLC-related death were compared among the RT and no radiation therapy (NRT) groups by using Kaplan-Meier analysis and competitive risk analysis. RESULTS: In a total of 329 129 observations, 147 847 of whom had been treated with RT. And 6799 patients developed SLC. Receiving radiotherapy was related to a higher risk of developing SLC for TC patients (adjusted HR, 1.25; 95% CI, 1.19-1.32; P < 0.001). The cumulative incidence of developing SLC in TC patients with RT (3.8%) was higher than the cumulative incidence (2.9%) in TC patients with NRT(P). The incidence risk of SLC in TC patients who received radiotherapy was significantly higher than the US general population (SIR, 1.19; 95% CI, 1.14-1.23; P < 0.050). CONCLUSIONS: Radiotherapy for TC was associated with higher risks of developing SLC compared with patients unexposed to radiotherapy.

Histology-specific standardized incidence ratio improves the estimation of second primary lung cancer risk.

BACKGROUND: Lung cancer (LC) survivors are at increased risk for developing a second primary cancer (SPC) compared to the general population. While this risk is particularly high for smoking-related SPCs, the published standardized incidence ratio (SIR) for lung cancer after lung cancer is unexpectedly low in countries that follow international multiple primary (IARC/IACR MP) rules when compared to the USA, where distinct rules are employed. IARC/IACR rules rely on histology-dependent documentation of SPC with the same location as the first cancer and only classify an SPC when tumors present different histology. Thus, SIR might be underestimated in cancer registries using these rules. This study aims to assess whether using histology-specific reference rates for calculating SIR improves risk estimates for second primary lung cancer (SPLC) in LC survivors. METHODS: We (i) use the distribution of histologic subtypes of LC in population-based cancer registry data of 11 regional cancer registries from Germany to present evidence that the conventional SIR metric underestimates the actual risk for SPLC in LC survivors in registries that use IARC/IACR MP rules, (ii) present updated risk estimates for SPLC in Germany using a novel method to calculate histological subtype-specific SIRs, and (iii) validate this new method using US SEER (Surveillance, Epidemiology, and End Results Program) data, where different MP rules are applied. RESULTS: The adjusted relative risk for lung cancer survivors in Germany to develop an SPLC was 2.98 (95% CI 2.53-3.49) for females and 1.15 (95% CI 1.03-1.27) for males using the novel histology-specific SIR. When using IARC/IACR MP rules, the conventional SIR underestimates the actual risk for SPLC in LC survivors by approximately 30% for both sexes. CONCLUSIONS: Our proposed histology-specific method makes the SIR metric more robust against MP rules and, thus, more suitable for cross-country comparisons.

Risk of Subsequent Primary Cancers Among Adult-Onset 5-Year Cancer Survivors in South Korea: Retrospective Cohort Study.

BACKGROUND: The number of cancer survivors who develop subsequent primary cancers (SPCs) is expected to increase. OBJECTIVE: We evaluated the overall and cancer type-specific risks of SPCs among adult-onset cancer survivors by first primary cancer (FPC) types considering sex and age. METHODS: We conducted a retrospective cohort study using the Health Insurance Review and Assessment database of South Korea including 5-year cancer survivors diagnosed with an FPC in 2009 to 2010 and followed them until December 31, 2019. We measured the SPC incidence per 10,000 person-years and the standardized incidence ratio (SIR) compared with the incidence expected in the general population. RESULTS: Among 266,241 survivors (mean age at FPC: 55.7 years; 149,352/266,241, 56.1% women), 7348 SPCs occurred during 1,003,008 person-years of follow-up (median 4.3 years), representing a 26% lower risk of developing SPCs (SIR 0.74, 95% CI 0.72-0.76). Overall, men with 14 of the 20 FPC types had a significantly lower risk of developing any SPCs; women with 7 of the 21 FPC types had a significantly lower risk of developing any SPCs. The risk of developing any SPC type differed by age; the risk was 28% higher in young (<40 years) cancer survivors (SIR 1.28, 95% CI 1.16-1.42; incidence: 30 per 10,000 person-years) and 27% lower in middle-aged and older (≥40 years) cancer survivors (SIR 0.73, 95% CI 0.71-0.74; incidence: 80 per 10,000 person-years) compared with the age-corresponding general population. The most common types of FPCs were mainly observed as SPCs in cancer survivors, with lung (21.6%) and prostate (15.2%) cancers in men and breast (18.9%) and lung (12.2%) cancers in women. The risks of brain cancer in colorectal cancer survivors, lung cancer in laryngeal cancer survivors, and both kidney cancer and leukemia in thyroid cancer survivors were significantly higher for both sexes. Other high-risk SPCs varied by FPC type and sex. Strong positive associations among smoking-related cancers, such as laryngeal, head and neck, lung, and esophageal cancers, were observed. Substantial variation existed in the associations between specific types of FPC and specific types of SPC risk, which may be linked to hereditary cancer syndrome: for women, the risks of ovarian cancer for breast cancer survivors and uterus cancers for colorectal cancer survivors, and for men, the risk of pancreas cancer for kidney cancer survivors. CONCLUSIONS: The varying risk for SPCs by age, sex, and FPC types in cancer survivors implies the necessity for tailored prevention and screening programs targeting cancer survivors. Lifestyle modifications, such as smoking cessation, are essential to reduce the risk of SPCs in cancer survivors. In addition, genetic testing, along with proactive cancer screening and prevention strategies, should be implemented for young cancer survivors because of their elevated risk of developing SPCs.

Pulmonary lesion after surgery for renal cancer: progression or new primary?

PURPOSE: To investigate clinical and radiological differences between kidney metastases to the lung (RCCM +) and metachronous lung cancer (LC) detected during follow-up in patients surgically treated for Renal Cell Carcinoma (RCC). METHODS: cM0 surgically-treated RCC who harbored a pulmonary mass during follow-up were retrospectively scrutinized. Univariate logistic regression assessed predictive features for differentiating between LC and RCCM + . Multivariable analyses (MVA) were fitted to predict factors that could influence time between detection and histological diagnosis of the pulmonary mass, and how this interval could impact on survivals. RESULTS: 87% had RCCM + and 13% had LC. LC were more likely to have smoking history (75% vs. 29%, p < 0.001) and less aggressive RCC features (cT1-2: 94% vs. 65%, p = 0.01; pT1-2: 88% vs. 41%, p = 0.02; G1-2: 88% vs. 37%, p < 0.001). The median interval between RCC surgery and lung mass detection was longer between LC (55 months [32.8-107.2] vs. 20 months [9.0-45.0], p = 0.01). RCCM + had a higher likelihood of multiple (3[1-4] vs. 1[1-1], p < 0.001) and bilateral (51% vs. 6%, p = 0.002) pulmonary nodules, whereas LC usually presented with a solitary pulmonary nodule, less than 20 mm. Univariate analyses revealed that smoking history (OR:0.79; 95% CI 0.70-0.89; p < 0.001) and interval between RCC surgery and lung mass detection (OR:0.99; 95% CI 0.97-1.00; p = 0.002) predicted a higher risk of LC. Conversely, size (OR:1.02; 95% CI 1.01-1.04; p = 0.003), clinical stage (OR:1.14; 95% CI 1.06-1.23; p < 0.001), pathological stage (OR:1.14; 95% CI 1.07-1.22; p < 0.001), grade (OR:1.15; 95% CI 1.07-1.23; p < 0.001), presence of necrosis (OR:1.17; 95% CI 1.04-1.32; p = 0.01), and lymphovascular invasion (OR:1.18; 95% CI 1.01-1.37; p = 0.03) of primary RCC predicted a higher risk of RCCM + . Furthermore, number (OR:1.08; 95% CI 1.04-1.12; p < 0.001) and bilaterality (OR:1.23; 95% CI 1.09-1.38; p < 0.001) of pulmonary lesions predicted a higher risk of RCCM + . Survival analysis showed a median second PFS of 10.9 years (95% CI 3.3-not reached) for LC and a 3.8 years (95% CI 3.2-8.4) for RCCM + . The median OS time was 6.5 years (95% CI 4.4-not reached) for LC and 6 years (95% CI 4.3-11.6) for RCCM + . CONCLUSIONS: Smoking history, primary grade and stage of RCC, interval between RCC surgery and lung mass detection, and number of pulmonary lesions appear to be the most valuable predictors for differentiating new primary lung cancer from RCC progression.

Association between diabetes and subsequent malignancy risk among older breast cancer survivors.

Type II diabetes is associated with cancer risk in the general population but has not been well studied as a risk factor for subsequent malignancies among cancer survivors. We investigated the association between diabetes and subsequent cancer risk among older (66-84 years), 1-year breast cancer survivors within the linked Surveillance Epidemiology and End Results (SEER)-Medicare database using Cox regression analyses to quantify hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). Among 133 324 women, 29.3% were diagnosed with diabetes before or concurrent with their breast cancer diagnosis, and 10 452 women developed subsequent malignancies over a median follow-up of 4.3 years. Diabetes was statistically significantly associated with liver (HR = 2.35, 95% CI = 1.48 to 3.74), brain (HR = 1.94, 95% CI = 1.26 to 2.96), and thyroid cancer risks (HR = 1.38, 95% CI = 1.01 to 1.89). Future studies are needed to better understand the spectrum of subsequent cancers associated with diabetes and the role of diabetes medications in modifying subsequent cancer risk, alone or in combination with cancer treatments.

High incidence of lung cancer death after curative endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND AND AIM: Following treatment of superficial esophageal squamous cell carcinoma (ESCC), surveillance for a second primary malignancy (SPM) is necessary. However, detailed evidence regarding the timing and prognosis of SPMs is insufficient. We aimed to clarify the details of SPMs and their effects on patient outcomes. METHODS: This retrospective, multicenter study involved 11 hospitals. Patients with superficial ESCC curatively resected using endoscopic submucosal dissection between May 2005 and December 2012, were included in this study. RESULTS: The 5-year survival rate of 187 patients was 92.6% during a median follow-up duration of 96.8 months. Thirty-one patients died, 14 of whom died of SPMs. Compared to patients with SPMs detectable by esophagogastroduodenoscopy (EGD), patients with SPMs detectable only by modalities other than EGD had a significantly higher mortality rate (p < 0.001). Patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Univariate and multivariate analyses showed that multiple Lugol-voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91-6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08-11.41). CONCLUSIONS: SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC. We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages.

Clinicopathological features, prognostic factor analysis, and survival nomogram of patients with double primary cancers involving lung cancer.

BACKGROUND: Although the incidence of double primary cancers (DPCs) involving lung cancer is rising, they have not been studied sufficiently. This study retrospectively analyzed the clinicopathological and prognostic characteristics of DPC patients with lung cancer and developed a survival nomogram to predict the individual OS rates. METHODS: We included 103 DPC patients with lung cancer from Shengjing Hospital between 2016 and 2021. Based on the 6-month cancer occurrence interval, the cases were categorized as synchronous DPCs (sDPCs) or metachronous DPCs (mDPCs). Furthermore, the mDPCs were subdivided based on whether the lung cancer occurred first (LCF cohort) or the other cancer occurred first (OCF cohort). RESULTS: Among the patients, 35 (33.98%) and 68 (66.02%) had sDPCs and mDPCs, respectively. In the mDPCs cohort, 18 (26.47%) belonged to the LCF cohort and 50 (73.53%) to the OCF cohort. The most frequent primary cancer sites were the breast (27.18%), colorectum (22.33%), and urinary system (18.45%). Independent risk factors for progression-free survival were Stage IV lung cancer (p = 0.008) and failure to undergo radical lung cancer surgery (p = 0.028). The risk factors for OS included squamous carcinoma (p = 0.048), Stage IV lung cancer (p = 0.001), single cancer resection plus drug therapy (p < 0.001), drug therapy alone (p = 0.002), failure to undergo radical lung cancer surgery (p = 0.014), and chemotherapy (p = 0.042). The median OS was 37 months, with 3- and 5-year rates of 50.9% and 35.9%, respectively. CONCLUSION: DPCs involving lung cancer account for 1.11% of cases. The breast, colorectum, and urinary system were the most common extra-pulmonary sites, and mDPCs were more frequent than sDPCs. Radical lung cancer surgery significantly affects prognosis, and drug therapy alone may be preferable when only one tumor is operable. The developed nomogram can accurately predict individual 3-year and 5-year OS rates.

Rate of Benign and Malignant Secondary Tumors Associated With Nevus Sebaceous: A Systematic Review and Meta-Analysis.

BACKGROUND: Nevus sebaceous (NS) is a rare congenital skin lesion affecting approximately 0.3% of all newborns. Although benign, NS lesions can harbor malignant secondary tumors. The published rate of development of these malignant tumors varies. This meta-analysis aimed to identify the rate of malignant and benign secondary neoplasms occurring in NS. METHODS: A literature search was conducted using PubMed, Embase, and Web of Science from inception to April 2023. Eligible studies reported incidence or risk of secondary neoplasms in patients with NS. Two independent reviewers screened studies, extracted data, and assessed the quality of included studies. The primary outcome was the pooled incidence of secondary neoplasms. Studies with sample sizes greater than 50 patients were eligible for meta-analysis using the random-effects model. RESULTS: Twenty-eight studies were identified, 22 of which were eligible for meta-analysis. The overall rate of secondary neoplasms was 12.8% (95% confidence interval [Cl], 9.2%-17.6%). The rates of development of malignant and benign tumors were 2.4% (95% CI, 1.4%-4.1%) and 10.3% (95% CI, 7.5%-13.9%), respectively. The rate of development of basal cell carcinoma was 1.7% (95% CI, 0.9%-3.2%), whereas the rate of the development of syringocystadenoma papilliferum was 3.6% (95% CI, 2.5%-5.3%) and that if trichoblastoma was 2.6% (95% CI, 1.7%-3.8%). CONCLUSIONS: Although the rate of development of malignant tumors within a primary NS lesion is low, it is not negligible. Prophylactic early excision remains a viable approach to prevent secondary malignant neoplasms, address cosmetic and functional complications, and preempt the need for complex reconstruction in the future. We propose that resection of NS lesions in childhood remains a reasonable first-line option in the appropriate patient keeping in mind that it may leave an undesirable scar.

Risk of second primary thyroid cancer in cancer survivors.

A risk factor for thyroid cancer (TC) may be a history of former cancer and cancer therapy. The precise risk of a second primary thyroid carcinoma has not yet been revealed. In this study, we evaluated standardized incidence ratios (SIRs) of second primary thyroid cancer (SPTC) with consideration of different conditions and further analyzed the clinicopathological characteristics and survival of these patients. The cohort was selected from the US Surveillance, Epidemiology, and End Results (SEER) Program between 1975 and 2019. The standardized incidence ratios, morbidity risk, clinicopathological features, and survival of second primary thyroid carcinoma were analyzed. Propensity score matching (PSM) was used to balance covariates. Kaplan-Meier method was performed to assess the survival outcomes. Overall, 7066 patients with SPTC and 83,113 patients with primary TC were identified. The SIR of TC in tumor patients was 1.51/10,000, statistically higher than the natural population (0.94/10,000, P < 0.05). The most significant tumors contributing to the increased SIRs of SPTC were acute lymphocytic leukemia (3.49/10,000), Hodgkin's lymphoma-nodal (3.29/10,000), salivary gland cancer (3.23/10,000), and kidney and renal pelvis cancer (3.05/10,000). The incidence of TC increased significantly in tumor patients who received radiotherapy/chemotherapy before age 35. The age at diagnosis of the SPTC was much older than the primary TC (64.01 vs. 49.55 years, p < 0.001). The SPTC had a higher percentage of histological grades 3/4 (23.14% vs. 15.19%, p < 0.001). Survival analyses demonstrated a worse prognosis for the SPTC group compared to the primary TC group. But after PSM, the survival outcomes of the two groups tended to be equivalent (P = 0.584). The SIRs of TC are higher in tumor patients. The most significant factors contributing to the increased risk of SPTC were some specific former tumors and acceptance of radiotherapy/ chemotherapy before age 35. There was no significant difference in survival between SPTC and primary TC.

Malignant melanoma in a 12-year-old boy 17 months after completing hepatoblastoma treatment.

BACKGROUND: Melanoma is rare as a secondary malignant neoplasm among childhood cancer survivors. CASE: We report a case of a 12-year-old boy who developed malignant melanoma with systemic metastases 17 months after completing treatment for hepatoblastoma. The diagnosis was made unexpectedly based on a bone marrow examination. The patient did not respond to immune checkpoint inhibitor therapy and died 6 weeks after being diagnosed with melanoma. Whole-exome sequencing to examine 103 genes associated with cancer predisposition did not identify any germ-line variants. CONCLUSION: This case study provides a unique example of melanoma in a childhood cancer survivor following hepatoblastoma treatment but does not identify any candidate variant to link hepatoblastoma and melanoma.

A systematic review of population-based studies on metachronous metastases of colorectal cancer.

BACKGROUND: The occurrence of metachronous metastases (MM) of colorectal (CRC), colon (CC), and rectal (RC) cancer of population-based studies has not been compiled in a systematic review previously. METHODS: MEDLINE, Embase, and Cochrane Library were searched for primary studies of any design from inception until January 2021 and updated in August 2023 (CRD42021261648). The PRISMA guidelines were adopted, and the Newcastle-Ottawa Quality Assessment Scale used for risk of bias assessment. Outcomes on overall and organ-specific MM were extracted. A narrative analysis followed. RESULTS: Out of 2143 unique hits, 162 publications were read in full-text and 37 population-based cohort studies published in 1981-2022 were included. Ten studies adopted time-dependent analyses; eight were registry-based and seven had a low risk of bias. Three studies reported 5-year recurrence rate of MM overall of stages I-III; for CRC, it was 20.5%, for CC, it was 18% and 25.6%, and for RC, it was 23%. Four studies reported 5-year recurrence rate of organ-specific MM of stages I-III-for CRC, it was 2.2% and 5.5% for peritoneal metastases and 5.8% for lung metastases and for CC 4.5% for peritoneal metastases. Twenty-seven studies reported proportions of patients diagnosed with MM, but data on the length of follow-up was incomplete and varied widely. Proportions of patients with CRC stages I-III that developed MM overall was 14.4%-26.1% in 10 studies. In relation to the enrollment period, a downward trend may be discernible. CONCLUSION: Studies adopting a more appropriate analysis were highly heterogeneous, whereas uncertain data of partly inadequate studies may indicate that MM are overall declining.

Tongue cancer developing after haematopoietic stem cell transplantation for treatment of acute promyelocytic leukaemia: A case report.

Acute promyelocytic leukaemia (APL) is a form of acute myelogenous leukaemia. APL is characterised by anaemia due to suppression of normal haematopoiesis and infection. Haematopoietic stem cell transplantation (HSCT) is current option for the treatment of haematopoietic malignancies and is proving to be successful. Although HSCT has been effective for the treatment of haematopoietic malignant tumours, chronic graft-versushost disease (GVHD) but secondary cancers can occur, which is a serious complication and frequently involves the oral cavity and skin. Here, we report the case of tongue cancer occurring 17 years after transplantation in a patient who developed GVHD after haematopoietic stem cell transplantation and APL remission. To the best of our knowledge, this is the first report of secondary oral cancer after HSCT with APL as the primary disease.

Editorial: Multiple Myeloma: Molecular Mechanism and Targeted Therapy.

Multiple myeloma (MM) is a plasma cell disorder representing the second most common blood cancer [...].