Stem Cell Theory of Cancer: Origin of Metastasis and Sub-clonality.

Metastasis may be the secret weapon cancer uses to dominate and subjugate, to persist and prevail. However, it is no longer a secret when we realize that a stem cell has the same ways and means to fulfill its own omnipotence and accomplish its own omnipresence… and when we realize that a cancer cell has its own version of stem-ness origin and stem-like nature. In this perspective, we discuss whether stem-ness enables metastasis or mutations drive metastasis. We ponder about low-grade versus high-grade tumors and about primary versus metastatic tumors. We wonder about stochasticity and hierarchy in the genesis and evolution of cancer and of metastasis. We postulate that metastasis may hold the elusive code that makes or breaks a stem-cell versus a genetic theory of cancer. We speculate that the vaunted model of multistep carcinogenesis may be in error and needs some belated remodeling and a major overhaul. We propose that subsequent malignant neoplasms from germ cell tumors and donor-derived malignancies in organ transplants are quintessential experiments of nature and by man that may eventually empower us to elucidate a stem-cell origin of cancer and metastasis. Unfortunately, even the best experiments of cancer and of metastasis will be left unfinished, overlooked, or forgotten, when we do not formulate a proper cancer theory derived from pertinent and illuminating clinical observations. Ultimately, there should be no consternations when we realize that metastasis has a stem-cell rather than a genetic origin, and no reservations when we recognize that metastasis has been providing us some of the most enduring tests and endearing proofs to demonstrate that cancer is indeed a stem-cell rather than a genetic disease after all.

Subsequent malignant neoplasms in the pediatric age in retinoblastoma survivors in Argentina.

BACKGROUND: Retinoblastoma survivors in low- and middle-income countries are exposed to high-intensity treatments that potentially place them at higher risk of early subsequent malignant neoplasms (SMNs). METHODS: We followed 714 (403 [56.4%] nonhereditary and 311 [43.5%] hereditary) retinoblastoma survivors diagnosed from August 1987 to December 2016, up to the age of 16 years. We quantified risk of SMNs with cumulative incidence (CI) and standardized incidence ratios (SIR) analysis. Multivariate regression Cox model was used to determine the association of treatments and risk of SMNs. RESULTS: Median follow-up was of 9 years (range: 0.18-16.9) and 24 survivors (3.36%) developed 25 SMNs (n = 22 hereditary, n = 2 nonhereditary). SMNs included sarcomas (osteosarcomas, Ewing sarcomas, rhabdomyosarcomas; n = 12), leukemias (n = 5), and central nervous system tumors (CNS; n = 3). All cases of acute myeloid leukemia (AML) and most of Ewing sarcomas occurred within 5 years of retinoblastoma diagnosis. The type of SMN was the main indicator of mortality (five of five patients with leukemias, six of 12 with sarcomas, and zero of three with CNS tumors died). Compared to the general population, radiation increased the risk of Ewing sarcoma in hereditary survivors by 700-fold (95% CI = 252-2422.6) and chemotherapy increased the risk of AML by 140-fold (95% CI = 45.3-436). The CI of SMNs for hereditary survivors was 13.7% (95% CI = 8.4-22.1) at 15 years. CONCLUSION: Retinoblastoma survivors from Argentina are at higher risk of developing SMNs early in life compared to the general Argentinean population, especially those treated with radiation plus chemotherapy. AML and Ewing sarcoma presented within 5 years of retinoblastoma diagnosis are associated with chemotherapy and radiation exposure.

Ultrasound is superior to palpation for thyroid cancer detection in high-risk childhood cancer and BMT survivors.

PURPOSE: Thyroid cancer is a common subsequent malignant neoplasm in childhood cancer survivors (CCS). Patients who received radiotherapy (RT) to the head, neck, upper thorax, or total body irradiation (TBI) are considered to be at risk for subsequent thyroid cancer. Current Children's Oncology Group screening guidelines recommend annual neck palpation. Our objective was to determine if ultrasound (US) is more sensitive and specific than palpation to detect thyroid cancer in high-risk CCS and bone marrow transplant (BMT) survivors. METHODS: Electronic medical records of patients followed in a longitudinal survivorship clinic from January 1, 2010 to December 31, 2017 were reviewed. Inclusion criteria included history of RT to the head, neck, upper thorax, or TBI for primary therapy or preparation for BMT prior to the age of 20 years. RESULTS: Two hundred and twenty-five patients had documented palpation and 144 (64%) also had US evaluation. Mean radiation dose was 28.6 Gy. Sixteen of 225 patients (7.1%) developed a subsequent thyroid cancer at a mean of 9.7 years from the completion of RT. Sensitivity of US was 100% compared with 12.5% for palpation. US demonstrated higher accuracy, with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.87 versus 0.56 for palpation (P < 0.0001). CONCLUSION: Routine screening with US was more sensitive than palpation for detection of subsequent thyroid cancer after high-risk RT in CCS and BMT survivors. Screening US may lead to earlier detection of thyroid cancer in this population. Earlier diagnosis has the potential to decrease operative complexity, and earlier definitive therapy reduces the likelihood of metastatic disease.

Colon cancer as a subsequent malignant neoplasm in young adults.

BACKGROUND: The incidence of colon cancer (CC) is rising in younger adults and can occur de novo or in patients previously treated for another cancer. To the authors' knowledge, the impact on survival of CC occurring as a subsequent malignant neoplasm (SMN) has not been described for younger patients, which the authors anticipate to be lower with SMNs than that of primary CC. METHODS: Patients aged <50 years with CC in the 2004 through 2014 National Cancer Data Base were identified. Patients were stratified by primary or subsequent occurrence. The impact of SMN status on overall survival (OS) was evaluated. RESULTS: Of 41,915 patients, 2852 (6.8%) had colon SMNs. More patients with colon SMNs were aged 40 to 49 years compared with patients with primary CC (83% vs 77%; P < .001). Patients with colon SMNs presented with earlier clinical and pathological T, N, and M classifications (all P < .001). Colon SMNs more commonly occurred in the right colon, whereas primary CC was found to have a higher prevalence in the sigmoid colon (P < .001). Patients with colon SMNs more frequently underwent total colectomy (17% vs 5%; P < .001), but received less chemotherapy (53% vs 65%; P < .001). When adjusted for demographic, tumor, and treatment characteristics, SMN status was associated with a 23% decreased OS compared with primary CC (95% CI, 1.14-1.31; P < .001). Chemotherapy offered a 33% improvement in OS (95% CI, 0.56-0.8; P < .001). CONCLUSIONS: Colon SMNs in younger patients present at an earlier stage and are treated more aggressively surgically compared with primary CCs. Patients with SMNs of the colon have decreased survival, although chemotherapy offers a survival advantage. Further investigation is warranted to determine whether these disparities are due to the effects of cancer treatment or differences in tumor biology.

Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma-Identification of high-risk populations to guide surveillance: A report from the Late Effects Study Group.

BACKGROUND: Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations. METHODS: The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years. RESULTS: In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high-dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk. CONCLUSIONS: Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided.

Clinical characteristics and survival patterns of subsequent sarcoma, breast cancer, and melanoma after childhood cancer in the DCOG-LATER cohort.

PURPOSE: Childhood cancer survivors are at increased risk of developing subsequent malignant neoplasms (SMNs). We compared survival and clinical characteristics of survivors with SMNs (sarcoma, breast cancer, or melanoma) and a population-based sample of similar first malignant neoplasm (FMN) patients. METHODS: We assembled three case series of solid SMNs observed in a cohort of 5-year Dutch childhood cancer survivors diagnosed 1963-2001 and followed until 2014: sarcoma (n = 45), female breast cancer (n = 41), and melanoma (n = 17). Each SMN patient was sex-, age-, and calendar year-matched to 10 FMN patients in the population-based Netherlands Cancer Registry. We compared clinical and histopathological characteristics by Fisher's exact tests and survival by multivariable Cox regression and competing risk regression analyses. RESULTS: Among sarcoma-SMN patients, overall survival [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.23-2.87] and sarcoma-specific mortality (HR 1.91, 95% CI 1.16-3.13) were significantly worse compared to sarcoma-FMN patients (foremost for soft-tissue sarcoma), with 15-year survival rates of 30.8% and 61.6%, respectively. Overall survival did not significantly differ for breast-SMN versus breast-FMN patients (HR 1.14, 95% CI 0.54-2.37), nor for melanoma-SMN versus melanoma-FMN patients (HR 0.71, 95% CI 0.10-5.00). No significant differences in tumor characteristics were observed between breast-SMN and breast-FMN patients. Breast-SMN patients were treated more often with mastectomy without radiotherapy/chemotherapy compared to breast-FMN patients (17.1% vs. 5.6%). CONCLUSIONS: Survival of sarcoma-SMN patients is worse than sarcoma-FMN patients. Although survival and tumor characteristics appear similar for breast-SMN and breast-FMN patients, treatment differs; breast-SMN patients less often receive breast-conserving therapy. Larger studies are necessary to substantiate these exploratory findings.

Subsequent Malignant Neoplasm of Bone in Children and Adolescent-Possibility of Multimodal Treatment.

BACKGROUND: In recent years, modifications of treatment protocols introduced in pediatric oncology have resulted in a significant improvement in treatment outcomes. Unfortunately, the probability of subsequent malignant neoplasm (SMN) in this group of patients is 3 to 6 times higher than the general age-matched population. In this study, we sought to evaluate the treatment options for patients with secondary bone tumors after prior anti-cancer therapy. MATERIALS AND METHODS: Twenty-four patients (median age 12.9 years) with subsequent malignant bone tumors were treated according to oncological guidelines for bone sarcoma during the period 1991-2020. All patients had a standard tumor imaging and laboratory evaluation. All toxicities were documented. RESULTS: The median time from the first neoplasm to SMN was 7.6 years (range 2.4 to 16.3 years). All patients received chemotherapy and underwent surgery as a local control procedure. Two patients with Ewing sarcoma had additional radiation on the tumor bed. A complete response was achieved in 20 patients. With a median follow-up of 18.3 years (range 5.7 to 40.3 years), 18 patients (75%) are alive. The estimated 5-year post-subsequent bone malignant neoplasm survival was 74.5% (95% CI 55-95%). Fourteen patients required chemotherapy dose modification, and doxorubicin was discontinued in seven patients. One patient required a renal transplant two years after treatment. There were no other significant toxicities. CONCLUSIONS: The treatment of bone SMNs can be effective, although in many patients it is necessary to reduce the doses of drugs. Early detection and aggressive treatment can improve the outcome.

Long-Term Psychosocial Well-Being and Quality of Life Among Childhood Cancer Survivors Who Developed a Subsequent Malignant Neoplasm.

Childhood cancer survivors (CCS) are at increased risk of subsequent malignant neoplasms (SMNs). However, the impact of SMNs on long-term psychosocial functioning is unknown. In a cohort of 322 young adult CCS, survivors who developed a SMN (n = 43, 13.4%) did not report a significantly higher burden of fatigue, insomnia, depression, anxiety, or impaired quality of life on average 8 years after SMN diagnosis. They, however, endorsed significantly greater body image concerns. Our findings indicate that CCS with an SMN do not significantly differ from those without regarding most psychosocial outcomes in young adulthood, although clinicians may be vigilant for greater body image dissatisfaction.

Subsequent neoplasms in childhood cancer survivors.

OBJECTIVES: The aim of the study was to characterize subsequent neoplasm (SN) (malignant (SMN), benign (BSNs), and non-melanoma skin cancer (NMSC)) treated previously for a childhood solid malignant tumor at the Department of Pediatric Hematology and Oncology, Motol University Hospital, Prague. METHOD: We evaluated a cohort of 4059 childhood cancer survivors treated between 1975 and 2018. RESULTS: From 4059 survivors, 170 (4.3 %) developed at least one SMN - 193 SMNs in 170 survivors, 21 of them (0.5 % of all survivors) had two or more SMNs and 34 of them (0.8 %) had one SMN and one or more BSNs. Mortality for an SMN was 38.2 % i.e. 1.6 % of all survivors. The most frequent SMNs were thyroid carcinoma (37, 19.2 %), tumors of the central nervous system (25, 13.0 %), soft tissue sarcoma (23, 11.9 %), breast carcinoma (19, 9.8 %), and leukemia (11, 5.7 %). Genetic syndromes were present in 25 patients with SMNs (14.7 %) and in 16 patients with only BSNs (13.4 %). SMNs usually developed in second decade or later after finishing of therapy. We observed some not well known risk factors of SNs e.g. spinal irradiation or131-I metaiodobenzylguanidine radiotherapy in 2 cases of secondary thyroid cancer, cyclophosphamide therapy in all 8 cases of secondary urinary bladder sarcoma or 4 from 7 SNMSC developed SMN. CONCLUSIONS: We confirmed data from previous studies of SNs and observed some not so well known risk factors. Our results and the literature show that the incidence of SMNs is 3-10 % of survivors and is associated with high mortality.

Genetic analysis of subsequent second primary malignant neoplasms in long-term pancreatic cancer survivors suggests new potential hereditary genetic alterations.

BACKGROUND: The principal aim of this report was to study second primary malignant neoplasms (SMNs) in long-term survivors of pancreatic ductal adenocarcinoma (PDAC) with regard to the germline genetic background. PATIENTS AND METHODS: A total of 118 PDAC patients after a curative-intent surgery who were treated between 2006 and 2011 were analyzed. Of the 22 patients surviving for >5 years, six went on to develop SMNs. A genetic analysis of 219 hereditary cancer-predisposition and candidate genes was performed by targeted next-generation sequencing in germline DNA from 20 of these patients. RESULTS: Of all the radically resected PDAC patients, six patients went on to subsequently develop SMNs, which accounted for 27% of the long-term survivors. The median time to diagnosis of SMNs, which included two cases of rectal cancer, and one case each of prostate cancer, malignant melanoma, breast cancer, and urinary bladder cancer, was 52.5 months. At the time of analysis, none of these patients had died as a result of PDAC progression. We identified four carriers of germline pathogenic mutations in 20 analyzed long-term survivors. One carrier of the CHEK2 mutation was found among four analyzed patients who developed SMNs. Of the remaining 16 long-term PDAC survivors, 3 patients (19%) carried germline mutation(s) in the MLH1+ ATM, CHEK2, and RAD51D gene, respectively. CONCLUSION: This retrospective analysis indicates that SMNs in PDAC survivors are an important clinical problem and may be more common than has been acknowledged to be the case. In patients with good performance status, surgical therapy should be considered, as the SMNs often have a favorable prognosis.