Metastatic Pheochromocytoma/Paraganglioma Related to Primary Tumor Development in Childhood or Adolescence: Significant Link to SDHB Mutations

Purpose To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation began in childhood or adolescence. Patients and Methods From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the National Institutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients were found to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. Results Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHB mutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location. Conclusion The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation.

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Primary small intestinal neuroendocrine tumors are highly prevalent and often multiple before metastatic disease develops

Scandinavian Journal of Surgery ◽

10.1177/1457496919874484 ◽

2019 ◽

pp. 145749691987448 ◽

Cited By ~ 3

Author(s):

J. Eriksson ◽

O. Norlén ◽

M. Ögren ◽

H. Garmo ◽

C. Ihre-Lundgren ◽

...

Keyword(s):

Neuroendocrine Tumor ◽

Neuroendocrine Tumors ◽

Metastatic Disease ◽

High Rate ◽

Primary Tumors ◽

The People ◽

Swedish Cancer Registry ◽

The Mean ◽

Small Intestinal ◽

Diagnostic Modalities

Background: Small intestinal neuroendocrine tumors are the most common of small bowel malignancies with a clinical incidence of about 1 per 100,000 persons per year. There has been a threefold increase in the incidence of small intestinal neuroendocrine tumor during later decades, but there are no studies that clarify whether this is due to a true higher incidence or if the rise is a mere product of, for instance, improved diagnostic modalities. The aim of this study was to investigate the incidence of clinical as well as subclinical small intestinal neuroendocrine tumors found at autopsy as well as describing the frequency of concomitant malignancies in patients with small intestinal neuroendocrine tumor. Materials and methods: An autopsy registry from the Malmö county population from 1970 to 1982 with an 87% autopsy rate was used. The clinical autopsy reports for patients coded for the existence of “carcinoid tumor” were scrutinized for the presence of small intestinal neuroendocrine tumor, metastatic disease, and concomitant malignancies. Details of patients with clinically diagnosed small intestinal neuroendocrine tumor during this time period were gathered from the Swedish Cancer Registry. Results: The mean annual incidence of small intestinal neuroendocrine tumor during this period was 5.33 per 100,000 individuals, and the mean annual prevalence was 581 per 100,000. The cause of death in the majority of cases was not due to small intestinal neuroendocrine tumor. In total, 48% of the people with small intestinal neuroendocrine tumor had at least one other malignancy, most commonly colorectal cancer. Conclusion: Most small intestinal neuroendocrine tumors are subclinical, and persons living with them will often die due to other causes. There was a high rate of multiple primary tumors (40%), suggesting that multiple tumors seem to arise before the advent of metastatic disease. Moreover, a comparably high rate of associated colorectal carcinoma was found.

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Preclinical testing using tumors from genetically engineered mouse mammary models

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10067 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10067-10067

Author(s):

L. Varticovski ◽

M. G. Hollingshead ◽

M. R. Anver ◽

A. I. Robles ◽

J. E. Green ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Mouse Models ◽

Metastatic Disease ◽

Tumor Development ◽

Genetically Engineered ◽

Cell Suspensions ◽

Preclinical Testing ◽

Primary Tumors ◽

Tumor Bearing

10067 Background: Mouse models have been used extensively in preclinical testing of anticancer drugs. However, few of these models reflect the progression of human disease, and even fewer predict the performance of these drugs in clinical trials. Testing anticancer therapies in genetically engineered mouse (GEM) holds the promise of improving preclinical models and guiding the design of clinical trials. Unfortunately, the use of tumor-bearing GEM is hampered by the difficulty in simultaneously obtaining sufficient numbers of animals with the same stage of tumor development. The additional complexity in testing breast cancer therapies in the mouse is that all 10 mammary glands can develop tumors, frequently at different times. Methods: To circumvent the variable tumor latency and lack of synchrony in GEM, we transplanted tumor fragments or cell suspensions from multiple mammary tumor-bearing GEM into the mammary fat pad or subcutaneously into naïve syngeneic, immunodeficient athymic nude, or scid mice. Results: Tumors transplanted as fragments or cell suspensions derived from anterior mammary gland grew faster than the posterior tumors for serial passages without any significant morphologic differences. Cell suspensions using fresh or frozen cells were equally effective in generating tumors, and increasing the numbers of transplanted cells resulted in faster tumor growth. The transplantation strategy was reproducible in multiple breast cancer mouse models, including MMTV-PyMT, -Her2/neu, -wnt1/p53, BRCA1/p53, and others. Metastatic disease in the lungs was evident after removing the primary tumors at different rates for each mouse model. The transplanted primary tumors and the tumors arising in the original GEM had similar morphologic appearance and sensitivity to several chemotherapeutic and novel molecular targeted agents. Conclusions: We have established transplantable synchronous mammary tumors from GEM which also develop metastatic disease. These valuable mouse models are suitable for studying tumor-host interactions, tumor progression, and preclinical testing in a well-characterized molecular and genetic background. Testing these GEM tumors for conventional and novel molecular targeted therapies will be discussed. No significant financial relationships to disclose.

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Clinical Characteristics of Pheochromocytoma Patients With Germline Mutations in SDHD

Journal of Clinical Oncology ◽

10.1200/jco.2005.07.198 ◽

2005 ◽

Vol 23 (9) ◽

pp. 1894-1901 ◽

Cited By ~ 23

Author(s):

Hilde Dannenberg ◽

Francien H. van Nederveen ◽

Mustaffa Abbou ◽

Albert A. Verhofstad ◽

Paul Komminoth ◽

...

Keyword(s):

Family History ◽

Mutation Screening ◽

Gene Mutations ◽

Neurofibromatosis Type ◽

Adrenal Tumors ◽

Molecular Characteristics ◽

Primary Tumors ◽

Sdhd Mutation ◽

Familial Pheochromocytoma ◽

History Of

Purpose We examined the value of SDHD mutation screening in patients presenting with apparently sporadic and familial pheochromocytoma for the identification of SDHD-related pheochromocytomas. Patients and Methods This retrospective study involved 126 patients with adrenal or extra-adrenal pheochromocytomas, including 24 patients with a family history of multiple endocrine neoplasia 2, von Hippel-Lindau disease, neurofibromatosis type 1, or paraganglioma (PGL). Conformation-dependent gel electrophoresis and sequence determination analysis of germline and tumor DNA were used to identify SDHD alterations. The clinical and molecular characteristics of sporadic and hereditary tumors were compared. We reviewed the literature and compared our results with those from previously published studies. Results Pathogenic germline SDHD mutations were identified in three patients: two (2.0%) of the 102 apparently sporadic pheochromocytoma patients and one patient with a family history of PGL. These patients presented with multifocal disease (two of three multifocal patients) or with a single adrenal tumor (one of 82 patients). In the literature, mutations are mostly found in patients ≤ 35 years of age or presenting with multifocal or extra-adrenal disease. All patients with an SDHD mutation developed extra-adrenal tumors (pheochromocytomas or PGLs) at presentation or during follow-up. Conclusion SDHD gene mutations in patients presenting with apparently sporadic adrenal pheochromocytoma are rare. We recommend SDHD mutation screening for patients presenting with a family history of pheochromocytoma or PGL, multiple tumors, isolated adrenal or extra-adrenal pheochromocytomas, and age ≤ 35 years. Analysis of SDHD can also help to distinguish synchronous primary tumors from abdominal metastases.

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In Vivo Lymphatic Circulating Tumor Cells and Progression of Metastatic Disease

Cancers ◽

10.3390/cancers12102866 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2866

Author(s):

Mikyung Han ◽

Julia Alex Watts ◽

Azemat Jamshidi-Parsian ◽

Urooba Nadeem ◽

Mustafa Sarimollaoglu ◽

...

Keyword(s):

Flow Cytometry ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Metastatic Disease ◽

Primary Tumor ◽

High Sensitivity ◽

Disease Stage ◽

Primary Tumors ◽

Integrative Assessment

The dissemination of circulating tumor cells (CTCs) by lymph fluid is one of the key events in the development of tumor metastasis. However, little progress has been made in studying lymphatic CTCs (L-CTCs). Here, we demonstrate the detection of L-CTCs in preclinical mouse models of melanoma and breast cancer using in vivo high-sensitivity photoacoustic and fluorescent flow cytometry. We discovered that L-CTCs are be detected in pre-metastatic disease stage. The smallest primary tumor that shed L-CTCs was measured as 0.094mm×0.094mm, its volume was calculated as 0.0004 mm3; and its productivity was estimated as 1 L-CTC per 30 minutes. As the disease progressed, primary tumors continued releasing L-CTCs with certain individual dynamics. The integrated assessment of lymph and blood underlined the parallel dissemination of CTCs at all disease stages. However, the analysis of links between L-CTC counts, blood CTC (B-CTC) counts, primary tumor size and metastasis did not reveal statistically significant correlations, likely due to L-CTC heterogeneity. Altogether, our results showed the feasibility of our diagnostic platform using photoacoustic flow cytometry for preclinical L-CTC research with translational potential. Our findings also demonstrated new insights into lymphatic system involvement in CTC dissemination. They help to lay the scientific foundation for the consideration of L-CTCs as prognostic markers of metastasis and to emphasize the integrative assessment of lymph and blood.

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Emerging paradigms in metastasis research

Journal of Experimental Medicine ◽

10.1084/jem.20190218 ◽

2020 ◽

Vol 218 (1) ◽

Author(s):

Ashik Ahmed Abdul Pari ◽

Mahak Singhal ◽

Hellmut G. Augustin

Keyword(s):

Metastatic Disease ◽

Primary Tumor ◽

Holistic Approach ◽

Primary Tumors ◽

Metastatic Colonization ◽

Discovery Research ◽

Metastasis Research ◽

Recent Developments ◽

Rate Limiting ◽

Therapeutic Avenue

Historically, therapy of metastatic disease has essentially been limited to using strategies that were identified and established to shrink primary tumors. The limited efficacy of such treatments on overall patient survival stems from diverging intrinsic and extrinsic characteristics of a primary tumor and metastases originating therefrom. To develop better therapeutic strategies to treat metastatic disease, there is an urgent need to shift the paradigm in preclinical metastasis research by conceptualizing metastatic dissemination, colonization, and growth as spatiotemporally dynamic processes and identifying rate-limiting vulnerabilities of the metastatic cascade. Clinically, while metastatic colonization remains the most attractive therapeutic avenue, comprehensive understanding of earlier steps may unravel novel metastasis-restricting therapies for presurgical neoadjuvant application. Moving beyond a primary tumor-centric view, this review adopts a holistic approach to understanding the spatial and temporal progression of metastasis. After reviewing recent developments in metastasis research, we highlight some of the grand challenges and propose a framework to expedite mechanism-based discovery research feeding the translational pipeline.

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The Treatment and Outcome of Patients With Soft Tissue Sarcomas and Synchronous Metastases

Sarcoma ◽

10.1080/1357714021000022168 ◽

2002 ◽

Vol 6 (2) ◽

pp. 69-73 ◽

Cited By ~ 27

Author(s):

John M. Kane ◽

J. William Finley ◽

Deborah Driscoll ◽

William G. Kraybill ◽

John F. Gibbs

Keyword(s):

Overall Survival ◽

Soft Tissue ◽

Metastatic Disease ◽

Primary Tumor ◽

Strong Association ◽

Soft Tissue Sarcomas ◽

Poor Overall Survival ◽

Primary Tumors ◽

Synchronous Metastases ◽

Metastatic Sites

Introduction: There is a strong association between poor overall survival and a short disease-free interval for patients with soft tissue sarcomas (STS) and metastatic disease. Patients with STS and synchronous metastases should have a very dismal prognosis.The role of surgery in this subgroup of patients with STS has not been defined.Patients and Methods: A single-institution retrospective review was performed of 48 patients with STS and synchronous metastases in regard to patient demographics, presentation, tumor characteristics, metastatic sites, treatment, follow-up, and survival over a 27-year period.Results: Most primary tumors were ≥10 cm (58%), high-grade histology (77%), and located on the extremity (60%).The most frequent site of metastatic disease was the lung (63%); 27% of patients had metastases to ≥2 organ sites. Surgery to the primary tumor was performed in 94% of patients (n = 45) and 68% had additional radiation therapy (n = 32). Thirty- five percent of patients underwent at least one metastastectomy (n = 17). Chemotherapy was administered to 90% of patients (n = 43); 31% received ≥3 different regimens (n = 15) and 25% were given intra-arterial or intracavitary therapy (n = 12). Median overall survival was 15 months with a 21% 2-year survival. Local control of the primary tumor was achieved in 54% (n = 26), and metastastectomy was performed in 35% (n = 17). No analyzed factors were associated with an improvement in overall survivalConclusions: Despite multiple poor prognostic factors, the survival of patients with STS and metastases is comparable to those who develop delayed metastatic disease. However, unlike patients who present with metachronous disease, there was no improved survival observed for patients treated with metastastectomy. Consequently, treatment for patients with STS and synchronous metastases should be approached with caution. Surgical management of STS with synchronous metastases must be considered palliative and should be reserved for patients requiring palliation of symptoms. Patients must also be well informed of the noncurative nature of the procedure.

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DNA Methylation in INA, NHLH2, and THBS4 Is Associated with Metastatic Disease in Renal Cell Carcinoma

Cancers ◽

10.3390/cancers14010039 ◽

2021 ◽

Vol 14 (1) ◽

pp. 39

Author(s):

Olga Katzendorn ◽

Inga Peters ◽

Natalia Dubrowinskaja ◽

Joana M. Moog ◽

Christel Reese ◽

...

Keyword(s):

Dna Methylation ◽

Metastatic Disease ◽

Primary Tumor ◽

Renal Cell ◽

Progression Free Survival ◽

Classification Model ◽

Primary Tumors ◽

Independent Information ◽

Tumor Tissues ◽

Bivariate Logistic Regression

The detection of DNA methylation in primary tumor tissues could be relevant for early stratification of aggressive renal cell carcinomas (RCCs) as a basis for future personalized adjuvant therapy. Methylated TCGA KIRC based candidate CpG loci in INA, NHLH2, and THBS4 that are possibly associated with RCC metastasis were evaluated by pyrosequencing in 154 paired normal adjacent and primary tumor tissues, as well as in 202 metastatic tissues. Statistical analysis was carried out by bivariate logistic regression for group comparisons, log rank survival analysis, and unsupervised and supervised analysis for the classification of tumors. Increased methylation of INA, NHLH2, and THBS4 loci were significantly associated with distant metastasis in primary tumors (p < 0.05), tissue-specific hypermethylation in metastatic (p = 7.88 × 10−8, 5.57 × 10−10, 2.06 × 10−7) and tumor tissues (p = 3.72 × 10−24, 3.17 × 10−13, 1.58 × 10−19), and shortened progression free survival in patients (p = 0.03). Combined use of CpG site-specific methylation permits the discrimination of tissues with metastatic disease and reveals a significant contribution of CpG sites in all genes to the statistical classification model. Thus, metastasis in RCC is significantly associated with methylation alterations in INA, NHLH2, and THBS4 loci, providing independent information for the potential early detection of aggressive renal cancers as a rationale for stratifying patients to adjuvant therapies.

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The prognostic impact of RAS and TP53 mutation according to primary tumor location in colorectal liver metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3582 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3582-3582

Author(s):

Yongjun Cha ◽

Bun Kim ◽

Seung Jae Roh ◽

Moon Ki Choi ◽

Dong Woon Lee ◽

...

Keyword(s):

Primary Tumor ◽

Tp53 Mutation ◽

Gene Mutations ◽

Tumor Location ◽

Left Colon ◽

Prognostic Impact ◽

Primary Tumors ◽

Ras Mutation ◽

Primary Tumor Location ◽

Somatic Gene

3582 Background: Somatic gene mutations have been suggested to impact survival following resection of colorectal liver metastases (CRLM). However, most studies included a selected population with known mutation data and did not employ homogeneous methods. This study aimed to determine the prognostic impact of somatic gene mutations and microsatellite instability (MSI) in CRLM using a standardized protocol and assess their survival effects according to primary tumor location. Methods: A total of 568 patients who underwent resection of CRLM during 2001-2014 were identified from a prospectively maintained registry of the National Cancer Center. MassARRAY based mutation profiling of cancer-related genes ( KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, PTEN, APC, TP53)/MSI analysis was made in primary tumors from 538 (94.7%)/526 (92.6%) patients. Results: Primary tumor locations were: right colon for 51 (9.0%); transverse colon for 42 (7.4%); left colon for 238 (34.5%); rectum for 279 (49.1%) patients. Right sided tumors were associated shorter overall survival (OS) after liver resection compared to left colon primary tumors (5-year OS, 31.4% vs. 54.0% [ P = 0.011]). Mutation frequencies were: 45.9% for RAS ; 2.4% for BRAF ; 8.4% for PIK3CA ; 0.2% for PTEN ; 0.4% for MET ; 12.1% for APC ; 24.3% for TP53. RAS (5-year OS, 40.8% vs. 55.7% [ P = 0.001], PIK3CA (5-year OS, 31.1% vs. 50.5% [ P = 0.027]), and TP53 mutation (5-year OS, 42.7% vs. 50.8% [ P = 0.035]) were associated with worse OS after liver resection. On multivariable analyses, RAS (hazard rato [HR] 1.27; P = 0.033) and TP53 mutation (HR 1.35; P = 0.014) were significantly associated with poor OS after adjustment for covariates. Co-mutation in RAS/ TP53 (12.4%) was associated with the worst oncologic outcome (HR 1.81; P <.001). Notably, while the negative prognostic impact of RAS mutation did not differ significantly according to primary tumor location, the adverse effect of TP53 mutation was limited to rectal cancer (interaction P = 0.002). In this study, MSI-high (2.3%) was not associated with survival. Conclusions: Both RAS and TP53 mutation are associated with worse survival following CRLM resection. In contrast to RAS mutation, the negative prognostic impact of TP53 mutation appears to be limited to CRLM from the rectal origin.

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The Potential Role of Selected miRNA in Uveal Melanoma Primary Tumors as Early Biomarkers of Disease Progression

Genes ◽

10.3390/genes11030271 ◽

2020 ◽

Vol 11 (3) ◽

pp. 271 ◽

Cited By ~ 3

Author(s):

Joanna Patrycja Wróblewska ◽

Michał Stefan Lach ◽

Adam Ustaszewski ◽

Katarzyna Kulcenty ◽

Matthew Ibbs ◽

...

Keyword(s):

Uveal Melanoma ◽

Metastatic Disease ◽

Primary Tumor ◽

The Cancer Genome Atlas ◽

Differentially Expressed ◽

Primary Tumors ◽

Oncogenic Pathways ◽

Micro Rnas ◽

Mirna Expression Data ◽

Metastatic Risk

Uveal melanoma (UM) is the most common primary tumor of the eye diagnosed in adults, associated with a high risk of metastasis and thereby, poor prognosis. Among known risk factors for the development of metastatic disease is the loss of BAP1 expression and chromosome 3 monosomy in the primary tumor. However, the expression levels of specific micro RNAs (miRNA) in tumor tissue may also serve as a valuable marker for determining the risk of metastatic disease in patients with primary uveal melanoma. In our study, we analyzed the miRNA expression data of cases selected from The Cancer Genome Atlas study on uveal melanoma, and determined a panel of 15 miRNAs differentially expressed between patients with primary and metastatic disease. Next, 6 miRNAs were validated on a group of 46 tumor samples from primary and metastatic patients. We have shown, that expression of hsa-miR-592, hsa-miR-346, and hsa-miR-1247 was significantly increased, while hsa-miR-506 and hsa-miR-513c were decreased in the tumors of patients with metastatic disease. Hsa-miR-196b expression did not differ between the two subgroups, however, we showed significant correlation with BAP1 expression. Moreover, hsa-miR-592 also showed correlation with monosomy 3 tumors. Gene ontology analysis revealed involvement of those miRNAs with cellular processes mediating the metastatic process. Our results showed that miRNAs play an important role in the deregulation of several oncogenic pathways in UM and can, thereby, promote metastatic spread to distant organs. Moreover, differentially expressed miRNAs may be used as an interesting biomarker for the assessment of metastatic risk in uveal melanoma patients.

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Expression of CEACAM1 in pulmonary adenocarcinoma cells and their metastases

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.17071 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 17071-17071

Author(s):

E. Laack ◽

O. Schult-Kronefeld ◽

I. Burkholder ◽

M. Görn ◽

B. Andritzky ◽

...

Keyword(s):

Lymph Node ◽

Metastatic Disease ◽

Lung Tissue ◽

Primary Tumor ◽

Distant Metastases ◽

Pulmonary Adenocarcinoma ◽

Normal Lung Tissue ◽

Normal Lung ◽

Primary Tumors ◽

Adenocarcinoma Cells

17071 Background: The cell adhesion molecule CEACAM1 is involved in intercellular adhesion and is expressed in a variety of normal human tissues such as mammary gland, colonic mucosa and prostate. In cases of malignant transformation of these tissues a down regulation or loss of CEACAM1 has been shown. In contrary, CEACAM1 is not expressed in normal lung tissue or melanocytes and it has been demonstrated that a expression in these tissues is associated with the development of metastatic disease. The aim of the present investigation was to analyze a possible association between the expression of CEACAM1 in pulmonary adenocarcinoma cells and their lymph node and hematogenous metastatic cells. Methods: CEACAM1 expression was immunhistochemically evaluated in primary tumor cells, cells in lymph nodes and in distant metastases of 96 patients with metastatic adenocarcinoma of the lung who had undergone surgery between 1999 and 2002. Results: An expression of CEACAM1 has been shown in 78 of 96 primary tumors. We found a significant positive correlation between the CEACAM1 expression on the cells of the primary tumor and the lymph node metastases (p<0.005) and the hematogenous metastases (p<0.05). Conclusion: As shown before, CEACAM1 is not expressed in normal lung tissue but in most primary adenocarcinomas of the lung. We are the first to demonstrate, that its expression is preserved in the lymph node and hematogenous metastases in metastatic disease implicating that its expression is of functional significance of both metastatic sites. No significant financial relationships to disclose.

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