Intratumor heterogeneity in clear cell renal cell carcinoma: a review for the practicing pathologist

López, José I.

doi:10.1111/apm.12500

Cited by 27 publications

(18 citation statements)

References 38 publications

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“…Once arrived at this point, the key question is as follows: How can pathologists overcome this deficiency? An increase in the number of random samples would obviously increase the probability of finding the hidden ITH, as it has been empirically proposed recently 14, 17, 25 , but, how large must such an increase should be? Although (as far as we know) there is no answer to these questions at this time, it is possible to increase the number of samples to some degree while keeping the same cost fixed.…”

Section: A Solutionmentioning

confidence: 98%

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A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma

López

Cortés

2016

F1000Res

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Intratumor heterogeneity (ITH) is an inherent process in cancer development which follows for most of the cases a branched pattern of evolution, with different cell clones evolving independently in space and time across different areas of the same tumor. The determination of ITH (in both spatial and temporal domains) is nowadays critical to enhance patient treatment and prognosis. Clear cell renal cell carcinoma (CCRCC) provides a good example of ITH. Sometimes the tumor is too big to be totally analyzed for ITH detection and pathologists decide which parts must be sampled for the analysis. For such a purpose, pathologists follow internationally accepted protocols. In light of the latest findings, however, current sampling protocols seem to be insufficient for detecting ITH with significant reliability. The arrival of new targeted therapies, some of them providing promising alternatives to improve patient survival, pushes the pathologist to obtain a truly representative sampling of tumor diversity in routine practice. How large this sampling must be and how this must be performed are unanswered questions so far. Here we present a very simple method for tumor sampling that enhances ITH detection without increasing costs. This method follows a divide-and-conquer (DAC) strategy, that is, rather than sampling a small number of large-size tumor-pieces as the routine protocol (RP) advises, we suggest sampling many small-size pieces along the tumor. We performed a computational modeling approach to show that the usefulness of the DAC strategy is twofold: first, we show that DAC outperforms RP with similar laboratory costs, and second, DAC is capable of performing similar to total tumor sampling (TTS) but, very remarkably, at a much lower cost. We thus provide new light to push forward a shift in the paradigm about how pathologists should sample tumors for achieving efficient ITH detection.

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Section: A Solutionmentioning

confidence: 98%

“…CCRCC is a paradigm of a heterogeneous tumor from several viewpoints 10– 17 , where not only different CCRCCs are distinct from each other, but the ITH within the same CCRCC is also high. CCRCC presents ITH patterns which vary from obvious to subtle depending on very different approaches.…”

Section: The Contextmentioning

confidence: 99%

A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma

López

Cortés

2016

F1000Res

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“…There are no specific rules for this; the running definition of an appropriate sample is "representative" but what it needs to be representative for remains open. López et al [29,30] have come up with a simple but promising sampling approach. Rather than using a single 1.5 × 1.5 cm sample, this might be divided into nine 0.25-cm 2 samples, not from a single site but preferably randomly distributed over the tumor.…”

Section: What Are the Consequences Of Molecular Tumor Heterogeneity Imentioning

confidence: 99%

Tumor Heterogeneity: Will It Change What Pathologists Do

Bosman

2017

Pathobiology

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Although the notion that tumors are heterogeneous is well rooted in diagnostic pathology, the extent of this heterogeneity at the molecular level and its impact on (targeted) treatment choice will certainly influence the practice of pathology. Even though the consequences of tumor heterogeneity for cancer care are as yet incompletely understood, pathologists can contribute to solving major scientific and clinical problems related to tumor heterogeneity by rethinking guidelines for tumor sampling, to have a more comprehensive covering of intratumor heterogeneity in the available tumor tissue samples. They should develop guidelines and/or technology to adequately document sample characteristics such as percentage of tumor cells in a sample. They need to contribute to training of bioinformaticians in the field of cancer pathobiology and integrate such well-trained bioinformaticians in the workflow leading to a final pathology report. They also need to redefine postgraduate training programs in diagnostic pathology to address the need for in-depth training in molecular cancer pathobiology. Pathologists might contribute more to making the public at large aware of the importance of data sharing. Finally, pathologists should support the creation of consortia in which clinical and molecular data are shared with the translational research community.

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“…CCRCC is a paradigm of a heterogeneous tumor from several viewpoints 11 – 18 , where not only different CCRCCs are distinct from each other, but the ITH within the same CCRCC is also high. CCRCC presents ITH patterns which vary from obvious to subtle depending on very different approaches.…”

Section: The Contextmentioning

confidence: 99%

A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma

López

Cortes

2016

F1000Res

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Discuss this article AbstractIntratumor heterogeneity (ITH) is an inherent process in cancer development which follows for most of the cases a branched pattern of evolution, with different cell clones evolving independently in space and time across different areas of the same tumor. The determination of ITH (in both spatial and temporal domains) is nowadays critical to enhance patient treatment and prognosis. Clear cell renal cell carcinoma (CCRCC) provides a good example of ITH. Sometimes the tumor is too big to be totally analyzed for ITH detection and pathologists decide which parts must be sampled for the analysis. For such a purpose, pathologists follow internationally accepted protocols. In light of the latest findings, however, current sampling protocols seem to be insufficient for detecting ITH with significant reliability. The arrival of new targeted therapies, some of them providing promising alternatives to improve patient survival, pushes the pathologist to obtain a truly representative sampling of tumor diversity in routine practice. How large this sampling must be and how this must be performed are unanswered questions so far. Here we present a very simple method for tumor sampling that enhances ITH detection without increasing costs. This method follows a divide-and-conquer (DAC) strategy, that is, rather than sampling a small number of large-size tumor-pieces as the routine protocol (RP) advises, we suggest sampling many small-size pieces along the tumor. We performed a computational modeling approach to show that the usefulness of the DAC strategy is twofold: first, we show that DAC outperforms RP with similar laboratory costs, and second, DAC is capable of performing similar to total tumor sampling (TTS) but, very remarkably, at a much lower cost. We thus provide new light to push forward a shift in the paradigm about how pathologists should sample tumors for achieving efficient ITH detection.

show abstract

Intratumor heterogeneity in clear cell renal cell carcinoma: a review for the practicing pathologist

Cited by 27 publications

References 38 publications

A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma

A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma

Tumor Heterogeneity: Will It Change What Pathologists Do

A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma

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