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Ann Thorac Surg 2010;90:388-396. doi:10.1016/j.athoracsur.2010.03.059
© 2010 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Comparative Mutational Profiling in the Assessment of Lung Lesions: Should It Be the Standard of Care?

Susan D. Moffatt-Bruce, MD, PhDa,*, Patrick Ross, MD, PhDa, Marino E. Leon, MDb, Gang He, MDb, Sydney D. Finkelstein, MDc, Alexandru M. Vaida, MDa, O. Hans Iwenofu, MDb, Wendy L. Frankel, MDb, Charles L. Hitchcock, MD, PhDb

a Division of Cardiothoracic Surgery, Department of Surgery, Ohio State University, Columbus, Ohio
b Division of Thoracic Pathology, Department of Pathology, Ohio State University, Columbus, Ohio
c RedPath Integrated Pathology, Pittsburgh, Pennsylvania

Accepted for publication March 16, 2010.

* Address correspondence to Dr Moffatt-Bruce, Ohio State University Medical Center, N835 Doan Hall, 410 W 10th Ave, Columbus, OH 43210 (Email: susan.moffatt-bruce{at}osumc.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background: Discerning primary versus metastatic lung lesions is problematic. Comparative mutational profiling (CMP) involves genetic and point mutation analysis of lesions to facilitate this. We sought to review our experience in cases of two lung lesions or head and neck cancer and lung lesions to determine whether a significantly clinical problem existed, what standard processes were in place to address it, and whether a new diagnostic standard was required.

Methods: Between January 1, 2007, and October 31, 2008, CMP was used in 24 cases of two lung lesions or a head and neck cancer and lung lesion. Routine hematoxylin and eosin stain examination and immunohistochemistry were performed as appropriate. The CMP involved DNA sequencing for specific oncogene point mutations and a panel of allelic imbalance markers. Metastatic cancer required demonstration of concordant mutations affecting the same allele copy in different cancer deposits.

Results: The patient mean age was 62 years; there were 13 men and 11 women. The cases involved two lung lesions (n = 13) or a head and neck cancer and a lung lesion (n = 11). Standard pathology examination was unable to discriminate the lesions, and they were subsequently differentiated by CMP. Fifteen discordant CMP results were interpreted as independent primaries; 9 cases were concordant, consistent with metastatic disease.

Conclusions: Discerning primary versus metastatic disease when dealing with lung lesions is a clinically significant problem. Comparative mutational profiling was found to be useful and reliable to assess the relatedness of multiple cancer lesions when routine pathology assessment was unable to.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Thoracic surgeons are often faced with trying to discern whether lung masses are primary or metastatic processes when a patient has two lung lesions or another neoplastic process and a lung lesion. This differentiation is absolutely essential to planning patient care and prognosticating patient outcomes. Currently, tissue specimens undergo routine staining with hematoxylin and eosin staining and immunohistochemistry (IHC) staining of cytoplasmic, nuclear, and cell surface antigens to discern the histogenesis of each lesion. However, when these techniques are unable to differentiate between a primary and a metastatic process, comparative mutational profiling (CMP) is appropriate. We sought to determine whether discerning lung masses as primary or metastatic was a clinical problem, what standard processes were in place to address it, and whether a new diagnostic standard was required.

Beyreuther first described synchronous lung lesions in 1924 [1]. The actual frequency of multiple lung lesions varies from 0.8% to 14.5%, depending on whether it is calculated from a cancer registry, autopsy series, or surgical series [2]. The criteria of Martini and Melamed [3] currently being used to resolve this problem is more subjective than objective in that it is based on tumor morphology, location, presence or absence of carcinoma in situ, vascular invasion, metastases, and other empirical features and not on objective molecular genetic features. Recent data have suggested that an aggressive surgical approach is well justified and safe for patients with truly synchronous primary lung cancers, further emphasizing the need for diagnostic accuracy and often a multidisciplinary approach to patient management [4–9].

Owing to common predisposing risk factors, lung cancer and head and neck cancer often coexist. Additionally, the risk of developing a subsequent malignancy is very high for lung cancer patients, with and without prior primary malignancies [10]. Synchronous tumors, defined as neoplasms that present within 6 months, and metachronous tumors, defined as those presenting more than 6 months after the index tumor, must be differentiated from metastatic processes originating from the head and neck primary [11, 12]. The diagnostic dilemma compounds the treatment choices that can be offered to these patients [10]. Comparative mutational profiling involves DNA sequencing for specific oncogene point mutations and a panel of allelic imbalance markers. Metastatic cancer required demonstration of concordant mutations affecting the same allele copy in different cancer deposits. This technology has been used in reference to other cancers including those originating from breast, pancreatic, lung, and head and neck with success [13–21].

To date, clinical and pathologic staging of lung lesions is suboptimal in achieving the goals of assessing prognosis and selecting therapy. Even more clinically challenging is the occurrence of a lung nodule in the presence of a second nodule or another neoplastic process, such as head and neck cancer. Although technologic developments have advanced, we have been slow to use them to shape our clinical practice. Herein we examine our experience and follow-up using CMP to help discern the pathologic staging of lung nodules presenting in the presence of another lung nodules or head and neck cancer so as to determine clinical therapy and better delineate prognosis.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
The clinical records of the Ohio State University Cardiothoracic Surgery service were retrospectively reviewed from January 1, 2007, to October 30, 2008, after having obtained Institutional Review Board approval (OSU 2008C0049). A total of 24 cases involving patients with a lung lesion with either a second lung nodule or a preexisting or synchronous head and neck neoplasm were identified (Table 1). The cases were from 13 men and 11 women with a mean age of 62 years (range, 51 to 80). Thirteen cases involved more than one lung lesion. Eleven cases involved a head and neck lesion and a lung lesion. The majority of the cases had surgical biopsies, but 7 cases included tissue obtained only by fine need aspirates. Thirteen of the involved lesions were identified within less than 6 months of each other (synchronous). The remaining cases were metachronous, in that they appeared on average 39 months later (range, 7 months to 10 years; Table 1).


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  		Table 1 Patient Demographics
 
The corresponding reports and slides were retrieved from the pathology files (Ohio State University Medical Center, Department of Pathology). The corresponding tumor sections were routinely embedded in paraffin; 4-µm sections were obtained and stained with hematoxylin and eosin. Some cases were stained with mucicarmine to help discern adenocarcinoma. In several cases, extensive IHC was performed at the discretion of the individual pathologist. The IHC stains were used for each case as dictated by the clinical scenario, as detailed in Table 2. The antibodies used in these cases included p63, vimentin, AE1/AE3, cytokeratin cocktail, CK5/6, epithelial membrane antigen (EMA), CAM5.2, CK19, CK7, CK20, S100, BerEP4, MOC-31, mCEA, B72.3, CDX-2, calretinin, D2-40, Wilms tumor-1 (WT-1), CD30, CD45, CD117, calponin, smooth muscle myosin heavy chain, HHF-35, smooth muscle actin, thyroid transcription factor-1 (TTF-1), PE-10, epidermal growth factor receptor (EGFR), PrTS, thyroglobulin, CD56, chromogranin, synaptophysin, ER, PR, BRST-2, Her2/neu, CD5, HMB-45, Melan-A, HCG, PLAP, AFP, and Ki67.


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  		Table 2 Biopsy Specimens, Immunohistochemistry and Loss of Heterozygosity (LOH) Performed
 
In each of these 24 cases, samples were sent for CMP because routine hematoxylin and eosin or IHC staining did not clearly define how the tumors were related to each other. A total of eight unstained, 4-µm thick sections from selected tumor blocks were cut and mounted on noncoated slides per the guidelines of RedPath Integrated Pathology (Pittsburgh, PA). The unstained tissue section displayed sufficient contrast under light or dark field conditions to carry out detailed microdissection. Multiple microdissection targets were taken from each site of identified cancer formation to characterize intratumoral heterogeneity. Comparative mutational profiling involved both DNA sequencing for specific oncogene point mutation detection (KRAS-2) and a broad panel of loss of heterozygosity (LOH) cancer-associated markers (Table 2). The LOH study was quantitative (polymerase chain reaction/capillary electrophoresis), enabling not only the detection of a LOH marker but also defining the specific allele copy due to different parental copies affected by imbalance (copy 1 versus copy 2) as well as the temporal sequence of mutational acquisition over time. The marker panel targeted 1p, 3p, 5q, 9p, 10q, 17p, 17q, 18q, 21q, and 22q.

Thresholds for accurate discrimination between true genomic loss and fluctuations related to nucleic acid amplification were established. When one allele was not represented in a microdissected neoplastic tissue sample, this was considered a genomic deletion. Minor degrees of allele peak variation were addressed with simple algorithms dividing allelic ratios of lesional cells by that of normal cells. Normal ranges for each allele pair of a given marker based on a large numbers of normal specimens (n > 1,000) from patients without evidence of ongoing neoplastic disease were used as controls. The 95% confidence thresholds for minimal significant allelic loss were accordingly defined. The proportion of mutated cells within an individual microdissected sample were also calculated based on dividing the allele peak height ratio of the microdissected cancer target by the allele peak height ratio for nonneoplastic internal control. The proportion utilized the information from all the tumor microdissection targets, which were then averaged. Metastatic cancer required demonstration of concordant LOH affecting the same allele copy acquired early in temporal acquisition between different cancer deposits. Independent or separate cancer primaries required complete discordance with respect to temporal sequence of acquisition or specific allele copy involvement, or both. By extending the comparative broad panel analysis to the specific allele copy and temporal sequence of mutational acquisition, discrimination between metastasis versus new primary cancer formation was achieved. The tumors were classified as de novo or metastasis based on three levels of concordance: (1) marker affected—tumors were considered concordant if 50% or more of the same markers were mutated; (2) the same parental origin allele gene copy was affected, and (3) the temporal sequence of mutation suggested a progressive accumulation of the LOH in the population of tumor cells.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Pathology Assessment
The cases that involved a differentiation between squamous cell carcinomas represented 13 of the 24 cases. Immunohistochemistry staining was not performed in 10 of these cases based on our ongoing experience that IHC staining was not useful in differentiating squamous cell carcinomas of the head and neck and lung primaries. In the remaining cases, the IHC stains, ranging from 1 to 31 (mean 4.5) were chosen by the individual pathologists responsible for the cases based on clinical scenario (Table 2). Each case was worked up separately by the pathologist assigned, thus accounting for a variable number of immunohistochemical stains. We have since developed a process that identifies these difficult cases and assigned them accordingly to one pulmonary pathologist. In all 24 cases, standard pathology examination, including hematoxylin and eosin or IHC staining was inadequate to discriminate if the lesions were separate primaries (discordant) or metastatic lesions (concordant). Figure 1 demonstrates a case in which IHC stains were unable to resolve relatedness to the two lung lesions. Although squamous cell carcinomas were difficult to distinguish, adenocarcinomas were also problematic to distinguish in 11 of the 24 cases.


Figure 1
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  		Fig 1. (A) Core biopsy of a left upper lobe lung nodule in patient 2 showing a well-differentiated adenocarcinoma (hematoxylin and eosin, original magnification x200). (B) Tumor cells consistent with adenocarcinoma obtained by computed tomography-guided fine needle aspiration (FNA) of the left lower lobe lung nodule (papanicolaou stain, original magnification x400). (C) Core biopsy of the left upper lobe lesion stained for thyroid transcription factor-1 showing positive staining by tumor cells (original magnification x200). (D) Core biopsy of the left upper lobe tumor stained for cytokeratin 7 showing a positive reaction by tumor cells (original magnification x200). (E) Tumor cells obtained by FNA of left lower lung nodule and embedded in a cell block stain for cytokeratin 7 (original magnification x400). Despite the apparent similar immunohistochemical profiles shown, the lung tumors in this case were found to be discordant by comparative mutational profiling.

 
Comparative Mutational Profiling: Discordant Versus Concordant?
All the cases referred for CMP were determined to be metastatic (concordant mutations) or independent primary tumors (discordant mutations; Table 2). Of the 24 cases referred for CMP, 15 were found to be discordant and thus representing two primary neoplastic processes. This could therefore be interpreted as a 63% discordance rate. Ten of the 14 discordant cases involved two separate lung lesions; five involved head and neck primaries separate from a lung primary (Fig 2). Although there was a tendency for the lung lesions to be discordant, this was not statistically significant (paired t test).


Figure 2
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  		Fig 2. Synchronicity of lung lesions relative to concordance. Lesions that were detected within 6 months of each other were deemed synchronous (lighter hatched bars). (A) Among the patients with two lung lesions, there was a tendency, although not statistically significant, for the discordant lesions to occur synchronously. (B) Among the patients with a head and neck primary and a lung lesion, there was no significant difference in the timing of presentation of the lesion relative to the concordance of the lesion. (Darker hatched bars = metachronous).

 
Synchrony of Lesions Relative to Concordance Versus Discordance
Of the 24 cases undergoing CMP, 13 cased involved lesions that appeared synchronously. Of these 13 synchronous cases, 10 were discordant lesions. Eleven of the 24 cases appeared more than 7 months apart, or metachronously, and of these, 5 were determined to be discordant and 6 were concordant (Fig 2). There was a tendency for the lung lesions that presented synchronously to be discordant. The discordant cases, representing two separate primaries, occurred on average 52 months apart (range, 24 months to 9 years). The concordant cases, representing metastatic disease, occurred on average 57 months apart (range, 7 months to 10 years). Therefore, the synchrony of the lesions could not be used to determine the potential for the lesions in question to be separate primaries or metastases.

Clinical Implications: Treatment Options Revisited for Discordant Lesions?
Surgical or additional therapy options were revisited for each of the patients with discordant lesions. Additional surgical intervention was offered in 9 of the 15 discordant cases (Table 3). The reasons for not offering further surgical intervention included lack of physiologic reserve (n = 3), patient declined (n = 2), and requirement for a pneumonectomy (n = 1). All patients who underwent further surgical intervention tolerated their surgical procedures without complications and were discharged home. In 11 of the 15 discordant cases, the management of the patient was altered either in increased surveillance alone (n = 3), additional surgical intervention (n = 6), or chemotherapy administration (n = 2). Recurrence developed in 2 patients: patient 5 at 12 months, and patient 17 at 8 months. Of note, patient 5 was stage IIIB at presentation. Patient 5 had a recurrence that was analyzed by CMP to verify that indeed the recurrence was a result of one of the original synchronous squamous cell lung cancers. The remainder of the patients remain alive and disease free, although some have had very short follow-up times (mean 24 months; range, 15 to 30; Table 3).


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  		Table 3 Outcomes for Discordant Patients
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Currently, characterization of a lung lesion is based on clinical and pathologic findings. The clinical scenario is complicated when two lung lesions or a lung lesion and another primary neoplasm are present at initial presentation. In many cases, it is difficult to ascertain, with certainty, the relationship between two tumors that appear to have identical pathologic features. As a thoracic oncology service, we started using CMP analysis when faced with clinically indiscernible scenarios despite the most diligent pathologic examination. Of our 24 cases, we found that 63% of the lesions were not related (discordant) and therefore represented two primaries. Nine of the 15 discordant patients were offered further surgical intervention. The potential for under diagnosing or misdiagnosing these patients was, therefore, considered to be significant. The CMP was performed on samples ranging from as small as fine-needle aspirations and cores, to large surgical resections. The average turn around time was 7 days, and was done at no additional cost to the patient.

There are numerous publications to support our use of CMP in the assessment of lung multiple lesions and head and neck cancers and lung lesions [14–16, 18, 20–22]. These studies have evaluated patterns of LOH of commonly altered tumor suppressor genes in lung carcinogenesis to help determine the technical feasibility and adaptability to provide an accurate and reliable test. Furthermore, investigators have addressed the potential influence of genetic intratumor heterogeneity on the interpretation of the genotypic data, in an effort to fortify all testing parameters. Different forms of sample are often provided. As such, studies have been taken to ensure accuracy independent of the sample size or type. This form of validation allows the use of minimally invasive techniques before any sort of surgical intervention that may be completely unnecessary and may lead to unwanted complications.

Comparative mutational profiling can also be used in the assessment of cytologic specimens such as those obtained by percutaneous and endoscopic aspirates as in the case of pancreatic cyst fluid [19, 23–25]. When patients present with pancreatic cysts, diagnostic dilemmas often exist as to their neoplastic potential. Since operative intervention for pancreatic lesions is often associated with significant morbidity, CMP has been shown to offer the potential for noninvasive diagnostics.

When applying new technology that ultimately has the potential to affect patient outcomes, care must be taken. The reliability of this technique has been extensively discussed both at our own institution and at the laboratory that performs the analysis. The statistical probability of CMP can be approximated conservatively as follows. The LOH mutations can exist in three states: (1) no LOH, (2) LOH mutation present involving the shorter allele copy, or (3) LOH mutation present involving the longer allele copy. Thus, when one site of cancer is compared for a single LOH mutation for a particular marker to the second site of cancer, if the second cancer is unrelated to the first site of cancer (new primary), the second cancer site has a 1 in 3 probability (0.33) of matching. However, if the analysis is extended to two LOH mutations, the probability of random matching is 3n or 32, or 1 chance in 9 (0.11). One can see how the ability to discriminate by CMP becomes more confident when the comparison is based upon several mutations, and hence the broad panel approach.

The KRAS point mutation is a special case in which discrimination is significantly higher. Unlike LOH where three states (no LOH, LOH shorter allele copy, LOH longer allele copy) exist, in the case of the KRAS point mutation, at least nine different forms of point mutations can occur, leading to 10 different states, consisting of (1) no point mutation (codon 12 GGT, codon 13 GGC); (2) codon 12 serine (AGT); (3) codon 12 arginine (CGT); (4) codon 12 cysteine (TGT); (5) codon 12 aspartic acid (GAT); (6) codon 12 alanine (GCT); (7) codon 12 valine (GTT); (8) codon 13 aspartic acid (GAC); and (9) codon 13 cysteine (TGC) and codon 13 valine (GTC). When one cancer has a KRAS point mutation, then the probability that an independent second primary cancer will randomly match the KRAS status is 1 in 10 (0.10). Thus, taking a typical case in which one cancer has a KRAS point mutation and four LOH mutations that CMP shows match the status of a second site of cancer, the probability that this could occur by chance is (101)(34) or 1 in 1 in 810, or 0.0012. This estimate is conservative because first, the comparison is limited to mutated markers and does not take into account the status of nonmutated markers that may match and could further reduce the unlikelihood of a random match, and second, this calculation does not take into account temporal sequence of mutation accumulative, where not only do all the mutations have to match perfectly but also the sequence of mutation acquisition has to match, as is the case with CMP. The calculation is an approximation that can be improved further by defining the specific frequency of each unique mutation, which here is assumed to be equal. However, this approximation is reasonable given the current understanding of KRAS and LOH mutation in lung cancer.

The possibility that metastatic lesions may not have the exact mutational signature, and that CMP may falsely determine discordance, is an important concern given that cancer is generally regarded as a chaotic process of mutation accumulation. It is reasonable to pay close attention to mutational variability, which could create discordances (differences) in the mutational profile of a single cancer when comparison is made between different sites of tumor deposition. It is for this reason that multiple microdissection targets are taken of each tumor sites to understand the variability that may exist in each individual case. At the same time, it has been well shown both experimentally and clinically that cancer is a stepwise process of mutation accumulation guided by clonal expansion wherein growth-stimulatory mutations are acquired, leading a transition from normal to precancer and then to cancer.

In prior work it has been shown that, while there is molecular heterogeneity within a cancer as it evolves, clonal expansion is operative in all cases, and the fundamental mutational profile of acquired mutations is dominant and a reliable marker of individual cancer growth and spread. Two studies are cited here. The first involved colorectal cancers associated with pericolonic and lymph node spread in which multiple microdissection targets were taken of the primary tumor as well as from different microscopic loci within the metastatic tumor deposits of each patient cancer [26]. In every instance, the mutational profile of early acquired high clonality mutations was preserved. The approach clearly showed the degree of mutational heterogeneity within each tumor, and it did not interfere with the ability to define the mutational profile of each cancer as it spread. So reliable was maintenance of the mutational profile that it was possible to determine from which precise location within each cancer the metastatic clone of cells arose [26]. In a study involving multinodular hepatocellular carcinoma, mutational profiling was used to differentiate de novo new primary liver cancer formation from single liver cancer with intrahepatic metastatic spread [27]. This use of CMP could downstage HCC in patients shown to have new primary cancer formation. In this retrospective analysis of liver cancer patients treated by autologous liver transplantation, CMP accurately restaged patients correlated with outcome [27].

The only limitation of CMP in this regard is the requirement that there be mutational change detected in two or more sites of cancer. The greater the number of detectable mutations, especially mutations that are high clonality (clonally expanded), the stronger will be the probability for discrimination. For common epithelial cancers of adulthood, the panel of markers used in this study is more than adequate to effect discrimination with a high degree of certainty. The marker panel could be expanded if additional detectable mutations are required; however, the discriminating ability of this panel has proven adequate. Gains operate in the same way as losses, hence, of preferred characterization as allelic imbalance or loss of heterozygosity. Although the markers used here are closely linked to well-known tumor suppressor genes that undergo loss, it is possible that gains may affect the same regions. We prefer to regard these as imbalances in copy number, and they represent intrinsic stable markers with which to compare different sites of cancer deposition. Copy neutral alterations do occur in cancer, and CMP does not depend on their occurrence. Rather, CMP is one technique that makes use of our expanding knowledge of the human genome to translate into a practical and timely system the information to advance tissue analysis.

The benefit of metastastectomy is not to be minimized, and should certainly be entertained. However, when prognosticating and counseling the patient, this CMP information is invaluable. Therapeutic pulmonary metastastectomy is accepted therapy for pulmonary metastases. However, more than 50% of patients who undergo this treatment will experience recurrences, many within the same lobe [28]. Although surgical metastastectomy remains the most common and first-line standard among local therapies, nonsurgical alternatives including thermal ablation and stereotactic body radiotherapy have become increasingly popular because they are generally less invasive than surgery and have demonstrated considerable promise in eradicating macroscopic tumor [29]. The lung is the major organ for distant metastasis from head and neck cancers, and pulmonary metastastectomy is indicated for selected cases. The efficacy of surgical treatment for pulmonary metastatic lesions from head and neck cancers has not been thoroughly examined. The database developed by the Metastatic Lung Tumor Study Group of Japan was retrospectively reviewed. The overall 5-year survival rate after pulmonary metastastectomy was 26.5%, and the median survival time was 26 months. As determined by univariate analysis, poor prognostic factors were oral cavity cancers, lymph node metastasis, a disease-free interval of 24 months or less, and incomplete resection. Male sex, oral cavity cancers, lymph node metastasis, and incomplete resection were poor prognostic factors for pulmonary metastases, but there is the potential for a good surgical outcome for carefully selected patients [30].

The presentation of a patient with two lesions, the relatedness of which is uncertain, is commonplace on a busy thoracic surgery service and presents clinically challenging dilemmas. The role of sound pathologic examination must be emphasized and is often diagnostic. However, when routine staining with hematoxylin and eosin and IHC are inconclusive, CMP offers additional information and a unique opportunity to truly discern the relatedness of lesions. The ease of use, availability, and potential for important additional information has led us to ask: CMP in the assessment of lung lesions: should it be the standard of care? Prospective studies as to whether or not CMP actually improves survival and therapeutic decision processes are ongoing and will be needed to completely answer this important clinical question.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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Susan D. Moffatt-Bruce
Patrick Ross
Alexandru M. Vaida
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