Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards

ASCO University
Jun 14, 2017 6:46 AM

Participant Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Liang Cheng (Pathologist from Indiana University) and Gauri Varadhachary (Medical Oncologist from UT MD Anderson Cancer Center).
 


This discussion is based on a TAPUR, cancer of unknown primary patient case.

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Comments

14661

ASCO University
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 14, 2017 6:49 AM

Patient Case

Medical history and diagnostics: The patient is a 48-year-old man who presented in August of 2012 with progressive abdominal discomfort. Past medical history was positive for controlled hypertension. Mild diabetes controlled with diet and intentional weight loss of 20 pounds over the last 5 years. No significant surgical history and no significant family history.

Imaging on presentation: CT scan with IV contrast revealed a right sided retroperitoneal mass (Figure 1). Renal protocol was utilized. No liver or kidney lesions identified. There was a tiny hypodensity that was too small to characterize along the inferior aspect of the kidney on the left kidney and likely a cyst.

There was no paraaortic lymphadenopathy. Pericaval and interaortocaval lymphadenopathy noted. The larger of the two areas measured 5.9 x 4.6 cm.

The mass in the retroperitoneum contacted the inferior vena cava. It compressed the cava but whether it involves the cava is not determined on CT. It also contacted the right common iliac artery. The mass contacted the ureter. A few bowel loops are contacted but there was no evidence of obstruction.

Scrotal ultrasound was negative. PET CT showed no new areas of disease.  

Laboratory Studies: He had a biopsy on 09/2012. IHC positive for AE1/AE3 and EMA, negative for PSA, MART-1, S100, CDX2, TTF-1, CEA, CK7 and CK20. Positive for vimentin and focally positive for CD10.

There was some questionable uptake in the distal sigmoid colon, and a colonoscopy was done and 3 tiny tubular polyps were removed polyps but otherwise no primary seen. Upper endoscopy was negative.

He had normal tumor markers including beta HCG and AFP. PSA was normal.

Diagnosis: The initial working diagnosis is poorly differentiated neoplasm favoring sarcomatoid carcinoma (Figure 2). Additional molecular work-up was ordered and a cancer classifier tissue of origin test came back with the statement that the patient had 93% chance of being renal cell carcinoma.

The final revised diagnosis was unknown primary presenting as sarcomatoid carcinoma with renal profile, presented with isolated retroperitoneal mass in contact with IVC.

Clinical Course: The patient’s scans were reviewed in multidisciplinary conference and plan was to proceed with chemotherapy with gemcitabine and taxotere for sarcomatoid carcinoma. Following 4 cycles of chemotherapy, patient underwent a repeat scan with response and then surgery (radiation and surgery options were discussed extensively in conference). Given the good response to chemo and no evidence of disease outside the retroperitoneal mass site, surgical consolidation was planned. He underwent exploratory laparotomy, radical excision of right retroperitoneal/pelvic mass with right ureterolysis and vascular mobilization.

Final pathology was unchanged:  no adjuvant chemotherapy or radiation was planned.

Patient did well for 3 years with surveillance scans and presented with mild right sided rib discomfort. Scans showed a 5th rib metastases, T7 uptake and L3 uptake, a lung nodule measuring 2.1 cm and mediastinal adenopathy (subcarinal nodal disease, 2.5 cm).   He underwent biopsy of the lung lesion and it was recurrent sarcomatoid carcinoma.

Priya Tiwari, MD
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 17, 2017 1:24 AM

We have used gemcitabine with sunitinib in two patients with metastatic sarcomatoid Renal CellCarcinoma. Both patients responded. However, duration of response in one patient was 7 months and in another 13 months.

14666

ASCO University
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 14, 2017 6:50 AM

Discussion Questions

1.    What defines sarcomatoid carcinoma on pathology?

2.    Are additional ancillary studies, including immunostainings, beneficial to evaluate site of origin (this tumor was CD10 focally positive)?

3.    What are the front line therapy options for this rare pathology?

4.    What is the role of genomics and its impact on therapy?

14676

Liang Cheng
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 19, 2017 9:09 AM

Course Faculty Response

1.    Sarcomatoid carcinoma is a rare aggressive tumor with morphological and immunohistochemical evidence of both epithelial and mesenchymal differentiation (Cheng, 2011). It can occur in every organ capable of developing carcinoma. Typically, these tumors are composed of undifferentiated spindled or pleomorphic cells that still retain expression of epithelial markers, such as keratin AE1/3, Cam5.2, and EMA.

2.    Immunohistochemistry plays an essential role in the evaluation of CUP (Kandalaft, 2016). Many organ specific immunostainings are now available in routine surgical pathology practice. Initial immunohistochemical work-up should include broad lineage evaluation to establish the nature of the tumor (lymphoid/hematopoietic, melanocytic, adrenal, neuroendocrine, soft tissue/mesenchymal, germ cell, or epithelial origin) (Conner, 2015) (Cheng, 2007). By definition, carcinoma, with or without spindle cell morphology, is of epithelial origin, and should be positive for at least one of epithelial biomarkers tested.  After establishing epithelial origin of the tumor, the following organ specific biomarkers are commonly used to determine the primary site: TTF1/napsin A (for lung primary), CDX2/CK7/CK20/villin (for colon cancer), Hepar1/arginase-1/glypican 3 (for hepatocellular carcinoma), PAX8/RCC-Ma/CD10/CA IX (for renal cancer), thyroglobulin/TTF1 (for thyroid cancer), uroplakin III/GATA3/p63 (for bladder cancer), ER/PR/mammoglobin/GCDFP/GATA3 (for breast cancer), PSA/PSAP/P501S/NKX3.1 (for prostate cancer). It should be noted that the sensitivity and specificity of each immunostatining vary, depending on specific antibody clone, antigen retrieval, and IHC platform. Clinicopathologic correlations are mandatory in interpreting IHC results. As noted in this case, the tumor was focally positive for CD10. Additional renal biomarkers, such as PAX8, could be used to further investigate tumor origin.

Other ancillary studies, such as fluorescence in situ hybridization (FISH) test, could also be helpful in establishing tumor origin (Cheng, 2017).

14681

Gauri R. Varadhachary, MD
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 19, 2017 9:12 AM

Course Faculty Response

1.    Before we evaluate the management of sarcomatoid carcinoma, which is a rare pathology, I would like to start with a quick overview of CUP. Cancer of unknown primary (CUP) is a diverse group of cancers with poor prognosis and an unmet research need. The reported incidence of CUP varies with the practice setting, and averages 2% to 4% of all cancers. Not unlike other solid tumors, the classification of CUP continues to evolve and the taxonomy and management of CUP has matured over the last 15 years with the use of sophisticated imaging and pathologic tools.  In the era of tailored therapeutics, this presents both an opportunity and a challenge. Despite the inability to perform direct validation (i.e. primary tumor), the use of the indirect validation methods with immunohistochemistry (IHC), imaging, and treatment response has allowed us to treat CUP cancers based on the putative primary cancer designation. This has been further challenged with genomic characterization, including cancer classifier assays (tissue of origin, ToO) and next generational sequencing assays identifying ‘actionable aberrations’ of interest, inside and outside the tissue specific cellular framework. Despite advances, we struggle with the undifferentiated and mixed histology neoplasms which often remain unclassifiable after exhaustive testing.

One such entity is the sarcomatoid carcinoma CUP cancers, seen in 2% or less presentations and diagnosis is based on morphology and immunohistochemical stains as reviewed by Dr. Cheng. Adequate tissue sampling is essential to the diagnosis of CUP cancers and even more so for rare subtypes. Although individual IHCs have modest specificity and sensitivity in this setting, their predictive value improves with recognition of patterns that are strongly indicative of specific tumors. To label a CUP cancer as sarcomatoid carcinoma, IHC profile should have sarcoma and carcinoma lineage markers positive as noted in this case.

2.    Currently the diagnosis of CUP is based on the radiographic features, pattern of spread, risk factors and pathologic findings. IHC is integral to CUP work up and the use of IHC is based on the premise that there is concordance in the expression profiles of primary and metastatic cancers.  IHC can help establish most tumor lineages (carcinoma, lymphoma, sarcoma, melanoma, etc.). Using light microscopy and IHC, a putative primary tumor may be assigned in up to a third of CUP cases (Varadhachary, 2011).  IHC can also suggest biomarkers studies with potential therapeutic impact (e.g. Kras, EGFR, Her2, MSI-H and ALK mutations).

3.    There is no prospective data on the best front line therapy for patients with sarcomatoid carcinoma CUP cancers. Our approach is based on data available from CUP empiric therapies and management of sarcomas and carcinomas and overlapping therapies with benefit.  A small study of 35 patients with CUP showed the combination of Gemcitabine-docetaxel was effective with 1 CR and 13 PRs, with the overall response rate 40% (95% confidence interval, 28 –52%).  The median overall survival time was 10 months (range, 0 –32 months) (Pouessel, 2004). There is data to show activity of Gemcitabine and docetaxel in metastatic soft tissue sarcomas (STS) as well. In a retrospective review, 133 patients were treated with gemcitabine and docetaxel including 76 leiomyosarcomas and 57 other histologies (Bay, 2006). Majority of the patients were previously treated (17% were treatment naïve). The overall response rate was 18 percent (24 % for leiomyosarcoma). At 12 and 24 months, 51 and 15 percent of patients were still alive for leimyosarcomas and other histologies, respectively. Gemcitabine +docetaxel has been compared to gemcitabine alone in metastatic STS in a randomized trial (Pautier, 2012) with improved PFS and PS in the combination arm. The objective response rate with combined therapy was higher (16 versus 8 percent), as was PFS (6.2 versus 3 months) and overall survival (17.9 versus 11.5 months). However, there was greater toxicity including edema and constitutional symptoms in the combination arm. Additionally, Gem and docetaxel have independent use in multiple epithelial cancers and therefore the combination is our favored front line cytotoxic option for patients with sarcomatoid carcinoma.

4.    At a very high level, we struggle with the same questions regarding the role, timing and impact on survival of genomic testing in CUP like any known solid tumor outside of the usual label indications. Also, most CUP tumors likely have multiple mutations (averaging 4.2 genomic alterations per tumor in study by Ross et al, JAMA oncol 2014) and determining oncogenic drivers and which to target is perhaps, today, best understood in the cellular context though that too is being challenged after FDA’s approval for pembrolizumab in a disease agnostic indication of MSI-H tumors. Attempts to demonstrate the independent value of NGS by measuring its impact on management decisions or survival are challenging, relating to trial design and CUP heterogeneity. The traditional prospective randomized trial design is difficult because an adequately powered trial would require a significant number of CUP patients and still run the risk of ambiguous results. Data from the M-PACT (Molecular Profiling–Based Assignment of Cancer Therapeutics ) trial developed at the National Cancer Institute (NCI), IMPACT2 (Initiative for Molecular Profiling and Advanced Cancer Therapy), which is a collaboration of Foundation Medicine and the University of Texas MD Anderson Cancer Center and TAPUR (Targeted Agent and Profiling Utilization Registry, ASCO) to name a few, will help us further learn more regarding the utility of NGS in solid tumors and data can be extrapolated to CUP cancers.

14686

ASCO University
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 19, 2017 9:14 AM

Patient Case Update

Tumor tissue was sent for additional testing - genomic test report from NGS assay showed multiple mutations. Somatic point mutations were identified in TP53, SAV1, PBRM1, and SETD2. Somatic indels were found in ZFHX3, and GLIS2. A germline frameshift mutation (p. Q409fs) was identified in MSH2. The report suggests that there is tumor is associated with a high mutation burden at 52 total somatic mutations. PDL1 immunostainings showed strong membranous stainings in 70% of tumor cells.  Immunostainings for PAX8 were performed and were negative.

Given the germline mutation in MSH2 and the high mutation burden, the MTB supported use of anti-PD1/anti-PDL1 therapy on protocol.

14691

ASCO University
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 19, 2017 9:14 AM

Discussion Questions

1.    What is the role of biomarker (including iPDL1 immunohistochemistry) in defining response to anti-PDL1 immunotherapy (in CUP and particularly this case)?

2.    What are the current challenges in NGS in CUP and therapy options for CUP patients?

14706

Anis Toumeh, MD
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 21, 2017 1:41 PM

One the main, and not so talked about, challenges is insurance coverage for molecular testing/Cancer type ID, and NGS for CUPs. We do struggle with that quite often. 

14711

Liang Cheng
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 23, 2017 9:39 AM

Course Faculty Response

1.    Immune checkpoint inhibitors have revolutionized the treatment of a variety of cancers, including CUP (Topalian, 2016) (Boussiotis 2016).  There is an urgent need for predictive biomarker(s) that could accurately predict anti-PD-1 and anti-PD-L1 immunotherapy. Evaluation of PD-L1 expression by immunohistochemistry is useful in guiding treatment decisions in certain tumor types, such as lung cancers. Nonetheless, its role in CUP is far from certain. Both PD-L1 positive and negative tumors have shown responses to anti-PD-L1 immunotherapy (Chen, 2017) (Lesterhuis, 2017) (Montironi, 2017). Positive criteria and method for PD-L1 immunohistochemistry vary among different tumor types in clinical trials. Nonetheless, CUP with PD-L1 expression in >50% tumor cells should be considered positive.

Other than protein biomarkers (such PD-L1 expression by IHC), RNA and DNA-based biomarkers are also used in a variety of tumors and clinical trial settings (Khagi, 2017). On May 23, 2017, FDA granted accelerated approval of anti-PD-1 drug, KEYTRUDA (pembrolizumab) for the treatment of cancers with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). It is reasonable approach to treat CUP patients with MSI-H or dMMR.  

Additionally, detection of tumor mutation burden (TMB) and neoantigen load also holds promise as predictive biomarker(s) despite technical difficulties and method divergence. PD-L1 amplification was also reported in a CUP patient who responded to anti-PD-1 therapy (Groschel, 2016).

2.    Comprehensive genomic profiling /NGS has emerged as an important clinical tool in the diagnostic workup and targeted therapeutics in the CUP management (Economopoulou, 2015). In a recent phase II clinical trial of 45 CUP patients, the investigators found that gene expression profiling can predict tumor response and survival in patients prospectively treated with platinum/taxane-based therapy (Yoon, 2016). Microarray DNA methylation signatures could significantly improve the diagnoses and guide precise therapies associated with better patient outcome (Moran, 2016).

Nonetheless, many technical, regulatory, and economic challenges remain to be solved for the widespread use of genomic profiling/NGS in routine clinical practice.  For further readings on this topic, I would recommend two recent review articles, wonderfully written and summarized by Dr. Varadhachary (Varadhachary, 2015) (Varadhachary, 2014).

14716

Gauri R. Varadhachary, MD
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 23, 2017 9:41 AM

Course Faculty Response

1.    Currently, the role of Anti-PD1/PDL1 therapy in CUP is not defined. As discussed by Dr. Cheng, Pembrolizumab is approved for MSI-H/ dMMR patients for a disease agnostic indication and any CUP patient that fits current clinical guidelines and histopathology features that are indicative of Lynch syndrome needs testing. Therefore, close attention to family history and IHC on pathology is crucial to make connections and picking up on patterns. The universal testing for MSI with IHC or PCR-based methods in CUP patients remains to be seen. Cellular context remains a guiding feature although the role of anatomical primary (none exists) and use of CPB therapy remains controversial in the CUP research community. Emerging use of antiPD1/PDL1 therapies in other cancers and prospective studies in CUP will help determine testing and therapy guidelines. Our group is currently evaluating antiPD therapy in CUP cancers (ASCP TPS #3103). Although not limited to subtypes, there is a significant interest in enrolling patients with CUP isolated disseminated lymphadenopathy, viral directed CUP cancers including HPV (+) CUP and those who have an IHC profile of those known cancers for which anti-PD therapy has been approved.  In the case discussed above, sarcomatoid carcinoma presenting as CUP with no significant family history, we would not routinely do MSI, antiPDL1 testing or consider use of CPB therapy.

2.    The evolving role of routine NGS in known cancers does influence management CUP cancers. As the genomic and proteomic characterization of malignancies is refined, fewer and fewer malignancies may be assigned to the CUP designation (and we are beginning to see that in this era of novel diagnostics). For example, the incidence of intrahepatic cholangiocarcinoma (ICC) in the U.S. continues to rise, whereas the incidence of CUP is declining during this same time period (Saha, 2016). Because liver is a common site of CUP presentation, ICC can be misdiagnosed as CUP. With trials available for FGFR fusions/mutations and IDH1 mutations, it is important to differentiate ICC from CUP.  Today, the histopathology and radiographic pattern of spread (i.e. cellular context) help guide use of biomarkers with therapeutic intent (RAS, ALK, her-2). The main challenge is that in the absence of an anatomical primary, the approved therapies are not always accessible for select CUP pts. As costs decrease, and rationale use of molecular guided therapy is better understood in various known cancers, it will definitely impact treatment of all-comers CUP and hopefully provide an improved understanding of the biology of this entity.

14721

Liang Cheng
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 28, 2017 8:46 PM

Course Faculty Summary

•    In the era of genomically directed therapy, investigation of tumor origin is still important and relevant for the assessment of prognosis and planning of subsequent treatment for patients who initially present with cancer of unknown primary.
•    There are diverse morphologic manifestations of carcinoma of unknown primary (CUP). A panel of immunostainings, including germ cell tumor markers, should be included in the initial investigation of tumor origin. .
•    Integrating genomic testing in the CUP management poses many technical challenges, but rapid progress is being made to overcome these challenges. Improper or inadequate  reimbursement by health insurers for NGS testings remains one of major hurdles.
•    Immune checkpoint blockade has been successful in treating a variety of advanced stage malignancies, including CUP. Predictive immune checkpoint biomarkers, including testing for microsatellite instability-high (MSI-H)) or mismatch repair deficient (dMMR), should be further explored in best treatment selection for CUP patients. 

14726

Gauri R. Varadhachary, MD
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 28, 2017 8:47 PM

Course Faculty Summary

•    Not unlike other solid tumors, the classification of CUP continues to evolve and the taxonomy and management of CUP has matured over the last 2 decades with the use of sophisticated imaging and pathologic tools.  
•    Despite advances, we struggle with the undifferentiated and mixed histology neoplasms (e.g. sarcomatoid carcinoma) defined as CUP; these often remain unclassifiable after exhaustive testing. Focused IHC and communication between clinical teams is essential.
•    NGS has a definite role in  select CUP patients who are candidates for therapy and it’s role, timing and clinical impact data needs to mature.  Role of cellular context is being challenged and prospective trials will help define the role.
•    As immunotherapy treatments advance in known cancers, its use will manifest in CUP cancers (e.g MSI –high tumors).

14731

ASCO University
Re: Cancer of Unknown Primary (June 2017): Molecular Oncology Tumor Boards
Jun 28, 2017 8:48 PM

Thank you to Drs. Cheng and Varadhachary for leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim credit on ASCO University by clicking here.

Please check back in mid-July for a new case in this series related to ovarian cancer.