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Address for correspondence: Jonathan Riess, MD, MS, Division of Hematology Oncology, UC Davis Comprehensive Cancer Center, 4501 X Street Suite 3016, Sacramento, CA 95817.
Affiliations
Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Davis, CA
Address for correspondence: Jonathan Riess, MD, MS, Division of Hematology Oncology, UC Davis Comprehensive Cancer Center, 4501 X Street Suite 3016, Sacramento, CA 95817.
This case signifies the importance of obtaining tumor comprehensive genomic profiling (CGP) as it has utility in cancer type classification and helping in diagnosing recurrence/metastasis or separately occurring primary tumors. CGP can also help guiding treatment as in this case separately occurring Inflammatory Myofibroblastic Tumor had ALK fusion and responded to crizotinib. As treatment progresses, new biopsies should be obtained and CGP used to evaluate for appearance of any new genomic alterations, in order to guide further therapy.
The clinical use of genomic profiling to distinguish intrapulmonary metastases from synchronous primaries in non–small-cell lung cancer: a mini-review.
In recent years, the identification of altered driver oncogenes in EGFR, ALK, ROS1 among others has provided an opportunity for the development and approval of matched targeted therapy. ALK occurs in ∼3% to 6% of NSCLC, and the most common ALK rearrangement gene products result from the fusion of the 5′-region of the EML4 gene to exon 20 of the ALK gene, the latter attaching the kinase domain.
NSCLC patients with activating ALK fusions have shown sensitivity to ALK receptor tyrosine kinase (RTK) inhibitors, such as alectinib, brigatinib, lorlatinib and crizotinib.
Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.
IMTs are very rare and account for 0.04% to 0.1% of all pulmonary neoplasms, though these are the most common primary lung tumor in the pediatric population.
Early clinical evidence suggests that ALK fusion positive IMT are sensitive to ALK TKI with response rates and clinical efficacy that maybe comparable to ALK positive NSCLC.
Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial.
The relationship between NSCLC tumors and IMT tumors is unknown and to our knowledge no case report has shown a potential recurrence of NSCLC with a separate transformation to IMT tumor arguing for a potential common cell of origin for both malignancies.
Case
A 78-year-old male former smoker (10 pack-years, 5-7 pipes/week, quit over 30 years ago) presented with a soft tissue IMT of the trachea at ∼2.5 years into the timeline displayed in Figure 1B. About 2 years prior, the patient was diagnosed with a stage IIIA lung adenocarcinoma of the right upper lobe with 2 metabolically active lymph nodes in the right paratracheal region with right mid paratracheal lymph node confirmed to be metastatic adenocarcinoma at initial pathologic staging. The patient received 4 cycles of neoadjuvant cisplatin/pemetrexed showing a significant decrease in metabolic activity at the right paratracheal lymph node (9→2.7 SUV max), and a decrease in size (2.7→2.1 cm) at the right upper lobe lung mass. Chemotherapy was followed by video-assisted thorascopic surgical upper lobectomy, with subsequent histopathology demonstrating ypT1bN0M0 grade 3 disease. A PET-CT showed no sign of residual/recurrent/metastatic disease ∼about 6 months after initial lung adenocarcinoma diagnosis.
Figure 1Details on the Patient's detected ALK Rearrangement and Treatment Course. (A) The ALK fusion product is the result of EML4 at (exons 1-6) and ALK (exons 17-29). (B) Timeline of the patient's diagnosis, treatment, and diagnostic testing. The x-axis shows patient events and the y-axis denotes duration of the event in years. (Green = Treatment, Red = Foundation One Sample, Black = Cancer Present, Yellow = Diagnostic Test).
Approximately 2 years after completing surgery and chemotherapy for his Stage IIIA NSCLC adenocarcinoma, surveillance follow-up CT chest showed multiple bilateral sub-centimeter pulmonary nodules, new compared to prior CT chest. PET/CT scan demonstrated progressive FDG avid sub-centimeter pulmonary nodules, lymph nodes in the left supraclavicular region and bilateral mediastinum also concerning for metastatic disease. He underwent diagnostic bronchoscopy and was diagnosed with an IMT with near obstruction of the distal trachea on bronchoscopy (Figure 1B). The tumor was shown to have ALK positivity by IHC and ALK FISH (Figure 2). The patient received 5 fractions of palliative chest radiotherapy, and then initiated crizotinib treatment. The patient also had a fine needle aspiration of the right supraclavicular lymph node that showed recurrent lung adenocarcinoma with insufficient tissue for molecular testing. To further investigate the genomic profiles of these tumors, tissue was sent to Foundation Medicine Inc. (FMI) for testing. Two separate Foundation CGP tests were run on tumor material from the patient: an F1CDx assay (DNA only) was ran on lung tissue from the initial lobectomy specimen of the patient's lung adenocarcinoma, and a F1Heme assay (a combined DNA and RNA assay) was run on recent IMF tumor from the trachea obtained during bronchoscopy.
Comprehensive genomic profiling reveals diverse but actionable molecular portfolios across hematologic malignancies: implications for next generation clinical trials.
. The patients’ F1CDx and F1Heme results were used to compare the genomic alterations in the patient's Lung Adenocarcinoma and the IMT.
Figure 2(A) H&E stain: lobectomy specimen demonstrating invasive mucinous adenocarcinoma. (B) Higher magnification of malignant mucinous glands. (C) Papanicolaou stain: FNA of the left supraclavicular lymph node showing metastatic mucinous adenocarcinoma. Inset: higher magnification. (D) H&E stain: FNA of the left supraclavicular lymph node showing similar morphology to lung primary. (E) H&E stain: endobronchial biopsy specimen compatible with inflammatory myofibroblastic tumor (IMT). Inset: higher magnification. (F) Tumor cells positive for ALK-1 immunohistochemical stain. (G to H) FISH analysis of the ALK locus consistent with an ALK rearrangement in the tracheal mass biopsy.
The results from the F1CDx assay on the lung adenocarcinoma (Biopsy 1) revealed an activating EML4-ALK fusion, EML4 exons 1-6 fused to ALK exons 17 to 29 (114 supporting read pairs) (Table 1, Figure1A). This tumor also harbored other genomic alterations (GAs) including CDKN2A/B loss and an inactivating TP53 G244D mutation.
The patient's subsequent F1Heme assay on the IMF tumor on trachea (Biopsy 2) also detected an EML4-ALK fusion with identical breakpoints to the fusion found in the F1CDx assay, EML4 exons 1 to 6 fused to ALK exons 17 to 29 (122 supporting read pairs). The ALK fusion was confirmed to be expressed through detection in the RNA-seq analysis that was carried out in parallel for the F1Heme assay. Along with the ALK fusion, both cancers also shared CDKN2A/B loss and several variants of unknown significance. A predicted inactivating PTEN splice site 210-12_219del22 mutation (MAF = 30.89%) was found in the F1Heme assay.
Table contains genomic alterations that were detected on the patients’ CGP reports (+ = detected, - = not detected). The first column denotes the specific alteration detected, the second column denotes alterations detected in the Lung Adenocarcinoma, the third column denotes alterations detected in the putative IMT, and the fourth column denotes alterations detected in the most recent soft tissue biopsy. Biopsy number corresponds to the chronological order in which the biopsies were obtained.
Abbreviations: VUS = Variant of Undetermined Significance.
The patient responded to crizotinib treatment with a partial response seen in the tracheal lesion (4.1 cm→2.5 cm) and decrease in size of surrounding lymph nodes as well as subcm pulmonary nodules (Figure 3). The initial PET-CT of the tracheal mass, approximately 2.5 years after the lung adenocarcinoma diagnosis, showed metabolic activity corresponding to an SUV max of 11.5. Follow up PET-CT has shown an interval improvement in metabolic activity at the site of the tracheal mass, 6 months after (SUV max of 4.3) and 9 months after (SUV max of 4.0). The patient was maintained on crizotinib for about 6 months with initial response to treatment, until interval PET-CT showed an increase in activity of the right paratracheal node that was consistent with disease progression; at which time the patient was switched to alectinib. The treatment with alectinib was complicated by renal dysfunction and creatinine kinase elevation, which required a treatment holiday and a dose reduction. Short-interval follow-up showed disease progression and worsening respiratory symptoms which prompted a switch from alectinib to lorlatinib after about 3 months of therapy. An endobronchial biopsy (Biopsy 3) of the trachea and right bronchus demonstrated an IMT with detection of the same ALK fusion without any ALK-TKI resistance mechanisms noted on molecular profiling (Table 1, Figure 1B). The patient subsequently developed worsening symptoms and PET-CT showed continued progression of the disease with concern for airway collapse, despite endoscopic tumor debridement and stent placement by pulmonology. He was initiated on systemic therapy and completed 2 cycles of carboplatin/pemetrexed with CT chest showing progressive disease. At this point, the patient elected to pursue hospice.
Figure 3CT with contrast and PET/CT imaging of chest showing response to crizotinib. (A, C): Baseline chest CT with contrast image (green arrow) indicating right perihilar soft tissue mass with distal trachea invasion, biopsy proven IMT. (B, D): Decrease of the tumor burden after initiation of crizotinib ((para)tracheal mass 4.1 cm → 2.8 cm) with shrinkage of associated LAD and subcm pulmonary nodules). (E): PET/CT showing large signal uptake at baseline. (F): PET/CT showing reduction in signal after initiation of crizotinib. (G): Baseline activity of the left supraclavicular lymph node biopsy proven recurrent lung adenocarcinoma (yellow arrow) (H): Complete response at the left supraclavicular lymph node after initiation of crizotinib.
Herein, we present the first known case of an ALK rearranged NSCLC-adenocarcinoma transforming to an ALK rearranged IMT upon recurrence. Shared EML4-ALK rearrangement with identical breakpoints and additional shared GA strongly suggest a common origin with the IMT being a recurrence of the lung adenocarcinoma.
ALK rearrangements are common in NSCLC, and are more common in non-smokers (about 5.7% of cases).
Based on the morphology and immunophenotype this tracheal tumor was diagnosed as a soft tissue IMT after both intradepartmental and outside expert review. CGP showed a shared genomic origin between both adenocarcinoma and IMT in the patient, which prompted physicians to re-diagnose the IMT as possible histologic transformation from the initial lung adenocarcinoma based on specific GA that were shared between the former lung tumor and recent tracheal malignancy.
In patients that display co-occurring or re-occurring tumors, CGP can determine a diagnosis between metastasis/recurrence or a separately occurring primary tumor.
The clinical use of genomic profiling to distinguish intrapulmonary metastases from synchronous primaries in non–small-cell lung cancer: a mini-review.
ALK fusions are detected in a variety of carcinomas, leiomyosarcomas, lymphomas, glioma, neuroblastoma and melanoma. IMTs are unique however, as the frequency of ALK fusions in IMTs is the highest by far of all tumor types including NSCLC
Clinicopathological study of 18 cases of inflammatory myofibroblastic tumors with reference to ALK-1 expression: 5-year experience in a tertiary care center.
Comparison of the clinical and immunohistochemical features, including anaplastic lymphoma kinase (alk) and p53, in inflammatory myofibroblastic tumors.
The origins of this tumor are not well understood despite putative myofibroblastic origin, and no “in situ” or premalignant origins have ever been documented.
This case displays the clinical utility of CGP as a diagnostic tool for the precise classification of cancer types. The patient's lung adenocarcinoma shared a near complete overlap in GAs with a chronologically distant IMT suggesting the IMT was a recurrence of the prior lung adenocarcinoma. However, the patient's IMT was histologically distinct from the lung adenocarcinoma, displaying typical IMT morphology. Furthermore, the histological IMT and immunophenotype diagnosis was independently verified by an external pathologist. A precedent for a primary lung tumor and subsequent IMT has not been previously reported in the literature, let alone with CGP, which establishes the shared genomic heritage of these tumors. While the cellular origin of IMTs is not well understood, this case suggests that IMTs may arise as metaplastic carcinomas from epithelial precursor cells-of-origin. No clear mechanisms of resistance emerged on repeat biopsy of IMT after progression on ALK TKI. New NF1 and POLE mutations were detected that were variants of undetermined significance as was a FANCL mutation that is part of the Fanconi Anemia DNA repair pathway and may disrupt FANCL RNA splicing, which has no clear relationship to ALK TKI resistance (Table 1). CGP of different tumor histologies when they occur within the same patient may help clarify whether they represent histologic transformation of recurrent disease versus a separate new primary malignancy.
Conclusion
Non-small-cell lung cancer (NSCLC) management has changed drastically in recent years. The treatment strategy is largely guided by the genetic tumor profile obtained at the time of the diagnosis. At recurrence repeat tissue biopsy and comprehensive genomic profile can prove useful in characterization of the recurrence and in guiding future treatment.
Disclosure
Omar Hamdani, Nava Almog, Brian Alexander and Siraj Ali are employees of Foundation Medicine Inc. Jonathan Riess has received consulting/honoraria from Novartis, Roche/Genentech and Blueprint and has received research funding (to institution) from Merck, Novartis, Spectrum, AstraZeneca and Revolution Medicines. The other authors indicated no financial relationships.
References
Klempner SJ
Ou S-HI
Costa DB
et al.
The clinical use of genomic profiling to distinguish intrapulmonary metastases from synchronous primaries in non–small-cell lung cancer: a mini-review.
Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.
Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial.
Comprehensive genomic profiling reveals diverse but actionable molecular portfolios across hematologic malignancies: implications for next generation clinical trials.
Clinicopathological study of 18 cases of inflammatory myofibroblastic tumors with reference to ALK-1 expression: 5-year experience in a tertiary care center.
Comparison of the clinical and immunohistochemical features, including anaplastic lymphoma kinase (alk) and p53, in inflammatory myofibroblastic tumors.
Substitution - nonsense mutation.
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