Revolving Door of Histologic Transformation—Tumor Heterogeneity Complicating the Management of EGFR-Mutated Lung Adenocarcinoma: A Case of Jekyll and Hyde

SCLC transformation is increasingly recognized in EGFR-mutated (EGFRm) adenocarcinoma as acquired resistance and may occur more frequently with highly potent EGFR inhibition.1, 2, 3 SCLC transformations represent an early clonal divergence event and typically occur in EGFRm tumors harboring frequently concurrent RB1 and TP53 alterations.⁴ The best clinical strategies for such patients remain unclear, especially in the setting of up-to-date chemoimmunotherapy regimens for de novo SCLC.⁵

A 61-year-old male former smoker underwent lobectomy for a right upper lobe pT2aN2M0 lung adenocarcinoma with EGFRm (exon 19 deletion, Fig. 1). He received four cycles of adjuvant cisplatin and pemetrexed chemotherapy and radiotherapy complicated by severe pneumonitis. After 1 year, he experienced pathologically confirmed mediastinal nodal recurrence and was given osimertinib with an excellent response. Unfortunately, after 15 months, progression was noted in multiple lymph nodes and in new metastases to the chest wall and liver. A brain magnetic resonance image, at this time, was negative for central nervous system (CNS) metastases. The biopsy specimen of the right side of the chest wall mass that revealed SCLC transformation (Fig. 2A), and plasma circulating tumor DNA (ctDNA) confirmed his baseline EGFR exon 19 deletion plus additional alterations in TP53, PTEN, and PIK3CA and notably did not reveal an RB1 alteration. He was treated with carboplatin, etoposide, and atezolizumab whereas osimertinib was discontinued given its contraindication with the checkpoint inhibitors. The imaging result after four cycles revealed an excellent response in all the disease sites.

Figure 1.

Timeline of the progression of the patient’s NSCLC and dates of therapy. Aug, August; del, deletion; Feb, February; Jan, January; Mar, March; R, right; RT, radiation therapy; s/p, status post; Sept, September; SRS, stereotactic radiosurgery.

Figure 2.

(A) FNA (cellblock, H&E stain) results of the chest wall mass with malignant small cells revealing scant cytoplasm and crushing artifact (TTF1 positive and Napsin-A negative). Chromogranin reveals focal rare staining (×400). (B) FNA results of a mediastinal lymph node (cellblock, H&E stain) with malignant glands consistent with adenocarcinoma (positive for TTF1 and Napsin-A) with focal neuroendocrine differentiation (CD56 positive) (×400). (C) Surgical pathology tissue biopsy (H&E stain) results revealing classic features of small cell carcinoma; pleomorphic cells with increased nuclear-to-cytoplasmic ratio, very scant cytoplasm, nuclear molding, and stippled chromatin. High Ki67 index and staining for neuroendocrine markers (synaptophysin and CD56) (×400). FNA, fine needle aspiration; H&E, hematoxylin and eosin.

After three cycles of maintenance atezolizumab, he developed rapidly worsening pain and clinical decline, and subsequent imaging revealed dramatic interval disease progression including extensive lung, liver, adrenal, bony, and brain involvement. The result of mediastinal lymph node biopsy revealed adenocarcinoma with focal neuroendocrine differentiation (Fig. 2B). Plasma ctDNA result revealed the same set of alterations as previously. The patient was treated with radiotherapy to both a painful right femoral metastasis and a left cerebellar metastasis. Osimertinib was reinitiated immediately, and 1 week after completion of radiotherapy, carboplatin and abraxane were added. The patient did not experience pneumonitis (a clinical concern with reintroduction of osimertinib after immunotherapy). After the initiation of chemotherapy, the patient had rapid clinical improvement including in nonradiated disease sites, and after three cycles of chemotherapy, computed tomography scan results revealed an excellent radiographic response. After six cycles of chemotherapy, he continued on osimertinib monotherapy for 2 months until another fulminant progression event occurred with massive liver, nodal, and bony involvement, without CNS progression. The biopsy result confirmed resurgence of SCLC (Fig. 2C), leading to very rapid demise of the patient 29 months after his initial cancer recurrence.

Our case illustrates the complexities of managing EGFRm lung cancer given the potential for clonal heterogeneity and adaptive changes with serial therapies.¹ Importantly, plasma ctDNA could not clearly diagnose the histologic transformations evident on repeat tissue biopsies, highlighting the importance of serial invasive tissue monitoring and the potential need for exploring other serum-based markers such as pro-gastrin–releasing peptide and neuron-specific enolase. There remain questions as to the benefit of the continuation of osimertinib with chemotherapy, in particular, to potentially provide better CNS control; such studies of osimertinib, continued beyond progression, are being planned.² Furthermore, our case highlights the potential concerns as to how and if one should incorporate immunotherapy in the management of such patients—an area needing further research as to treatment choices and proper monitoring of ctDNA-based tumor dynamics. More data are urgently needed on the outcomes with chemoimmunotherapy in EGFRm SCLC to guide management.