Hepatoid Carcinoma of the Lung with Anaplastic Lymphoma Kinase Gene Rearrangement

Case Report

A 56-year-old African American former light smoker female presented with a 3-month history of atypical chest pain, dry cough, intermittent night sweats and 20-pound weight loss. Physical examination revealed reproducible pain at the right sternal border with clear lung fields and no lymphadenopathy. A 1.5 cm nodular opacity in the right midlung was noted on a posteroanterior chest x-ray. Computed tomography (CT) showed minimal pericardial effusion in addition to a 5.5 cm mass extending from the right anterior cardiophrenic angle into the chest wall (Figure 1A), a 1.8 cm mass in the lateral segment of the right middle lobe (Figure 1B), and a 1.9 cm right pleural-based mass posterior to the inferior vena cava. Laboratory evaluation showed anemia of chronic disease with hemoglobin of 9.7 g/dL, serum alpha-fetoprotein (AFP) of 2.0 ng/mL, and β-hCG of < 2.0 IU/L. Percutaneous core needle biopsy of the right chest wall mass revealed large atypical cells with hepatic differentiation (Figure 2A, B). Immunohistochemical staining and molecular profiling results (Table 1) included positivity for antibodies to HepPar-1 (Figure 2C) and the presence of ALK gene rearrangement.

Figure 1.

Baseline CT scan showing masses in the anterior chest wall (A, arrow) and right middle lobe of the lung (B, arrow). After two months of therapy with crizotinib, a restaging CT scan showed over 30% reduction in the chest wall mass (C, arrow), near complete resolution of the right middle lobe lung mass (D, arrow), and about 20% reduction in the right pleural-based mass (not shown).

Figure 2.

Romanowski (A, 200x) and Hematoxylin and Eosin (B, 400x) staining showing large atypical cells with round to oval hyperchromatic nuclei, prominent nucleoli and moderate to abundant dense cytoplasm arranged in trabecular aggregates morphologically suggestive of hepatic differentiation. Immunocytochemical analysis of cellblock section with antibodies to HepPar-1 (C, 400x) demonstrated a positive granular cytoplasmic staining pattern.

Table 1.

Results of immnohistochemical staining and molecular profiling analysis on patient’s tumor tissue

Immunohistochemistry
AE1/AE3, CAM5.2, CK7, CK5/6, HepPar-1, Claudin 4, EMA (cytoplasmic), OCT4, CEA, CD10	Positive
Calretinin, WT-1, AFP	Equivocal
TTF-1, BHCG, CK20, vimentin, GCDFP-15, p63, CHG, thyroglobulin, RCC	Negative
Molecular profiling
EGFR (exons 18–21), KRAS (exons 2, 3), BRAF (exon 15), AKT (exon 1), PIK3CA (exons 9, 20), NRAS (exons 2, 3)	Wild type
HER2	No amplification by FISH (HER2/CEP17 ratio 1.3). Copy number gain (4–5 copies per cell) scored in 23 of 50 (46%) cells.
ALK	Positive rearrangement signal in 179 of 246 (72.8%) nuclei by FISH analysis using ALK break apart rearrangement probe.

AFP, alpha-fetoprotein; ALK, anaplastic lymphoma kinase; BHCG, beta-human chorionic gonadotropin; BRAF, v-raf murine sarcoma viral oncogene homolog B1, AKT, v-akt murine thymoma viral oncogene homolog; CEA, carcinoembryonic antigen; CEP17, chromosome 17 centromere; CHG, chromogranin; CK, cytokeratin; EGFR, epidermal growth factor receptor, NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; EMA, epithelial membrane antigen; FISH, fluorescent in situ hybridization; GCFP-15, gross cystic disease fluid protein-15; HepPar-1, hepatocyte paraffin-1; HER2, epidermal growth factor receptor 2; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; OCT4, octamer-binding transcription factor 4; PIK3CA, phosphoinositide-3-kinase catalytic alpha polypeptide; RCC, renal cell carcinoma antigen; TTF-1, thyroid transcription factor-1; WT-1, Wilms’ tumor-1.

The patient was started on crizotinib 250 mg orally every 12 hours, leading to resolution of her symptoms and anemia within approximately two weeks. CT scans were performed every two months with the first scan showing significant reduction in the baseline lesions (Figure 1C, D). The patient discontinued crizotinib for radiologic progression of lung disease six months following initiation of therapy.

Discussion

The World Health Organization (WHO) classifies hepatoid carcinomas as a subtype of hepatoid adenocarcinoma, first described in the stomach as tubular or papillary adenocarcinoma with sheets of neoplastic cells resembling hepatocellular carcinoma (HCC).¹ Hepatoid adenocarcinomas often occur in organs arising from the primitive foregut.² Histological types other than adenocarcinoma can be associated with hepatoid differentiation.³ Currently, there are no specific tissue markers to differentiate between HCC and hepatoid carcinoma. For example, HepPar-1, a sensitive marker for HCC, is also commonly expressed by hepatoid adenocarcinomas.²

The ALK tyrosine kinase inhibitor (TKI) crizotinib has shown significant activity in the nearly 5% of non-small cell lung cancer (NSCLC) patients that harbor ALK gene rearrangements, with response rates of 61–83%.⁴ The response to crizotinib observed in our case is important since hepatoid carcinomas have a poor prognosis and are often resistant to chemotherapy. A review of 14 cases of hepatoid adenocarcinomas of the lung showed a median survival of only 4.5 months.² There are no reported cases of hepatoid carcinoma of the lung treated with a TKI. The multikinase inhibitor sorafenib has resulted in progression-free survival of seven months in a patient with pancreatic hepatoid carcinoma who died a year after diagnosis⁵ and temporary clinical improvement in a patient with hepatoid adenocarcinoma in the peritoneal cavity who died six months after diagnosis.²

To our knowledge, this case represents the first report of ALK gene rearrangement in a patient with hepatoid carcinoma, suggesting an important role for molecular profiling-directed therapy in NSCLC patients with rare and aggressive histologies.