Primary Hepatic Small Cell Carcinoma: Two Case Reports, Molecular Characterization and Pooled Analysis of Known Clinical Data

Case Reports

Case report 1. A 73-year-old Black male, never-smoker, presented to our Institution with sudden-onset acute renal failure and hyperkalemia. His past medical history was significant for hypertension, type II diabetes mellitus, and adenocarcinoma of the prostate diagnosed 11 years prior to presentation treated with radical prostatectomy, brachytherapy and intermittent androgen deprivation.

Radiological findings: Computed tomographic (CT) scan with intravenous contrast of the abdomen and pelvis revealed the presence of an enlarged liver with innumerable poorly defined focal lesions throughout all segments, suspicious for malignancy (Figure 1A). The spleen was not enlarged. The pancreas and adrenal glands were grossly unremarkable. There were multiple enlarged lymph nodes seen predominantly in para-aortic, paracaval and retroaortic regions down to the level of the femoral artery. There was a significant bilateral hydroureteronephrosis as a result of obstruction from lymphadenopathy.

Histopathological findings: A percutaneous biopsy of one of the liver lesions was performed which showed the presence of an infiltrating poorly differentiated malignant tumor. The cells infiltrated the liver in a nesting and clustering pattern (Figure 2A). They exhibited extensive mitosis, single-cell necrosis and nuclear molding, suggestive of a high-grade neuroendocrine carcinoma. The immunohistochemistry profile was positive for chromogranin, synaptophysin (Figure 2B) and CD56. The Ki-67 score was 95%, which confirmed the presence of SCC (Figure 2C).

Clinical course: The patient subsequently had a complicated course in the hospital and was diagnosed with metabolic acidosis and respiratory distress due to worsening renal and liver function despite percutaneous stent placements and initiation of dialysis. He was transferred to the medical Intensive Care Unit, intubated and placed on a mechanical ventilator while inotropic drugs were used to maintain his blood pressure. The patient died of hepatic and renal failure with lactic acidosis and hypotension 30 days from his initial presentation.

Autopsy findings: During the gross examination, the Glisson's capsule was irregular with multiple subcapsular lesions. The cut surface showed extensive parenchymal replacement by grey tan tumor nodules measuring from 1 to 3 cm. The tumor appeared centered in the liver with only locoregional nodal metastases noted. Paraesophageal and para-aortic lymph nodes appeared to be enlarged and replaced with tumor. No lesions were noted in the lungs. The pancreas and all other organs appeared unremarkable. These findings were corroborated with microscopy and immunohistochemistry and the tumor was identical in all respects to that originally found on histopathological examination. No intracranial or spinal metastases were detected on neuropathological examination. No evidence of prostate cancer was found at autopsy.

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Figure 2.

Images A-C are from patient 1, whereas images D-F are from patient 2 (all magnification ×20). A: Liver biopsy, hematoxylin and eosin (H&E) staining. Biopsy shows sheets of cells with scant cytoplasm, nuclear molding, apoptotic cells, and scattered mitotic figures. Rare residual hepatocytes are present. B: Liver biopsy, synaptophysin staining. Strong diffuse positivity. C: Liver biopsy, Ki-67 staining. Strong positivity in 95% of cells. D: Liver biopsy, H&E staining. Biopsy shows cells with scant cytoplasm and nuclear molding in a background of fibrosis. E: Liver biopsy, synaptophysin staining. Strong diffuse positivity. F: Liver biopsy, Ki-67 staining. Strong positivity in 90% of cells.

Case report 2. A 64-year-old Hispanic female, former smoker, presented with new-onset icterus and abdominal pain to our Institution. Her past medical history was significant for type II diabetes mellitus, hypertension and hyperlipidemia. A follow-up visit and laboratory check performed two months prior to presentation with an outside provider were within normal limits.

Radiological findings: CT scan of the chest, abdomen and pelvis with intravenous contrast showed the presence of a dominant necrotic liver mass that involved the lower right lobe and the quadrate lobe (Figure 1B). It measured 15.4 cm ×12 cm ×13 cm in length, anterior–posterior diameter and width, respectively. Enlarged lymph nodes at the porta hepatis and portacaval lymph nodes were found to be obstructing the common hepatic duct, causing extrinsic narrowing of the portal vein and left renal vein. Right pericardiophrenic nodes were also enlarged. The greater omentum and anterior peritoneum were involved by direct tumor extension. Large esophageal varices were noted. No radiographic evidence of a primary esophageal, colonic or lung mass was found.

Histopathological findings: A percutaneous biopsy of the dominant liver lesions was performed. It showed the presence of necrotic tissue, hemorrhage and clusters of small blue round cells (Figure 2D). Immunohistochemistry profile was positive for chromogranin, synaptophysin (Figure 2E) and CD56. The Ki-67 score was 90%, which confirmed the presence of a rapidly proliferating neuroendocrine tumor diagnosed as SCC originating from the liver (Figure 2F).

Clinical course: The patient was admitted for inpatient work-up and treatment. She developed progressive jaundice with severe hyperbilirubinemia (total bilirubin of 21.8 g/dl). She developed altered sensorium and gastrointestinal hemorrhage from esophageal varices. Despite aggressive supportive care, the patient succumbed to liver failure, variceal bleeding and hepatorenal syndrome on the 46th hospital day.

Autopsy findings: At autopsy, the target tumor was centered in the liver with locoregional extension. The liver was found to harbor a 23 cm ×23 cm ×17 cm mass protruding through the capsule, involving the gallbladder and head of the pancreas, and extending to the pericolonic adipose tissue of the transverse colon. The spleen, kidneys, adrenals, and thoracic organs were uninvolved with malignancy. These findings were corroborated with microscopy and immunohistochemistry and the tumor was identical in all respects to that found on the original histopathological examination. No intracranial or spinal metastases were detected on neuropathological examination.

Molecular analysis. Formalin-fixed tissue was obtained at autopsy from the cut sections of the tumor arising from the liver. DNA was extracted from the tissue using the QIAamp DNA FFPE tissue kit (Qiagen, Valencia, CA, USA). Sequencing of the samples was performed using the OncoScan FFPE assay. (Affymetrix, Santa Clara, CA, USA). Please refer to the supplementary files at http://cristinam09.wix.com/shastri-supplem-data in order to review the results of the OncoScan analysis. The OncoScan analysis allows for the screening of single nucleotide variants and small insertions and deletions in nine cancer genes which are V-Raf murine sarcoma viral oncogene homolog 1 (BRAF), V-K1-Ras2 kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase catalytic alpha (PIK3CA), neuroblastoma ras viral oncogene homolog (NRAS), tumor protein (TP53) covering a total of 65 variants. We were unable to identify any mutation within these regions for patient case 2. On the contrary, the analysis of patient case 1 revealed the presence of several mutations with high confidence in seven genes (Table I). One mutation was a small deletion in PTEN resulting in a frameshift (PTEN: p.K267fs*9:c.800delA); a small insertion in EGFR leading to a frame shift (EGFR: p.H773_V774insNPH:c.2319_2320ins9); 27 additional mutations were mapped to NRAS, PIK3CA, EGFR, BRAF, PTEN, KRAS and TP53; two non-sense mutations were identified leading to a premature stop of TP53 and PTEN; and an additional complex alteration was found in EGFR. We next assessed the potential pathogenicity of these mutations in patient case 1 using ClinVar, (http://www.ncbi.nlm.nih.gov/clinvar/) and COSMIC (http://cancer.sanger.ac.uk/cosmic/) The majority were predicted to be pathogenic. Four mutations in the EGFR gene lacked a clear pathogenicity prediction but were all associated with response to treatment with tyrosine kinase inhibitors.

Literature search strategy and data extraction for systematic review and pooled analysis of published cases. Our systematic review of the literature on HSCC was conducted using the electronic databases PubMed, SciVerse Scopus, Google Scholar (last search, June 2015). The search strategy included the following key words variably combined: “liver cancer”, “small cell cancer”, “extrapulmonary small cell cancer”, “liver neuroendocrine cancers”, “primary small cell cancer of the liver”. We assessed all associated publications to retrieve the most eligible studies. Moreover, their reference lists were searched manually to find other relevant publications. We included the data from the two patients presented in the current report. We did not apply any language restrictions. Two investigators independently searched the literature and independently extracted data from each eligible study.

Statistical analysis. All statistical analyses were performed using R (Foundation for Statistical Computing, Vienna, Austria)(18). We performed an exploratory pooled analysis of all reported HSCC cases (19-32) in order to calculate descriptive statistics and to perform survival analyses. Univariate Cox regression models were constructed to determine the association of age at diagnosis, gender, tumor size in centimeters, presence or absence of lymph node or distant metastases, chemotherapy treatment, and surgical treatment with overall survival. The small sample size of reported cases precluded multivariate analyses. A p-value less than 0.05 was considered statistically significant.

Results of pooled analysis. Our search yielded 14 case reports that were reviewed in detail (19-32). Five of these studies did not provide data on overall survival and were thus excluded from the survival analysis (20, 22-24). Thus, a total of 14 patients (including the two cases reported in the present study) were included in our analyses (Table I). The median follow-up period was 3.5 months. The mean patient age was 63.8 years (standard deviation=15.6 years, range=34-89 years). The mean tumor size was 8.7 cm (standard deviation=4.05 cm, range=3.2-17.0 cm). Nine out of 14 patients (64.3%) were male and 8/14 patients (57.1%) had lymph node metastases. Only out of 14 patients (7.1%) was found to have distant metastases. In addition, 7/14 (50%) of patients underwent chemotherapy and 7/14 (50%) underwent surgery. Four out of 14 patients (28.6%) underwent both chemotherapy and surgical resection of their tumor. Autopsy was performed in 6 out of 14 patients (42.9%).

Figure 3 shows the Kaplan–Meier curve for overall survival in patients with primary HSCC. The median overall survival from diagnosis was 4 months. The results of univariate Cox regression analyses are shown in Table II. Although the protective effect of chemotherapy was sizable, it did not reach statistical significance (hazard ratio=0.42, 95% confidence interval=0.1-1.67; p=0.216). On the other hand, surgical resection of HSCC was significantly associated with longer overall survival (hazard ratio=0.13, 95% confidence interval=0.03-0.69; p=0.016). The Kaplan–Meier curves of the seven patients who underwent surgery compared with the seven who did not are presented in Figure 4. All patients who did not undergo surgery died within 5 months of diagnosis, whereas five out of seven (71.4%) patients who had surgical resection of their tumor were alive by the end of follow-up.