Fatal Myelotoxicity Following Palliative Chemotherapy With Cisplatin and Gemcitabine in a Patient With Stage IV Cholangiocarcinoma Linked to Post Mortem Diagnosis of Fanconi Anemia

Abstract

Unrecognized genome instability syndromes can potentially impede the rational treatment of cancer in rare patients. Identification of cancer patients with a hereditary condition is a compelling necessity for oncologists, giving varying hypersensitivities to various chemotherapeutic agents or radiation, depending on the underlying genetic cause. Omission of genetic testing in the setting of an overlooked hereditary syndrome may lead to unexpected and unbearable toxicity from oncological standard approaches. We present a case of a 33-year-old man with an early-onset stage IV intrahepatic cholangiocarcinoma, who experienced unusual bone marrow failure and neutropenic fever syndrome as a consequence of palliative chemotherapy containing cisplatin and gemcitabine, leading to a fatal outcome on day 25 of his first chemotherapeutic cycle. The constellation of bone marrow failure after exposure to the platinum-based agent cisplatin, the presence of an early-onset solid malignancy and the critical appraisal of further phenotypical features raised suspicion of a hereditary genome instability syndrome. Whole-exome sequencing from buccal swab DNA enabled the post mortem diagnosis of Fanconi anemia, most likely linked to the fatal outcome due to utilization of the DNA crosslinking agent cisplatin. The patient's phenotype was exceptional, as he never displayed significant hematologic abnormalities, which is the hallmark of Fanconi anemia. As such, this case stresses the importance to at least question the possibility of a hereditary basis in cases of relatively early-onset malignancy before defining an oncological treatment strategy.

Keywords: FANCA; cholangiocarcinoma; fanconi anemia; genomic instability; myelotoxicity.

Figure 1

The patient's intrahepatic cholangiocarcinoma, which was classified as TNM: cT3, cN1, cM1, and stage IV tumor [according to AJCC/UICC staging criteria (6)]. (A,B) CT scan demonstrates multiple liver lesions, exemplary shown on two different axial layers. (A) Arrows indicate right-sided cholestasis, caused by a hypodense lesion in liver segments IV/VIII. (B) Asterisk marks a large, lobular-configured tumor mass in liver segment II, that dorsally crosses liver capsule. (C) A representative axial CT scan layer shows multiple bilateral lung noduli, interpreted as pulmonary metastases (indicated by red arrows). A framed image section is displayed as magnified inset in the top left corner of (C). A likely single spleen metastasis and enlargement of retroperitoneal lymph nodes are not shown. (D) The unaffected pancreas neighboring the infiltrated liver is depicted in four serial CT scan layers in coronal plane (consecutively numbered 1–4 from ventral to dorsal). The border between both organs (highlighted by dashed ovals) is not obviously violated by infiltrating tumor tissue, arguing against a primarily pancreatic origin of malignancy. (E,F) Histology from ultrasound-guided liver-biopsy. (E) H&E stain shows infiltrates of an adenocarcinoma with scattered duct formation and a desmoplastic stroma component. (F) High-power field from inset in (E) demonstrates frequent mitoses (indicated by arrow-heads). Immunohistochemistry (not shown) reveals positivity for CK7 and DPC4 and negativity for Hep Par 1, CK20, TTF1, CDX-2, and PSMA, consistent with a tumor of biliopancreatic origin.

Figure 2

Identification of causative FANCA mutations. (A) Pedigree of the family. Filled and open symbols denote affected and healthy individuals, respectively; an arrow indicates the index patient, diagonal lines indicate deceased status. The mutation status is shown next to each symbol. (B) Agarose gel electrophoresis of FANCA RT-PCR products performed using lymphocyte-derived RNA of the patient's brother (B) who bears the heterozygous c.710-3A>G mutation, and a healthy individual (C), generated using primers F5′-AAGGCATTGTG AGCCTGCAAGA-3′ and R5′-ACAGGGCTGTGAGTGAGTATCTGA-3′. The 436-bp wild-type RT-PCR amplicon was amplified in both the patient's brother (B) and the control (C), using exon 8 flanking primers. A second, smaller PCR product of ~350 bp was only obtained in the patient's brother (B), corresponding to skipping of exon 8 (exon 8 contains 83 bp). The 400, 300, and 200 bp reference bands of the molecular marker (M) are indicated.