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It is characterized by subacute onset gait instability that further develops into a pancerebellar syndrome
[2]
with vertigo, diplopia, dysarthria, and truncal and appendicular ataxia . Characterized by severe loss of
cerebellar Purkinje cells, PCD is related to several antineuronal antibodies, such as anti-Yo, anti-Hu, and
[3]
anti-CV2/CRMP5 antibodies . Anti-CV2 antibodies, also known as anti-CRMP5 (collapsing response-
mediator protein 5) antibodies, are well-established biomarkers of PCD associated with small cell lung
[4]
cancer (SCLC), thymoma, and probably prostatic adenocarcinoma . However, no antibodies are identified
in approximately 40% of patients with a PCD due to unclear etiology of PCD or the limited detective
[5,6]
technologies utilized .

The cancer is primarily driven by the accumulation of somatic mutations in the genome, along with
the contributions of epigenetic and transcriptomic alterations over one’s lifetime. Revolutionary high-
throughput DNA sequencing has become a promising and indispensable technique to study cancer . On
[7]
[8,9]
rare occasions, patient presents with a PCD months to years before cancer is diagnosed . Therefore,
whether the detection of certain mutations is available for clinical use in the ultra-early diagnosis of
patients with PCD is worthy of further investigation.

This case highlights the fact that the detection of certain mutations by next-generation sequencing might
plays a key role in ultra-early diagnosis of malignancy in a patient only displaying a PCD.

CASE REPORT
A 75-year-old man presented with a four-month history suggestive of progressive cerebellar symptoms in
the form of nausea, vomiting, unsteadiness upon walking, unclear speech, and occasional choking when
drinking water. He was treated in a local hospital. Cervical and cranial magnetic resonance imaging
examinations and an electroencephalogram showed no obvious abnormalities. The cerebrospinal fluid
(CSF) biochemical test showed a protein level of 0.5 g/L (the rest is unknown) at this time.

He was admitted to our hospital on four occasions subsequently. Lumbar puncture was performed twice, and
3
the results showed normal intracranial pressure. Cytology test results showed 6-11 white blood cells/mm , with
a higher proportion of lymphocytes. Anti-CV2 antibodies were detected in both serum and CSF utilizing
immunoblot techniques, but not immunofluorescence. The cancer-driven mutations were captured at the
first visit by next-generation sequencing technology in CSF, and the results showed that eight genes (TSC2,
DNMT1, CIC, FGF6, NSD1, TSHR, CRLF2, and EPPK1) had high-frequency mutations. Positron emission
tomography-computed tomography scanning was performed in the third visit and no obvious lesions
were seen in the parenchyma of the bilateral cerebellar hemisphere, with no signals of density or glucose
metabolism changes in those areas.

Chest CT scanning was performed four times [Figure 1]. The first two scans only showed a right lower lobe
inflammatory focus. The third scan showed old inflammation, along with enlargement of primary lymph
nodes and the fourth scan performed on his fourth visit showed that the enlarged lymph nodes under the
aortic arch were larger than before, and a shadow of soft tissue around the aortic arch of the left lower lobe
probably reflected a malignant lesion. Histopathological evaluation of a biopsy specimen obtained from
the posterior segment of the lung tissue revealed features of small cell cancer. Immunohistochemistry of
the lung tissue was positive for CD117, CD56, CK8/18, Syn, and TTF-1 and negative for CgA, CK7, and P40,
with a Ki-67 value-added index of 90%. Therefore, morphological combined with immunohistochemical
results supported the diagnosis of SCLC, seven months after the cancer-driven mutations were detected.
The patient was given small doses of dexamethasone and rituximab (100 mg), and the further treatment
was administered at his local hospital’s oncology department.