Abstract
Small cell cancer (SCC) of the gallbladder is a rare and highly aggressive malignancy. We report here a case diagnosed by positron emission tomography/computed tomography (PET-CT) combined with tumour markers. A 51-year-old man presented with pain in his neck, shoulder, back, lumbar and right thigh. Ultrasonography showed an isoechoic mass in the gallbladder, and a magnetic resonance image (MRI) scan showed multiple retroperitoneal occupations and multiple vertebral bone destruction with pathological fractures. Blood analysis showed elevated levels of tumour markers including neuron-specific enolase (NSE) and PET/CT images showed extensive distant metastases. A diagnosis of primary SCC of the gallbladder was made following exclusion of the possibility of metastasis from other organs. The use of biomarkers with immunohistochemical findings and PET/CT imaging, will assist clinicians in the identification and understanding of the pathology of this disease.
Background
Small cell carcinoma (SCC) is a highly malignant, poorly differentiated neuroendocrine tumour, which typically presents as a primary pulmonary neoplasm. 1 Extrapulmonary SCCs are rare, and account for only 0.1–0.4% of all cancers. 2 They have similar pathological features to SCC and are found in a variety of tissues; the gastrointestinal tract and genitourinary system are the most common sites.3,4 Among SCCs of the digestive system, oesophageal neoplasms are the most common and account for 16% of all reports. 5 Other sites include, stomach, colon, rectum, anus and gallbladder. SCCs of the gallbladder are rare and account for 8% of those of the digestive system. 6 We report here, a patient with SCC of the gallbladder diagnosed by positron emission tomography and computed tomography (PET-CT) combined with tumour markers.
Case presentation
A 51-year-old man who had developed lumbar and right thigh pain with no obvious cause four months previously, presented to our centre because his symptoms had worsened over the past month, and were accompanied by neck, shoulder and back pain that seriously affected his sleep. An outpatient magnetic resonance image (MRI) scan of his cervical and lumbar spine showed: multiple bone destruction of T12 vertebral appendage, lumbar 1 and 3 vertebral appendage (suggesting bone metastases); multiple nodes in retroperitoneum (suggesting lymph nodes); cervical 7 vertebral body occupancy, with a pathological fracture. Ultrasound showed an isoechoic mass in his gallbladder, multiple solid retroperitoneal occupations and an enlarged prostate with calcification. No obvious deformity of the spine and extremities were shown on physical examination. The patient did not have lower extremity radiating pain, right scapular pressure pain, or problems with bilateral shoulder mobility or neck mobility. His muscle strength and tone for each muscle group of his extremities were normal. He did not have any significant abnormality in skin sensation in both lower limbs but he could not lie supine and so the straight leg raise test and bilateral ‘4-character’ test of both lower limbs could not be determined.
The results of initial laboratory tests showed that most haemodynamic parameters were elevated as were liver enzymes (Table 1). For example, blood tests showed increased white blood cells (WBC) of 12.1 × 109/l, total bilirubin of 14.9 mg/l, direct bilirubin of 8.2 mg/l, and alkaline phosphatase (ALP) of 143 IU/l. His C-reactive protein (CRP) was 45 mg/l. In addition, several tumour markers were elevated (Table 1); these included: alpha-fetoprotein (AFP); CA72-4; Cyfra21-1 and neuron-specific enolase (NSE). Other tumour markers were within normal ranges (i.e., carcinoembryonic antigen [CEA]; serum ferritin [SF]; total prostate-specific antigen [t-PSA]; free prostate-specific antigen [f-FPSA]; cancer antigen 50 [CA50]; squamous cell carcinoma antigen [SCCA]; progastrin-releasing peptide [ProGRP]; CA19-9; CA242; S-100).
Laboratory analyses.
AFP, alpha-fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; APO-B, apolipoprotein B; AST, aspartate aminotransferase; CRP, C reactive protein; GGT, γ-glutamyl transpeptidase; HBDH, hydroxybutyrate dehydrogenase; LDH, lactate dehydrogenase; NSE, Neuron-specific enolase; WBC, white blood cell.
18F-fluordeoxyglucose (FDG) positron emission tomography combined with computed tomography (PET-CT) maximum-intensity projection (MIP) image on the third day after admission showed: hypermetabolic soft tissue density occupancy of the gallbladder; multiple hypermetabolic lymph nodes or soft tissue density nodules in the left neck, left supra/inferior clavicular region, mediastinum, right axilla, bilateral rib diaphragm angle region, abdominal cavity and retroperitoneum; multiple hypermetabolic lesions with bone destruction and partial soft tissue mass formation in bone/bone marrow throughout the body; pathological fracture of the right 9th posterior rib (Figure 1).
18F -fluordeoxyglucose (FDG) positron emission tomography combined with computed tomography (PET-CT) maximum-intensity projection (MIP) image showed hypermetabolic soft tissue density occupying the gallbladder (broad black arrow) with SUVmax 13.0. Multiple hypermetabolic lesions were demonstrated throughout the body (e.g., multiple lymph nodes metastasis (narrow black arrows) with SUVmax of 8.0∼18.7 and multiple bone/bone marrow metastasis (dashed arrows) with SUVmax of 6.3∼25.2.
All of the aforementioned suggested a high possibility of malignant lesions, and were indicative of primary SCC of the gallbladder with multiple metastases. Puncture biopsy of the gallbladder was performed on the sixth day following admission. Immunohistochemistry findings of neuroendocrine markers were as follows: cytokeratin pan (panCK) (+); synaptophysin (Syn) (+); CD56 (+); CD20 (−); CD3 (−); Desmin (−); smooth muscle actin (SMA) (−); myogenic differentiation 1 (MyoD1) (−); S-100 (−), CD34 (−). The findings confirmed gallbladder cancer with regional lymph node metastasis. The patient was treated with conservative therapy and achieved remission. He refused further treatment and was discharged from hospital.
The reporting of this study conforms to CARE guidelines. 7 Written informed consent was obtained from the patient before publishing his anonymised data. The study was approved by the Ethics Committee of the Third Hospital of Hebei Medical University (No. W2021-047-1).
Discussion
Gallbladder SCC is a rare and highly aggressive malignancy that accounts for only 2.2% of all gallbladder tumours and 0.2% of all neuroendocrine tumors.8,9 Age at presentation has been reported to vary from 38–81 years and the disease is more common in women.8,9 Prognosis is poor because of its insidious onset, atypical clinical symptoms, rapid disease progression, and often distant metastases by the time of detection. 10 Despite aggressive management, overall median survival has been estimated to be 4–6 months. 11 Some studies have found that gallbladder cancer was associated with several paraneoplastic syndromes and that hyponatremia was associated with SCC of the gallbladder. 12 The authors suggested that this sign could be used as an indicator of SCC of the gallbladder. 12 However, for most patients with gallbladder cancer, the patients only present with symptoms such as abdominal discomfort, and nausea and vomiting, and so a preoperative diagnosis is difficult because of the non-specific symptoms. 11 The diagnosis of this disease is mainly based on imaging findings and immunohistochemical tests following cholecystectomy. 8
The aetiology of gallbladder SCC is unknown, but it is thought that tumours may have originated from the epithelial tissue of the gallbladder or from the malignant transformation of the neural crest of the gallbladder mucosa. 13 Another hypothesis is that the neoplasm may have originated from tumour stem cells with multiple differentiation potentials in a neuroendocrine direction. 14 Cell morphology and growth pattern in gallbladder SCC are similar to those in small cell lung carcinoma with pathological features such as round or spindle-shaped cells which grow diffusely and are arranged in sheets, cords or nests. 15
SCC tumour cells show mostly focal staining in immunohistochemical studies.9,11 In addition, they express neuroendocrine markers such as neuron-specific enolase (NSE), synaptophysin (Syn), progastrin-releasing peptide (ProGRP) and CD56.9,11,16,17 Serum NSE positivity in patients with SCC is as high as 72%, and NSE levels have been found to correlate with tumour size and extensive metastasis.18,19 In differentiating small cell lung carcinoma from non-small cell lung carcinoma, serum NSE is a commonly used tumour marker with a specificity of 85% and accuracy of 82%. 20 In the present case, serum NSE was significantly elevated (>370 ng/ml), which was highly suggestive of the possibility of a neuroendocrine tumour based on the absence of neurological lesions. ProGRP is a precursor of the proliferative factor gastrin-releasing peptide (GRP). Its elevation is commonly found in gastrointestinal neuroendocrine tumours, small cell lung carcinoma, medullary thyroid carcinoma and SCC of the digestive system; it has a higher diagnostic efficiency and better specificity compared with NSE. 21 Although ProGRP has been reported to have a positive rate of 70–90% in patients with small cell lung carcinoma, 22 25% patients may be negative for ProGRP at first diagnosis. 23 Therefore, its evaluation is often combined with an assessment of NSE to improve the diagnostic sensitivity. Although NSE was elevated in our patient, his ProGRP levels were within normal range. Thyroid transcription factor-1 (TTF-1) is usually expressed in alveolar epithelial cells, but some studies have found a high rates of TTF-1 positivity in extra pulmonary SCC. 24 Moreover, one study found TTF-1 was expressed in several cases of gallbladder SCC. 25 We did not assess TTF-1 in this study. We believe that pathological diagnosis of gallbladder SCC should not rely exclusively on the immunophenotype because reliable tumour markers are yet to be defined. 26
By contrast with small cell lung carcinoma, which has a high incidence and definite characteristics, the imaging presentation of SCC of the gallbladder lacks specificity, and tends to show thickening of the gallbladder wall with accompanying neoplastic masses, some of which may cause an increase in gallbladder volume and dilatation of the common bile duct. 27 The low incidence of the disease has had an impact on the generalizability of its imaging features. In the present case, 18F-FDG PET/CT images showed that the patient had widespread metastases in multiple sites and organs. The tumour in the primary site was small, but distant metastases were more extensive and hypermetabolic than the primary site. These features of the neoplasm are related to the high malignancy and aggressiveness of gallbladder SCC. Importantly, PET/CT images can be used to screen/exclude suspicious tumours throughout the body with a large field of view. Indeed, several authors suggest that 18F-FDG PET/CT is a valuable diagnostic imaging method for the detection of gallbladder SCC.9,11,28 However, it is still difficult to diagnose gallbladder SCC solely by imaging. Combining imaging results with clinical information may be the key to a better prognosis for this disease.
In the present case, the patient’s initial symptom was pain at multiple sites. Blood analysis showed elevated levels of tumour markers including NSE, and PET/CT images showed extensive distant metastases. The patient did not show any significant foci of metabolic elevation in the lungs, which excluded small cell lung carcinoma. In addition, the prostate imaging performance and PSA levels were normal, and so prostate cancer was also excluded. In the search for primary foci, only the gallbladder showed abnormal density and metabolic foci; other sites were bone, lymph node and soft tissue metastases.
Despite our case being a middle-aged man and the rarity of the disease, the combination of PET/CT images with laboratory and immunohistochemical findings and NSE hyperplasia, confirmed a diagnosis of SCC of the gallbladder. Although uncommon, gallbladder SCC tumours should be included in the differential diagnosis of poorly differentiated malignant tumours in a male patient following exclusion of the possibility of small cell lung carcinoma and prostate cancer. The use of biomarkers with immunohistochemical findings and PET/CT imaging, will assist clinicians in the identification and understanding of the pathology of this disease.
