Case Presentation
The seven patients consisted of six females and one male, and the median age at diagnosis was 40.1 years (range 23-51) (Table 1). The duration from initial symptom presentation to final diagnosis ranged from 2 months to 3 years (Table 1). The most common symptoms of all the seven the patients with glucagonoma in the present study are presented in Table 1.
Table 1
Patient presentation, tumor Characteristics and treatments.
Patient
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
Male/female
|
F
|
F
|
F
|
F
|
F
|
F
|
M
|
Age at diagnosis (years)
|
25
|
44
|
47
|
49
|
51
|
23
|
42
|
Symptoms at diagnosis
|
|
NME
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
Diabetes
|
N (but with IGT)
|
N (but with
IGT)
|
Y
|
Y
|
Y
|
Y
|
Y
|
Stomatitis (glossitis and
cheilitis included)
|
N
|
N
|
N
|
Y
|
N
|
Y
|
N
|
Weight loss
|
N
|
N
|
Y
|
Y
|
Y
|
N
|
Y
|
Anemia
|
N
|
N
|
Y
|
Y
|
Y
|
Y
|
N
|
Diarrhea
|
N
|
N
|
Y
|
N
|
N
|
N
|
N
|
DVT
|
N
|
N
|
N
|
Y
|
N
|
N
|
N
|
The first department visited
|
Dermatology
|
Dermatology
|
Dermatology
|
Dermatology
|
Dermatology
|
Dermatology
|
Dermatology
|
Biochemical diagnosis and
disease extent
|
|
Was skin biopsy diagnostic?
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
Plasma glucagon (pg/mL)
|
217
|
720
|
3155
|
1720
|
920
|
>800
|
269
|
Glucagon immunostain
|
+
|
+
|
ND
|
+
|
+
|
+
|
+
|
Ki-67
|
8%
|
10%
|
10%
|
NA
|
1. 1%
2. 8%
|
30%
|
8%
|
CgA (ng/mL)
|
+
|
+
|
ND
|
+
|
1. -
2. +
|
+
|
+
|
NSE (ng/mL)
|
43.05
|
+
|
29.65
|
+
|
19.54
|
Normal
|
+
|
SSTR2
|
+
|
-
|
ND
|
-
|
1. -
2. ±
|
+
|
+
|
Gastrin (pg/mL)
|
ND
|
-
|
ND
|
-
|
1. -
2. ±
|
-
|
-
|
Syn
|
+
|
+
|
ND
|
+
|
1. -
2. +
|
+
|
+
|
ESR
|
ND
|
ND
|
ND
|
ND
|
ND
|
ND
|
ND
|
Time from symptoms to
diagnosis (months)
|
8
|
3
|
2
|
24
|
12
|
14
|
36
|
Pancreatic tumor location
|
Head
|
Head
|
Tail
|
Tail
|
Body and tail
|
Head
|
Head
|
Tumor size (cm)
|
3.1×2.3×1.6
|
3.5×2.1×2.0
|
2.3×2.0×2.0
|
8.0×5.0×3.5
|
6.5×5.0×4.5
|
4.2×6.0×5.0
|
4.2×5.0×4.7
|
Location of metastasis
|
N
|
N
|
Liver
|
Liver, lymph
nodes
|
Liver, lymph
nodes
|
Liver
|
N
|
TNM staging
|
IIa (T2, N0, M0)
|
IIa (T2, N0,M0)
|
IV (T2, Nx, M1)
|
IV (T3, N1, M1)
|
IV (T3, N1, M1)
|
IV (T3, N0, M1)
|
IIb (T3, N0, M0)
|
Surgery
|
R-PPPD
|
PD
|
ND
|
DP+splenectomy
|
1. LDP +
splenectomy +
liver nodule biopsy
resection
2. Open
exploration+
adhesionolysis +
pancreatectomy
|
PD+ hepatic
metastasectomy
|
PD
|
Somatostatin analogue
|
Octreotide LAR
30 mg×1/month
|
Octreotide
100 µg×3/day
|
Octreotide LAR
30 mg×1/month
|
Octreotide
600 µg/day
|
Octreotide LAR
30 mg×1/month
|
Octreotide LAR
30 mg×1/month
|
Octreotide
100 µg×3/day
|
Amino acid infusions
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
Chemotherapy
|
N
|
N
|
N
|
N
|
Sulfatinib;
Everolimus
|
N
|
N
|
PRRT
|
N
|
N
|
N
|
90Y-DOTALAN
200 mCi × 2
|
N
|
N
|
N
|
Other treatments
|
N
|
N
|
N
|
TACE, RFA
|
TACE
|
N
|
N
|
Glucagon after surgery
(pg/mL)
|
103
|
233
|
ND
|
816
|
ND
|
315
|
110
|
Symptoms improved
|
3 days after
surgery
|
1 week after
surgery
|
N
|
Y
|
1 day after surgery
|
3 days after
surgery
|
1 day after
surgery
|
Survival (months)
|
Alive
|
Alive ( > 5
years)
|
11 ( diagnosis)
13 (first symptom)
|
63 (diagnosis)
78 (first symptom)
|
156 (diagnosis)
168 (first symptom)
|
Alive
|
Alive
|
Normal glucagon levels < 200 pg/mL. NME, necrotizing migratory erythema; DVT, deep vein thrombosis; IGT, impaired glucose tolerance; R-PPPD, robotassisted pylorus-preserving pancreaticoduodenectomy; DP, distal pancreatectomy; PD, pancreaticoduodenectomy; TACE, transarterial chemoembolization; PRRT, peptide receptor radioligand therapy; RFA, radiofrequency ablation N, no; Y, yes; ND, not done; NA, not available. |
NME was the first symptom in all the patients (Figure 1). One patient presented with repeated stomatitis, atrophic glossitis along with erythema as the first symptom. All the patients reported in this study had a delayed diagnosis. All the patients (7/7) visited the dermatology department first with a complaint of pruritic and painful polymorphic rash affecting of several months’ duration. The rash initially appeared at different places such as extremities, faces, ankles, gluteal regions, perineum, groins, lower back or abdomens. Then the erythema slowly progressed throughout the body. The boundary of rash is not clear and part of the lesions are fused in large areas. Erosion, exudation and necrosis can be seen in the center of some erythema. Topical steroids treatment led to a temporary improvement of the erythema in 6 of 7 patients, but it still occurred repeatedly and the erythema reoccurred accompanied by even much severer pruritus and pain. There was only patient who was treated with topical steroids but without any clinical improvement.
While not all of the patients initially had diabetes, all of the patients eventually developed diabetes (5/7) or IGT (2/7). Other symptoms included stomatitis and glossitis (2/7), weight loss (4/7), anemia (4/7), diarrhea (1/7), DVT (1/7) (Table 1). Among these symptoms, NME and diabetes or IGT were present in all the patients and may be considered tumor-specific symptoms.
Examinations and disease diagnosis
Skin biopsies were performed in all seven cases, and NME was diagnosed by the pathologist in all cases. Serum plasma glucagon level was significantly elevated (range 217–3155 pg/mL; normal <200 pg/mL) in all patients before surgery. Other biochemical abnormalities are outlined in Table 1.
Upon diagnosis, the primary tumors were identified by abdominal enhanced computed tomography (CT) in 4 of 7 cases, and by magnetic resonance imaging (MRI) in 3 of 7 cases in our patient cohort. Other modalities used for diagnosis were ultrasonography (3/7), liver metastasis biopsy (2/7), laparoscopic pancreatic biopsy (3/6) and skin biopsy (7/7). All patients had histopathological confirmation of the neuroendocrine tumor.
Four tumors were located in the head of the pancreas, two tumors were located in the tail, and one was located in the body and tail of the pancreas. Four patients presented with hepatic metastases upon diagnosis and two cases were found liver and lymph nodes metastases. Initial tumor stage, size, sites of metastasis, pathologic characteristics and proliferation index are detailed in Table 1. Other lymph nodes metastatic foci were found in two patients (patient 5 and 6) (Table1).
Therapy
The available treatment modalities used in our patients and the overall response to treatment are presented in Tables 1. Six of seven cases received surgical resection (5 in our hospital, 1 in other hospital), involving pancreaticoduodenectomy (PD) (4/6) and distal pancreatectomy (DP) (2/6). Of the 4 patients who received PD and the 2 patients who received DP, 1 patient each also received combined hepatic metastasectomy (Table 1). For all the 6 patients received surgery, the skin lesions improved gradually within 3 days after the surgery and postoperative plasma glucagon levels sharply decreased or even back to normal levels. One patient (patient 3) did not undergo surgical resection and was only treated with somatostatin analogues because multiple liver metastases had been found at diagnosis. All the 7 patients received somatostatin analogue and amino acid infusions. Four of seven patients received octreotide LAR and the other 3 of 7 patients got octreotide treatment. Patient 4 also undergone transarterial chemoembolization (TACE), radiofrequency ablation (RFA) and 90Y-DOTALAN due to liver metastasis. Patient 5 received chemotherapy (sulfatinib; everolimus) and TACE treatment.
Pathological characteristics
The primary tumor size ranged from 3.1×2.3×1.6 cm to 8.0×5.0×3.5 cm. Metastases were found in three of the six patients during surgery. Pathologists diagnosed patient 4 with poorly differentiated pancreatic islet cell tumors, and other diagnosed patients with moderate differentiated pancreatic islet cell tumors. Immunohistochemistry confirmed the final diagnosis of glucagonoma. The Ki-67 index was 8–10% for patient 1,2,3,5 and 7, 30% for patient 6, and was not tested in the patient 4. Other immunohistochemical stainings for chromogranin A (CgA), synaptophysin (Syn) and somatostatin receptor 2 (SSTR2) were also included (Figure 2). In summary, 5 patients had had a grade 2 (G2) tumor, and patient 6 had a grade 3 (G3) tumor.
Follow-up
By the time of follow-up in October 2021, three out of seven patients had died and all the deaths were disease related. The mean time to disease-related death was 6.4 years (range 0.9–13) from diagnosis and 7.2 years (range 1.1–14) from initial clinical manifestations.