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Abstract

Primary squamous cell carcinoma of the pancreas is sporadic and rarely reported. This uncommon disease is characterized by rapid proliferation, high aggressiveness, and poor prognosis. To date, no standard treatment regimen has been established for this malignancy. The present study reported on a patient diagnosed with primary squamous cell carcinoma of the pancreas who showed recurrence after radical resection and adjuvant chemotherapy. The patient was refractory to salvage therapy with cytotoxic drugs, anti-angiogenesis drugs, and even immune checkpoint inhibitors, resulting in a poor prognosis. Notably, the Ki-67 proliferation index, a marker of tumor cell proliferation, increased from 40% in the surgical specimen to 80% in the recurrent tumor within 2 months. In addition, the literature on clinical characteristics as well as treatment options and their efficacy in patients with squamous cell carcinoma of the pancreas was reviewed and summarized to improve the understanding of the disease and treatment choices. This case report offers valuable insights into squamous cell carcinoma of the pancreas progression and underscores the need for further research on this aggressive malignancy.

Keywords

Squamous cell carcinoma pancreas refractory case report review

Introduction

Primary squamous cell carcinoma (SCC) of the pancreas (SCCP), a rare malignant tumor accounting for ∼0.5%–2% of all pancreatic carcinomas, has been considered a cancer type characterized by rapid proliferation, high aggressiveness, resistance to treatment, and poor prognosis.^1–3 Due to its low incidence, no standard treatment regimen has been established, making the management of the disease particularly challenging. In recent years, various therapeutic approaches, including surgery, chemotherapy, radiotherapy, anti-angiogenesis therapies, and immune checkpoint inhibitors, have been explored in clinical practice with mixed results.^4–8 With the exception of surgery, which offers a significant survival advantage, the other treatments have shown limited efficacy in addressing SCCP. The present study reported the case of a patient diagnosed with primary SCCP who exhibited rapid progression following radical resection and adjuvant chemotherapy. The patient was refractory to salvage treatments, including cytotoxic drugs, anti-angiogenesis therapies, and immune checkpoint inhibitors, leading to a poor prognosis. Notably, the Ki-67 proliferation index, a marker of tumor cell proliferation, increased from 40% in the surgery specimen to 80% in the recurrent tumor within 2 months. In the present study, the clinical implications of this increase in the Ki-67 index were discussed and the impact of surgery in such cases was assessed. In addition, the literature on clinical characteristics, treatment options, and outcomes for patients with SCCP was reviewed and summarized to enhance the understanding of this disease and its treatment strategies.

Case report

A 70-year-old Chinese man was admitted to Quzhou People’s Hospital (Quzhou, China) in February 2022 with mild abdominal pain that had persisted for 1 week. The patient’s medical history included smoking (1.5 packs per day for 46 years), alcohol consumption (∼40 years), and hypertension, for which he had been taking 150 mg irbesartan daily for 3 years. The patient reported no other medical or family history. His physical examination on admission failed to detect any abnormal signs in the abdomen. In February 2022, abdominal magnetic resonance imaging (MRI) showed a large space-occupying lesion on the body and tail of the pancreas, along with spleen involvement. In addition, chest computed tomography (CT) and brain MRI indicated no suspicious lesion in the lungs or brain. Positron emission tomography-CT (PET-CT) was recommended before surgery but was refused by the patient, and no endobronchial ultrasound biopsy was performed preoperatively. Subsequently, endoscopic ultrasound and fine-needle aspiration (EUS-FNA) was performed; the results demonstrated atypical SCC. Furthermore, the patient’s SCC antigen level was elevated at 7.2 ng/mL (normal range: 0–1.5 ng/mL), whereas carcinoembryonic antigen (CEA) and CA19-9 levels were within the normal range. Based on a multidisciplinary treatment decision, which included medical doctors, surgeons, and the patient, upfront surgery was recommended, as there was no established neoadjuvant regimen for SCCP. The patient underwent radical pancreatosplenectomy with partial gastrectomy, left adrenalectomy, peripancreatic lymph node dissection, and jejunostomy on day 12 after admission. The surgery was successful, achieving a R0 resection with negative margins. Pathological analysis confirmed poorly differentiated SCCP, with invasion of the peripancreatic tissue and parenchyma of the spleen. The primary tumor on the body and tail of the pancreas was R0 removed according to the surgery record and pathological findings. Immunohistochemistry showed P40 and P63 positivity, GATA binding protein 3 negativity, and a Ki-67 index of 40%. The final diagnosis was stage III SCCP (pT4N0M0) according to the American Joint Committee on Cancer 8^th edition.⁹ Postoperative CT in March 2022 showed no evidence of recurrence (Figure 1(a) and (b)). Adjuvant chemotherapy was initiated with regimen AG (gemcitabine (1000 mg) on days 1 and 8 + nab-paclitaxel (130 mg) on days 1 and 8, every 21 days) from the end of March 2022. After two cycles, abdominal CT revealed a new lesion, 2.6 × 2.1 cm, near the greater curvature of the stomach, suggesting tumor metastasis (Figure 1(c) and (d)). As a second-line treatment, the patient was prescribed a salvage regimen consisting of toripalimab (a programmed cell death 1 inhibitor, 240 mg intravenously on day 1 every 21 days) and anlotinib (an oral multiple-target agent, 10 mg per day on days 1–14 every 21 days). However, after 2 months, abdominal CT in July 2022 showed disease progression, with growth of the lesion near the greater curvature of the stomach and new liver metastasis (Figure 1(e) and (f)). As a third-line treatment, the patient received cisplatin (70 mg/m²) combined with S-1 (an oral fluoropyrimidine-based chemotherapy regimen composed of tegafur, gimeracil, and oteracil potassium, 50 mg each time, administered orally twice daily on days 1–14 every 21 days). Unfortunately, after only one cycle, the patient could not tolerate the treatment due to severe vomiting and fatigue and transitioned to palliative care. The patient passed away in September 2022, 7 months after the initial diagnosis, due to liver failure caused by tumor invasion (Figure 1(g) and (h)). To clarify the histological nature of the recurrence, a gastroscopic biopsy was performed during disease progression. Histopathological examination confirmed recurrent SCCP (Figure 2(a) and (b)). Immunohistochemistry of the recurrent tumor indicated CK20 (Figure 2(c)) and caudal type homeobox 2 (a marker for tumors of gastrointestinal origin) (Figure 2(d)) negativity; P63 (Figure 2(e)), P40 (Figure 2(f)), and CK5/6 (Figure 2(g)) positivity; and a Ki-67 index of 80% (Figure 2(h)). A summary of the diagnostic approach, treatment regimens, and changes in targeted lesions is presented in Figure 3.

Figure 1.

Variations in the targeted lesions near the greater curvature of the stomach and liver metastasis indicated on CT/MRI images during treatment (red arrowheads). (a) CT from March 2022, no evidence of recurrent tumor near the greater curvature of the stomach. (b) CT from March 2022, no evidence of liver metastases. (c) CT from May 2022, recurrent tumor near the greater curvature of the stomach. (d) CT from May 2022, no evidence of liver metastases. (e) CT from July 2022, progression of the recurrent tumor near the greater curvature of the stomach. (f) CT from July 2022, development of multiple liver metastases. (g) MRI from September 2022, further progression of the recurrent tumor and liver metastasis and (h) MRI from September 2022, further progression of liver metastasis. CT: computed tomography; MRI: magnetic resonance imaging.

Figure 2.

Histological findings of the recurrent tumor based on (a and b) hematoxylin and eosin-stained gastroscopic biopsy tissue; (a) 10× magnification and (b) 20× magnification. Immunohistochemistry outcomes at 10× magnification: (c) CK20 (negative), (d) caudal type homeobox 2 (negative; a marker for tumors of gastrointestinal origin), (e) P63 (positive), (f) P40 (positive), (g) CK5/6 (positive), and (h) Ki-67 (80% positive). The nuclei are counterstained in blue, and positive staining appears as brown. CK: cytokeratin.

Figure 3.

Overview of the approaches to diagnosis, treatment regimens, and variations in the targeted lesions. PD-1: programmed cell death protein 1; BSC: best supportive care; S-1: oral fluoropyrimidine-based chemotherapy regimen composed of tegafur, gimeracil, and oteracil potassium.

Discussion

Primary SCCP is a rare tumor type, accounting for only 0.5%–2% of all primary pancreatic malignancies.^1–3 It is known for its highly invasive nature. The biology of SCCP remains largely elusive, and its prognosis is generally poor.³ The present case study reported on a patient diagnosed with SCCP who experienced the characteristic rapid progression after radical resection and two cycles of adjuvant chemotherapy. The patient was refractory to multiple salvage treatments, ultimately resulting in a poor prognosis. Of note, a significant increase in the Ki-67 proliferation index was observed, which rose from 40% in the surgical specimen to 80% in the recurrent tumor within 2 months. To the best of our knowledge, the present study was the first report of such a phenomenon in clinical practice. Although the underlying mechanism remains elusive, the observed increase in the Ki-67 index may be associated with the rapid progression of the recurrent tumor. This case may encourage further research into the progression of this disease.

The pancreas, a digestive organ, does not naturally contain squamous epithelium, and the origins of SCCP are thus elusive. Most pancreatic cancers follow a progression from normal tissue epithelium to low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, and eventually invasive carcinoma, with >90% of cancers resulting in pancreatic ductal adenocarcinoma.¹⁰ There are several hypotheses about the origin of SCCP. Some researchers suggest that it may arise from adenocarcinomas that undergo squamous metaplasia, while others propose that pancreatic cancer stem cells can differentiate into either SCCP or adenocarcinoma.^2,11 Regardless of the precise origin, SCCP remains a diagnosis of exclusion that must be carefully considered. In the present case, the tumor was thoroughly examined by pathologists following radical surgery, and complete imaging was performed to confirm the diagnosis. Based on these findings, the diagnosis of stage III SCCP was finally made in the present case. In addition, obtaining pathological tissue by puncture is challenging in retroperitoneal organs, including the pancreas. EUS-FNA has become an essential tool for the diagnosis of solid pancreatic lesions, and it was also utilized in the pathological diagnosis of the present case. However, at times, the small sample size of EUS-FNA does not allow definitive conclusions to be drawn. In a recent trial, it was reported that the wet-suction technique in EUS-FNB resulted in a higher tissue core procurement rate than the slow-pull method.¹² Further application of the novel technique in clinical practice may contribute to the diagnosis of pancreatic lesions. Given the high recurrence rate of patients with SCCP following surgery, neoadjuvant chemotherapy may extend the time to recurrence after the surgical intervention, although robust evidence to support this hypothesis remains limited. Consequently, a specific preoperative diagnosis would definitely be helpful for the overall management of the disease, particularly for the proper selection between neoadjuvant chemotherapy and adjuvant chemotherapy in the present case.

The clinical characteristics of the present case were listed as follows: (a) large space-occupying lesion on the body and tail of the pancreas, along with spleen involvement; (b) elevated SCC antigen level at 7.2 ng/mL (normal range, 0–1.5 ng/mL), with CEA and CA19-9 levels within normal ranges; (c) lesion was pathologically confirmed as SCCP, without any adenocarcinoma component, from the surgical sample; (d) after radical resection and two cycles of adjuvant chemotherapy, recurrent tumor was observed with an abnormal increase in the Ki-67 index; (e) refractory to salvage therapy regimens with cytotoxic drugs, anti-angiogenesis, or even immune checkpoint inhibitors; and (f) aggressive biological behavior with poor prognosis. In addition, the literature on clinical characteristics, treatment options, and treatment efficacy in patients with SCCP was reviewed and summarized to improve the understanding of the disease and its treatment choices.

A search in Medline (https://pubmed.ncbi.nlm.nih.gov) and Embase (https://www.embase.com) databases using the key words “squamous cell carcinoma” and “pancreas” identified 48 SCCP cases (Table 1), the largest review to date, covering cases published between 1980 and 2022.^{3–8,11,13–48} Clinical characteristics including author, gender, age, primary tumor locations, and invasive/metastatic site as well as therapeutic regimens and prognosis were reviewed and extracted. As shown in Table 1, the patients’ age ranged from 33 to 81 years, with a mean age of 63.5 years and a male-to-female ratio of 26:22. The primary tumors were located in the head (n = 23), neck (n = 13), and tail (n = 18) of the pancreas, with eight cases involving two locations. Local invasions or metastasis were detected in most of the patients (45/47) at the initial diagnosis. A total of 20 patients (20/45) received radical or palliative surgery for the primary tumor in the pancreas. The median overall survival time for the included patients was 7 (range: 1–42) months. The Ki-67 index was reported in only two cases, with a positivity rate of 30%. Of note, the patient in the present study also had a survival time of 7 months, and the cause of the rapid increase in the Ki-67 index following surgery and chemotherapy remains elusive. There is no clear explanation for this phenomenon, and it is possible that the survival of more aggressive SCCP cells following adjuvant chemotherapy contributes to the increased Ki-67 index. Ki-67 protein is known to be a marker of tumor cell population, and its high expression has been associated with poor prognosis in other cancer types, such as pancreatic neuroendocrine tumors, breast cancer, and endometrial cancer.^49–53 A retrospective study found that Ki-67 levels increased in over half of the patients who experienced recurrence following radical surgery for enteropancreatic neuroendocrine tumors, which is consistent with the finding of the present study.⁵¹ This suggests that Ki-67 may be a valuable predictor of postoperative disease progression in pancreatic malignancies.⁵³ In addition, the hypothesis regarding Ki-67 index variability in enteropancreatic neuroendocrine tumors suggests that genetic intramural heterogeneity or drug resistance may play a role.^54,55 However, the reasons for Ki-67 index variability in SCCP remain elusive. To explore this further, a whole-exome sequencing (WES) study has been planned by our group to investigate the potential molecular characteristics associated with the present case.

Table 1.

Clinical characteristics, treatment, and outcomes of squamous cell carcinoma of the pancreas.

Author(s), year	Sex	Age, years	Tumor site	Invasion/metastasis	Therapy	OS	Ref.
Ruecker et al., 2022	M	73	Tail	Spleen/kidney/colon/gastric	Surgery	6+	13
Li et al., 2022	F	70	Body	Spleen	Surgery	NR	8
Ardengh et al., 2022	F	46	Body/Tail	Splenic vein	Surgery, adjuvant CT (gemcitabine)	NR	14
Yang et al., 2021	F	54	Neck	Gastric, splenic vein	IO, CT (gemcitabone, nab-paclitaxel)	16+	15
Qiu et al., 2021	M	64	Body/Tail	Liver	N/A	3+	3
Li et al., 2021	F	55	Head	Duodenum, liver, bone	Surgery, CT (oxaliplatin, S-1, docetaxel, cisplatin), apatinib	11	16
Kim et al., 2021	F	75	Tail	Gastric	Surgery, CT (oxaliplatin, capecitabine)	42	17
Guo et al., 2021	M	63	Tail	Splenic artery	Surgery	18+	18
Kumar et al., 2019	M	60	Tail	Splenic vessel	Surgery, perioperative CT (gemcitabine)	12	7
Alajlan et al., 2019	M	79	Tail	Splenic artery, gastric, liver	N/A	3	6
Zhang and Cai, 2018	F	56	Body	Splenic vessel, gastric	CCRT	12	19
Zhang et al., 2018	F	64	Body	Gastric	CCRT, CT (paclitaxel, cisplatin), nimotuzumab, endostar	8	5
Lin et al., 2018	M	61	Head	Gastroduodenal artery, liver	RT	2	11
Rowe et al., 2016	F	81	Head/neck	Portal vein	BSC	NR	4
Mehta et al., 2015	M	73	Tail	Splenic vein and artery, kidney	BSC	2	20
Kashani et al., 2015	F	76	Tail	Liver	NR	NR	21
Ben Kridis et al., 2015	M	48	Head	Superior mesenteric artery	CT (5-FU, cisplatin), RT	9	22
Thomas et al., 2014	M	60	Tail	Liver, bone	BSC	NR	23
Schultheis et al., 2014	F	57	Tail/body	Splenic vein	CCRT, surgery	9	24
De Souza et al., 2014	M	61	Body	Liver, gastric	CT (gemcitabine, cisplatin, 5-FU)	7	25
Brijbassie et al., 2014	F	60	NR	Splenic vein	CCRT, surgery	NR	26
Sharma et al., 2013	M	57	Body/tail	Liver	CT (gemcitabine, cisplatin)	NR	27
Nikfam et al., 2013	F	66	Body/tail	Superior mesenteric artery, celiac artery	CT (gemcitabine, oxaliplatin)	9	28
Zacharia et al., 2012	F	68	Head	Superior mesenteric artery	BSC	3	29
Kodavatiganti et al., 2012	M	70	Head	Superior mesenteric vessel, duodenum, liver	Surgery, CT (5-FU, cisplatin, docetaxel)	15	30
Aurello et al., 2012	F	58	Body, tail	Gastric, spleen, colon, renal capsule, adrenal gland	Surgery, CT (5-FU, cisplatin)	3+	31
Adachi, 2011	F	67	Body	Splenic artery, gastric artery, gastric	Surgery, RT	11	32
Rana et al., 2009	M	50	Head	Duodenum, regional lymph nodes	BSC	NR	33
Lai et al., 2009	F	76	Tail	Liver	NR	NR	34
Chen et al., 2008	M	55	Head	Liver	Surgery	10	35
Al-Shehri et al., 2008	F	48	Head	Liver	CT (gemcitabine, carboplatin), BSC	4	36
Song, 2007	M	78	Head	NR	Surgery	NR	37
Anagnostopoulos et al., 2006	M	72	Head	Mesenteric vessels	Palliative surgery	4	38
Sawai et al., 2005	M	77	Body/tail	Peripheral splenic artery, gastric	Surgery	14	39
Brown et al., 2005	M	56	Tail	Spleen, gastric, liver	Surgery	4	40
Minami et al., 2001	M	62	Body/tail	Spleen, gastric, colon	Surgery	16+	41
Itani et al., 1999	M	68	Head	None	Surgery	3	42
Itani et al., 1999	M	63	Head	Lung	CT (5-FU, cisplatin), RT	1	42
Itani et al., 1999	M	80	Head	Lung, liver, bone	CT (5-FU, cisplatin), RT	1.5	42
Itani et al., 1999	M	79	Head	None	RT	3.5	42
Itani et al., 1999	M	63	Head	Lung, liver, bone	Cisplatin, vinblastine	7	42
Itani et al., 1999	M	38	Head	Lung, liver	RT	1	42
Kubota et al., 1997	F	73	Head	Posterior superior pancreatoduodenal artery	Surgery	NR	43
Nakashima et al., 1995	F	79	Head	Colon, retroperitoneum	BSC	1.5	44
Koduri et al., 1994	F	69	Head	Superior mesenteric artery	RT	7+	45
Beyer et al., 1992	F	33	Head	Duodenum, portal vein	Surgery, BSC	9+	46
Fajardo et al., 1988	M	61	Head	Splenic vein, liver	CT (5-FU, cisplatin), RT	NR	47
Sears et al., 1980	F	70	Head	Duodenum	Surgery, RT	3.5	48

5-FU: 5-fluorouracil; BSC: best supportive care; CCRT: concurrent chemoradiotherapy; CT: chemotherapy; F: female; IO: immunotherapy; M: male; N/A; not applicable; NR: not reported; OS: overall survival; RT: radiotherapy; S-1: an oral fluoropyrimidine-based chemotherapy regimen composed of tegafur, gimeracil, and oteracil potassium.

There are certain limitations to this case report. The most significant is the lack of molecular characterization of the tumor sample. To address this, WES testing has been planned by our group. In addition, the cause of the rapid increase in the Ki-67 index remains elusive and warrants further investigation. Furthermore, due to financial constraints, esophageal endoscopy or PET-CT examinations were not conducted to completely rule out the possibility of SCC metastasizing from other sites.

In summary, the present study reported the case of a patient with SCCP who exhibited rapid progression after radical resection and adjuvant chemotherapy and was resistant to multiple salvage treatment options, resulting in a poor prognosis. Of note, an unusual and rapid increase in the Ki-67 index was observed following surgery and adjuvant chemotherapy. This case may encourage further research into the mechanisms underlying such aggressive disease behavior.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251345957 - Supplemental material for Primary squamous cell carcinoma of the pancreas with treatment-refractory characteristics: A case report and literature review

Supplemental material, sj-pdf-1-imr-10.1177_03000605251345957 for Primary squamous cell carcinoma of the pancreas with treatment-refractory characteristics: A case report and literature review by Jian Wang, Dingting Zheng and Jianxin Chen in Journal of International Medical Research

Footnotes

Acknowledgments

The authors thank the patient for his participation and agreement to the publication of the report.

Author contributions

Jian Wang: Data curation, Investigation, Writing—Original draft preparation. Dingting Zheng: Data curation, Software, Writing—Original draft preparation. Jianxin Chen: Conceptualization, Methodology, Software, Writing—Original draft preparation, Writing—Reviewing and Editing.

Availability of data and materials

All data generated or analyzed during this study are included in this article.

Consent for publication

Written informed consent was obtained from the patient’s relatives for publication of this case report and any accompanying images.

Declaration of conflicting interests

The authors report no conflict of interest in this work.

Ethics approval and consent to participate

The publication of the present case details was approved by Ethical Committee of People’s Hospital of Quzhou (2022-007). The reporting of this study adheres to the Case Report (CARE) guidelines.⁵⁶

Funding

The study was supported by the Instructional Project of Quzhou (cat. nos. 2020057 and 2021005), Science and Technology Key Project of Quzhou (cat. nos. 2022K48 and 2021K21), ‘New 115’ Talent Project of Quzhou, and ‘258’ Talent Project of Quzhou.

ORCID iD

Jianxin Chen

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