Background: Despite major advancements, effective treatment for patients with SMARCB1-deficient cancers has remained elusive. Here, we report the first case of a SMARCB1-deficient undifferentiated carcinoma in the rectum expressing high PD-L1 and responding to a PD-1 inhibitor, as well as with low tumor mutation burden (TMB), proficient mismatch repair (MMR) and BRAF V600E mutation. Case presentation: A 35-year-old man visited our hospital complaining of increased defecation frequency, bloody stools and weight loss of 3 kg for one month. Colonoscopy revealed an ulcerated and irregular mass approximately 8–12 cm from the anus. Surgical resection was performed. Histopathological findings revealed that the tumor cells had poor connectivity with each other; each cell had eosinophilic cytoplasm and a polymorphic nucleus. Brisk mitotic activity and necrosis were frequently observed in the tumor cells. Immunohistochemical examination showed that the tumor cells were negative for SMARCB1. The tumor proportion score (TPS) of PD-L1 (22C3) expression was 95%, and the combined positive score (CPS) was 100; the tumor was mismatch repair (MMR) proficient. Next-generation sequencing showed a low tumor mutation burden (TMB), as well as the BRAF V600E mutation. The final diagnosis was SMARCB1-deficient undifferentiated carcinoma. Chemotherapy was useless in this case. His tumor recurred during chemotherapy, and he then received targeted therapy with tirelizumab, an inhibitor of PD-1. At present, his general condition is good. A recent computed tomography (CT) scan showed that the tumor had disappeared, indicating that the immunotherapy was effective. Astonishingly, his most recent follow-up was in August, and his condition continued to improve with the tumor has disappeared. Conclusion: SMARCB1‑deficient undifferentiated carcinoma in the rectum is extremely rare, and it has aggressive histological malignancy and poor progression. The observed response to PD-1 inhibitors suggests a role for prospective use of SMARCB1 alterations as a predictive marker for immune checkpoint blockade.
Keywords: Response; PD-L1; SMARCB1; Rectal carcinoma; Case report
Wenjuan Shen and Yi Pan contribute equally to this work.
SMARCB1 (SWI/SNF-related matrix-associated act independent regulator of chromatin subfamily B member 1, also known as INI-1 and BAF47) is a tumor-suppressor gene located on chromosome 22q11.2 [[
A 35-year-old man visited our hospital complaining of increased defecation frequency, bloody stools and weight loss of 3 kg for one month. The patient denied any history of malignant tumors. And the patient also denied any family history of malignant tumors. Physical rectal examination revealed a circumferential mass with poor activity. Blood was noted by digital rectal exam. Laboratory findings showed that the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were within the normal range. Colonoscopy suggested an ulcerated and irregular mass approximately 8-12 cm from the anus with obvious lumen stenosis (Fig. 1A and B). The biopsy result of the rectum lesion indicated poorly differentiated adenocarcinoma. A computed tomography (CT) scan showed a wall-thickening lesion in the sigmoid colon and upper rectum (Fig. 1C and D). Multiple regional lymph nodes showed strengthening signals. The lung and liver were unremarkable.
Graph: Fig. 1Clinical findings. A, B Colonoscopy revealed an ulcerated and irregular mass approximately 8-12 cm from the anus with obvious lumen stenosis. C, D Computed tomography (CT) shows thickened walls of the sigmoid and upper rectum. Multiple regional lymph nodes showed strengthening signals
The surgical specimen consisted of a sigmoid and rectal segment measuring approximately 15 cm in length, with a luminal diameter varying from approximately 5 cm at the proximal end to 9.0 cm at the distal end. The tumor, measuring 6.5 cm×6.2 cm×1.5 cm, occupied 3/4 of the rectal lumen. It presented as a well-demarcated mass lesion with central deep ulceration (Fig. 2A). The cut surface showed a grayish-white or grayish-yellow solid tumor with central hemorrhage and necrosis. The tumor had invaded through the muscularis propria into the peri-rectal tissues (Fig. 2B). Forty-six lymph nodes were retrieved from the adipose tissue surrounding the bowel wall, with a diameter of 0.3 cm (4.5×3.5×1.5 cm).
Graph: Fig. 2Pathological findings. A, B The tumor, measuring 6.5 cm × 6.2 cm × 1.5 cm, occupied 3/4 of the rectal lumen. It presented as a well-demarcated mass lesion with central deep ulceration. The cut surface showed a grayish-white or grayish-yellow solid tumor with central hemorrhage and necrosis. The tumor had invaded through the muscularis propria into the peri-rectal tissues. C-G Histopathological findings revealed that the tumor cells had poor connectivity, eosinophilic cytoplasm and a polymorphic nucleus. H Metastasis was observed in regional lymph nodes
Histopathological findings revealed that the tumor cells had poor connectivity, eosinophilic cytoplasm and a polymorphic nucleus (Fig. 2C). These characteristics are called rhabdoid features because the morphology of these cells is similar to that of rhabdomyosarcoma tumor cells. These rhabdoid cells contained vesicular nuclei with prominent nucleoli and a significant amount of eosinophilic cytoplasm (Fig. 2D and E). Brisk mitotic activity was a frequent finding (Fig. 2E and F). The remaining 35% of the maximal cut surface was not evaluated due to necrosis (Fig. 2G). The tumor had invaded the peri-rectal tissues and showed lymph-vascular and perineural invasion. The surgical margins were tumor free. Metastasis was observed in 12 of the 46 regional lymph nodes retrieved (Fig. 2H).
Immunohistochemistry results showed that the tumor cells were positive for both epithelial (cytokeratin AE1/AE3, Fig. 3A) and mesenchymal (Vimentin, Fig. 3B) cell markers. Tumor cells showed weak positivity for SATB2 (Fig. 3C). However, CDX-2 (Fig. 3D) and CEA (Fig. 3E), which are markers of colonocyte differentiation, were negative. Ki-67, which shows proliferative ability, was as high as 95% (Fig. 3F). Notably, the tumor cells showed complete loss of INI-1 (SMARCB1 protein), which is normally expressed in the nucleus (Fig. 4A). Nuclear expression was retained in neighboring nonneoplastic cells. They were diffusely positive for BRG1 (SMARCA4, Fig. 4B), BRM (SMARCA2, Fig. 4C) and ARID1A1 (Fig. 4D). Impressively, the tumor proportion score (TPS) of PD-L1 (22C3) expression was 95%, and the combined positive score (CPS) was 100 (Fig. 4E and F). However, probing for MMR proteins, including MLH1 (Fig. 5A), MSH2 (Fig. 5B), MSH6 (Fig. 5C) and PMS2 (Fig. 5D), revealed proficient MMR, suggesting low microsatellite instability (low-MSI) or microsatellite stability (MSS). Additional immunohistochemical staining for BRAF V600E (Fig. 5E) and p53 (Fig. 5F) mutant proteins indicated strong and diffuse expression. The tumor cells were negative for CK7, CK20, CD56, ChrA, Desmin, MyoD1, Melan A, S-100, HER-2 and LCA (Supplementary Fig. 1).
Graph: Fig. 3Immunohistochemistry results of tumor cells. The tumor cells were positive for cytokeratin AE1/AE3 (A) and vimentin (B). The tumor cells showed weak positivity for SATB2 (C). CDX-2 (D) and CEA (E) were negative. Ki-67(F) was as high as 95%
Graph: Fig. 4Immunohistochemistry results of tumor cells. A The tumor cells showed complete loss of INI-1 (SMARCB1 protein). B-D The tumor cells were diffusely positive for BRG1 (SMARCA4), BRM (SMARCA2) and ARID1A. E and F The tumor proportion score (TPS) of PD-L1 (22C3) expression was 95%, and the combined positive score (CPS) was over 100
Graph: Fig. 5Immunohistochemistry for therapeutic markers in tumor cells. A-D MLH1, MSH2, MSH6 and PMS2 indicated proficient MMR. E and F BRAF V600E and p53 mutant protein expression were strong and diffuse
Next-generation sequencing was also performed, and the tumor exhibited a tumor mutation burden (TMB) of 5.84 mutations/megabase (Supplementary Fig. 2A) and microsatellite stability (MSS, Supplementary Fig. 2B). The results also indicated the presence of BRAF (c.1799T>A, p.V600E) mutation and TP53 (c.818 G>A, p.R273H) mutation.
The final pathological diagnosis was SMARCB1‑deficient undifferentiated carcinoma, pT3N2bM0 (Stage IIIc), according to the World Health Organization classification of digestive system tumors, 5th edition. Postoperative adjuvant chemotherapy was administered using XELOX (capecitabine oxaliplatin). Unfortunately, the tumor recurred while the patient was receiving chemotherapy (Fig. 6A). Then, he received targeted therapy with tirelizumab, a monoclonal antibody against PD-1. At present, he has received 4 cycles of immunotherapy, and his general condition is good. A computed tomography (CT) scan showed that the tumor had disappeared (Fig. 6B), indicating that the above immunotherapy was effective. At nearly one year postoperatively, the patient was still alive, and his general condition was good. Astonishingly, his most recent follow-up was in August, and his condition continued to improve with the tumor has disappeared.
Graph: Fig. 6Follow-up condition of the patient. A The tumor recurred during chemotherapy. B The recent computed tomography (CT) scan showed that the tumor had disappeared after the patient received 4 cycles of immunotherapy
We describe an uncommon case of a middle-aged man presenting with SMARCB1-deficient undifferentiated carcinoma. To the best of our knowledge, this is the first case report of SMARCB1-deficient undifferentiated carcinoma in the rectum expressing high PD-L1 and responding to PD-1 inhibitors, as well as with low tumor mutation burden (TMB), proficient mismatch repair (MMR) and BRAF V600E mutation.
The SWI/SNF complex functions in chromosome modeling and regulates gene transcription, cell proliferation, lineage-specific differentiation, and DNA damage repair. Inactivating mutations in the subunits can lead to deficiency of the SWI/SNF complex and thus influence cell differentiation; it is usually associated with undifferentiated histological morphology and highly aggressive clinical behavior. Villatoro et al. [[
Immune checkpoint blockade for cancer therapy with anti-programmed death ligand 1 (anti-PD-L1) antibodies has been approved, highlighting a dynamic change in the field of immuno-oncology. Some established biomarkers include deficient MMR/microsatellite instability-high (MSI-H) [[
In BRAF, a missense mutation (V600E) of exon 15 codon 600 activates downstream signaling [[
Forrest SJ et al. found many INI-1-negative tumors express PD-L1, suggest that clinical trials of immune checkpoint inhibitors are warranted in INI-1-negative pediatric cancers [[
Overall, we propose that PD-L1, BRAF V600E, and MMR protein immunohistochemical staining should be performed for all SWI/SNF-deficient undifferentiated carcinomas. However, it remains necessary to assess more cases with detailed information on clinical treatment and prognosis and then to determine if these cases require different treatment strategies, particularly for advanced or recurrent cases.
SMARCB1-deficient undifferentiated carcinoma in the rectum is extremely rare, and it has aggressive histological malignancy and poor progression. The response to PD-1 inhibitors of the tumor described herein suggests a role for prospective use of SMARCB1 alterations as a predictive marker for immune checkpoint blockade. Further prospective clinical trials of immunotherapy in patients with SWI/SNF complex aberrations and malignancies are urgently needed.
Wenjuan Shen and Yi Pan wrote the manuscript. Shuangmei Zou proposed the research, assisted in drafting the manuscript and reviewed the histopathological findings. All authors have read and approved the final manuscript.
This work was supported by National Natural Science Foundation of China (NSFC) No. 81903019 and CAMS Innovation Fund for Medical Sciences (CIFMS) No. 2021-I2M-C&TA-017.
Not applicable.
The use of human samples was approved by the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. The data used in this research are part of standard-of-care hospital routine.
The authors declare no competing interests.
Graph: Additional file 1: Figure 1. The tumor cells were negative for CK7, CK20, CD56, ChrA, Desmin, MyoD1, Melan A, S-100, HER-2 and LCA.
Graph: Additional file 2: Figure 2. Next-generation sequencing showed a tumor mutation burden (TMB) of 5.84 mutations/megabase (A) and microsatellite stability (B).
• SMARCB1
- SWI/SNF-related matrix-associated act independent regulator of chromatin subfamily B member 1
• CRC
- Colorectal cancer
• MMR
- Mismatch repair
• MSI
- Microsatellite instability
• MSS
- Microsatellite stability
• TMB
- Tumor mutation burden
• PD-L1
- Programmed death ligand 1
• TPS
- Tumor proportion score
• CPS
- Combined positive score
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By Wenjuan Shen; Yi Pan and Shuangmei Zou
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