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Table of Contents
Year : 2019  |  Volume : 6  |  Issue : 3  |  Page : 140-146

Pathologic complete response to bevacizumab-FOLFIRI in metastatic colonic undifferentiated carcinoma with rhabdoid features

1 Department of Surgery, Division of Colorectal Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
2 Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
3 Department of Surgery, Division of Colorectal Surgery, Kaohsiung Veterans General Hospital, Kaohsiung; School of Medicine, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan

Date of Submission26-Sep-2018
Date of Decision24-Nov-2018
Date of Acceptance05-Dec-2018
Date of Web Publication20-Aug-2019

Correspondence Address:
Dr. Chao-Wen Hsu
Department of Surgery, Division of Colorectal Surgery, Kaohsiung Veterans General Hospital, No. 386, Dazhong 1st Road, Zuoying District, Kaohsiung City 81362
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCRP.JCRP_24_18

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Undifferentiated colorectal carcinoma with rhabdoid features is unusual, aggressive, and resistant to chemotherapy. Compared to rhabdoid phenotype, immunohistochemistry is a more reliable way of detecting undifferentiated colorectal carcinoma with rhabdoid features. An increasing number of studies have reported that defects in core subunits of the switch/sucrose-nonfermenting complex may play an important role in the formation of rhabdoid tumors. Herein, we report the first case, to the best of our knowledge, with a pathologic complete response after neoadjuvant chemotherapy. A 65-year-old Taiwanese female had carcinoma over the ascending colon and multiple metastases to mesenteric lymph nodes and peritoneum. The immunohistochemical findings resembled those of rhabdoid features. She had received neoadjuvant chemotherapy with bevacizumab plus irinotecan with leucovorin and 5-fluorouracil (modified FOLFIRI). Follow-up computed tomography and surgical specimens revealed a favorable outcome. The effectiveness of neoadjuvant multiagent therapy for this rare carcinoma may inspire future research of tumorigenesis and novel treatments.

Keywords: Colonic neoplasms, metastasis, neoadjuvant therapy, rhabdoid tumor

How to cite this article:
Hsieh TC, Liu HW, Hsu CW. Pathologic complete response to bevacizumab-FOLFIRI in metastatic colonic undifferentiated carcinoma with rhabdoid features. J Cancer Res Pract 2019;6:140-6

How to cite this URL:
Hsieh TC, Liu HW, Hsu CW. Pathologic complete response to bevacizumab-FOLFIRI in metastatic colonic undifferentiated carcinoma with rhabdoid features. J Cancer Res Pract [serial online] 2019 [cited 2022 Oct 3];6:140-6. Available from: https://www.ejcrp.org/text.asp?2019/6/3/140/264843

  Introduction Top

Undifferentiated colorectal carcinoma with rhabdoid features is extremely uncommon, and only 27 cases have been reported previously.[1],[2],[3] Histopathologic heterogeneity makes it challenging to diagnose malignant rhabdoid tumors (RTs). In practice, these rhabdoid features may not be readily recognized by pathologists. The characteristics of cells can range from definite rhabdoid to epithelioid features.[2] Immunohistochemical findings have been suggested to be a more reliable test in identifying undifferentiated rhabdoid colorectal carcinoma. In general, rhabdoid neoplasms are positive for pan-cytokeratin (pan-CK), vimentin, epithelial membrane antigen, and smooth muscle actin but typically negative for desmin and myogenic differentiation markers. Recent studies have shown that extrarenal RTs may share identical or similar deletions of switch/sucrose-nonfermenting (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), RCB1 (also known as INtegrase Interactor 1 [INI1]/SNF5/Brahma-related gene-1-associated factors 47) with renal RTs.[2] Nevertheless, there is currently no consensus on the treatment for this rare type of colorectal cancer, and most patients die within 6 months after the initial diagnosis.[1] For patients with advanced colorectal cancer, fluoropyrimidine-based chemotherapy, either with the modified FOLFIRI regimen or 5-fluorouracil plus folinic acid plus oxaliplatin, FOLFOX-4, are recognized as first-line treatments.[4] Adding bevacizumab, the monoclonal antibody, against vascular endothelial growth factor (VEGF) to FOLFIRI or FOLFOX has revealed modest activity for metastatic colorectal cancer.[5]

To the best of our knowledge, this is the first case of the use of neoadjuvant therapy to treat undifferentiated colorectal rhabdoid carcinoma. This is also the first case to demonstrate a complete pathologic response of a colorectal malignant RT. There was no evidence of residual tumor either macroscopically or microscopically. The promising outcome, in this case, may shed light on developing innovative treatment strategies.

  Case Report Top

A 65-year-old Taiwanese female initially presented with abdominal pain for 3 weeks. Whole-abdominal computed tomography (CT) scan showed a mass lesion enhancement over the ascending colon which directly invaded or was adherent to nearby structures [Figure 1]a. There were metastatic lesions in the multiple para-aortic and mesenteric lymph nodes and peritoneum. The radiological staging was cT4bN2bM1b. Exploratory laparoscopy demonstrated multiple peritoneal carcinomatoses and ascites accumulation. The pathological report indicated metastatic mesentery carcinomas. Colon fiberscopy revealed an ulcerative tumor of 5 cm in size over the cecum, and a biopsy was performed [Figure 2]. Pathological findings showed undifferentiated carcinoma, consisting of clusters of poorly differentiated neoplastic cells in the nests, sheets, and single-cell pattern with desmoplastic stromal reaction [Figure 3]a. Neither specific differentiation nor origin was noted. The tumor cells were positive for pan-CK and CK (CAM5.2); a few scattered cells were positive for CK20 and negative for CK7, paired box 8, caudal-related homeobox gene 2 (CDX2), and synaptophysin immunostaining [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]f. Further immunohistochemistry tests were focally weakly positive for SMARCB1 (INI1) and 50% positive for vimentin [Figure 3]g and [Figure 3]h. The cells that were positive for vimentin also demonstrated paranuclear accentuation, which is a representative immunohistochemical finding in most gastrointestinal rhabdoid carcinomas. Testing for mismatch repair proteins revealed the loss of MutL homolog 1 and postmeiotic segregation increased Saccharomyces cerevisiae 2 nuclear expressions but intact MutS protein homolog 2 and 6 expression, suggesting a high level of microsatellite instability [Figure 3]i, [Figure 3]j, [Figure 3]k, [Figure 3]l. Roche KRAS mutation test v2 identified a mutation in B-Raf murine sarcoma viral oncogene homolog codon 600, but no v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (RAS) and neuroblastoma RAS viral oncogene homolog gene mutations were detected. The staining results were generally in favor of undifferentiated carcinoma with rhabdoid features. Pan-CK had a paranuclear accentuation that also resembled a RT of the gastrointestinal tract. After a joint meeting with a pathologist and an oncologist, neoadjuvant chemotherapy was decided. The patient was initially given one cycle of mFOLFIRI and three cycles of bevacizumab plus mFOLFIRI. A follow-up CT scan 3 months after the initial assessment revealed evidence of a decrease in tumor burden. There were remarkably regressive changes in previous bulky lymph nodes over the mesentery, celiac trunk, and para-aortic space, and the residual lymph nodes at the ileocecal region were about 4.2 cm in size [Figure 1]b. Before she underwent right hemicolectomy and resection of ileostomy 5 months after her initial presentation, she received one cycle of mFOLFIRI alone plus five cycles of combined neoadjuvant chemotherapy. Macroscopically, there was no identifiable residual mass lesion in the resected specimen, except for a focal mildly ulcerative lesion, which may have been a postchemotherapy scar [Figure 4]. No viable tumor cells were identified in microscopy [Figure 5]a and [Figure 5]b. Postchemotherapy changes such as foamy histiocytes and giant cell reactions were observed [Figure 5]c and d]. Lymph nodes found in the tumor bed region and the pericolic region revealed reactive hyperplasia and necrosis without evidence of metastasis [Figure 5]e. A postsurgical follow-up CT scan illustrated no evidence of local reoccurrence and ill-defined fatty infiltration at the mesenteric root, corresponding to the previous lymphadenopathies [Figure 1]c. The final pathologic staging represented a complete response to neoadjuvant therapy (ypT0N0M0). The postoperative course was remarkable for poor surgical wound healing and abdominal wall abscess formation at the prior colostomy site 1 month after the operation. A CT scan detected a right lower quadrant abscess but no local reoccurrence [Figure 1]d. She recovered well after wet dressing changes and ultrasound-guided abscess drainage. Eighteen months after her first visit, there were no signs of reoccurrence. She had received one cycle of postoperative bevacizumab plus mFOLFIRI and had taken oral uracil-tegafur plus leucovorin for 2 months.
Figure 1: Abdominal computed tomography (a) before treatment, demonstrating a contrast-enhanced mass lesion over the ascending colon with direct invasion or adhesion to surrounding structures. (b) After treatment, showing regressive changes of the abdominal mass. (c) Postsurgical follow-up revealed no evidence of reoccurrence. (d) Postoperative poor wound healing and abdominal wall abscess formation without evidence of reoccurrence 6 months after her initial presentation

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Figure 2: Colon fiberscopy revealed an ulcerative tumor of 5 cm in size

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Figure 3: Pathological findings showed (a) poorly differentiated cells and the staining results of (b) cytokeratin AE1/AE3 (pan-cytokeratin), (c) CAM5.2, (d) CK20, (e) CK7 (f) CDX2 (g) switch/sucrose-nonfermenting-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, (h) vimentin, (i) MLH1, (j) PMS2, (k) MSH2, and (l) MSH6

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Figure 4: Gross specimen of resected large intestine, from the terminal ileum to T-colon after treatment with neoadjuvant therapy composed of bevacizumab plus modified FOLFIRI. Note the focal mildly ulcerative lesion, measuring 1.8 cm × 1.2 cm × 1 cm at the tumor bed

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Figure 5: Postchemotherapy changes. (a and b) No viable tumor cells with (b) revealing giant cell reaction. (c) Foamy histiocytes and (d) giant cells. (e) Lymph node necrosis

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  Discussion Top

We summarized all documented cases of malignant colorectal RTs in the literature as shown in [Table 1].[1],[2],[3],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24] The mean age of the 28 cases (including ours) was 61.4 years, and there were 16 males and 12 females. The distribution throughout the colon was roughly equal. Nearly half (13/28) of the cases had metastasis, which may reflect the aggressive nature and poor prognosis of malignant RTs. Almost all of the cases were positive for pan-CK and vimentin, which is consistent with the immunohistochemical findings of malignant RTs at other sites of the human body. Immunohistochemical results also set these RTs apart from adenocarcinoma. In addition, 9/11 cases were negative for CDX2, a specific marker for adenocarcinoma of gastrointestinal origin, 14/16 cases were negative for both CK7 and CK20, whereas colorectal adenocarcinoma is usually negative for CK7 and positive for CK20. In our case, although the histological pattern did not demonstrate a definite rhabdoid feature, the immunohistochemical findings are consistent with the reported cases.
Table 1: Summary of all cases of undifferentiated colorectal rhabdoid carcinoma in the literature

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Most of the patients with undifferentiated rhabdoid colorectal carcinoma only received surgical resection. This may be due to the previous understanding that chemotherapy and radiotherapy are inefficient against malignant RTs.[10] Before our case, only six cases were given chemotherapy. Pancione et al. gave their patient routine adjuvant chemotherapy which was discontinued after CT showed evidence of progression. This case was later given a trial of four cycles of bevacizumab-based and two cycles of cetuximab-based therapy without significant benefits.[16] The case then received adjuvant capecitabine and oxaliplatin but died within 6 months.[17] One case who completed 12 cycles of adjuvant FOLFOX was alive without evidence of reoccurrence when the paper was published (>36 months[18]). Nevertheless, Kalyan et al. reported disease progression despite treatment with FOLFOX.[24] The regimen we applied, bevacizumab, is commonly administered with FOLFIRI or FOLFOX as the first-line chemotherapy for advanced colorectal cancer with promising outcomes. In contrast, Samalavicius et al. prescribed FOLFIRI without bevacizumab, and their patient experienced a rapid spread of metastasis.[19] VEGF is related to wound healing. Therefore, bevacizumab could possibly have contributed to the poor surgical wound healing in our patient.

Recent studies have reported that there is often a deletion, mutation, loss, or reduced transcription of SMARCB1[2] in RTs. Despite other immunohistochemical features similar to those of RTs, our case had a positive SMARCB1 nucleus expression. In fact, only 3/9 cases reported a loss of nuclear SMARCB1 [Table 1]. However, rhabdoid features may be related to other SWI/SNF subunits such as SMARCA2/ 4 and AT-rich interaction domain 1A.[2] One case series of malignant gastrointestinal RTs reported that 12/13 (92%) cases had deficiencies in at least one of the four SWI/SNF subunits,[2] and more SWI/SNF pathway deficits may be reported as future investigations increase our understanding of the association between the SWI/SNF pathway and tumorigenesis. Therefore, it is reasonable to assume that there may have been a loss of the expression of other SWI/SNF subunits in our case. Unfortunately, the limitation of our surgical pathology service prevented us from validating this hypothesis.

  Conclusion Top

This case highlights the recognition of colorectal RTs and the promising response to neoadjuvant bevacizumab plus mFOLFIRI. Although known for the unique rhabdoid phenotype, this rare type of neoplasm is better recognized with the specific features of immunohistochemical findings. Among 28 reported cases, our case is the first to incorporate chemotherapy before surgery. We also demonstrated a pathological complete response of metastatic colorectal cancer. Further studies are required to illustrate the pathogenesis and improve the outcome of this rare colorectal carcinoma.

Declaration of patient consent

We have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgments & Financial support

This work was supported by Kaohsiung Veterans General Hospital, Taiwan and assisted in part by the Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Taiwan.

Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1]


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