Accepted Manuscript Case report of rhabdoid colon cancer and review of literature A. Kalyan, G. Pasricha, D. Monga, A. Singhi, N. Bahary PII:
S1533-0028(14)00103-0
DOI:
10.1016/j.clcc.2014.09.013
Reference:
CLCC 173
To appear in:
Clinical Colorectal Cancer
Received Date: 5 August 2014 Accepted Date: 17 September 2014
Please cite this article as: Kalyan A, Pasricha G, Monga D, Singhi A, Bahary N, Case report of rhabdoid colon cancer and review of literature, Clinical Colorectal Cancer (2014), doi: 10.1016/j.clcc.2014.09.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
Case report of rhabdoid colon cancer and review of literature Kalyan A1, Pasricha G2, Monga D2, Singhi A3 and Bahary N1 1
AC C
EP
TE D
University of Pittsburgh, Department of Hematology and Oncology 2 Allegheny General Hospital- Western Pennsylvania Hospital - Departments of Hematology and Oncology 3 University of Pittsburgh, Department of Pathology
ACCEPTED MANUSCRIPT
RI PT
Clinical Points: - Rhabdoid colon cancers are extremely rare but are highly aggressive. - The hallmark histological findings of rhabdoid tumors are an eccentrically located and large nucleus, prominent nucleoli, and cytosolic aggregates of intermediate filaments. - There are limited treatment options but multidrug regimens, which include cisplatin, cyclophosphamide, etoposide and actinomycin, may offer some responses.
M AN U
SC
Abstract: Rhabdoid colon carcinomas are rare, aggressive tumors with minimal treatment options. Histologically, they are characterized by large, eccentrically placed nucleus with prominent nucleoli and cytosolic aggregates. Here, we present a case of a 31-year-old female with rhabdoid colon cancer of the cecum and the treatment course. In addition, we also reviewed the literature for similar cases and discuss possible treatment options for such a rare case.
EP
TE D
Introduction Rhabdoid colon cancer (RC) is an extremely rare tumor type with only a few cases in the literature. It is a highly aggressive tumor with no proven effective treatment. The hallmark histological findings of rhabdoid tumors are an eccentrically located and large nucleus, prominent nucleoli, and cytosolic aggregates of intermediate filaments (Remo A, 2012). Here, we describe a case of a rhabdoid tumor arising at the cecum in a 31-year-old female. Her tumor lacked the classic colonic adenocarcinoma immunoprofile, yet grossly originated within the cecum. Molecular sequencing identified a KRASp.Q61H and TP53p.R273H mutations. Despite resection of her primary, at which time no metastatic disease was noted, and subsequent chemotherapy, as metastatic disease appeared, she died 18 weeks later. Her case underscores the need for better understanding of the aggressive biology of this rare tumor to offer better insight into molecularly directed treatment paradigms for rhabdoid tumors.
AC C
Clinical Case The patient, a 31-year-old female with no significant past medical history (PMH) and in excellent overall health, noted intermittent mid to right upper quadrant epigastric pain and weight loss of 5lbs over 1 month in July 2012. After failing a trial of symptomatic treatment for presumed gastrointestinal reflux disease, she underwent esophagogastroduodenoscopy (EGD), which did not demonstrate any areas of concern. Thereafter, she presented to an outside emergency department with worsening abdominal complaints. A CT scan at that time demonstrated multiple mildly dilated small bowel loops in the right lower quadrant with a transition point near the ileocecal valve, where there was focal short segment thickening of the terminal ileum. In the right lower quadrant, mesenteric edema and engorgement with localized ascites, along with enlarged mesenteric lymph nodes up to 1.2 cm in diameter, were seen.
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Emergency Personnel consideration was of either an initial presentation of inflammatory bowel disease (IBD) or a malignancy. Therefore, she underwent a colonoscopy revealing edema and contact bleeding at the cecum. A biopsy from this area was consistent with a poorly differentiated carcinoma. A follow up MRI demonstrated an irregular, eccentric, circumferential mural thickening of bowel at the level of the cecum. She underwent an elective hemicolectomy on 8/10/2012 that revealed an infiltrating 7 cm tumor with extensive necrosis and tumor arising from the cecum and extending through the submucosa, muscularis propria, subserosa and focally involving the serosal surface. The carcinoma was metastatic to 9 of 15 lymph nodes, pathologically staged as pT4a pN2b. Histologically, the tumor was composed of discohesive neoplastic cells with large, paranuclear cytoplasmic hyaline inclusions resulting in an eccentrically placed nucleus and imparting a rhabdoid appearance. The nuclei were large, oval and vesicular with each containing at least one basophilic nucleolus. Multiple mitotic figures, including atypical forms, were identified. Interspersed among the neoplastic cells were areas of prominent tumor necrosis. In addition, focal areas of glandular differentiation with mucin production were identified suggesting an adenocarcinoma origin.
TE D
Immunohistochemistry (IHC) showed focal cytokeratin positivity with AE1/AE3 but negative staining with cytokeratin 7, cytokeratin 20 and CDX-2. Additional staining of the tumor revealed focal strong staining with CAM5.2 and negative staining with CDX2, PAX-5, CD3, CD30, ALK-1, S-100 protein, desmin, smooth muscle actin, CD117, CD34, ERG, and ER. There was no loss of nuclear INI1 expression and mismatch repair proteins, PMS2 and MSH6, demonstrated intact nuclear expression. The tumor cells were also negative for neuroendocrine markers (synaptophysin, chromogranin and CD56), melanoma markers (HMB45, MelanA and MITF), MOC-31, polyclonal CEA and Ber-EP4.
AC C
EP
Targeted mutational detection of the tumor utilizing an Ion Torrent sequencing panel to assess 739 cancer-associated mutations in 46 cancer-related genes (see Table 1) revealed no BRAF (exon 15), KRAS (exon 2) mutations, but did identify mutations in KRAS exon 3(p.Q61H) and TP53 exon 8 (p.R273H). In an attempt to aid the pathological and molecular data supporting a colonic origin for this tumor, it was analyzed using the bioTheranostics CancerTYPEID® platform. CancerTYPEID® uses the differential expression of 92 genes to help determine the origin of a particular tumor. This analysis yielded a diagnosis of melanoma with 90% probability. However, the negative IHC results for S-100 protein and MelanA and the presence of a KRAS codon 61 mutation strongly argue that this was an erroneous result. Her original CT imaging and subsequent resection demonstrated no evidence of metastatic disease. In September 2013, 3 ½ weeks postoperatively, a PET/CT scan was obtained in anticipation of adjuvant chemotherapy for her colonic primary. It revealed multiple new bilobar metastases in the liver along with several foci of radiotracer uptake in the right lower quadrant
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
consistent with inflammatory or metastatic nodes, as well as a new destructive metastatic massin the left anterior 6th rib. Given the rapid progression of her disease and the pathological similarites of rhabdoid tumors to sarcomatous processes, we elected to treat her with an anthracycline and platinum based regimen with known gastrointestinal efficacy (epirubicin, capecitabine and oxaliplatin or EOX). She initially received one cycle of mFOLFOX6 while awaiting insurance approval of epirubicin for her now metastatic tumor with concomitant palliative radiosurgery to the left 6th rib resulting in complete abatement of her pain. Her first two cycles of EOX were uneventful, but beginning with the third cycle, she began to complain of sharp abdominal pain and nausea that progressed to include vomiting after about 1 week. Repeat PET/CT imaging revealed significant growth of her hepatic lesions, an irregular mesenteric mass in the right mid abdomen causing partial duodenal obstruction, bilateral hydronephrosis due to new adenopathy, and several new FDG avid masses within the serosa, mesentery, and iliac vessels and surrounding the colonic anastomosis. In addition, a new FDG avid lytic boney lesion within the right ileum and regrowth of her left 6th rib lesions were identified.
TE D
Shortly after this PET/CT scan, she was admitted to the hospital with a high-grade obstruction in the 2nd part of the duodenum. This was partially relieved by placement of a 22 mm x 120 mm enteral wall stent. Unfortunately, she developed worsening hydronephrosis requiring the placement of bilateral nephrostomy tubes. Shortly thereafter, she developed hepatic failure from worsening hepatic tumor burden and a hematological pattern consistent with disseminated intravascular coagulation (DIC). With an overall decline in her performance status, she and her family elected to forgo further attempts at chemotherapy and she entered hospice care, dying within 4 months of her diagnosis.
AC C
EP
Discussion Rhabdoid tumors were first described by Beckwith and Palmer to describe an aggressive variant of Wilms tumor, characterized by rhabdomyoblast-like features but lacking true rhabdomyosarcomatous differentiation (J.B. Beckwith, 1978). Later studies have categorized this variant as malignant rhabdoid tumors of the kidney. However, similar lesions arising in the soft tissue and other sites have been reported and referred to as malignant extrarenal rhabdoid tumors (MERT). Malignant extra-renal rhabdoid tumor (MERT) has been accepted as a clinicopathological entity of its own. There have only been about 12 cases of small intestinal MERTs reported to date in the literature to our knowledge (Salamanca J, 2008) (see table 2 for summary) and only a handful of colonic MERTs overall. These tumors are fatal with an overall survival of less than 12 months (Pancione M, 2013) (Ohgaki M, 2003) from diagnosis. MERTs of the gastrointestinal tract are more aggressive, with over 75% of the patients dying within 6 months of the initial diagnosis (Tóth L, 2010) (Lee SH, 2013).
ACCEPTED MANUSCRIPT
RI PT
The histologic hallmarks of MERTs is an eccentrically located and large nucleus, prominent nucleoli, and cytosolic aggregates of intermediate filaments (Remo A, 2012). Review of the pathology of all cases available in the literature demonstrates that eccentric nuclei are the common feature among all MERTs. Additionally, in cases where there were coexisting adenocarcinoma and rhabdoid features, the rhabdoid features remained similar between them all (Lee SH, 2013).
M AN U
SC
Historically, all of the rhabdoid colorectal cancers reported in the literature primarily affect the older age group, with ages ranging from 62 to 84 years. To our knowledge, this case presented here involves the youngest to date. Recent reviews suggest that these tumors are large and tend to be located in the transverse colon or proximal ascending colon (Tóth L, 2010) (Lee SH, 2013). Of the 12 cases in the literature, 6 cases demonstrated a mixed histology with adenocarcinoma and rhabdoid features, while the other 6 had 'pure' rhabdoid features (Lee SH, 2013) (Pancione M, 2013) (Tóth L, 2010) (Remo A, 2012)
TE D
It has been recently postulated that right-sided MERTs arise in a pathway that is distinct to that of the normal adenoma to carcinoma sequence (Pancione M, 2013). In their two cases, loss of MLH1 was observed coincident with a BRAF V600E mutation. They hypothesized that methylation of the MLH1 gene is somehow associated with MERTs. However, of 5 other cases reporting microsatellite stability, two demonstrated microsatellite instability (both in the cecum) (Remo A, 2012) and three cases the tumors were microsatellite stable (MSS). In the present case, molecular testing revealed mutations in KRAS and TP53 and no evidence of microsatellite instability by immunohistochemistry or BRAF mutation
AC C
EP
Effective treatment of colonic MERTS has proven elusive. This patient was initially treated with 5FU-based chemotherapy (specifically mFOLFOX) and subsequently with the addition of epirubicin as EOX, with the hope that the morphologic similarities to sarcomas might yield a response to an anthracycline based regimen. Recently, Horazdovsky et al. (2013) reviewed 167 pediatric patients with extra renal rhabdoid tumor cases where patients were treated with radiation, chemotherapy or surgery. Of the 167 patients, 69 patients were treated with surgical resection (both partial and complete) and this was associated with a 74% risk reduction in death. Of the included 167 patients, 89 patients with complete follow up received various combination chemotherapy regimens that included some of the following agents: cisplatin, VP16, cyclophosphamide, actinomycin and Adriamycin. No survival benefit was seen with chemotherapy or with the inclusion of radiation. In this study, 59 patients with follow-up received doxorubicin based chemotherapy and inclusion of this did not demonstrate an overall survival advantage (p=0.84). A subgroup analysis of 81 patients who received actinomycin chemotherapy compared to those who did not suggested that actinomycin combination therapy was associated with a 73% risk reduction in death (HR 0.28). While only 17 patients were available for follow-up, univariate analysis demonstrated superiority (Horazdovsky R, 2013).
ACCEPTED MANUSCRIPT
RI PT
Our patient succumbed quickly to her disease despite undergoing a complete resection and subsequent chemotherapy. The poor outcome seen in this case and in other reported gastrointestinal MERTS challenges us to better define the molecular changes that could provide insights into molecularly targeted agents that might prove beneficial. In addition, the uniformly poor outcome of these tumors with standard gastrointestinal regimens suggests that we should consider alternative multi-agent therapies in the future.
Bibliography
AC C
EP
TE D
M AN U
SC
1. Weeks DA, B. J. (1989). Rhabdoid tumor. an entity or a phenotype? Archives of Pathology , 113, 113. 2. Wick MR, R. J. (1995). Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Semin Diagn Pathol , 12, 233–248. 3. Chang JH, D. A. (2004). Malignant Extrarenal Rhabdoid Tumor of the Bladder: 9-Year Survival After Chemotherapy and Partial Cystectomy. Journal of Urology , 171 (2), 820-821. 4. Horazdovsky R, M. J. (2013). Surgery and Actinomycin Improve Survival in Malignant Rhabdoid Tumor. Sarcoma , 2013, 1-8. 5. J.B. Beckwith, N. P. (1978). Histopathology and prognosis of Wilms' tumor: results from the First National Wilms' Tumor Study. Cancer , 41, 1937–1948. 6. Lee SH, S. H. (2013). Rhabdoid Colorectal Carcinomas: Reports of Two Cases. Korean Journal of Pathoogy , 47 (4), 372-377. 7. Nakamura I, N. K. (1999). Malignant rhabdoid tumor of the colon: report of a case. Surg Today , 29(10):1083-7. 8. Ohgaki M, H. A. (2003). An extrarenal malignant rhabdoid tumor suspected to originate from the mesentery in an adult: report of a case. Surg Today , 33(7):556-9. 9. Pancione M, R. A. (2013). Right-sided rhabdoid colorectal tumors might be related to the Serrated Pathway. Diagnostic Pathology , 8 (31), 1-7. 10. Salamanca J, N. M.-E. (2008). Undifferentiated carcinoma of the jejunum with extensive rhabdoid features: Case report and review of the literature. APMIS , 116, 941-6. 11. Remo A, Z. C. (2012). Rhabdoid Carcinoma of the Colon: A Distinct Entity With Very Aggressive Behavior - A Case Report Associated With Polyposis Coli and Review of the literature. International Journal of Surgical Pathology , 20 (2), 185-190. 12. Tóth L, N. Z. (2010). Primary rhabdoid cancer of the ileum: a case report and review of the literature. Pathol Res Pract. , 206, 110-115.
ACCEPTED MANUSCRIPT
Table1: Ion Torrent next generation sequencing. Genes that tested positive Gene KRAS TP53
Exon 3 8
Protein p.Q61H p.R273H
cDNA c.183A>C c.818g>A
EP
TE D
M AN U
SC
BRAF PIK3CA HRASNRAS ABL1 CDKN2A FGFR1 FGFR2 FGFR3 KIT VHL ERBB2 ERBB4 ALK CTNNB1 HNF1A MET SMO AKT1 NPM1 SRC JAK2 PTEN STK11 APC JAK3 PTPN11 ATM RB1 NOTCH1 FLT3 MLH1 SMAD4 GNAS CSF1R FBXW7 SMARCB1 PDGFRA
AC C
GFR RET IDH1 CDH1 MPL
RI PT
Genes that that tested negative
Mutation type Substitution substitution
ACCEPTED MANUSCRIPT
Table 2: Summary of Intestinal Rhabdoid Tumors in Literature
Nakamura al. (1999) Marcus et (1996) Narimantas al. (2013) Lee et (2013)
Age/Sex et 76(male)
Cecum
14cm
Time to death from diagnosis 12 weeks
al. 84 (female)
7cm
Unknown
et 49 (male)
Transverse colon Rectum
7cm
7 months
al. 62 (male)
Sigmoid colon
4.5cm
Unknown
Rectum
6.5cm
4 weeks
Tumor Size
AC C
EP
TE D
M AN U
SC
83 (female)
Primary Site
RI PT
Author
AC C
EP
TE D
M AN U
SC
Figure 1: Mass seen in the iliocecal valve area during endoscopy.
RI PT
ACCEPTED MANUSCRIPT
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
Figure 2: Histologic findings of a case of a rhabdoid colon carcinoma. A, At low magnification, the tumor was composed of discohesive cells with patchy areas of interspersed tumor necrosis. B and C, The neoplastic cells were medium-to-large in size with amphophilic to slightly eosinophilic cytoplasm with paranuclear, hyaline inclusions resulting in an eccentrically placed nucleus and imparting a rhabdoid appearance. D, Immunohistochemical assessment revealed cytokeratin AE1/AE3 positivity consistent with a rhabdoid carcinoma.
S1533-0028(14)00103-0
DOI:
10.1016/j.clcc.2014.09.013
Reference:
CLCC 173
To appear in:
Clinical Colorectal Cancer
Received Date: 5 August 2014 Accepted Date: 17 September 2014
Please cite this article as: Kalyan A, Pasricha G, Monga D, Singhi A, Bahary N, Case report of rhabdoid colon cancer and review of literature, Clinical Colorectal Cancer (2014), doi: 10.1016/j.clcc.2014.09.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
Case report of rhabdoid colon cancer and review of literature Kalyan A1, Pasricha G2, Monga D2, Singhi A3 and Bahary N1 1
AC C
EP
TE D
University of Pittsburgh, Department of Hematology and Oncology 2 Allegheny General Hospital- Western Pennsylvania Hospital - Departments of Hematology and Oncology 3 University of Pittsburgh, Department of Pathology
ACCEPTED MANUSCRIPT
RI PT
Clinical Points: - Rhabdoid colon cancers are extremely rare but are highly aggressive. - The hallmark histological findings of rhabdoid tumors are an eccentrically located and large nucleus, prominent nucleoli, and cytosolic aggregates of intermediate filaments. - There are limited treatment options but multidrug regimens, which include cisplatin, cyclophosphamide, etoposide and actinomycin, may offer some responses.
M AN U
SC
Abstract: Rhabdoid colon carcinomas are rare, aggressive tumors with minimal treatment options. Histologically, they are characterized by large, eccentrically placed nucleus with prominent nucleoli and cytosolic aggregates. Here, we present a case of a 31-year-old female with rhabdoid colon cancer of the cecum and the treatment course. In addition, we also reviewed the literature for similar cases and discuss possible treatment options for such a rare case.
EP
TE D
Introduction Rhabdoid colon cancer (RC) is an extremely rare tumor type with only a few cases in the literature. It is a highly aggressive tumor with no proven effective treatment. The hallmark histological findings of rhabdoid tumors are an eccentrically located and large nucleus, prominent nucleoli, and cytosolic aggregates of intermediate filaments (Remo A, 2012). Here, we describe a case of a rhabdoid tumor arising at the cecum in a 31-year-old female. Her tumor lacked the classic colonic adenocarcinoma immunoprofile, yet grossly originated within the cecum. Molecular sequencing identified a KRASp.Q61H and TP53p.R273H mutations. Despite resection of her primary, at which time no metastatic disease was noted, and subsequent chemotherapy, as metastatic disease appeared, she died 18 weeks later. Her case underscores the need for better understanding of the aggressive biology of this rare tumor to offer better insight into molecularly directed treatment paradigms for rhabdoid tumors.
AC C
Clinical Case The patient, a 31-year-old female with no significant past medical history (PMH) and in excellent overall health, noted intermittent mid to right upper quadrant epigastric pain and weight loss of 5lbs over 1 month in July 2012. After failing a trial of symptomatic treatment for presumed gastrointestinal reflux disease, she underwent esophagogastroduodenoscopy (EGD), which did not demonstrate any areas of concern. Thereafter, she presented to an outside emergency department with worsening abdominal complaints. A CT scan at that time demonstrated multiple mildly dilated small bowel loops in the right lower quadrant with a transition point near the ileocecal valve, where there was focal short segment thickening of the terminal ileum. In the right lower quadrant, mesenteric edema and engorgement with localized ascites, along with enlarged mesenteric lymph nodes up to 1.2 cm in diameter, were seen.
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Emergency Personnel consideration was of either an initial presentation of inflammatory bowel disease (IBD) or a malignancy. Therefore, she underwent a colonoscopy revealing edema and contact bleeding at the cecum. A biopsy from this area was consistent with a poorly differentiated carcinoma. A follow up MRI demonstrated an irregular, eccentric, circumferential mural thickening of bowel at the level of the cecum. She underwent an elective hemicolectomy on 8/10/2012 that revealed an infiltrating 7 cm tumor with extensive necrosis and tumor arising from the cecum and extending through the submucosa, muscularis propria, subserosa and focally involving the serosal surface. The carcinoma was metastatic to 9 of 15 lymph nodes, pathologically staged as pT4a pN2b. Histologically, the tumor was composed of discohesive neoplastic cells with large, paranuclear cytoplasmic hyaline inclusions resulting in an eccentrically placed nucleus and imparting a rhabdoid appearance. The nuclei were large, oval and vesicular with each containing at least one basophilic nucleolus. Multiple mitotic figures, including atypical forms, were identified. Interspersed among the neoplastic cells were areas of prominent tumor necrosis. In addition, focal areas of glandular differentiation with mucin production were identified suggesting an adenocarcinoma origin.
TE D
Immunohistochemistry (IHC) showed focal cytokeratin positivity with AE1/AE3 but negative staining with cytokeratin 7, cytokeratin 20 and CDX-2. Additional staining of the tumor revealed focal strong staining with CAM5.2 and negative staining with CDX2, PAX-5, CD3, CD30, ALK-1, S-100 protein, desmin, smooth muscle actin, CD117, CD34, ERG, and ER. There was no loss of nuclear INI1 expression and mismatch repair proteins, PMS2 and MSH6, demonstrated intact nuclear expression. The tumor cells were also negative for neuroendocrine markers (synaptophysin, chromogranin and CD56), melanoma markers (HMB45, MelanA and MITF), MOC-31, polyclonal CEA and Ber-EP4.
AC C
EP
Targeted mutational detection of the tumor utilizing an Ion Torrent sequencing panel to assess 739 cancer-associated mutations in 46 cancer-related genes (see Table 1) revealed no BRAF (exon 15), KRAS (exon 2) mutations, but did identify mutations in KRAS exon 3(p.Q61H) and TP53 exon 8 (p.R273H). In an attempt to aid the pathological and molecular data supporting a colonic origin for this tumor, it was analyzed using the bioTheranostics CancerTYPEID® platform. CancerTYPEID® uses the differential expression of 92 genes to help determine the origin of a particular tumor. This analysis yielded a diagnosis of melanoma with 90% probability. However, the negative IHC results for S-100 protein and MelanA and the presence of a KRAS codon 61 mutation strongly argue that this was an erroneous result. Her original CT imaging and subsequent resection demonstrated no evidence of metastatic disease. In September 2013, 3 ½ weeks postoperatively, a PET/CT scan was obtained in anticipation of adjuvant chemotherapy for her colonic primary. It revealed multiple new bilobar metastases in the liver along with several foci of radiotracer uptake in the right lower quadrant
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
consistent with inflammatory or metastatic nodes, as well as a new destructive metastatic massin the left anterior 6th rib. Given the rapid progression of her disease and the pathological similarites of rhabdoid tumors to sarcomatous processes, we elected to treat her with an anthracycline and platinum based regimen with known gastrointestinal efficacy (epirubicin, capecitabine and oxaliplatin or EOX). She initially received one cycle of mFOLFOX6 while awaiting insurance approval of epirubicin for her now metastatic tumor with concomitant palliative radiosurgery to the left 6th rib resulting in complete abatement of her pain. Her first two cycles of EOX were uneventful, but beginning with the third cycle, she began to complain of sharp abdominal pain and nausea that progressed to include vomiting after about 1 week. Repeat PET/CT imaging revealed significant growth of her hepatic lesions, an irregular mesenteric mass in the right mid abdomen causing partial duodenal obstruction, bilateral hydronephrosis due to new adenopathy, and several new FDG avid masses within the serosa, mesentery, and iliac vessels and surrounding the colonic anastomosis. In addition, a new FDG avid lytic boney lesion within the right ileum and regrowth of her left 6th rib lesions were identified.
TE D
Shortly after this PET/CT scan, she was admitted to the hospital with a high-grade obstruction in the 2nd part of the duodenum. This was partially relieved by placement of a 22 mm x 120 mm enteral wall stent. Unfortunately, she developed worsening hydronephrosis requiring the placement of bilateral nephrostomy tubes. Shortly thereafter, she developed hepatic failure from worsening hepatic tumor burden and a hematological pattern consistent with disseminated intravascular coagulation (DIC). With an overall decline in her performance status, she and her family elected to forgo further attempts at chemotherapy and she entered hospice care, dying within 4 months of her diagnosis.
AC C
EP
Discussion Rhabdoid tumors were first described by Beckwith and Palmer to describe an aggressive variant of Wilms tumor, characterized by rhabdomyoblast-like features but lacking true rhabdomyosarcomatous differentiation (J.B. Beckwith, 1978). Later studies have categorized this variant as malignant rhabdoid tumors of the kidney. However, similar lesions arising in the soft tissue and other sites have been reported and referred to as malignant extrarenal rhabdoid tumors (MERT). Malignant extra-renal rhabdoid tumor (MERT) has been accepted as a clinicopathological entity of its own. There have only been about 12 cases of small intestinal MERTs reported to date in the literature to our knowledge (Salamanca J, 2008) (see table 2 for summary) and only a handful of colonic MERTs overall. These tumors are fatal with an overall survival of less than 12 months (Pancione M, 2013) (Ohgaki M, 2003) from diagnosis. MERTs of the gastrointestinal tract are more aggressive, with over 75% of the patients dying within 6 months of the initial diagnosis (Tóth L, 2010) (Lee SH, 2013).
ACCEPTED MANUSCRIPT
RI PT
The histologic hallmarks of MERTs is an eccentrically located and large nucleus, prominent nucleoli, and cytosolic aggregates of intermediate filaments (Remo A, 2012). Review of the pathology of all cases available in the literature demonstrates that eccentric nuclei are the common feature among all MERTs. Additionally, in cases where there were coexisting adenocarcinoma and rhabdoid features, the rhabdoid features remained similar between them all (Lee SH, 2013).
M AN U
SC
Historically, all of the rhabdoid colorectal cancers reported in the literature primarily affect the older age group, with ages ranging from 62 to 84 years. To our knowledge, this case presented here involves the youngest to date. Recent reviews suggest that these tumors are large and tend to be located in the transverse colon or proximal ascending colon (Tóth L, 2010) (Lee SH, 2013). Of the 12 cases in the literature, 6 cases demonstrated a mixed histology with adenocarcinoma and rhabdoid features, while the other 6 had 'pure' rhabdoid features (Lee SH, 2013) (Pancione M, 2013) (Tóth L, 2010) (Remo A, 2012)
TE D
It has been recently postulated that right-sided MERTs arise in a pathway that is distinct to that of the normal adenoma to carcinoma sequence (Pancione M, 2013). In their two cases, loss of MLH1 was observed coincident with a BRAF V600E mutation. They hypothesized that methylation of the MLH1 gene is somehow associated with MERTs. However, of 5 other cases reporting microsatellite stability, two demonstrated microsatellite instability (both in the cecum) (Remo A, 2012) and three cases the tumors were microsatellite stable (MSS). In the present case, molecular testing revealed mutations in KRAS and TP53 and no evidence of microsatellite instability by immunohistochemistry or BRAF mutation
AC C
EP
Effective treatment of colonic MERTS has proven elusive. This patient was initially treated with 5FU-based chemotherapy (specifically mFOLFOX) and subsequently with the addition of epirubicin as EOX, with the hope that the morphologic similarities to sarcomas might yield a response to an anthracycline based regimen. Recently, Horazdovsky et al. (2013) reviewed 167 pediatric patients with extra renal rhabdoid tumor cases where patients were treated with radiation, chemotherapy or surgery. Of the 167 patients, 69 patients were treated with surgical resection (both partial and complete) and this was associated with a 74% risk reduction in death. Of the included 167 patients, 89 patients with complete follow up received various combination chemotherapy regimens that included some of the following agents: cisplatin, VP16, cyclophosphamide, actinomycin and Adriamycin. No survival benefit was seen with chemotherapy or with the inclusion of radiation. In this study, 59 patients with follow-up received doxorubicin based chemotherapy and inclusion of this did not demonstrate an overall survival advantage (p=0.84). A subgroup analysis of 81 patients who received actinomycin chemotherapy compared to those who did not suggested that actinomycin combination therapy was associated with a 73% risk reduction in death (HR 0.28). While only 17 patients were available for follow-up, univariate analysis demonstrated superiority (Horazdovsky R, 2013).
ACCEPTED MANUSCRIPT
RI PT
Our patient succumbed quickly to her disease despite undergoing a complete resection and subsequent chemotherapy. The poor outcome seen in this case and in other reported gastrointestinal MERTS challenges us to better define the molecular changes that could provide insights into molecularly targeted agents that might prove beneficial. In addition, the uniformly poor outcome of these tumors with standard gastrointestinal regimens suggests that we should consider alternative multi-agent therapies in the future.
Bibliography
AC C
EP
TE D
M AN U
SC
1. Weeks DA, B. J. (1989). Rhabdoid tumor. an entity or a phenotype? Archives of Pathology , 113, 113. 2. Wick MR, R. J. (1995). Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Semin Diagn Pathol , 12, 233–248. 3. Chang JH, D. A. (2004). Malignant Extrarenal Rhabdoid Tumor of the Bladder: 9-Year Survival After Chemotherapy and Partial Cystectomy. Journal of Urology , 171 (2), 820-821. 4. Horazdovsky R, M. J. (2013). Surgery and Actinomycin Improve Survival in Malignant Rhabdoid Tumor. Sarcoma , 2013, 1-8. 5. J.B. Beckwith, N. P. (1978). Histopathology and prognosis of Wilms' tumor: results from the First National Wilms' Tumor Study. Cancer , 41, 1937–1948. 6. Lee SH, S. H. (2013). Rhabdoid Colorectal Carcinomas: Reports of Two Cases. Korean Journal of Pathoogy , 47 (4), 372-377. 7. Nakamura I, N. K. (1999). Malignant rhabdoid tumor of the colon: report of a case. Surg Today , 29(10):1083-7. 8. Ohgaki M, H. A. (2003). An extrarenal malignant rhabdoid tumor suspected to originate from the mesentery in an adult: report of a case. Surg Today , 33(7):556-9. 9. Pancione M, R. A. (2013). Right-sided rhabdoid colorectal tumors might be related to the Serrated Pathway. Diagnostic Pathology , 8 (31), 1-7. 10. Salamanca J, N. M.-E. (2008). Undifferentiated carcinoma of the jejunum with extensive rhabdoid features: Case report and review of the literature. APMIS , 116, 941-6. 11. Remo A, Z. C. (2012). Rhabdoid Carcinoma of the Colon: A Distinct Entity With Very Aggressive Behavior - A Case Report Associated With Polyposis Coli and Review of the literature. International Journal of Surgical Pathology , 20 (2), 185-190. 12. Tóth L, N. Z. (2010). Primary rhabdoid cancer of the ileum: a case report and review of the literature. Pathol Res Pract. , 206, 110-115.
ACCEPTED MANUSCRIPT
Table1: Ion Torrent next generation sequencing. Genes that tested positive Gene KRAS TP53
Exon 3 8
Protein p.Q61H p.R273H
cDNA c.183A>C c.818g>A
EP
TE D
M AN U
SC
BRAF PIK3CA HRASNRAS ABL1 CDKN2A FGFR1 FGFR2 FGFR3 KIT VHL ERBB2 ERBB4 ALK CTNNB1 HNF1A MET SMO AKT1 NPM1 SRC JAK2 PTEN STK11 APC JAK3 PTPN11 ATM RB1 NOTCH1 FLT3 MLH1 SMAD4 GNAS CSF1R FBXW7 SMARCB1 PDGFRA
AC C
GFR RET IDH1 CDH1 MPL
RI PT
Genes that that tested negative
Mutation type Substitution substitution
ACCEPTED MANUSCRIPT
Table 2: Summary of Intestinal Rhabdoid Tumors in Literature
Nakamura al. (1999) Marcus et (1996) Narimantas al. (2013) Lee et (2013)
Age/Sex et 76(male)
Cecum
14cm
Time to death from diagnosis 12 weeks
al. 84 (female)
7cm
Unknown
et 49 (male)
Transverse colon Rectum
7cm
7 months
al. 62 (male)
Sigmoid colon
4.5cm
Unknown
Rectum
6.5cm
4 weeks
Tumor Size
AC C
EP
TE D
M AN U
SC
83 (female)
Primary Site
RI PT
Author
AC C
EP
TE D
M AN U
SC
Figure 1: Mass seen in the iliocecal valve area during endoscopy.
RI PT
ACCEPTED MANUSCRIPT
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
Figure 2: Histologic findings of a case of a rhabdoid colon carcinoma. A, At low magnification, the tumor was composed of discohesive cells with patchy areas of interspersed tumor necrosis. B and C, The neoplastic cells were medium-to-large in size with amphophilic to slightly eosinophilic cytoplasm with paranuclear, hyaline inclusions resulting in an eccentrically placed nucleus and imparting a rhabdoid appearance. D, Immunohistochemical assessment revealed cytokeratin AE1/AE3 positivity consistent with a rhabdoid carcinoma.
