Clin J Gastroenterol (2013) 6:429–433 DOI 10.1007/s12328-013-0422-x
CASE REPORT
Malignant peripheral nerve sheath tumor of the colon in a patient with von Recklinghausen’s disease: report of a case Sanjay Marwah • Jai Prakash Gurawalia • Kapil Dev Sheoran • Nisha Marwah • Sumiti Gupta Hansraj Ranga
•
Received: 6 July 2013 / Accepted: 27 August 2013 / Published online: 17 September 2013 Ó Springer Japan 2013
Abstract Malignant peripheral nerve sheath tumor (MPNST) arising from the colon is an extremely rare clinical entity. We report one such case of an adult female with neurofibromatosis type I who presented with pain and a lump in her abdomen. A computed tomographic scan revealed a 10 9 8-cm mass in the splenic flexure of her colon that was compressing its lumen, but the results of a colonoscopy were normal. Segmental resection of the left colon was performed based on the clinical possibility of gastrointestinal stromal tumor. However, on histopathological examination and immunohistochemical staining, the final diagnosis came out to be MPNST. This case highlights that, although rare, the possibility of MPNST should be considered when dealing with extramucosal colonic wall tumors. Keywords Large gut
malignant schwannoma, malignant neurilemmoma, and neurofibrosarcoma, for tumors of neurogenic origin and similar biological behavior [1]. It is the most common sarcoma arising in the setting of von Recklinghausen’s disease. Criteria for diagnosis include demonstration of origin from a nerve, presence of Schwann cells, presence of neurofibromata, nuclear palisading on microscopy and immune histochemical findings of S-100 protein. It commonly occurs in the peripheral nerve of the limbs or body, spinal cord, and the central nervous system. There have been very few cases of gastrointestinal MPNST reported in the literature [2]. Although there are several reports of colonic schwannoma [3], MPNST of the colon is extremely rare [2]. This case report is therefore considered especially unusual.
Neurofibromatosis type I MPNST
Introduction The malignant peripheral nerve sheath tumor (MPNST) is the malignant counterpart to benign soft tissue tumors such as neurofibromas and schwannomas. The World Health Organization coined the term MPNST, replacing previous heterogeneous and often confusing terminology such as S. Marwah (&) J. P. Gurawalia K. D. Sheoran H. Ranga Department of Surgery, Post Graduate Institute of Medical Sciences, 2452, Sector I, HUDA, Rohtak 124001, India e-mail: [email protected] N. Marwah S. Gupta Department of Pathology, Post Graduate Institute of Medical Sciences, Rohtak 124001, India
Case report A 30-year-old female presented with dull aching pain in the left upper abdomen that had persisted for 6 years and a lump that had gradually progressed there in the last 2 months. She denied any history of alteration in bowel habits, blood in stools, or urinary symptoms. There were multiple cafe´ au lait spots and cutaneous nodules all over the body suggestive of neurofibromatosis type I (NF I). She had no family history of neurofibromatosis. On abdominal examination, a 10910-cm lump was present in the left hypochondrium that was firm, smooth, moving on respiration and mobile from side to side. Contrast-enhanced CT (CECT) of the abdomen detected a large, mixed-density attenuated lesion approximately 1098 cm arising from the splenic flexure of the colon and compressing the colonic lumen (Fig. 1). However, a colonoscopy showed a smooth bulge in the splenic flexure that was easily passable but no
123
430
Clin J Gastroenterol (2013) 6:429–433
Fig. 2 Nodular tumor mass arising from the serosal surface of the colon Fig. 1 CECT of the abdomen showing a large, mixed-density attenuated lesion (blue arrow) arising from the splenic flexure of the colon and compressing the colonic lumen (red arrow)
intraluminal pathology. In view of these findings, the patient was referred to surgery based on the clinical possibility of a gastrointestinal stromal tumor (GIST) arising from the colonic wall. On exploration, a 10 9 10 9 6-cm nodular mass was present on the serosal surface of the colon at the splenic flexure underneath dilated superficial vessels (Fig. 2). There were no significant mesenteric lymph nodes. The rest of the intestines and liver were normal. Segmental resection of the colon with end-to-end anastomosis was performed. The intraluminal mucosal folds of the colon appeared normal. The tumor was then macroscopically circumscribed on the cut section, and found to be grey white, homogenous and subserosal with normal colonic mucosa. On histopathologic examination, the tumor was found to be subserosal extending into the muscularis propria and submucosa. It was composed of spindle cells arranged in fascicles, revealing moderate pleomorphism and abundant typical and atypical mitosis. After immunohistochemical (IHC) staining the tumor cells were shown to be diffusely positive for vimentin and focally positive for S-100 (Fig. 3). Desmin and SMA were present in intestinal wall muscles whereas CD117 and NSE were consistently absent. On the basis of these pathological findings, the tumor was diagnosed as MPNST. The Ki-67 labeling index (LI) was approximately 20 % (Fig. 4). IHC staining for P53 was also performed on the tissue sections and was found to be negative. Postoperatively, the patient had an uneventful recovery and had no recurrence during up to 1 year of follow-up. However, at 18 months she presented again with pain in her abdomen, weight loss and a hard, fixed lump in the left lumbar region. CECT of the abdomen revealed recurrence at the anastomotic site with paraaortic
123
lymphadenopathy (Fig. 5). She was advised to undergo reexploration, which she declined, and was lost to follow-up.
Discussion MPNST is a high-grade sarcoma that arises from a major or minor peripheral nerve branch or sheath of peripheral nerve fibers [4, 5]. It is commonly seen in the lower limbs, head, neck, thorax, paravertebral area and lower limbs [6]. The MPNST may occur sporadically or may be found in patients with von Recklinghausen’s disease, also known as NF1. In our case, the patient showed characteristic features of NF1 in the form of multiple cafe´ au lait spots and nodular skin lesions all over the body. Some studies have found that MPNST patients with NF1 have different clinicopathological characteristics compared with non-NF1 patients with MPNST. People with NF1 have a 10 % lifetime risk of developing an MPNST [7], but the incidence of MPNST in non-NF1 cases is only 0.001 % [8]. NF1 patients with MPNST are significantly younger at diagnosis than those without NF1 [9]. The tumor site is mostly axial in NF1 patients whereas non-NF1 patients usually have tumors on the extremities [9]. It has been observed that in NF1 patients, MPNSTs are inherently more aggressive, their natural tumor defense systems are weaker, and they are often diagnosed at a late stage, thus resulting in more advanced tumors and poor prognosis [10]. The possible explanation for late presentation of MPNST in NF1 patients is that they may not be as concerned about the appearance of new swellings as are nonNF1 patients. Moreover, NF1 patients have a shorter life expectancy compared with non-NF1 patients due to high incidence of MPNST as well as higher mortality rate from brain tumors and respiratory diseases [11]. However, gender, tumor grade, initial metastases, and remission
Clin J Gastroenterol (2013) 6:429–433
431
Fig. 3 Photomicrograph of a malignant peripheral nerve sheath tumor (MPNST) of the colon. a Tumor in the serosa extending into the muscularis propria and submucosa. The mucosa is normal. (H&E,
940). b Tumor cells arranged in fascicles, revealing moderate pleomorphism and high mitotic activity (H&E, 9400). c, d Tumor cells showing immunoreactivity for vimentin (c) and S-100 (d)
Fig. 4 IHC staining for Ki67 Labeling Index—20 %
Fig. 5 Follow-up CECT of the abdomen showing local recurrence (red arrow) and paraaortic lymphadenopathy (blue arrow)
123
432
status are not found to be different in non-NF1 and NF1associated MPNST [10]. Within the abdomen, MPNSTs mostly arise in the retroperitoneal nerves as painless masses that grow silently until they involve surrounding structures, then producing pain, obstruction, neurological deficits, and bone erosion. Due to late diagnosis, they bear high rates of metastasis, recurrence and poor prognosis [12]. The MPNST that develops from preexisting plexiform neurofibromas is highly aggressive [7]. Although MPNSTs are known to arise anywhere from the esophagus to the rectum, there are only occasional reports of MPNST involving the gastrointestinal tract [13– 16]. The occurrence of MPNSTs in the colon is even rarer [2]. In a study of over 600 mesenchymal tumors of the colon and rectum, 20 cases of colonic schwannoma were identified, but none of them were histologically or clinically malignant [3]. Schwartz [17] reported a case of MPNST (previously known as malignant schwannoma) arising from the sigmoid colon in a young adult who did not have NF1. The author considered the possible role of schistosomal infection in the development of this rare malignancy due to the presence of numerous schistosome ova adjacent to the tumor. Park et al. [18] reported an aggressive case of colonic MPNST without NF1 that presented as a lump in the abdomen and was diagnosed as malignant GIST on abdominal CECT. On exploration, an advanced tumor was seen in the descending colon with multiple serosal nodules, adherent small gut and liver metastases. The final diagnosis of MPNST was made on the basis of immunohistochemical findings of strong positivity for S-100 protein and Leu-7 and negativity for smooth muscle markers, c-kit and CD34. In the present case also, the patient presented with a lump in the abdomen that was initially diagnosed as malignant GIST of the splenic flexure of the colon, and the final diagnosis turned out to be MPNST on immunohistochemistry analysis. However, the disease was localized to the colon without any distant spread, possibly due to early detection and prompt surgical intervention. Lee et al. [2] reported another case of MPNST arising in the colon of a 2-day-old newborn without NF 1 who presented with intestinal obstruction and underwent emergency hemicolectomy. There was no evidence of distant metastasis and the patient remained free of recurrence for up to 17 months of follow-up. Due to the rarity of the disease, there are no specific symptoms described for intestinal MPNST. Two major complaints reported in the literature are intestinal obstruction and hemorrhage [15]. However, the patient in our case presented with an abdominal lump and features of obstruction and bleeding were absent due to extramucosal,
123
Clin J Gastroenterol (2013) 6:429–433
exophytic growth. Similarly, there are no definite radiological features described for the MPNST of the colon. Preoperative diagnosis is very difficult and imaging modalities are only able to locate lesions in the colonic wall. It is usually not possible to make the diagnosis based on endoscopic biopsy since mucosal abnormalities may be minimal [15]. In one report of esophageal MPNST, it was possible to make the diagnosis preoperatively based on endoscopic biopsy [14]. However, even on histology, it is frequently difficult to make a diagnosis of MPNST since it presents a wide variety of histological appearances and conventional histological examinations cannot readily distinguish it from leiomyosarcoma, which is more commonly observed in the intestine [19]. The diagnosis is thus usually made after resection based on histopathology and immunohistochemistry. Furthermore, the molecular heterogeneity of MPNSTs has been recently explored in detail [20, 21]. A recent study was conducted to determine the extent of molecular heterogeneity within and between 10 MPNSTs, derived from 10 unrelated NF1 patients, by determining the differences in the levels of loss of heterozygosity (LOH) at the NF1, TP53, RB1, CDKN2A, and PTEN gene loci. The results indicated that 70 % of the MPNST tumors studied exhibited molecular heterogeneity between sections of the same tumor sample [21]. Some small studies have reported TP53 mutations in up to 70 % of NF1-associated MPNSTs [22, 23] while others have reported that TP53 mutations are rare in MPNST [10, 24]. The results of these studies suggest that larger similar studies are required to better understand the mechanisms of NF1 tumorigenesis, and also for evaluation of therapeutic sensitivities and the efficacy of potential drug treatments for NF1-associated MPNSTs. The optimal treatment of MPNST of the colon is not well established due to its rarity. MPNST has the highest recurrence rate of any sarcomas [25], and adequate initial treatment gives the best chance of survival [6]. Since preoperative diagnosis is not possible in the majority of cases, radical excision according to oncologic principles should thus be attempted in all cases for optimal chances of achieving a cure. However, the role of surgery is often limited to a palliative debulking since cases usually present with advanced and metastatic disease [18]. Chemotherapy with various protocols has been attempted after surgical treatment of gastrointestinal MPNST, but no controlled studies on the efficacy of chemotherapy have been carried out [16]. Moreover, MPNST in the gastrointestinal tract, unlike other sites, seems to hardly benefit from radiation therapy. The recurrence usually occurs in the abdominal cavity, the paraaortic lymph nodes, or in the scar of a radical resection of gastrointestinal MPNST, presumably due to the implantation of tumor cells [16]. The reported
Clin J Gastroenterol (2013) 6:429–433
5-year survival rates for MPNST are between 41 and 52 % [26]. The prognostic factors are tumor size, tumor grade and extent of resection [26, 27]. In the present case, segmental resection of the colon proved insufficient and the patient developed local recurrence after 18 months. In conclusion, this report highlights that the possibility of MPNST should be kept as a differential diagnosis while dealing with colonic tumors of mesenchymal origin. There are no definite radiological investigations and diagnosis is usually based on histopathological, and immunohistochemical studies. Once diagnosed, the treatment of choice is radical surgery, as is done for MPNST of other sites. The case should ideally be managed by a multidisciplinary team familiar with both soft tissue sarcomas and NF1. In the near future, the molecular analysis of MPNSTs is likely to develop new therapeutic options that might improve overall survival.
433
10.
11.
12.
13.
14. 15.
Disclosure Conflict of Interest: The authors declare that they have no conflict of interest. Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from all patients for being included in the study.
16.
17.
18.
19. 20.
References 1. Wanebo JE, Malik JM, VandenBerg SR, Wanebo JH, Driesen N, Persing JA. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 28 cases. Cancer. 1993;71:1247–53. 2. Lee YJ, Moon H, Park ST, Ha WS, Choi SG, Hong SC, et al. Malignant peripheral nerve sheath tumor arising from the colon in a newborn: report of a case and review of the literatures. J Pediatr Surg. 2006;41:e19–22. 3. Miettinen M, Shekitka KM, Sobin LH. Schwannoma in the colon and rectum. Am J Surg Pathol. 2001;25:846–55. 4. D’Agostino AN, Soule EH, Miller RH. Sarcoma of the peripheral nerves and somatic soft tissues associated with multiple neurofibromatosis (Von Recklinghausen’s disease). Cancer. 1963;16: 1015–27. 5. Cashen DV, Parisien RC, Raskin K, Hornicek FJ, Gebhardt MC, Mankin HJ. Survival data for patients with malignant schwannoma. Clin Orthop Relat Res. 2004;426:69–73. 6. Ghosh BC, Ghosh L, Huvos AG, Fortner JG. Malignant schwannoma. A clinicopathologic study. Cancer. 1973;31: 184–90. 7. Tucker T, Wolkenstein P, Revuz J, Zeller J, Friedman JM. Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology. 2005;65:205–11. 8. Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res. 2002;62:1573–7. 9. Porter DE, Prasad V, Foster L, Dall GF, Birch R, Grimer RJ. Survival in malignant peripheral nerve sheath tumours: a
21.
22.
23.
24.
25.
26.
27.
comparison between sporadic and neurofibromatosis type 1-associated tumours. Sarcoma. 2009;2009:756395. doi:10.1155/ 2009/756395. Kolberg M, Høland M, Agesen TH, Brekke HR, Liestøl K, Hall KS, et al. Survival meta-analyses for[1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncol. 2013;15:135–47. doi:10.1093/neuonc/ nos287. Masocco M, Kodra Y, Vichi M, Conti S, Kanieff M, Pace M, et al. Mortality associated with neurofibromatosis type 1: a study based on Italian death certificates (1995–2006). Orphanet J Rare Dis. 2011;25(6):11. doi:10.1186/1750-1172-6-11. Basile U, Cavallaro G, Polistena A, Giustini S, Orlando G, Cotesta D, et al. Gastrointestinal and retroperitoneal manifestations of type 1 neurofibromatosis. J Gastrointest Surg. 2010;14:186–94. doi:10.1007/s11605-009-0940-5. Catania G, Puleo C, Cardı` F, Catalano F, Iuppa A, Buffone A. Malignant schwannoma of the rectum: a clinical and pathological contribution. Chir Ital. 2001;53:873–7. Manger T, Pross M, Haeckel C, Lippert H. Malignant peripheral nerve sheath tumor of the esophagus. Dig Surg. 2000;17:627–31. Bees NR, Ng CS, Dicks-Mireaux C, Kiely EM. Gastric malignant schwannoma in a child. British J Radiol. 1997;70:952–5. Nozu T, Takahashi A, Asakawa H, Uehara A, Kohogo Y, Suzuki T. Malignant intestinal schwannoma: a case report and a review of the literature in Japan. Intern Med. 1995;34:1101–5. Schwartz DA. Malignant schwannoma occurring with Schistosoma japonicum: a case report. Southeast Asian J Trop Med Public Health. 1982;13:601–5. Park YS, Lim SJ, Kim WH, Ham EK. Malignant peripheral nerve sheath tumor in descending colon. Korean J Pathol. 2002;36: 179–83. Hansen D, Pedersen A, Pedersen KM. Malignant intestinal schwannoma. Case report. Acta Chir Scand. 1990;156:729–32. Spurlock G, Knight S, Thomas N, Kiehl T, Guha A, Upadhyaya M. Molecular evolution of a neurofibroma to malignant peripheral nerve sheath tumor (MPNST) in an NF1 patient: correlation between histopathological, clinical and molecular findings. J Cancer Res Clin Oncol. 2010;136:1869–80. doi:10.1007/ s00432-010-0846-3. Thomas L, Mautner VF, Cooper DN, Upadhyaya M. Molecular heterogeneity in malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1. Hum Genomics. 2012;6:18. doi:10.1186/1479-7364-6-18. Legius E, Dierick H, Wu R, Hall BK, Marynen P, Cassiman JJ, et al. TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes Cancer. 1994;10:250–5. Leroy K, Dumas V, Martin-Garcia N, Falzone MC, Voisin MC, Wechsler J, et al. Malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1: a clinicopathologic and molecular study of 17 patients. Arch Dermatol. 2001;137:908–13. Taubert H, Wurl P, Bache M, Meye A, Berger D, Holzhausen HJ, et al. The p53 gene in soft tissue sarcomas: prognostic value of DNA sequencing versus immunohistochemistry. Anticancer Res. 1998;18:183–7. Collin C, Godbold J, Hajdu S, Brennan M. Localized extremity soft tissue sarcomas an analysis of factors affecting survival. J Clin Oncol. 1987;5:601–12. Wong WW, Hirose T, Scheithauer BW, Schild SE, Gunderson LL. Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys. 1998;42:351–60. Casanova M, Ferrari A, Spreafico F, Luksch R, Terenziani M, Cefalo G, et al. Malignant peripheral nerve sheath tumors in children: a single institution twenty-year experience. J Pediatr Hematol Oncol. 1999;21:509–13.
123
CASE REPORT
Malignant peripheral nerve sheath tumor of the colon in a patient with von Recklinghausen’s disease: report of a case Sanjay Marwah • Jai Prakash Gurawalia • Kapil Dev Sheoran • Nisha Marwah • Sumiti Gupta Hansraj Ranga
•
Received: 6 July 2013 / Accepted: 27 August 2013 / Published online: 17 September 2013 Ó Springer Japan 2013
Abstract Malignant peripheral nerve sheath tumor (MPNST) arising from the colon is an extremely rare clinical entity. We report one such case of an adult female with neurofibromatosis type I who presented with pain and a lump in her abdomen. A computed tomographic scan revealed a 10 9 8-cm mass in the splenic flexure of her colon that was compressing its lumen, but the results of a colonoscopy were normal. Segmental resection of the left colon was performed based on the clinical possibility of gastrointestinal stromal tumor. However, on histopathological examination and immunohistochemical staining, the final diagnosis came out to be MPNST. This case highlights that, although rare, the possibility of MPNST should be considered when dealing with extramucosal colonic wall tumors. Keywords Large gut
malignant schwannoma, malignant neurilemmoma, and neurofibrosarcoma, for tumors of neurogenic origin and similar biological behavior [1]. It is the most common sarcoma arising in the setting of von Recklinghausen’s disease. Criteria for diagnosis include demonstration of origin from a nerve, presence of Schwann cells, presence of neurofibromata, nuclear palisading on microscopy and immune histochemical findings of S-100 protein. It commonly occurs in the peripheral nerve of the limbs or body, spinal cord, and the central nervous system. There have been very few cases of gastrointestinal MPNST reported in the literature [2]. Although there are several reports of colonic schwannoma [3], MPNST of the colon is extremely rare [2]. This case report is therefore considered especially unusual.
Neurofibromatosis type I MPNST
Introduction The malignant peripheral nerve sheath tumor (MPNST) is the malignant counterpart to benign soft tissue tumors such as neurofibromas and schwannomas. The World Health Organization coined the term MPNST, replacing previous heterogeneous and often confusing terminology such as S. Marwah (&) J. P. Gurawalia K. D. Sheoran H. Ranga Department of Surgery, Post Graduate Institute of Medical Sciences, 2452, Sector I, HUDA, Rohtak 124001, India e-mail: [email protected] N. Marwah S. Gupta Department of Pathology, Post Graduate Institute of Medical Sciences, Rohtak 124001, India
Case report A 30-year-old female presented with dull aching pain in the left upper abdomen that had persisted for 6 years and a lump that had gradually progressed there in the last 2 months. She denied any history of alteration in bowel habits, blood in stools, or urinary symptoms. There were multiple cafe´ au lait spots and cutaneous nodules all over the body suggestive of neurofibromatosis type I (NF I). She had no family history of neurofibromatosis. On abdominal examination, a 10910-cm lump was present in the left hypochondrium that was firm, smooth, moving on respiration and mobile from side to side. Contrast-enhanced CT (CECT) of the abdomen detected a large, mixed-density attenuated lesion approximately 1098 cm arising from the splenic flexure of the colon and compressing the colonic lumen (Fig. 1). However, a colonoscopy showed a smooth bulge in the splenic flexure that was easily passable but no
123
430
Clin J Gastroenterol (2013) 6:429–433
Fig. 2 Nodular tumor mass arising from the serosal surface of the colon Fig. 1 CECT of the abdomen showing a large, mixed-density attenuated lesion (blue arrow) arising from the splenic flexure of the colon and compressing the colonic lumen (red arrow)
intraluminal pathology. In view of these findings, the patient was referred to surgery based on the clinical possibility of a gastrointestinal stromal tumor (GIST) arising from the colonic wall. On exploration, a 10 9 10 9 6-cm nodular mass was present on the serosal surface of the colon at the splenic flexure underneath dilated superficial vessels (Fig. 2). There were no significant mesenteric lymph nodes. The rest of the intestines and liver were normal. Segmental resection of the colon with end-to-end anastomosis was performed. The intraluminal mucosal folds of the colon appeared normal. The tumor was then macroscopically circumscribed on the cut section, and found to be grey white, homogenous and subserosal with normal colonic mucosa. On histopathologic examination, the tumor was found to be subserosal extending into the muscularis propria and submucosa. It was composed of spindle cells arranged in fascicles, revealing moderate pleomorphism and abundant typical and atypical mitosis. After immunohistochemical (IHC) staining the tumor cells were shown to be diffusely positive for vimentin and focally positive for S-100 (Fig. 3). Desmin and SMA were present in intestinal wall muscles whereas CD117 and NSE were consistently absent. On the basis of these pathological findings, the tumor was diagnosed as MPNST. The Ki-67 labeling index (LI) was approximately 20 % (Fig. 4). IHC staining for P53 was also performed on the tissue sections and was found to be negative. Postoperatively, the patient had an uneventful recovery and had no recurrence during up to 1 year of follow-up. However, at 18 months she presented again with pain in her abdomen, weight loss and a hard, fixed lump in the left lumbar region. CECT of the abdomen revealed recurrence at the anastomotic site with paraaortic
123
lymphadenopathy (Fig. 5). She was advised to undergo reexploration, which she declined, and was lost to follow-up.
Discussion MPNST is a high-grade sarcoma that arises from a major or minor peripheral nerve branch or sheath of peripheral nerve fibers [4, 5]. It is commonly seen in the lower limbs, head, neck, thorax, paravertebral area and lower limbs [6]. The MPNST may occur sporadically or may be found in patients with von Recklinghausen’s disease, also known as NF1. In our case, the patient showed characteristic features of NF1 in the form of multiple cafe´ au lait spots and nodular skin lesions all over the body. Some studies have found that MPNST patients with NF1 have different clinicopathological characteristics compared with non-NF1 patients with MPNST. People with NF1 have a 10 % lifetime risk of developing an MPNST [7], but the incidence of MPNST in non-NF1 cases is only 0.001 % [8]. NF1 patients with MPNST are significantly younger at diagnosis than those without NF1 [9]. The tumor site is mostly axial in NF1 patients whereas non-NF1 patients usually have tumors on the extremities [9]. It has been observed that in NF1 patients, MPNSTs are inherently more aggressive, their natural tumor defense systems are weaker, and they are often diagnosed at a late stage, thus resulting in more advanced tumors and poor prognosis [10]. The possible explanation for late presentation of MPNST in NF1 patients is that they may not be as concerned about the appearance of new swellings as are nonNF1 patients. Moreover, NF1 patients have a shorter life expectancy compared with non-NF1 patients due to high incidence of MPNST as well as higher mortality rate from brain tumors and respiratory diseases [11]. However, gender, tumor grade, initial metastases, and remission
Clin J Gastroenterol (2013) 6:429–433
431
Fig. 3 Photomicrograph of a malignant peripheral nerve sheath tumor (MPNST) of the colon. a Tumor in the serosa extending into the muscularis propria and submucosa. The mucosa is normal. (H&E,
940). b Tumor cells arranged in fascicles, revealing moderate pleomorphism and high mitotic activity (H&E, 9400). c, d Tumor cells showing immunoreactivity for vimentin (c) and S-100 (d)
Fig. 4 IHC staining for Ki67 Labeling Index—20 %
Fig. 5 Follow-up CECT of the abdomen showing local recurrence (red arrow) and paraaortic lymphadenopathy (blue arrow)
123
432
status are not found to be different in non-NF1 and NF1associated MPNST [10]. Within the abdomen, MPNSTs mostly arise in the retroperitoneal nerves as painless masses that grow silently until they involve surrounding structures, then producing pain, obstruction, neurological deficits, and bone erosion. Due to late diagnosis, they bear high rates of metastasis, recurrence and poor prognosis [12]. The MPNST that develops from preexisting plexiform neurofibromas is highly aggressive [7]. Although MPNSTs are known to arise anywhere from the esophagus to the rectum, there are only occasional reports of MPNST involving the gastrointestinal tract [13– 16]. The occurrence of MPNSTs in the colon is even rarer [2]. In a study of over 600 mesenchymal tumors of the colon and rectum, 20 cases of colonic schwannoma were identified, but none of them were histologically or clinically malignant [3]. Schwartz [17] reported a case of MPNST (previously known as malignant schwannoma) arising from the sigmoid colon in a young adult who did not have NF1. The author considered the possible role of schistosomal infection in the development of this rare malignancy due to the presence of numerous schistosome ova adjacent to the tumor. Park et al. [18] reported an aggressive case of colonic MPNST without NF1 that presented as a lump in the abdomen and was diagnosed as malignant GIST on abdominal CECT. On exploration, an advanced tumor was seen in the descending colon with multiple serosal nodules, adherent small gut and liver metastases. The final diagnosis of MPNST was made on the basis of immunohistochemical findings of strong positivity for S-100 protein and Leu-7 and negativity for smooth muscle markers, c-kit and CD34. In the present case also, the patient presented with a lump in the abdomen that was initially diagnosed as malignant GIST of the splenic flexure of the colon, and the final diagnosis turned out to be MPNST on immunohistochemistry analysis. However, the disease was localized to the colon without any distant spread, possibly due to early detection and prompt surgical intervention. Lee et al. [2] reported another case of MPNST arising in the colon of a 2-day-old newborn without NF 1 who presented with intestinal obstruction and underwent emergency hemicolectomy. There was no evidence of distant metastasis and the patient remained free of recurrence for up to 17 months of follow-up. Due to the rarity of the disease, there are no specific symptoms described for intestinal MPNST. Two major complaints reported in the literature are intestinal obstruction and hemorrhage [15]. However, the patient in our case presented with an abdominal lump and features of obstruction and bleeding were absent due to extramucosal,
123
Clin J Gastroenterol (2013) 6:429–433
exophytic growth. Similarly, there are no definite radiological features described for the MPNST of the colon. Preoperative diagnosis is very difficult and imaging modalities are only able to locate lesions in the colonic wall. It is usually not possible to make the diagnosis based on endoscopic biopsy since mucosal abnormalities may be minimal [15]. In one report of esophageal MPNST, it was possible to make the diagnosis preoperatively based on endoscopic biopsy [14]. However, even on histology, it is frequently difficult to make a diagnosis of MPNST since it presents a wide variety of histological appearances and conventional histological examinations cannot readily distinguish it from leiomyosarcoma, which is more commonly observed in the intestine [19]. The diagnosis is thus usually made after resection based on histopathology and immunohistochemistry. Furthermore, the molecular heterogeneity of MPNSTs has been recently explored in detail [20, 21]. A recent study was conducted to determine the extent of molecular heterogeneity within and between 10 MPNSTs, derived from 10 unrelated NF1 patients, by determining the differences in the levels of loss of heterozygosity (LOH) at the NF1, TP53, RB1, CDKN2A, and PTEN gene loci. The results indicated that 70 % of the MPNST tumors studied exhibited molecular heterogeneity between sections of the same tumor sample [21]. Some small studies have reported TP53 mutations in up to 70 % of NF1-associated MPNSTs [22, 23] while others have reported that TP53 mutations are rare in MPNST [10, 24]. The results of these studies suggest that larger similar studies are required to better understand the mechanisms of NF1 tumorigenesis, and also for evaluation of therapeutic sensitivities and the efficacy of potential drug treatments for NF1-associated MPNSTs. The optimal treatment of MPNST of the colon is not well established due to its rarity. MPNST has the highest recurrence rate of any sarcomas [25], and adequate initial treatment gives the best chance of survival [6]. Since preoperative diagnosis is not possible in the majority of cases, radical excision according to oncologic principles should thus be attempted in all cases for optimal chances of achieving a cure. However, the role of surgery is often limited to a palliative debulking since cases usually present with advanced and metastatic disease [18]. Chemotherapy with various protocols has been attempted after surgical treatment of gastrointestinal MPNST, but no controlled studies on the efficacy of chemotherapy have been carried out [16]. Moreover, MPNST in the gastrointestinal tract, unlike other sites, seems to hardly benefit from radiation therapy. The recurrence usually occurs in the abdominal cavity, the paraaortic lymph nodes, or in the scar of a radical resection of gastrointestinal MPNST, presumably due to the implantation of tumor cells [16]. The reported
Clin J Gastroenterol (2013) 6:429–433
5-year survival rates for MPNST are between 41 and 52 % [26]. The prognostic factors are tumor size, tumor grade and extent of resection [26, 27]. In the present case, segmental resection of the colon proved insufficient and the patient developed local recurrence after 18 months. In conclusion, this report highlights that the possibility of MPNST should be kept as a differential diagnosis while dealing with colonic tumors of mesenchymal origin. There are no definite radiological investigations and diagnosis is usually based on histopathological, and immunohistochemical studies. Once diagnosed, the treatment of choice is radical surgery, as is done for MPNST of other sites. The case should ideally be managed by a multidisciplinary team familiar with both soft tissue sarcomas and NF1. In the near future, the molecular analysis of MPNSTs is likely to develop new therapeutic options that might improve overall survival.
433
10.
11.
12.
13.
14. 15.
Disclosure Conflict of Interest: The authors declare that they have no conflict of interest. Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from all patients for being included in the study.
16.
17.
18.
19. 20.
References 1. Wanebo JE, Malik JM, VandenBerg SR, Wanebo JH, Driesen N, Persing JA. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 28 cases. Cancer. 1993;71:1247–53. 2. Lee YJ, Moon H, Park ST, Ha WS, Choi SG, Hong SC, et al. Malignant peripheral nerve sheath tumor arising from the colon in a newborn: report of a case and review of the literatures. J Pediatr Surg. 2006;41:e19–22. 3. Miettinen M, Shekitka KM, Sobin LH. Schwannoma in the colon and rectum. Am J Surg Pathol. 2001;25:846–55. 4. D’Agostino AN, Soule EH, Miller RH. Sarcoma of the peripheral nerves and somatic soft tissues associated with multiple neurofibromatosis (Von Recklinghausen’s disease). Cancer. 1963;16: 1015–27. 5. Cashen DV, Parisien RC, Raskin K, Hornicek FJ, Gebhardt MC, Mankin HJ. Survival data for patients with malignant schwannoma. Clin Orthop Relat Res. 2004;426:69–73. 6. Ghosh BC, Ghosh L, Huvos AG, Fortner JG. Malignant schwannoma. A clinicopathologic study. Cancer. 1973;31: 184–90. 7. Tucker T, Wolkenstein P, Revuz J, Zeller J, Friedman JM. Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology. 2005;65:205–11. 8. Ferner RE, Gutmann DH. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res. 2002;62:1573–7. 9. Porter DE, Prasad V, Foster L, Dall GF, Birch R, Grimer RJ. Survival in malignant peripheral nerve sheath tumours: a
21.
22.
23.
24.
25.
26.
27.
comparison between sporadic and neurofibromatosis type 1-associated tumours. Sarcoma. 2009;2009:756395. doi:10.1155/ 2009/756395. Kolberg M, Høland M, Agesen TH, Brekke HR, Liestøl K, Hall KS, et al. Survival meta-analyses for[1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncol. 2013;15:135–47. doi:10.1093/neuonc/ nos287. Masocco M, Kodra Y, Vichi M, Conti S, Kanieff M, Pace M, et al. Mortality associated with neurofibromatosis type 1: a study based on Italian death certificates (1995–2006). Orphanet J Rare Dis. 2011;25(6):11. doi:10.1186/1750-1172-6-11. Basile U, Cavallaro G, Polistena A, Giustini S, Orlando G, Cotesta D, et al. Gastrointestinal and retroperitoneal manifestations of type 1 neurofibromatosis. J Gastrointest Surg. 2010;14:186–94. doi:10.1007/s11605-009-0940-5. Catania G, Puleo C, Cardı` F, Catalano F, Iuppa A, Buffone A. Malignant schwannoma of the rectum: a clinical and pathological contribution. Chir Ital. 2001;53:873–7. Manger T, Pross M, Haeckel C, Lippert H. Malignant peripheral nerve sheath tumor of the esophagus. Dig Surg. 2000;17:627–31. Bees NR, Ng CS, Dicks-Mireaux C, Kiely EM. Gastric malignant schwannoma in a child. British J Radiol. 1997;70:952–5. Nozu T, Takahashi A, Asakawa H, Uehara A, Kohogo Y, Suzuki T. Malignant intestinal schwannoma: a case report and a review of the literature in Japan. Intern Med. 1995;34:1101–5. Schwartz DA. Malignant schwannoma occurring with Schistosoma japonicum: a case report. Southeast Asian J Trop Med Public Health. 1982;13:601–5. Park YS, Lim SJ, Kim WH, Ham EK. Malignant peripheral nerve sheath tumor in descending colon. Korean J Pathol. 2002;36: 179–83. Hansen D, Pedersen A, Pedersen KM. Malignant intestinal schwannoma. Case report. Acta Chir Scand. 1990;156:729–32. Spurlock G, Knight S, Thomas N, Kiehl T, Guha A, Upadhyaya M. Molecular evolution of a neurofibroma to malignant peripheral nerve sheath tumor (MPNST) in an NF1 patient: correlation between histopathological, clinical and molecular findings. J Cancer Res Clin Oncol. 2010;136:1869–80. doi:10.1007/ s00432-010-0846-3. Thomas L, Mautner VF, Cooper DN, Upadhyaya M. Molecular heterogeneity in malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1. Hum Genomics. 2012;6:18. doi:10.1186/1479-7364-6-18. Legius E, Dierick H, Wu R, Hall BK, Marynen P, Cassiman JJ, et al. TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes Cancer. 1994;10:250–5. Leroy K, Dumas V, Martin-Garcia N, Falzone MC, Voisin MC, Wechsler J, et al. Malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1: a clinicopathologic and molecular study of 17 patients. Arch Dermatol. 2001;137:908–13. Taubert H, Wurl P, Bache M, Meye A, Berger D, Holzhausen HJ, et al. The p53 gene in soft tissue sarcomas: prognostic value of DNA sequencing versus immunohistochemistry. Anticancer Res. 1998;18:183–7. Collin C, Godbold J, Hajdu S, Brennan M. Localized extremity soft tissue sarcomas an analysis of factors affecting survival. J Clin Oncol. 1987;5:601–12. Wong WW, Hirose T, Scheithauer BW, Schild SE, Gunderson LL. Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys. 1998;42:351–60. Casanova M, Ferrari A, Spreafico F, Luksch R, Terenziani M, Cefalo G, et al. Malignant peripheral nerve sheath tumors in children: a single institution twenty-year experience. J Pediatr Hematol Oncol. 1999;21:509–13.
123
