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A Huge Pelvic-Abdominal Malignant GIST Tumour in a Patient with Neurofibromatosis Type 1: Case Report and Literature Review

A Huge Pelvic-Abdominal Malignant GIST Tumour in a Patient with Neurofibromatosis Type 1: Case... Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 6590307, 9 pages https://doi.org/10.1155/2020/6590307 Case Report A Huge Pelvic-Abdominal Malignant GIST Tumour in a Patient with Neurofibromatosis Type 1: Case Report and Literature Review 1,2 2 2 Islam Omar , Hani Alsaati, and Ejaz Waris Furness General Hospital, UHMBT, NHS, UK Oncology Center, King Hamad University Hospital, Bahrain Correspondence should be addressed to Islam Omar; islamfawzyomar@hotmail.com Received 29 May 2019; Revised 25 August 2019; Accepted 23 December 2019; Published 4 January 2020 Academic Editor: Mauro Cives Copyright © 2020 Islam Omar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gastrointestinal stromal tumours are rare tumours of the gastrointestinal tract (GIT) accounting for 0.1%–3% of all gastrointestinal tumours. The most common location is the stomach (55%) followed by the small bowel (31.8%), colon (6%), other various locations (5.5%), and the oesophagus (0.7%). They may also occur in extraintestinal locations. The signs and symptoms of GIST depend on the tumour’s location and size. Gastrointestinal bleeding is one of the most common symptoms. Other signs and symptoms include abdominal discomfort, pain or distention; intestinal obstruction, and weight loss. The association between the development of GISTs and neurofibromatosis 1 (NF1) has been established. NF1-associated GISTs tend to have a distinct phenotype, and the absence of KIT/PDGRFα mutations in turn has implications on further management when they do not respond well to imatinib treatment. Here, we present one of the largest GISTs reported in the literature with a total volume of 25:3 × 20 × 14 cm + 27:9× 23 × 8 cm and an overall weight of 7.3 kg, which developed in a 43-year-old female patient with NF1 and was resected on an emergency basis due to the rapid deterioration and development of abdominal compartment syndrome. Pathology assessment showed a malignant GIST composed of spindle cells with elongated nuclei with necrosis, marked pleomorphism and numerous giant cell. The mitotic count was >15/50 HPF, Ki 67 was 80%, and the lymphovascular invasion was clear. Immunohistochemistry investigations showed that Vimentin, CD117, and DOG1 were positive, while BCL-2 and CD99 were focal positives. Pan-CK, S-100, CD34, Desmin, SMA, and HMB-45 were negatives. 1. Introduction incidence suggestive of genetic predisposition, whereas others are associated with neurofibromatosis and Carney’s Gastrointestinal stromal tumours are rare tumours of the triad [5]. GIT (see comment above) accounting for 0.1%–3% of all GISTs are believed to arise from the interstitial cells of gastrointestinal tumours [1, 2]. The most common location Cajal or related stem cells [8]. In most cases of GISTs, there is gastric (55%) followed by the small bowel (31.8%), colon is a mutation of C-KIT oncogene, which is responsible for (6%), other various locations (5.5%), and the oesophagus the formation of a protein called KIT. Accordingly, KIT (0.7%) [3]. They may also occur in the extraintestinal loca- (CD117) positivity is observed in 95% of cases [2]. Platelet- tions like the mesentery and omentum and in exception- derived growth factor receptor alpha (PDGFRAα) mutations ally rare sites like the gallbladder, urinary bladder, and play a role in GIST pathogenesis [9]. prostate [4]. Benign GISTs outnumber the malignant ones by a margin of 10 : 1. Clinical presentation depends on the site The tumour shows no strong sex predilection and usually occurs in adults [5], with a mean reported age of 50.6 years and size of the tumour and may include abdominal pain, [6]. GIST is extremely uncommon in children and adoles- gastrointestinal bleeding from ulceration of the overlying cents [7]. Some instances of GISTs show a pattern of familial mucosa, or signs of obstruction. However, small tumours 2 Case Reports in Oncological Medicine Figure 1: External compression on the sigmoid and descending colon with neither obstruction nor intraluminal lesion. may be asymptomatic. The major clinical findings are upper Figure 2: A huge cystic mass occupying almost the whole pelvic and abdominal ulcer-like pain, dyspepsia, iron-deficiency anae- abdominal cavity. The mass is lobulated with enhancing the mia, gastrointestinal bleeding, nausea, vomiting, palpable peripheral soft tissue components and septations, displacing all abdominal mass, and weight loss [10, 11]. Also, GISTs with bowel posteriorly. an intra-abdominal abscess have been reported [12, 13]. Many studies confirmed the association between the development of GISTs and neurofibromatosis 1 (NF1) [14–17]. GISTs associated with NF1 seem however to have a distinct phenotype and the absence of KIT/PDGRFα mutations which has, in turn, an implication on further management where they do not respond well to Imatinib treatment [18–20]. Here, we present a case of a huge pelvic-abdominal GIST in a known patient of NF1 who showed rapid progression over a short time mounting to abdominal compartment syndrome. Consequently, she underwent emergency surgical excision. 2. Case Presentation A 42-year-old female is a known case of familial NF1. She and her identical twin in addition to her only brother are all affected by NF1. She has no family history of malignancy, Figure 3: Whole-body PET CT showing multiple amalgamated has not had previous surgery, and has no other comorbidi- masses exhibiting peripheral patchy FDG activity with low-grade ties. Initially, she presented with fatigue, cough, and short- FDG avid areas of peritoneal thickening/fat stranding suggesting peritoneal involvement. Low-grade FDG avid small prehepatic ness of breath. She sought medical advice, and a low node measures 8 mm with diffusely activated bone marrow. haemoglobin of 4 g/dl was discovered. She was resuscitated and received a blood transfusion. She had a history of consti- pation and change of stool calibre and melena. Clinical examination showed an abdominal mass which was con- liver, lung, or the bones, and the scanned parts of the bowel firmed by the US ultrasound later. An urgent OGD and a loops showed no abnormalities. colonoscopy were done. OGD revealed normal upper GI Tumour markers were done and showed AFP (2.8 μg/L), study while the colonoscopy showed external compression CA 125 (154.7 U/ml), CA 15-3 (10.5 U/ml), CEA (0.3 μg/L), on the sigmoid and descending colon with neither obstruc- CA 19-9 (5.4 U/ml), and B-HCG (0.9 mIU/ml). For staging, tion nor intraluminal lesion (Figure 1). a whole-body PET CT scan (Figure 3) was done and showed After stabilisation, the patient was then referred to our multiple amalgamated, well-defined, oval-to-round soft tis- tertiary oncology centre for further evaluation. A CT scan sue masses extending from right subhepatic and lumbar (Figure 2) was done which revealed a huge cystic mass regions just behind the anterolateral aspects of the anterior occupying almost the whole pelvic and abdominal cavity, abdominal wall down to the pelvis, compressing the bowel which was lobulated with enhancing peripheral soft tissue loops. These masses exhibited heterogeneous fluid and soft components and septations. Moreover, a mild free-flowing tissue densities as well as peripheral patchy FDG activity. peritoneal fluid was noted with diffuse subcutaneous tissue They were associated with low-grade FDG, avid areas of oedema. Of note, there were no signs of metastasis to the peritoneal thickening, and fat stranding with pelvic ascites, Case Reports in Oncological Medicine 3 performed with bilateral salpingo-oophorectomy. Since the sigmoid colon was found adherent to the tumour, resection of the sigmoid colon and colostomy creation were done. Moreover, the involved segments of the small bowel were resected and primarily anastomosed. The grossly involved peritoneum was resected. On gross pathological examination, the overall weight of the specimen was 7.3 kg. The first specimen (Figure 5(a)) was a huge mass with dimensions of 25:3 × 20 × 14 cm. The mass was firm, greyish white with nodular surface, and partially capsulated. There were multiple foci of haemorrhage, con- gestion, and necrosis. The cut surface of the mass showed a variegated appearance with focal greyish white areas. There were also focal areas of mucinous cystic degeneration, haem- orrhage, and necrosis. A small bowel segment 8.5 cm in length by 3.2 cm in circumference was found adherent to the mass. On opening the bowel segment, its mucosa was unremarkable. However, the serosal surface adhered to the mass. The second specimen (Figure 5(b)) came with dimen- sions of 27:9 × 23 × 8 cm. The external surface of the mass was nodular, partially capsulated, and showed foci of conges- tion, haemorrhage, and necrosis. Along with that, an exuda- tive membrane was found on the surface. The cut surface was glistening, shiny, and having a variegated appearance with focal areas of haemorrhage and necrosis in addition to Figure 4: Intraoperative findings showing a huge lobulated mass, marked cystic degeneration. occupying most of the pelvic and abdominal cavities with the Histopathology examination (Figure 6) of the two huge involvement of the sigmoid colon and small bowel. The weight of masses showed features of a malignant neoplasm. It was the resected mass exceeded 7.3 kg. composed of spindle cells with elongated nuclei arranged in fascicles. Moreover, there was marked pleomorphism suggesting peritoneal involvement. Also, a low-grade FDG and numerous tumour giant cells. The mitotic count was avid small prehepatic node was detected which measured >15/50 HPF. Additionally, there were poorly differentiated 8 mm in diameter. Additionally, features of a diffusely acti- areas with 20% necrosis. The tumour was of the high- grade type. vated bone marrow were noted, likely proliferative in response to anaemia. Risk assessment according to Fletcher et al.’s criteria [23] showed that the tumour was of high risk. Margins of the Given the previous scans, the origin of the mass was not clear and was thought to be of ovarian origin. The patient resected small and large bowel loops were free from tumour was being optimised and prepared for surgery. At that time, invasion. However, evidence of lymphovascular invasion was clear. Immunohistochemistry investigations (Figure 7) melena was stopped, but the patient continued to complain of shortness of breath, constipation, abdominal pain, and showed that Vimentin, CD117, and DOG1 were positives, distention. BCL-2 and CD99 were focal positives, Pan-CK, S-100, In an attempt to fully optimize the patient for definitive CD34, Desmin, SMA, and HMB-45 were negative, and surgery, all the efforts were carried out to ameliorate the Ki-67 was 80%. Two segments of the small bowel were resected weighing abdominal distention and the mass effects through NGT, uri- nary catheterization, and strict fluid balance management. 675 g. The first segment measured 26 cm in length by 4.8 cm Unfortunately, the mass effect was out of control due to the in circumference. A polypoid, soft-to-firm, and tan-to-grey huge size of the tumour and the patient started to experience in colour mass was found adherent to its serosal surface mea- tachycardia and tachypnea. Abdominal pressure measure- suring 8×5:2× 1:3cm. It was 10.1 cm away from the closest margin, and 17.7 cm away from the distant margin. On open- ment showed a pressure approaching 26 mmHg, a value that met a grade IV ACS [21]. ing the small bowel segment, the entire length of mucosa was At that stage, the decision was taken to do emergency gangrenous with an area of perforation identified, measuring surgery to avoid the expected consequences of ACS [22]. 7.6 mm, it was 8.5 cm away from the closest margin. Exploratory laparotomy was performed after bilateral ure- The second segment of the small bowel measuring 27.9 cm in length and a 5.3 cm circumference, with a polyp- teral stenting. A huge intra-abdominal mucinous mass was found (Figure 4) coming from the pelvis with no clear origin. oid grey soft-to-firm mass, was found adherent to the serosal There was involvement of the peritoneum, small bowel, sig- surface, measuring 36:5×6:7× 3:4cm. The mass was 9.5 cm moid colon, and upper rectum. Moreover, multiple areas of away from the closest margin and 9.6 cm away from the dis- the small bowel were involved, around 80 cm from the tant margin. Grossly, it did not appear to involve the mucosa. On opening the lumen, the mucosal surface, at the level of ileocaecal junction. Therefore, excision of the mass was 4 Case Reports in Oncological Medicine (a) (b) Figure 5: (a) Gross pathology of the first mass showing a huge mass with dimensions of 25:3 × 20 × 14 cm which was greyish white in color with nodular surface and partially capsulated. There were multiple foci of hemorrhage, congestion, and necrosis. (b) Gross pathology of the second mass measuring 27:9 × 23 × 8 cm. Its external surface was nodular, partially capsulated, and showed foci of congestion, haemorrhage, and necrosis. mass attached to the serosa, was flattened and the remaining 1:5cm and both weighed 47 g. The second piece came from mucosa showed an area of stricture measuring 2:5×1cm, the left peritoneal layer which measured 18 × 5:5×0:8cm 4.3 cm away from the closest margin with no perforation. and weighed 25 g. The right peritoneum specimen was posi- Histopathology examination of the bowel loops showed thin- tive for tumour infiltration where sections revealed tumour ning out of the wall with tumour infiltration into the mesen- infiltration of the fibrofatty tissue. The left peritoneal layer teric fat, reaching up to the muscular layer but the resection showed small ectopic adrenal tissue and was positive for margins were negative. tumour infiltration. One segment of the sigmoid colon was included and Specimens of the ovaries and fallopian tubes revealed a measured 27.9 cm in length by 8 cm in circumference. left ovary measuring 3:5×2:4×1:2cm with the left fallopian The specimen was received with an attached mesentery tube measuring 5× 1:2. The overall weight of the left ovary and weighed 299 g. A polypoid grey tan firm mass was and fallopian tube was 12 g. The right ovary and the attached found adherent to the mesenteric fat, measuring 10:5× fallopian tube with surrounding fibrofatty tissue weighed 9 g. 3:6×2:1cm, and it was 2.1 cm away from the closest mar- The right ovary measured 3:2× 1:8×1:4cm. The attached gin. Upon opening the lumen, the mucosal surface along right fallopian tube measured 4:2×1:2cm. The attached the entire segment was normal with no strictures, perfora- fibrofatty tissue showed marked areas of congestion. Histo- tion, or diverticulosis. Histopathology examination of the pathology examination of the left ovarian mass revealed a sigmoid colonic wall showed tumour infiltration into the normal ovary and fallopian tube with tumour infiltration into mesenteric fat reaching up to the muscular layer with four the paratubal tissue. The right ovarian mass was free of reactive lymph nodes. The resection margins were clear. invasion. Another specimen was retrieved and included two pieces The conclusion of the pathology assessment came as of the peritoneum. The first from the right side measured high-risk GIST (pT4, pN0, pMx) with tumour invasion into 13 × 5:3×2:2cm along with a nodule measuring 2:8×2 × the left paratubal tissue, small and large bowel, in addition Case Reports in Oncological Medicine 5 (a) (b) (c) (d) Figure 6: Histopathology of the tumor. (a, b) The tumor composed of spindle cells with elongation. (c) Areas with necrosis. (d) High mitotic figures. (a) (b) (c) (d) Figure 7: Immunohistochemistry staining. (a) Positive CD117. (b) Positive DOG1. (c) Desmin negative. (d) S100 negative. to the right and left peritoneal tissues. The patient had an which recommended starting Imatinib therapy and genetic uneventful postoperative course and was discharged home. analysis. Unfortunately, genetic analysis was not available Her case was discussed in the national tumour board—MDT, in any local centre. Every effort was made to send the tissue 6 Case Reports in Oncological Medicine our knowledge, our patient had the largest reported GIST blocks abroad for genetic analysis; however, logistical obsta- cles aborted these endeavours. in the literature with a volume of 25:3 × 20 × 14 + 27:9× Although the patient received the first dose of Imatinib, 23 × 8 cm and the second heaviest tumour weighing 7.3 kg. GISTs are potentially aggressive forms of cancer that may her condition started to deteriorate over the next 2 months after surgery with persistent vomiting and gradual abdominal develop anywhere in the GI tract [28]. They most frequently distention. However, her stoma was functioning and a bar- metastasize within the abdominal cavity, especially the ium follow-through study confirmed the patency of her liver and peritoneum. Bone and lung metastases are far bowel. Because of the multiple admissions due to persistent less common [28, 29]. Very rare metastases to the skeletal muscles, adrenal gland, brain, testicles, and heart have also vomiting and abdominal distention, a CT scan was done which confirmed an aggressive recurrence. Because of the been reported [30–33]. Sizes larger than 10 cm cystic severe distention and again abdominal compartment syn- changes, high cellularity, mitotic figures >10/50 HPF, and drome, the patient was taken to the theatre where an aggres- coagulative necrosis are all more likely to be associated sive inoperable tumour was encountered. Laparostomy was with metastasis [34]. In our patient, the histopathology assessment classified performed. The abdomen was left open and covered with a Bogota bag. A few days after the second surgery, the patient the tumour as a high-risk malignant tumour. Although dis- passed away. tant spread to the liver or bones is excluded based on radio- logical staging, the tumour is proved to be locally aggressive spreading to the peritoneum, bowels, and paratubal tissues. 3. Discussion This is expected given the huge nature of the tumour, a The signs and symptoms of GIST depend on the tumour’s mitotic count of >15/50 HPF, and Ki-67of 80%. Association between GIST and NF1 is established since location and size, with highly malignant GISTs typically being large and symptomatic at the time of diagnosis. Gas- an old autopsy study had documented a GIST in one-third trointestinal bleeding is one of the most common symp- of the NF1 patients [35]. NF1-associated GISTs are typically reported as multiple, generally low-grade tumours that affect toms. Other signs and symptoms include abdominal discomfort, pain or distention, intestinal obstruction, and the jejunum, ileum, duodenum, and stomach [15, 36]. Salvi weight loss [24]. PF et al. [19] in a systematic review of 252 patients with In this case, there was a typical presentation with anae- NF1-associated GISTs reported that patients affected by mia, melena, and gradual abdominal distention. Although NF1-associated GISTs were younger and tumours were sig- nificantly smaller. Moreover, tumours were located mainly there was no complete obstruction, the patient gave a history of change of stool calibre and constipation, manifestations in the jejunum and ileum in the NF1 subgroup, whereas the that go with the external compression exerted by the huge main localization in the sporadic group was the stomach. tumour on the bowel. They also reported a prevalence of low-risk criteria in the GISTs arise in the muscularis propria layer of the stom- NF1 subgroup compared with the sporadic GISTs. In our case, the patient was young (43 years old), with the ach or intestinal wall. Small GISTs form intramural or serosal nodules and, as they grow and expand, may develop intra- tumour most probably originating from the small bowel—- luminal, intramural, and extraluminal components to vary- criteria that go with the previous literature. However, the ing degrees. The extraluminal component of a malignant tumour was huge and of the high-risk category, which were GIST may be so large that it is difficult to determine the site both striking features. The genetic basis for the association between NF1 and of origin [24, 25]. On the radiological basis, the tumour in our patient was GISTs is being elucidated. The genetic defect of NF1 disease first thought to have originated from the ovaries due to its is a mutation in the NF1 gene which encodes neurofibromin, pelvic-abdominal position and close proximity to the gonads. a tumour suppressor protein that regulates the cellular pro- However, on histopathology assessment, it was proved to liferation via inactivation of RAS through GTPase activity. RAS is known to stimulate signal transduction through the invade the left paratubal tissue planes only. Given its huge size and invasion of both the sigmoid colon as well as the MAP kinase pathway when activated. The resultant loss small bowels, the origin is not clear; however, the invasion of the function of neurofibromin predisposes to the to the small bowel was more aggressive with perforation development of benign and malignant tumours [37–39]. and stricture formation suggesting a small bowel origin. NF1-related GI disease has been described to occur in three principal forms: neurogenic tumours, stromal tumours, and Given the weight and volume of our tumour (overall weight of 7.3 kg—25:3 × 20 × 14 cm for the first mass and neuroendocrine tumours [40–42]. The most common of 27:9 × 23 × 8 cm for the second mass), it is one of the largest these GI manifestations in NF1 is GIST with one study indi- cating an incidence of 7% in the NF1 population and another GISTs reported in the literature. Koyuncuer et al. [26] reported a huge GIST originating from the stomach in a reporting a 150-fold increased risk as compared to the general population [35, 38]. 43-year-old male, which was 6.109 kg in weight and mea- sured 39 × 27 × 14 cm. Also, Cappellani et al. [27] reported GISTs in adults are typically sporadically occurring and a gastric GIST in a 67-year-old male, weighing 8.5 kg and are associated with somatic mutations in the KIT or PDGFRα gen measuring 37 × 24 × 13 cm. Moreover, Cruz et al. described e. However, 10%–15% of GISTs lack KIT or PDGFRα a gastric GIST in a 37-year-old male, which was 32 × 25 × mutations. These GISTs can be associated with NF1 or 21 in size and 3.75 kg in weight. Accordingly, to the best of can represent succinate dehydrogenase (SDH)-deficient Case Reports in Oncological Medicine 7 GISTs that include GIST in the Carney triad and the References Carney-Stratakis syndrome [43, 44]. [1] S. Phongkitkarun, C. Phaisanphrukkun, J. Jatchavala, and GISTs associated with Carney Triad, Carney Stratakis E. Sirachainan, “Assessment of gastrointestinal stromal syndrome, along with young and paediatric GISTs have been tumors with computed tomography following treatment with documented to have a loss of succinate dehydrogenase imatinib mesylate,” World Journal of Gastroenterology, subunit B (SDHB) expression [20, 45, 46]. vol. 14, no. 6, pp. 892–898, 2008. Based on the SDHB expression, it has been recently [2] I. K. Skandalos, N. F. 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A Huge Pelvic-Abdominal Malignant GIST Tumour in a Patient with Neurofibromatosis Type 1: Case Report and Literature Review

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Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 6590307, 9 pages https://doi.org/10.1155/2020/6590307 Case Report A Huge Pelvic-Abdominal Malignant GIST Tumour in a Patient with Neurofibromatosis Type 1: Case Report and Literature Review 1,2 2 2 Islam Omar , Hani Alsaati, and Ejaz Waris Furness General Hospital, UHMBT, NHS, UK Oncology Center, King Hamad University Hospital, Bahrain Correspondence should be addressed to Islam Omar; islamfawzyomar@hotmail.com Received 29 May 2019; Revised 25 August 2019; Accepted 23 December 2019; Published 4 January 2020 Academic Editor: Mauro Cives Copyright © 2020 Islam Omar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gastrointestinal stromal tumours are rare tumours of the gastrointestinal tract (GIT) accounting for 0.1%–3% of all gastrointestinal tumours. The most common location is the stomach (55%) followed by the small bowel (31.8%), colon (6%), other various locations (5.5%), and the oesophagus (0.7%). They may also occur in extraintestinal locations. The signs and symptoms of GIST depend on the tumour’s location and size. Gastrointestinal bleeding is one of the most common symptoms. Other signs and symptoms include abdominal discomfort, pain or distention; intestinal obstruction, and weight loss. The association between the development of GISTs and neurofibromatosis 1 (NF1) has been established. NF1-associated GISTs tend to have a distinct phenotype, and the absence of KIT/PDGRFα mutations in turn has implications on further management when they do not respond well to imatinib treatment. Here, we present one of the largest GISTs reported in the literature with a total volume of 25:3 × 20 × 14 cm + 27:9× 23 × 8 cm and an overall weight of 7.3 kg, which developed in a 43-year-old female patient with NF1 and was resected on an emergency basis due to the rapid deterioration and development of abdominal compartment syndrome. Pathology assessment showed a malignant GIST composed of spindle cells with elongated nuclei with necrosis, marked pleomorphism and numerous giant cell. The mitotic count was >15/50 HPF, Ki 67 was 80%, and the lymphovascular invasion was clear. Immunohistochemistry investigations showed that Vimentin, CD117, and DOG1 were positive, while BCL-2 and CD99 were focal positives. Pan-CK, S-100, CD34, Desmin, SMA, and HMB-45 were negatives. 1. Introduction incidence suggestive of genetic predisposition, whereas others are associated with neurofibromatosis and Carney’s Gastrointestinal stromal tumours are rare tumours of the triad [5]. GIT (see comment above) accounting for 0.1%–3% of all GISTs are believed to arise from the interstitial cells of gastrointestinal tumours [1, 2]. The most common location Cajal or related stem cells [8]. In most cases of GISTs, there is gastric (55%) followed by the small bowel (31.8%), colon is a mutation of C-KIT oncogene, which is responsible for (6%), other various locations (5.5%), and the oesophagus the formation of a protein called KIT. Accordingly, KIT (0.7%) [3]. They may also occur in the extraintestinal loca- (CD117) positivity is observed in 95% of cases [2]. Platelet- tions like the mesentery and omentum and in exception- derived growth factor receptor alpha (PDGFRAα) mutations ally rare sites like the gallbladder, urinary bladder, and play a role in GIST pathogenesis [9]. prostate [4]. Benign GISTs outnumber the malignant ones by a margin of 10 : 1. Clinical presentation depends on the site The tumour shows no strong sex predilection and usually occurs in adults [5], with a mean reported age of 50.6 years and size of the tumour and may include abdominal pain, [6]. GIST is extremely uncommon in children and adoles- gastrointestinal bleeding from ulceration of the overlying cents [7]. Some instances of GISTs show a pattern of familial mucosa, or signs of obstruction. However, small tumours 2 Case Reports in Oncological Medicine Figure 1: External compression on the sigmoid and descending colon with neither obstruction nor intraluminal lesion. may be asymptomatic. The major clinical findings are upper Figure 2: A huge cystic mass occupying almost the whole pelvic and abdominal ulcer-like pain, dyspepsia, iron-deficiency anae- abdominal cavity. The mass is lobulated with enhancing the mia, gastrointestinal bleeding, nausea, vomiting, palpable peripheral soft tissue components and septations, displacing all abdominal mass, and weight loss [10, 11]. Also, GISTs with bowel posteriorly. an intra-abdominal abscess have been reported [12, 13]. Many studies confirmed the association between the development of GISTs and neurofibromatosis 1 (NF1) [14–17]. GISTs associated with NF1 seem however to have a distinct phenotype and the absence of KIT/PDGRFα mutations which has, in turn, an implication on further management where they do not respond well to Imatinib treatment [18–20]. Here, we present a case of a huge pelvic-abdominal GIST in a known patient of NF1 who showed rapid progression over a short time mounting to abdominal compartment syndrome. Consequently, she underwent emergency surgical excision. 2. Case Presentation A 42-year-old female is a known case of familial NF1. She and her identical twin in addition to her only brother are all affected by NF1. She has no family history of malignancy, Figure 3: Whole-body PET CT showing multiple amalgamated has not had previous surgery, and has no other comorbidi- masses exhibiting peripheral patchy FDG activity with low-grade ties. Initially, she presented with fatigue, cough, and short- FDG avid areas of peritoneal thickening/fat stranding suggesting peritoneal involvement. Low-grade FDG avid small prehepatic ness of breath. She sought medical advice, and a low node measures 8 mm with diffusely activated bone marrow. haemoglobin of 4 g/dl was discovered. She was resuscitated and received a blood transfusion. She had a history of consti- pation and change of stool calibre and melena. Clinical examination showed an abdominal mass which was con- liver, lung, or the bones, and the scanned parts of the bowel firmed by the US ultrasound later. An urgent OGD and a loops showed no abnormalities. colonoscopy were done. OGD revealed normal upper GI Tumour markers were done and showed AFP (2.8 μg/L), study while the colonoscopy showed external compression CA 125 (154.7 U/ml), CA 15-3 (10.5 U/ml), CEA (0.3 μg/L), on the sigmoid and descending colon with neither obstruc- CA 19-9 (5.4 U/ml), and B-HCG (0.9 mIU/ml). For staging, tion nor intraluminal lesion (Figure 1). a whole-body PET CT scan (Figure 3) was done and showed After stabilisation, the patient was then referred to our multiple amalgamated, well-defined, oval-to-round soft tis- tertiary oncology centre for further evaluation. A CT scan sue masses extending from right subhepatic and lumbar (Figure 2) was done which revealed a huge cystic mass regions just behind the anterolateral aspects of the anterior occupying almost the whole pelvic and abdominal cavity, abdominal wall down to the pelvis, compressing the bowel which was lobulated with enhancing peripheral soft tissue loops. These masses exhibited heterogeneous fluid and soft components and septations. Moreover, a mild free-flowing tissue densities as well as peripheral patchy FDG activity. peritoneal fluid was noted with diffuse subcutaneous tissue They were associated with low-grade FDG, avid areas of oedema. Of note, there were no signs of metastasis to the peritoneal thickening, and fat stranding with pelvic ascites, Case Reports in Oncological Medicine 3 performed with bilateral salpingo-oophorectomy. Since the sigmoid colon was found adherent to the tumour, resection of the sigmoid colon and colostomy creation were done. Moreover, the involved segments of the small bowel were resected and primarily anastomosed. The grossly involved peritoneum was resected. On gross pathological examination, the overall weight of the specimen was 7.3 kg. The first specimen (Figure 5(a)) was a huge mass with dimensions of 25:3 × 20 × 14 cm. The mass was firm, greyish white with nodular surface, and partially capsulated. There were multiple foci of haemorrhage, con- gestion, and necrosis. The cut surface of the mass showed a variegated appearance with focal greyish white areas. There were also focal areas of mucinous cystic degeneration, haem- orrhage, and necrosis. A small bowel segment 8.5 cm in length by 3.2 cm in circumference was found adherent to the mass. On opening the bowel segment, its mucosa was unremarkable. However, the serosal surface adhered to the mass. The second specimen (Figure 5(b)) came with dimen- sions of 27:9 × 23 × 8 cm. The external surface of the mass was nodular, partially capsulated, and showed foci of conges- tion, haemorrhage, and necrosis. Along with that, an exuda- tive membrane was found on the surface. The cut surface was glistening, shiny, and having a variegated appearance with focal areas of haemorrhage and necrosis in addition to Figure 4: Intraoperative findings showing a huge lobulated mass, marked cystic degeneration. occupying most of the pelvic and abdominal cavities with the Histopathology examination (Figure 6) of the two huge involvement of the sigmoid colon and small bowel. The weight of masses showed features of a malignant neoplasm. It was the resected mass exceeded 7.3 kg. composed of spindle cells with elongated nuclei arranged in fascicles. Moreover, there was marked pleomorphism suggesting peritoneal involvement. Also, a low-grade FDG and numerous tumour giant cells. The mitotic count was avid small prehepatic node was detected which measured >15/50 HPF. Additionally, there were poorly differentiated 8 mm in diameter. Additionally, features of a diffusely acti- areas with 20% necrosis. The tumour was of the high- grade type. vated bone marrow were noted, likely proliferative in response to anaemia. Risk assessment according to Fletcher et al.’s criteria [23] showed that the tumour was of high risk. Margins of the Given the previous scans, the origin of the mass was not clear and was thought to be of ovarian origin. The patient resected small and large bowel loops were free from tumour was being optimised and prepared for surgery. At that time, invasion. However, evidence of lymphovascular invasion was clear. Immunohistochemistry investigations (Figure 7) melena was stopped, but the patient continued to complain of shortness of breath, constipation, abdominal pain, and showed that Vimentin, CD117, and DOG1 were positives, distention. BCL-2 and CD99 were focal positives, Pan-CK, S-100, In an attempt to fully optimize the patient for definitive CD34, Desmin, SMA, and HMB-45 were negative, and surgery, all the efforts were carried out to ameliorate the Ki-67 was 80%. Two segments of the small bowel were resected weighing abdominal distention and the mass effects through NGT, uri- nary catheterization, and strict fluid balance management. 675 g. The first segment measured 26 cm in length by 4.8 cm Unfortunately, the mass effect was out of control due to the in circumference. A polypoid, soft-to-firm, and tan-to-grey huge size of the tumour and the patient started to experience in colour mass was found adherent to its serosal surface mea- tachycardia and tachypnea. Abdominal pressure measure- suring 8×5:2× 1:3cm. It was 10.1 cm away from the closest margin, and 17.7 cm away from the distant margin. On open- ment showed a pressure approaching 26 mmHg, a value that met a grade IV ACS [21]. ing the small bowel segment, the entire length of mucosa was At that stage, the decision was taken to do emergency gangrenous with an area of perforation identified, measuring surgery to avoid the expected consequences of ACS [22]. 7.6 mm, it was 8.5 cm away from the closest margin. Exploratory laparotomy was performed after bilateral ure- The second segment of the small bowel measuring 27.9 cm in length and a 5.3 cm circumference, with a polyp- teral stenting. A huge intra-abdominal mucinous mass was found (Figure 4) coming from the pelvis with no clear origin. oid grey soft-to-firm mass, was found adherent to the serosal There was involvement of the peritoneum, small bowel, sig- surface, measuring 36:5×6:7× 3:4cm. The mass was 9.5 cm moid colon, and upper rectum. Moreover, multiple areas of away from the closest margin and 9.6 cm away from the dis- the small bowel were involved, around 80 cm from the tant margin. Grossly, it did not appear to involve the mucosa. On opening the lumen, the mucosal surface, at the level of ileocaecal junction. Therefore, excision of the mass was 4 Case Reports in Oncological Medicine (a) (b) Figure 5: (a) Gross pathology of the first mass showing a huge mass with dimensions of 25:3 × 20 × 14 cm which was greyish white in color with nodular surface and partially capsulated. There were multiple foci of hemorrhage, congestion, and necrosis. (b) Gross pathology of the second mass measuring 27:9 × 23 × 8 cm. Its external surface was nodular, partially capsulated, and showed foci of congestion, haemorrhage, and necrosis. mass attached to the serosa, was flattened and the remaining 1:5cm and both weighed 47 g. The second piece came from mucosa showed an area of stricture measuring 2:5×1cm, the left peritoneal layer which measured 18 × 5:5×0:8cm 4.3 cm away from the closest margin with no perforation. and weighed 25 g. The right peritoneum specimen was posi- Histopathology examination of the bowel loops showed thin- tive for tumour infiltration where sections revealed tumour ning out of the wall with tumour infiltration into the mesen- infiltration of the fibrofatty tissue. The left peritoneal layer teric fat, reaching up to the muscular layer but the resection showed small ectopic adrenal tissue and was positive for margins were negative. tumour infiltration. One segment of the sigmoid colon was included and Specimens of the ovaries and fallopian tubes revealed a measured 27.9 cm in length by 8 cm in circumference. left ovary measuring 3:5×2:4×1:2cm with the left fallopian The specimen was received with an attached mesentery tube measuring 5× 1:2. The overall weight of the left ovary and weighed 299 g. A polypoid grey tan firm mass was and fallopian tube was 12 g. The right ovary and the attached found adherent to the mesenteric fat, measuring 10:5× fallopian tube with surrounding fibrofatty tissue weighed 9 g. 3:6×2:1cm, and it was 2.1 cm away from the closest mar- The right ovary measured 3:2× 1:8×1:4cm. The attached gin. Upon opening the lumen, the mucosal surface along right fallopian tube measured 4:2×1:2cm. The attached the entire segment was normal with no strictures, perfora- fibrofatty tissue showed marked areas of congestion. Histo- tion, or diverticulosis. Histopathology examination of the pathology examination of the left ovarian mass revealed a sigmoid colonic wall showed tumour infiltration into the normal ovary and fallopian tube with tumour infiltration into mesenteric fat reaching up to the muscular layer with four the paratubal tissue. The right ovarian mass was free of reactive lymph nodes. The resection margins were clear. invasion. Another specimen was retrieved and included two pieces The conclusion of the pathology assessment came as of the peritoneum. The first from the right side measured high-risk GIST (pT4, pN0, pMx) with tumour invasion into 13 × 5:3×2:2cm along with a nodule measuring 2:8×2 × the left paratubal tissue, small and large bowel, in addition Case Reports in Oncological Medicine 5 (a) (b) (c) (d) Figure 6: Histopathology of the tumor. (a, b) The tumor composed of spindle cells with elongation. (c) Areas with necrosis. (d) High mitotic figures. (a) (b) (c) (d) Figure 7: Immunohistochemistry staining. (a) Positive CD117. (b) Positive DOG1. (c) Desmin negative. (d) S100 negative. to the right and left peritoneal tissues. The patient had an which recommended starting Imatinib therapy and genetic uneventful postoperative course and was discharged home. analysis. Unfortunately, genetic analysis was not available Her case was discussed in the national tumour board—MDT, in any local centre. Every effort was made to send the tissue 6 Case Reports in Oncological Medicine our knowledge, our patient had the largest reported GIST blocks abroad for genetic analysis; however, logistical obsta- cles aborted these endeavours. in the literature with a volume of 25:3 × 20 × 14 + 27:9× Although the patient received the first dose of Imatinib, 23 × 8 cm and the second heaviest tumour weighing 7.3 kg. GISTs are potentially aggressive forms of cancer that may her condition started to deteriorate over the next 2 months after surgery with persistent vomiting and gradual abdominal develop anywhere in the GI tract [28]. They most frequently distention. However, her stoma was functioning and a bar- metastasize within the abdominal cavity, especially the ium follow-through study confirmed the patency of her liver and peritoneum. Bone and lung metastases are far bowel. Because of the multiple admissions due to persistent less common [28, 29]. Very rare metastases to the skeletal muscles, adrenal gland, brain, testicles, and heart have also vomiting and abdominal distention, a CT scan was done which confirmed an aggressive recurrence. Because of the been reported [30–33]. Sizes larger than 10 cm cystic severe distention and again abdominal compartment syn- changes, high cellularity, mitotic figures >10/50 HPF, and drome, the patient was taken to the theatre where an aggres- coagulative necrosis are all more likely to be associated sive inoperable tumour was encountered. Laparostomy was with metastasis [34]. In our patient, the histopathology assessment classified performed. The abdomen was left open and covered with a Bogota bag. A few days after the second surgery, the patient the tumour as a high-risk malignant tumour. Although dis- passed away. tant spread to the liver or bones is excluded based on radio- logical staging, the tumour is proved to be locally aggressive spreading to the peritoneum, bowels, and paratubal tissues. 3. Discussion This is expected given the huge nature of the tumour, a The signs and symptoms of GIST depend on the tumour’s mitotic count of >15/50 HPF, and Ki-67of 80%. Association between GIST and NF1 is established since location and size, with highly malignant GISTs typically being large and symptomatic at the time of diagnosis. Gas- an old autopsy study had documented a GIST in one-third trointestinal bleeding is one of the most common symp- of the NF1 patients [35]. NF1-associated GISTs are typically reported as multiple, generally low-grade tumours that affect toms. Other signs and symptoms include abdominal discomfort, pain or distention, intestinal obstruction, and the jejunum, ileum, duodenum, and stomach [15, 36]. Salvi weight loss [24]. PF et al. [19] in a systematic review of 252 patients with In this case, there was a typical presentation with anae- NF1-associated GISTs reported that patients affected by mia, melena, and gradual abdominal distention. Although NF1-associated GISTs were younger and tumours were sig- nificantly smaller. Moreover, tumours were located mainly there was no complete obstruction, the patient gave a history of change of stool calibre and constipation, manifestations in the jejunum and ileum in the NF1 subgroup, whereas the that go with the external compression exerted by the huge main localization in the sporadic group was the stomach. tumour on the bowel. They also reported a prevalence of low-risk criteria in the GISTs arise in the muscularis propria layer of the stom- NF1 subgroup compared with the sporadic GISTs. In our case, the patient was young (43 years old), with the ach or intestinal wall. Small GISTs form intramural or serosal nodules and, as they grow and expand, may develop intra- tumour most probably originating from the small bowel—- luminal, intramural, and extraluminal components to vary- criteria that go with the previous literature. However, the ing degrees. The extraluminal component of a malignant tumour was huge and of the high-risk category, which were GIST may be so large that it is difficult to determine the site both striking features. The genetic basis for the association between NF1 and of origin [24, 25]. On the radiological basis, the tumour in our patient was GISTs is being elucidated. The genetic defect of NF1 disease first thought to have originated from the ovaries due to its is a mutation in the NF1 gene which encodes neurofibromin, pelvic-abdominal position and close proximity to the gonads. a tumour suppressor protein that regulates the cellular pro- However, on histopathology assessment, it was proved to liferation via inactivation of RAS through GTPase activity. RAS is known to stimulate signal transduction through the invade the left paratubal tissue planes only. Given its huge size and invasion of both the sigmoid colon as well as the MAP kinase pathway when activated. The resultant loss small bowels, the origin is not clear; however, the invasion of the function of neurofibromin predisposes to the to the small bowel was more aggressive with perforation development of benign and malignant tumours [37–39]. and stricture formation suggesting a small bowel origin. NF1-related GI disease has been described to occur in three principal forms: neurogenic tumours, stromal tumours, and Given the weight and volume of our tumour (overall weight of 7.3 kg—25:3 × 20 × 14 cm for the first mass and neuroendocrine tumours [40–42]. The most common of 27:9 × 23 × 8 cm for the second mass), it is one of the largest these GI manifestations in NF1 is GIST with one study indi- cating an incidence of 7% in the NF1 population and another GISTs reported in the literature. Koyuncuer et al. [26] reported a huge GIST originating from the stomach in a reporting a 150-fold increased risk as compared to the general population [35, 38]. 43-year-old male, which was 6.109 kg in weight and mea- sured 39 × 27 × 14 cm. Also, Cappellani et al. [27] reported GISTs in adults are typically sporadically occurring and a gastric GIST in a 67-year-old male, weighing 8.5 kg and are associated with somatic mutations in the KIT or PDGFRα gen measuring 37 × 24 × 13 cm. Moreover, Cruz et al. described e. However, 10%–15% of GISTs lack KIT or PDGFRα a gastric GIST in a 37-year-old male, which was 32 × 25 × mutations. These GISTs can be associated with NF1 or 21 in size and 3.75 kg in weight. Accordingly, to the best of can represent succinate dehydrogenase (SDH)-deficient Case Reports in Oncological Medicine 7 GISTs that include GIST in the Carney triad and the References Carney-Stratakis syndrome [43, 44]. [1] S. Phongkitkarun, C. Phaisanphrukkun, J. Jatchavala, and GISTs associated with Carney Triad, Carney Stratakis E. Sirachainan, “Assessment of gastrointestinal stromal syndrome, along with young and paediatric GISTs have been tumors with computed tomography following treatment with documented to have a loss of succinate dehydrogenase imatinib mesylate,” World Journal of Gastroenterology, subunit B (SDHB) expression [20, 45, 46]. vol. 14, no. 6, pp. 892–898, 2008. Based on the SDHB expression, it has been recently [2] I. K. Skandalos, N. F. 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