Leiomyosarcoma mimicking acute appendicitis: a cautionary tale!

Appendiceal neoplasms are rare, occurring in <1.4% of all appendicectomy specimens. Carcinoid tumours and adenocarcinomas comprise the majority of cases, however, lymphomas or sarcomas may also arise within the appendix. Appendiceal leiomyosarcomas are rare and to date, there remains a relative dearth of cases reported in the literature. Leiomyosarcomas are derived from the smooth muscle cells or mesenchymal stem cells committed to this line of differentiation. However, their pathogenesis and underlying genetic mechanism remains to be fully elucidated. Unbalanced karyotypic defects are the only shared features observed across different leiomyosarcoma subtypes. Children with AIDS have a higher incidence compared with adults, where the main pathology in individuals with HIV is Kaposi’s sarcoma and B-cell lymphoma. Although surgical excision with clear margins remains the treatment of choice, a good response to treatment with gemcitabine, docetaxel and trabectedin has been observed. The authors present the case of a 23-year-old female presenting to the emergency department with acute appendicitis. She underwent a laparoscopic converted to an open appendectomy. Her operation was complicated by a pelvic collection requiring percutaneous drainage and an ileus. Histopathological examination confirmed the diagnosis of a leiomyosarcoma, a rare mesenchymal tumour presenting in individuals with immune suppression. HIV serology was positive and she commenced anti-retroviral therapy. She remains under review in the Department of HIV Medicine.

HIV / AIDS, surgery

Mesenchymal tumours of the appendix are most often of the smooth muscle type, usually a leiomyoma, but rarely, a leiomyosarcoma, as described in this case. A leiomyosarcoma is a malignant neoplasm derived from smooth-muscle tissue and accounts for <1% of all malignant tumours. It is usually multifocal and involves the genitourinary or the gastro intestinal tract. It has been associated with HIV infection in children. It is extremely rare in adults, where it is more likely to be multifocal and affects the central nervous system.1 A role has been suggested for Epstein-Barr virus (EBV) as it can infect smooth-muscle cells, at least in patients with AIDS. It also has a predisposition for individuals in the fifth and sixth decade, following organ or stem cell transplantation, HIV/AIDS and in congenital immune deficiencies. Case presentation A 23-year-old woman, born in Ethiopia, but resident in the UK for 4 years presented to the emergency department with periumbilical pain radiating to her right iliac fossa. She described a 2-week history of suprapubic pain and urinary symptoms including pain on micturition. She reported rigors and fever of 39.8°C. She attended her general practitioner 3 days previously and was prescribed trimethoprim. She denied a history of pelvic inflammatory disease. This was her third presentation to the emergency department in 5 days. An abdominal radiograph showed faecal loading (figure 1). As her observations and laboratory investigations were normal she was discharged home. She had a 5-year history of indigestion, bloating, epigastric pain and constipation. She attended the emergency department 1 year previously with right upper quadrant abdominal pain thought to be gallbladder related. Laboratory investigations showed a low haemoglobin (11 g/L) with a normal MCV, a white cell count of 3.8×109/L and a lymphopenia. Protein electrophoresis showed increased gammaglobulins. Sickle cell and thalassaemia tests were negative. She had a slightly low iron level2 and a chronically raised erythrocyte sedimentation rate (ESR) of 42. Her vitamin B12 and folate were normal but her ferritin was reduced at 17. She had no symptoms of weight loss, diarrhoea or cough. Glandular fever, cytomegalovirus, hepatitis A, B and C serology were negative. The EBV nuclear antigen was positive indicating past infection. An abdominal ultrasound scan showed a normal spleen. Endomysial antibodies and an OGD were normal. HIV serology in Ethiopia 1 year previously was negative. She was taking no medications and had no allergies. She was a non-smoker, did not consume alcohol or take over the counter herbal remedies. Her observations were as follows: blood pressure (BP) 114/70 mm Hg, HR 98, SpO2 (oxygen saturation) 100% on air, RR 16 and temperature 38.9°C. There was no palpable lymphadenopathy. Cardiovascular and respiratory examination were unremarkable. Abdominal examination confirmed tenderness in her right iliac fossa. She was Rovsing’s sign positive. Digital rectal examination was unremarkable. Investigations Laboratory investigations showed a leucocytosis (12×109/L) and a CRP of 179 mg/L (table 1). A chest radiograph showed no evidence of pneumoperitoneum. Urinalysis showed a trace of nitrites and leucocytes, but no blood. A venous blood gas showed a metabolic acidosis. Table 1. | Haematology | Biochemistry | || | Haemoglobin | 110 g/L | Sodium | 138 mmol/L | | White cell count | 12×109/L | Potassium | 4.5 mmol/L | | Platelet count | 480x109/L | Urea | 2.2 mmol/L | | Mean cell volume | 78.7 fL | Creatinine | 49 | | Haematocrit | 0.33 L/L | eGFR | >60 | | Neutrophil count | 2.89 | Alkaline phosphatase | 89 | | Monocyte count | 0.29 | Alanine transaminase | 28 | | Eosinophil count | 0.01 | Bilirubin | 3 | | Lymphocytes | 0.82 | Calcium | 2.4 mmol/L | | Clotting | Albumin | 36 g/L | | | APTT | 35.0 | CRP | 179 mg/L | | Prothrombin time | 15.3 | Amylase | 61 | APTT, activated partial thromboplastin time; CRP, C reactive protein; eGFR, estimated glomerular filtraton rate. Differential diagnosis The clinical impression was of acute appendicitis, although a urinary tract infection, mesenteric adenitis or gynaecological pathology was considered in the differential diagnosis. Treatment She underwent a laparoscopic converted to an open appendectomy via a modified Lanz incision. Intravenous coamoxiclav was administered at the induction of anaesthesia. A large appendix mass containing a very dilated appendix with pus in the pelvis was observed. A drain was inserted and drainage established. Postoperatively, she was hypotensive, tachycardic and feverish (BP 90/60 mm Hg, HR 120 and temperature 38.7°C). Her abdomen was distended and bowel sounds were absent. An abdominal radiograph showed dilated small bowel loops (figure 2). She was hypokalaemic (K+ 3.3) with an acute kidney injury. Her C reactive protein (CRP) remained elevated at 264.6 ng/L. A CT abdomen and pelvis showed a collection superior and anterior to the bladder with evidence of proximal bowel dilatation suggestive of an ileus. A nasogastric tube was inserted. Ultrasound guided drainage of her collection was performed and 500 mL drained. She was discharged home uneventfully. Four days later, she presented to the emergency department with abdominal pain. She was tender on palpation of her right iliac fossa and her surgical site showed no evidence of infection. She was apyrexial, her white cell count was 4.3 and her CRP was 40. An abdominal ultrasound showed no evidence of a pelvic collection. She was discharged home. Outcome and follow-up Macroscopic examination of the appendicectomy specimen revealed a grey–white tumour occupying the lumen of the appendix measuring 22 mm in maximum dimension, with nearby areas of necrosis and haemorrhage. Histological examination confirmed that the luminal tumour had a smooth, rounded contour, covered by inflamed mucosa and attached to the wall of the appendix (figure 3). It consisted of interlacing fascicles of spindle cells, in areas arranged in a ‘herringbone’ proliferating pattern (figure 4A). The spindle cells had poorly defined cell outlines, a moderate amount of eosinophilic cytoplasm and ovoid to elongated blunt-ended nuclei showing focal nuclear atypia (figure 4B). Some foci of ischaemic necrosis was present, but coagulative necrosis was not seen. The tumour was mitotically active, with up to 12 mitoses/50 high power field (HPF) identified (figure 4B). Immunohistochemical stains showed that the tumour cells were strongly positive for h-Caldesmon (figure 5A) and smooth muscle actin (SMA) (figure 5B), CD117 (figure 5C) and desmin (figure 5D). CD34 and S100 protein were negative. Considering the young age of the patient, the unusual location of the tumour, the morphological features and immunophenotype displayed, the case was sent for specialist review. The consensus was that the tumour was of smooth muscle lineage and should be regarded as a low-grade leiomyosarcoma. While such tumours are exceptionally rare in this location, a subset of smooth muscle tumours (SMT) can occur in young patients who are immunocompromised and consequently a question regarding the HIV status of the patient was raised. A retroviral test confirmed the diagnosis of HIV: CD4 count 150 (13%) and viral load 50. Syphilis, toxoplasma, cryptococcal and cytomegalovirus investigations were negative. Prophylaxis with cotrimoxazole 960 mg three times weekly was initiated. She commenced treatment with Truvada (emtricitabine 200 mg/tenofovir 245 mg), darvnavir 800 mg od and ritonavir 100 mg. At present, her viral load remains undetectable. Her CD4 count is 590 (30%). She has been vaccinated against hepatitis B. She has maintained good immune reconstitution and remains under review in the department of HIV medicine.

The 1980s heralded the onset of the HIV epidemic. A high incidence of Kaposi’s sarcoma, non- hodgkin’s lymphoma and invasive cervical carcinoma was observed, suggesting a causal relationship between immunodeficiency and the development of these kind of malignancies. A plethora of pathologies can affect the appendix mimicking appendicitis. Congenital abnormalities of the appendix are indeed rare. The two most commonly reported pathologies are congenital absence and appendiceal duplication. Diverticulitis can also be misdiagnosed with appendicitis. Endometriosis of the appendix can present as an acute appendicitis, however, it can also present as intussusception, lower gastrointestinal bleeding and during pregnancy, perforation can occur. Vascular pathologies can also affect the appendix, either isolated or as part of a systemic vasculitis, most often polyarteritis nodosa. Von Recklinghausen’s disease can lead to neural proliferations of the appendix. It has also been hypothesised that mucosal and axial neuromas can progress to fibrous obliteration of the appendix. Appendiceal neoplasms are rare occurring in 0.9%–1.4% of all appendectomies.3 Carcinoid tumours and adenocarcinomas comprise the majority of these tumours and have an incidence of 32%–85% and 36%–65%, respectively.3 Mesenchymal tumours of the appendix are most often of the smooth muscle type, usually leiomyoma but rarely a leiomyosarcoma. Leiomyosarcoma represents 8%–10% of all sarcomas. Non-myogenic neoplasms such as a gastrointestial stromal tumour, granular cell tumour and Kaposi’s sarcoma rarely occurs. In the paediatric cohort, Burkitt’s lymphoma is the most prevalent haematological malignancy, whereas in adults, large cell lymphomas and low-grade B cell lymphomas predominate. Human herpes virus associated lymphomas such as primary effusion lymphoma, multicentric Castleman disease and plasmablastic lymphoma can present concurrently with Kaposi’s sarcoma. Secondary involvement of the appendix by leukaemia has also been reported. Lymphomas and sarcomas have an incidence of 1.7% and <1% arising within the appendix.3 Hatch et al and Charache reported the largest case series of appendiceal leiomyosarcoma involving five cases.4 5 Due to its rarity, there is a paucity of knowledge on its biological behaviour with most knowledge derived from the behaviour of sarcomas and from the experience of treating leiomyosarcomas of the colon. Gender predilection depends on the primary site of the tumours and there may be a bi-modal age distribution.6 In females, the majority of cases are retroperitoneal or involve the vena cava. In males, there is a mild predominance in non-cutaneous soft tissue sites and cutaneous leiomyosarcoma. Prior to the AIDS epidemic, SMTs including malignant leiomyosarcoma were exceedingly rare in the paediatric population. At present, SMTs are the second most common type of neoplasm arising in children with AIDS. It is an extremely rare tumour in children, with an annual incidence of <2 cases per 10 million children. In patients with AIDS or immunosuppression, EBV can infect smooth-muscle cells and contribute to the pathogenesis of leiomyosarcoma.1 McClain tested the hypothesis by studying tissue specimens of five leiomyosarcomas and two leiomyomas from five children and one young man with AIDS for evidence of HIV and EBV by in situ hybridisation and quantitative PCR.3 All the tumours contained the CD21 EBV receptor. Their results supported the hypothesis that EBV has an etiological role in the soft-tissue tumours that arise in patients with AIDS. EBV may contribute to smooth-muscle tumourigenesis in other immunosuppressed states as well.7 It has also been suggested that EBV infection precedes malignant transformation. In young patients, decreased immune surveillance, increased expression of the EBV receptor and high levels of EBV in plasma may contribute to the pathogenesis of SMTs. Purgina has performed a large analysis on cases of SMT arising in the setting of HIV infection. 2 EBV, a gamma herpes virus, seems to play no role in tumour pathogenesis in HIV-negative individuals. EBV has also been associated with Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin’s lymphoma, gastric carcinoma and the B-cell lymphomas that arise in organ transplant recipients. In addition, kidney, cardiac and liver transplantation are predisposing risk factors.2 Individuals with hereditary retinoblastoma have a cumulative risk of 13.1% for developing soft tissue sarcoma as a secondary malignancy, including leiomyosarcomas, which further supports the relevance of RB1 loss in sporadic cases.8 Uterine leiomyosarcomas are associated with the germline defects in TP53. The presenting symptoms are often non-specific resulting in a diagnostic challenge. Individuals may present with pain, a palpable mass, weight loss, constipation and acute or chronic constipation. Imaging studies for soft-tissue tumours include MRI and CT for retroperitoneal lesions. A CT chest and abdomen is required in the initial work-up because haematogenous spread to the liver and lung are common. Leiomyosarcoma is the the most common sarcoma giving rise to metastasis to the skin, soft-tissues and bone.9 The typical histopathological features include intersecting, sharply marginated fascicles of spindle cells with elongated, blunt ended nuclei. The cytoplasm varies from typically brightly eosinophilic to pale.10 Immunostains are positive for smooth muscle actin, desmin and h-caldesmon in 70% of cases. Over half of uterine leiomyosarcomas express oestrogen and progesterone receptors. Karyotypes are often associated with defects in TP53 or sometimes FANCA and ATM. Regions of chromosomal loss and gain have been reported. Losses in chromosome 10q11 to 21.2 and 13q14.3 to q21.1 and gains at 17p11 to p12 have been described.11 As in other soft-tissue sarcomas, histological grade, tumour size and depth are the major clinicopathological factors that establish the risk profile and are included in the American Joint Committee on Cancer staging system for soft-tissue sarcomas.12 Detection of EBV in tumour cells by in situ hybridisation differentiates the diagnosis of EBV-associated SMT which is a distinct clincopathological entity from conventional leiomyoma or leiomyosarcoma. EBV-SMT should be considered in the differential diagnosis of any SMT occurring in uncommon sites. Diagnosis often remains elusive until definitive surgical resection due to difficulty with smooth muscle identification under light microscopy. The standard surgical procedure is a wide excision with negative margins. Radiotherapy has been shown to improve local control with preservation of function, decreases local recurrence but without improvement in overall survival.13 Therefore, adjunctive radiotherapy is considered to be the standard of care in nearly all intermediate-grade or high-grade leiomyosarcomas of the extremities and trunk. Response rates to anthracycline-based chemotherapy are low (15%–30%) with no significant improvement in overall survival. Pazopanib, an oral kinase inhibitor targeting vascular endothelial growth factor receptor (VEGF-R), platelet derived growth factor receptor (PDGF-R) and tyrosine-protein kinase (c-KIT), showed promising activity in a large multiarm phase II trial.14 Non-compliance and adherence to antiretroviral therapy favours the emergence of malignancies difficult to treat. Learning points. Patients infected with HIV have an increased risk of developing any type of cancer due to immunosuppression and frequent coinfection with oncogenic viruses. Coinfection with EBV, human herpes Virus-8, cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human papilloma virus (HPV) can also occur. Non-compliance and non-adherence to antiretroviral therapy favours the emergence of malignancies difficult to treat. Prompt diagnosis and early initiation of antiretroviral therapy may decrease the incidence of cancer in HIV-infected individuals. The importance of recognising indicator disease for HIV infection to reduce patient morbidity and to reduce onward transmission. Footnotes Contributors: LD: wrote the case report. RDB: pathology slides and report. FM: pathology slides and report. FC: HIV medicine input. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Patient consent for publication: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

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