Immunohistochemical determination of mismatch repair gene product in colorectal carcinomas in a young indigenous African cohort.

BACKGROUND: Colorectal cancer (CRC) in the indigenous African population of South Africa is uncommon (age standardised incidence rates of 11.29 for males and 7.27/100 000 for females) and tends to occur at a young age. Lynch syndrome (LS), an inherited mismatch repair (MMR) gene abnormality, accounts for 3-4% of newly diagnosed CRCs in high incidence areas. There is some evidence that the contribution of an MMR abnormality to the overall CRC burden may be increased in low incidence areas. We aimed to determine the prevalence of MMR deficiency in an indigenous African population. METHODS: A cohort of 66 self-declared indigenous African patients, less than 50 years of age at diagnosis with CRC was identified from clinical and pathological records. The original histopathology was reviewed to confirm the diagnosis and features suggestive of MMR abnormality determined (pushing edge, mucinous, lymphocytic infiltration, Crohn's like reaction). Where sufficient tissue was available, samples were sectioned and stained for the four MMR proteins. RESULTS: Histopathological examination confirmed adenocarcinoma in 31 individuals. At least one feature suggestive of MMR was identified in 22 of these specimens. Twenty-seven cases were stained for all four MMR proteins using standard immunohistochemistry (IHC). MMR deficiency was found in 37% (n = 10/27) of cases. Median age of diagnosis was 35 years in the MMR-proficient group and 44 years in the MMR-deficient group, p < 0.008. No other significant differences between the groups were noted. CONCLUSION: MMR deficiency was common in colorectal carcinomas in the older patients in this cohort, but very young indigenous Africans CRCs do not appear to result from mismatch repair gene mutations.

A natural history of efavirenz drug-induced liver injury.

BACKGROUND: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, has been a component of first-line antiretroviral therapy (ART) in the South African HIV/AIDS programme since 2004. It is extensively used in ART programmes in other low- and middle-income countries. The natural history of the previously recognised EFV drug-induced liver injury (DILI) is not known. OBJECTIVES: To define and establish a causality assessment for EFV DILI and document its natural history by detailing a patient cohort. All relevant features characterising the patterns of clinical and histological injury, the duration of clinical and biochemical recovery and the associated mortality rate were documented. Factors associated with specific histological patterns of liver injury were analysed. METHODS: Patients were prospectively included after meeting causality and inclusion criteria for EFV DILI. Clinical, demographic and liver histological features (where possible) were documented from the time of presentation and throughout follow-up. Prednisone at 0.25 - 0.5 mg/kg was initiated at the discretion of the treating hepatologist. RESULTS: Fifty patients were prospectively included in the analysis. The median age was 34 (interquartile range (IQR) 29 - 39) years, males being older than females (p=0.014). Most (92%) were female, and 86% were of black African ethnicity. The median duration of ART at presentation was 6 months, with half of the women having initiated ART during pregnancy, at a median gestation of 24 (IQR 11 - 36) weeks. The median CD4 nadir at ART treatment initiation was 517 cells/µL, with no significant difference in CD4 nadir between those who were pregnant and those who were not (p=0.6). The median RUCAM (Roussel Uclaf Causality Assessment Method) score was 7, and among the 75% of patients who had liver biopsies, three histological patterns were identified: submassive necrosis (60%), nonspecific hepatitis (35%), and mixed cholestatic hepatitis (5%). On multivariate analysis, predictors for the development of submassive necrosis included younger age (<30 years; p=0.045), ART initiation in pregnancy (p=0.02), and a baseline CD4 count >350 cells/µL (p=0.018). For the nonspecific hepatitis group, pregnancy was also an associated factor (p=0.04). The mortality rate was 14%, with a median time from admission to death of 15 days. The median (IQR) time to initial hospital discharge was a lengthy 33 (24 - 52) days. Biochemical recovery was prolonged, necessitating a follow-up period of more than a year at an outpatient specialist clinic, with 86% of patients initiating a protease inhibitor-based ART regimen successfully. CONCLUSIONS: EFV DILI is a severe drug complication of ART with appreciable mortality and significant inpatient morbidity, requiring prolonged hospitalisation and follow-up.

Neuroendocrine neoplasms of the digestive tract: incorporating the 2019 WHO grading schema in the South African context.

BACKGROUND: The classification of gastrointestinal (GI) neuroendocrine neoplasms (NENs) has been updated in the WHO classification of tumours of the digestive tract. Mitotic rate and Ki-67 proliferation index are central to the histopathological grading of these tumours. Assessing these variables is not standardised in local practice. This study addresses this deficit in the South African context. METHODS: This is a retrospective audit of archival material of resection specimens of GI NENs (excluding appendix) at Groote Schuur Hospital from 2004 to 2017. We performed a mitotic count and immunohistochemistry for Ki-67 to reclassify tumours according to the 2019 WHO criteria. RESULTS: Thirty-five resection specimens were examined. These represented stomach (n = 5), jejunoileum (n = 17), colon (n = 7) and rectum (n = 6). The mean age at the time of resection was 56 years (range 32-72). Twenty-one cases (60%) were women and 14 (40%) were men. The majority (24/35) of tumours were classified as grade 1 well-differentiated neuroendocrine tumours (WD NETs), 8/35 were classified as grade 2 WD NETs and 3/35 were classified as small cell poorly differentiated neuroendocrine carcinomas (PD NECs). Re-classification resulted in 7/35 (20%) changes in tumour grade (4 upgraded, 3 downgraded). In most instances (7/8), the Ki-67 proliferation index was the determining factor in assigning tumour grade. CONCLUSION: This study has increased awareness of the recently updated WHO classification system. We conclude that an objective and systematic approach to counting of mitoses and determination of the Ki-67 proliferation index is recommended in routine practice.

Primary seromucinous cystadenocarcinoma of the mesentery.

A 72-year-old woman presented with a slow growing mass on the left side of the abdomen, which was found to originate from the mesentery of the descending colon. Histopathology revealed a seromucinous cystadenocarcinoma of the mesentery, a rare clinical entity occurring most often in females. There are only 20 cases reported in the literature. It is postulated that these tumours develop as a result of serous or mucinous metaplasia of pre-existing coelomic mesothelium. Surgical excision remains the mainstay of successful management.

A morphological and immunohistochemical evaluation of gastric carcinoma in the Western Cape province of South Africa.

BACKGROUND: Gastric resections for carcinoma are common, but gastric carcinoma in South Africa, and particularly within the Western Cape province, has not been well documented. METHOD: The objective of the study was to immunohistochemically evaluate HER2/ neu overexpression, determine aberrations in ß-catenin and epithelial-cadherin (E-cadherin) expression, and correlate these fi ndings with gastric carcinoma subtypes. RESULTS: Ninety-seven gastric adenocarcinoma resections were morphologically categorised as intestinal-, diffuse- or mixed-type adenocarcinomas, and immunohistochemically stained for ß-catenin, E-cadherin (extracellular and cytoplasmic domains) and HER2/neu. The results of staining were compared between the subtypes for statistically signifi cant differences. All 97 cases were confi rmed as gastric adenocarcinomas, with 39 (40%) intestinal- type, 51 (53%) diffuse-type, and 7 (7%) mixed-type tumours identifi ed. Patient ages ranged from 18-84 years. HER2/neu was overexpressed in 12 (12%) cases, with intestinal-type morphology (p = 0.017) reported in nine. Fourteen cases (14%) demonstrated abnormal ß-catenin localisation. Aberrant E-cadherin (extracellular domain) localisation occurred in 36 (37%) cases. Diffuse-type morphology was associated with a signifi cantly high proportion (p = ≤ 0.001). Aberrant E-cadherin (cytoplasmic domain) localisation occurred in 7 (7%) cases. A signifi cantly high proportion (six of these cases) (p = 0.023) of these was diffuse-type morphology. Eleven (11%) adenocarcinomas occurred in patients aged ≤ 40 years, with intestinal morphology reported in nine of these 11. Aberrant E-cadherin (extracellular domain) localisation was noted in seven of the 11, a signifi cantly high proportion when compared to that in the older patients (p = 0.025). CONCLUSION: Distinct immunomorphological correlations are apparent in tumours demonstrating HER2/neu overexpression or abnormal E-cadherin localisation. Intestinal morphology, poor differentiation and E-cadherin abnormalities are frequently demonstrated in tumours occurring in younger individuals.

Liver resection for non-cirrhotic hepatocellular carcinoma in South African patients.

BACKGROUND: We describe the clinicopathologic features and outcome of South African patients who have undergone hepatic resection for hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. METHODS: We utilised the prospective liver resection database in the Surgical Gastroenterology Unit at Groote Schuur Hospital, Cape Town, to identify all patients who underwent surgery for HCC with non-cirrhotic liver parenchyma between 1990 and 2008. RESULTS: Twenty-two patients (10 men, 12 women, 3 black, 19 white, median age 47 years, range 21-79 years) underwent surgery for non-cirrhotic HCC. Sixteen patients had non-fibrolamellar HCC (Group 1); 6 patients had fibrolamellar HCC (Group 2). Group 1 had a median age of 55 years, and 6 (38%) were men; group 2 had a median age of 21 years, and 5 (83%) were men. Most patients had a solitary tumour at diagnosis; median largest tumour diameters in Groups 1 and 2 were 10 cm (range 4-21) and 12 cm (range 4-17), respectively. Patients in Group 1 underwent extended right hepatectomy (N=3), right hepatectomy (N=3), left hepatectomy (N=3), partial hepatectomy (N=7), cholecystectomy (N=6), and appendicectomy (N=1). Patients in Group 2 underwent extended right hepatectomy (N=1), right hepatectomy (N=1), left hepatectomy (N=2), segmentectomy (N=2), and portal lymphadenectomy (N=3). Recurrence rates in Groups 1, 2, and overall were 81%, 100% and 86%, respectively. Median overall survival was 46 months, with 1-, 3-, and 5-year survival rates of 95%, 59% and 45%, respectively. In Group 1, median survival was 39 months, with 1-, 3-, and 5-year survival rates of 100%, 56% and 38% respectively. In Group 2, median survival was 61 months, with 1-, 3-, and 5-year survival rates of 83%, 67% and 67%, respectively. CONCLUSION: Despite aggressive surgical resection, HCC arising in normal liver parenchyma has a high recurrence rate and an ultimately poor outcome. This finding is similar to both the recent international experience of non-cirrhotic HCC and local experience of fibrolamellar HCC.

Oesophageal ulceration in HIV-infected patients.

OBJECTIVE: To determine the aetiology of oesophageal ulceration in HIV-infected patients. DESIGN: A retrospective clinical, endoscopic and histopathological analysis of patients with confirmed HIV infection and an oesophageal ulcer diagnosed on endoscopy. SETTING: A tertiary referral, gastrointestinal clinic in Cape Town. RESULTS: Fifty-one patients with HIV infection and oesophageal ulceration were seen from January 2001 to December 2007. Median CD4 count was 26 cells/microl. Mean age was 35.5 years. Sixty per cent of patients were female. Forty-nine per cent of oesophageal ulcers were idiopathic while 23% were caused by cytomegalovirus infection. The remainder were due to miscellaneous causes. CONCLUSION: A surprisingly small number of patients with HIV-associated oesophageal ulceration were seen during the study period. This may reflect local referral practices or the fact that patients with severe immunosuppression succumb before developing oesophageal ulcers. As in other series, idiopathic oesophageal ulcers and cytomegalovirus ulcers made up the majority of cases. Correct biopsy technique and appropriate histological and microbiological investigations are associated with improved diagnostic yield in these patients.

Ciliated hepatic foregut cyst: a rare cystic liver lesion.

Ciliated hepatic foregut cysts are an unusual congenital cause of cystic liver lesions. Although most are benign, 4.4% of reported cases have been shown to harbor squamous cell carcinoma. Diagnostic uncertainty or misdiagnosis frequently results in surgical exploration. We present a case of a ciliated hepatic foregut cyst and review this uncommon condition.