Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa.

AIMS: Colorectal carcinoma (CRC) is a common cause of morbidity and mortality worldwide, and an emerging public health problem in sub-Saharan Africa. Several authors have described an increased frequency of mismatch repair-deficient (dMMR) CRC in sub-Saharan Africa, but these tumours remain poorly characterised molecularly. We sought to interrogate the somatic molecular genetic landscape of dMMR CRC in a cohort of young patients to better inform Lynch syndrome (LS) screening strategies and personalised medicine approaches in our setting. METHODS: 32 patients (aged <60 years) were identified with dMMR CRC. DNA was extracted from selected formalin-fixed paraffin-embedded (FFPE) tissue resection samples and subjected to amplicon-based next-generation sequencing (NGS). RESULTS: Pathogenic or likely pathogenic variants were detected in the corresponding MMR gene in 14 of 18 (78%) MLH1/PMS2-deficient tumours, 5 of 8 (63%) MSH2/MSH6-deficient tumours, 1 of 4 (25%) tumours with isolated MSH6 loss and 0 of 2 tumours with isolated PMS2 loss. Previously unreported variants were identified in MLH1 (three) and MSH2 (one). Cases with a variant allele frequency suggesting a germline mutation were identified in MLH1 (eight), MSH2 (two) and MSH6 (one). Only one MMR gene variant was detected in more than one patient (MLH1 p.Q510*). Four POLE/POLD1 exonuclease domain variants were identified, one of which was previously unreported. CONCLUSION: The spectrum of disease-causing MMR gene variants in our population necessitates NGS testing for LS screening. This study also highlights the role of somatic testing on readily available FFPE samples to generate data on the epidemiology of CRC in different settings.

Genomic landscape of colorectal carcinoma in sub-Saharan Africa.

Our understanding of the molecular classification of colorectal carcinoma (CRC) has evolved significantly over the past two decades. Tumours can be broadly categorised as microsatellite stable (MSS), microsatellite instability (MSI) or CpG island-methylator phenotype. Prognostic and predictive information is provided by these categories. The overwhelming majority of the data on which these categories are based have originated from Europe and North America. There is a dearth of information represented from Africa and indigenous African patients. However, some small studies and preliminary data have shown significant differences in all of these groups. The prevalence of MSI in Africa is consistently reported as almost double that of European and North American data. Interestingly, BRAF V600E mutations and MLH1 promotor hypermethylation seem to be uncommon in Africa. The high proportion of MSI tumours is only partly accounted for by germline mutations in mismatch repair genes (Lynch syndrome), suggesting that there are likely to be other mechanisms at play. Within the MSS group, preliminary data suggest that the typical molecular pathways (Wingless/Integrated pathway activation) may not be as dominant in Africa. The purpose of this review is to summarise the current state of the molecular genetic landscape of CRC in Africa and provide insights into areas for further study.

TFE3-rearranged renal cell carcinoma with osseous metaplasia and indolent behaviour.

TFE3-rearranged renal cell carcinoma (RCC) is a rare but well characterised histological subtype of RCC with an aggressive clinical course and propensity for late metastases. Osseous metaplasia is an uncommon but well documented finding in clear cell, papillary and chromophobe RCC. We present the first case of a TFE3-rearranged RCC to be found harbouring metaplastic bone in a 47-year-old woman who presented with a slowly enlarging left flank mass over a 10 year period. This case report adds to the clinicopathological description of TFE3-rearranged RCC and suggests that larger studies are required to fully elucidate the prognosis of these tumours.

Metastatic prostate carcinoma presenting as a gluteal soft tissue mass.

Metastatic lesions from prostate adenocarcinoma to the bone and lymph nodes and less frequently to the lungs, pleura, liver and adrenal glands are well documented. The presence of soft tissue metastases from a prostate adenocarcinoma is extremely rare. We report a case of a 56-year-old male who presented with a 2-year history of a painless buttock mass. MRI showed a well-defined, right gluteal intermuscular soft tissue mass and multifocal hypointense lesions of the pelvic bones and appendicular skeleton suggestive of secondary metastatic disease. Tru-cut biopsy of the gluteal mass demonstrated metastatic adenocarcinoma. Further workup showed an elevated prostate-specific antigen, and acinar adenocarcinoma of the prostate was confirmed on transrectal biopsy of the prostate. Androgen deprivation therapy with long-acting three monthly goserelin and short-term cover with bicalutamide was initiated as was systemic taxane-based chemotherapy. He has shown an excellent PSA response and remains asymptomatic with complete resolution of the size of the gluteal metastasis at the most recent follow-up 9 months later.

Wilms' tumour with spinal cord involvement.

Spinal cord involvement of Wilms' tumour is rare. A 14-year-old girl presented with an abdominal mass, paraplegia and loss of bladder and bowel control. Radiological investigations confirmed the presence of a large intraabdominal mass with infiltration into the spinal canal with impingement of nerve roots and the spinal cord. Histopathological evaluation demonstrated a nephroblastoma. It was decided to commence prompt neoadjuvant chemotherapy to render the tumour amenable to surgical resection. The patient unfortunately demised before receiving her first dose. Early diagnosis and timeous initiation of treatment is critical in limiting morbidity and mortality associated with malignant spinal cord compression.

Pulmonary lymphangioleiomyomatosis with an associated giant renal angiomyolipoma.

Pulmonary lymphangioleiomyomatosis (LAM), a rare, progressive disease predominantly affecting the lungs of women of reproductive age, is often associated with renal angiomyolipoma (AML). We report the case of a 29-year-old female patient who presented to our obstetrics department at 37 weeks' gestation, complaining of abdominal pain, and constipation. Ultrasound noted a viable singleton with a large left-sided abdominal mass. After undergoing a caesarean section, she was referred to our urology department to assess her flank mass further. Computed tomography demonstrated a large, exophytic left renal mass measuring 22 cm x 16 cm x 13 cm, suggestive of an AML and numerous bilateral pulmonary cysts. A diagnosis of LAM and associated unilateral giant renal AML was made. As soon as she had fully recovered from her caesarean section, we removed the huge AML via a standard left-sided open nephrectomy without incident. We report this rare case of giant AML associated with LAM and review the literature about the association of these two conditions.

Eosinophilic Solid and Cystic Renal Cell Carcinoma With Melanin Pigment-Expanding the Morphological Spectrum.

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is an emerging entity in renal neoplasia with distinctive histopathological findings and a generally favorable prognosis. The presence of melanin pigment in a renal tumor typically prompts the observer to consider the microphthalmia-associated transcription family translocation renal cell carcinomas. We present a renal tumor occurring in a 19-year-old male patient which had the typical morphology of ESC-RCC but showed the additional finding of focal melanin pigment. This tumor showed strong and diffuse positive immunolabeling with paired box gene 8 and cytokeratin 20, and was negative with epithelial membrane antigen, carbonic anhydrase 9, CD117, cytokeratin 7, and transcription factor E3. Human melanoma black-45 showed focal positivity, but Melan-A was negative. Next-generation sequencing revealed a mutation in the TSC2 gene (c.4490C > G, p.[Pro1497Arg] and c.1257 + 1del) and break apart fluorescence in-situ hybridization with TFE3 and TFEB probes was negative. In this case report, we present the novel finding of melanin pigment occurring in a genetically proven and otherwise typical ESC-RCC, and briefly discuss the differential diagnostic considerations.

Gene of the month: H3F3A and H3F3B.

H3F3A and H3F3B genes are located at 1q42.12 and 17q25.1, respectively, and encode identical H3.3 core histone proteins which form part of the histone hetero-octamer complex. Histones function by packaging DNA into small units, the nucleosome, and are highly susceptible to epigenetic post-translational modification. H3 K27 mutations have been shown to inhibit the polycomb repressive complex 2, which is normally involved in epigenetic gene silencing. Mutations in H3F3A and H3F3B are increasingly recognised in a variety of solid tumours. Point mutations in H3F3A have been described in giant cell tumour of bone and paediatric-type diffuse high-grade gliomas. Mutations in H3F3B have been described in chondroblastoma. Loss of trimethylation of H3 K27 is characteristic of most sporadic and radiation-associated malignant peripheral nerve sheath tumours. Immunohistochemistry with a variety of novel antibodies directed against specific mutations, as well as loss of H3K27me3 staining, may be useful in specific settings and in diagnostically challenging cases.

Carbonic anhydrase IX: a regulator of pH and participant in carcinogenesis.

Carbonic anhydrase IX (CAIX) is a transmembrane metalloenzyme which is upregulated in tumour cells under hypoxic conditions. CAIX expression is induced by the accumulation of hypoxia-inducible factor-1α and has several downstream effects, including acidification of the extracellular pH, loss of cellular adhesion and increased tumour cell migration. CAIX is upregulated in a variety of solid organ tumours and has prognostic implications. High CAIX protein expression is a marker of poor prognosis in breast, lung, ovarian and bladder carcinomas. Conversely, low expression is an indicator of poor prognosis in clear cell renal cell carcinoma (CCRCC). CAIX immunohistochemistry is useful diagnostically to identify metastatic CCRCC, and the recently recognised clear cell papillary renal cell carcinoma. There is much interest in targeting CAIX with monoclonal antibodies and small molecule inhibitors. There are several small molecule inhibitors under development which have shown promising results in clinical trials. In this paper, we provide an overview of the role of CAIX in tumourigenesis and outline its use as a prognostic, diagnostic and therapeutic biomarker.

Fibrolamellar Carcinoma With Predominantly Pseudoglandular Architecture: A Potential Diagnostic Pitfall.

Biopsies of liver mass lesions are encountered frequently in general surgical pathology practice. The clinical differential diagnosis is typically hepatocellular carcinoma (HCC) versus metastatic adenocarcinoma. There are a variety of HCC variants that show a range of morphological appearances. The presence of malignant glands in the liver prompts the pathologist to consider adenocarcinoma, either metastatic or primary intrahepatic cholangiocarcinoma. It is important to remember that some variant patterns of HCC can show pseudoglandular growth. In this article, we present a case of fibrolamellar carcinoma that showed predominantly pseudoglandular growth to highlight the importance of a systematic approach and the routine use of a panel of immunohistochemical stains (HepPar1, CK7, and CD68).

Papillary thyroid carcinoma presenting as miliary nodules on chest roentgenogram in the paediatric setting: A case report.

INTRODUCTION: Papillary thyroid carcinoma (PTC) is the most common carcinoma to occur in childhood with a peak incidence between 11-17 years, and typically presents with advanced locoregional disease. Pulmonary metastases are seen in up to 46% of cases and should enter the differential diagnosis of miliary nodules seen on chest roentgenogram, even in regions where tuberculosis is endemic. PRESENTATION OF CASE: An 11-year-old male presented with a short history of cough, shortness of breath and constitutional symptoms. Examination revealed cervical lymphadenopathy and diffuse bilateral nodular infiltrates on the chest roentgenogram. Investigation for Mycobacterium tuberculosis was negative and this initiated biopsy of a cervical lymph node. Histopathological examination revealed metastatic PTC. Ultrasonography and magnetic resonance imaging (MRI) were performed for preoperative staging. The patient subsequently underwent total thyroidectomy with selective neck dissection. DISCUSSION: There are several potential causes when dealing with miliary nodules on chest roentgenogram. Thorough interrogation of the clinical, radiological, pathological and microbiological data is required to arrive at the correct diagnosis. Postoperative adjuvant therapy with radioactive iodine is recommended in children with metastatic disease, but this should be restricted preferably to a single dose to avoid the complication of pulmonary fibrosis. CONCLUSION: This case highlights the differential diagnostic considerations of a patient presenting with constitutional symptoms and a miliary pattern on chest roentgenogram. Carcinomas are uncommon in children but should not be forgotten.

Gene of the month: BCOR.

BCL-6 transcriptional corepressor (BCOR) gene is located at Xp11.4 and encodes a protein which is involved in transcriptional repression in association with BCL-6 and epigenetic silencing through polycomb repressive complex 1 (PRC1). BCOR mutations are being identified in an increasing number of tumours which are diverse in their anatomical location and clinical setting. Interestingly, these tumours share similar and overlapping histological features, namely small round blue cell morphology and a myxoid background with delicate capillary channels. Clear cell sarcoma of the kidney, primitive myxoid mesenchymal tumour of infancy and central nervous system high-grade neuroepithelial tumour with BCOR alteration all share similar internal tandem duplications in the polycomb-group really interesting new gene (RING) finger homolog ubiquitin-likefold discriminator domain of BCOR Translocations resulting in BCOR fusion with CCNB3, MAML3 and ZC3H7B have been identified in undifferentiated round cell sarcoma. Subsets of high-grade endometrial stromal sarcoma and ossifying fibromyxoid tumour which have a more aggressive clinical course have been shown to harbour ZC3H7B-BCOR fusions. BCOR immunohistochemistry is an established marker with diagnostic utility.

Blastic Plasmacytoid Dendritic Cell Neoplasm: An Uncommon Entity to Consider in the Differential Diagnosis of Cutaneous Lymphoma.

Cutaneous lymphomas are encountered infrequently in general surgical pathology practice, and the broad array of pathological entities poses a diagnostic challenge. Integration of clinical information, results of additional laboratory investigations, and an extensive immunohistochemical panel are essential in arriving at the correct diagnosis. We present a case of blastic plasmacytoid dendritic cell neoplasm that occurred in an unusual clinical setting. This case highlights the need for a broad differential diagnosis and an extensive immunohistochemical workup when approaching a cutaneous lymphoma.

Clear Cell Sarcoma of the Kidney.

Clear cell sarcoma of the kidney is an uncommon malignant pediatric renal neoplasm that typically presents in the 2- to 3-year age group and has a propensity for aggressive behavior and late relapses. Histologically, this tumor exhibits a great diversity of morphologic patterns that can mimic most other pediatric renal neoplasms, often leading to confusion and misdiagnosis. Until recently, adjunct immunohistochemical and molecular genetic tests to support the diagnosis were lacking. The presence of internal tandem duplications in BCL-6 coreceptor (BCOR) and a translocation t(10;17) creating the fusion gene YWHAE-NUTM2B/E have now been well accepted. Immunohistochemistry for BCOR has also been shown to be a sensitive and specific marker for clear cell sarcoma of the kidney in the context of pediatric renal tumors. Improved intensive chemotherapy regimens have influenced the clinical course of the disease, with late relapses now being less frequent and the brain having overtaken bone as the most common site of relapse.

Gene of the month: SDH.

Succinate dehydrogenase (SDH) is a heterotetrameric nuclear encoded mitochondrial protein complex which plays a role in the citric acid cycle and the electron transfer chain. Germline mutations in SDHA are associated with Leigh syndrome. Mutations in SDHB, SDHC and SDHD are found in an increasing number of neoplasms, most notably paragangliomas and wild-type gastrointestinal stromal tumours. SDH deficiency in these tumours has important prognostic implications, and also provides a novel target for molecular therapy. In this article, we outline the structure and function of SDH and provide a summary of its role in various diseases.