Case Studies in Medical Pathology

Brain Tumor Diagnosis and Molecular Features

A 40-year-old man presented with headache, nausea and visual complaints. A large enhancing lesion in the right frontal lobe was identified by magnetic resonance imaging (MRI) and the patient underwent debulking surgery. Histopathology and molecular genetic analysis of IDH1 and co-deletion of chromosomes 1p and 19 q status of the resected tissue revealed features consistent with the diagnosis of an oligodendroglioma. The patient was treated with a combination therapy of radiation and chemotherapy for a period of 4-5 weeks.

A female patient was diagnosed with Non-Hodgkins lymphoma at six years of age and at age 13 presented with rectal bleeding.  A colectomy was performed after a mass was identified by a colonoscopy. Her consanguineous parents (2^nd degree cousins) reported a colorectal cancer in a paternal uncle, and he was diagnosed at the age of 43 years with synchronous adenocarcinomas in the sigmoid and descending colon.

Microsatellite Instability (MSI) analysis and immunohistochemical (IHC) analysis of MMR proteins shows high MSI and loss of hMHS6 in non-malignant and malignant cells of the colonic mucosa. Sequence analysis of hMSH6 in the index patient displayed a homozygous single nucleotide deletion in exon 4 (c.691delG) leading to a frameshift and premature termination (p.Val231TyrfsX15).

A 30-year old woman attended for routine cervical screening. Her sample was reported as mild squamous cell dyskaryosis. HPV testing was performed on the sample. As a result of the outcome of the HPV test the woman was referred to colposcopy for further investigation. A large loop excision of the transformation zone was performed due to a suspicious area being identified on the cervix. The tissue was sent to histology for processing and reporting.

A 4-year old child was referred to a Consultant Nephrologist and following testing, the diagnosis was returned as inconclusive. It was thought possible that the child might be suffering either from Autosomal Dominant Polycystic Kidney Disease (ADPKD) or Autosomal Recessive Polycystic Kidney Disease (ARPKD), both of which are ciliopathies.

With reference to Case study 1, using a minimum of 5 references and a 750 maximum word limit for the case study, answer the following questions. (Total 25 marks)

1. In the case study the patient was diagnosed with an oligodendroglioma.

Describe 2 of the additional molecular alterations that frequently occur in this type of tumour. Explain how they are assessed and outline the microscopic (histological) features that are associated with a diagnosis of a grade II oligodendroglioma.        (15 marks)

2. In the case study, the patient was diagnosed with an oligodendroglioma. Would this tumour have mutant IDH1? Describe how the status of IDH1could be determined. How is this relevant to therapy?        (10 marks) 

With reference to Case study 2, using a minimum of 5 references and a 750 maximum word limit for the case study, answer the following questions.               

What tests can be used to confirm protein loss? (4 marks)

1. DNA Mismatch Repair is also compromised in HNPCC.  Explain the cause of HNPCC. (4 marks)

2. What is a homozygous deletion? (4 marks)

3. In what aspect of DNA MMR is hMHS6 involved? (3 marks)

4. What other forms of DNA repair exist? (5 marks)

5. Sequence analysis was used to identify the causative mutation.  Briefly state any indirect approaches to mutation detection. (5 marks)

With Reference to Case study 3, using a minimum of 5 references and a 750 maximum word limit for the case study, answer the following questions.(Total 25 marks)

Explain the adaptive process that takes place in the transformation zone that makes the cells more susceptible to the development of cervical disease.

Fixation is an important step in the preparation of tissues for histological samples. Tissues are then processed through to wax blocks.

1. Describe the steps involved in tissue processing and discuss the role of each  stage and the reagents used.

2. Discuss what forms of quality control would be involved in the laboratory.                    

With Reference to Case study 3, using a minimum of 5 references and a 750 maximum word limit for the case study, answer the following questions.(Total 25 marks)

Discuss the molecular and cellular characteristics that resulted in ARPKD being    classified as a ciliopathy.     

Discuss the personalised medicine approaches that could help ensure an accurate   diagnosis for this patient.