Pathology is the scientific study of disease, while clinical pathology is about integrating the morphologic, biochemical, and molecular analyses with the clinical information provided to achieve a definite diagnosis. Its major subdivisions include histopathology, cytopathology, haematopathology, chemical pathology, and medical microbiology. Other disciplines include medical genetics, immunology, virology, toxicology, and forensic pathology.
Clinical pathology is predominantly a consultant-delivered service and is a hidden speciality which is largely based in the clinical laboratory where pathological specimens are received, examined, and reported. It accounts for ~85% of patient diagnosis. In general, there is limited clinical contact with patients. Therefore, your exposure to clinical pathology depends largely on your medical school curriculum and your placement as pathology services have become increasingly centralized. But above all, pathology exposure depends on your enthusiasm and interest, therefore discuss with your local department to arrange for pathology shadowing if it is not routinely done.
Is a key speciality of clinical pathology that deals with the tissue diagnosis of disease based on biopsy material taken from the patient in the clinic, ward, and theatre or during postmortem examination. It plays a crucial role in patient care especially those with cancer by differentiating between benign and malignant neoplasms and establishing the primary origin of metastatic tumour. It is not only about diagnosis but also includes prevention and reducing the incidence and mortality from cancer through the cancer screening programmes. Some histopathologists also perform autopsies.
Or clinical biochemistry involves the investigation and interpretation of biochemical tests of bodily fluids (e.g. blood, urine, and CSF) to diagnose biochemical disorders, especially metabolic diseases. There is some direct patient contact in the clinic where biochemical investigations are usually requested such as metabolic bone disease and cardiovascular risk prevention clinics. In addition, metabolic diseases will be featured in other clinical rotations including clinical medicine, endocrinology, and paediatrics.
Involves examination of cells. This is subdivided into gynaecological cytology (cervical Pap smears) and diagnostic cytology (e.g. cavity fluid, FNA, CSF, and urine).
Involves the diagnosis of haematological disorders and malignancies derived from myeloid and lymphoid cells usually through a lymph node or bone marrow biopsy and peripheral blood smear. Ancillary techniques such as immunohistochemistry, molecular genetic/FISH, and flow cytometry play significant roles in supporting the diagnosis.
Does not only involve the investigation and diagnosis of infectious diseases, but also controls the spread of infection and provides advice on antimicrobial treatment. You will meet a consultant/registrar microbiologist regularly during some clinical ward rounds (e.g. intensive care).
Involves the investigation of deaths provided by the coroners and police (in England and Wales), where a forensic pathologist performs a detailed postmortem examination of criminal law cases (e.g. homicides, violent, death in custody, or suspicious deaths). You will have limited or no exposure to forensic cases.
Cases to see
You will be exposed to a huge variety of cases from different surgical and medical specialities. The following are some examples and diagnostic features of important surgical specimens. Please refer to individual specialty pages for clinical presentation and management.
Are usually small biopsies taken during endoscopy or colonoscopy. Look for chronic idiopathic inflammatory bowel disease: Crohn’s disease versus ulcerative colitis.
Gallbladder removed for gallstones and/or chronic cholecystitis is the commonest specimen. Histology shows chronic inflammation, Rokitansky–Aschoff sinus formation and fibromuscular hypertrophy.
Liver specimens are largely medical liver biopsies but you will also see liver biopsies for focal liver lesion, metastatic tumour, and cirrhosis (end-stage of chronic liver disease characterized by irreversible fibrosis and diffuse nodules formation). You should be aware of different causes of cirrhosis including alcoholic liver disease, viral hepatitis, PSC, PBC (positive anti-mitochondrial antibody serology), haemochromatosis, α1-antitrypsin deficiency, Wilson disease, and drugs. Complications include liver failure, portal hypertension, and risk for hepatocellular carcinoma.
Steatohepatitis is characterized by fatty changes with ballooning degeneration of hepatocytes and Mallory body formation with variable degrees of fibrosis ± lobular neutrophils. This could be alcoholic (ASH) or non-alcoholic steatohepatitis (NASH) secondary to obesity, DM, hypertension, and hyperlipidaemia. Correlation with clinical biochemistry and microbiology results is essential for infectious (especially viral hepatitis B, C) and autoimmune liver disease. For instance, autoimmune hepatitis will show high titres of anti-ANA, smooth muscle antibodies, and liver kidney microsomal antibodies.
• Include cytology (Pap smear, peritoneal washings) and surgical biopsies or resections.
• Hysterectomy for fibroids (leiomyomas) will be your commonest specimen in the gynaecological cut-up (well-circumscribed benign tumours; white-tan, whorled cut surface; interlaced smooth muscle).
• Different types of benign and malignant ovarian tumour using ovarian tumour FIGO staging. Advanced ovarian cancers have CA125 in the blood.
• Understand the risk factors for cervical intraepithelial neoplasia (CIN) such as early age at first intercourse, multiple sexual partners, and high-risk HPV infection. You will get brownie points by showing knowledge of the NHS cervical screening programme and HPV testing.
• A cervical cytology report will indicate with a result code whether the samples are inadequate (code 1), negative (2), or abnormal: mild dyskaryosis (3), moderate dyskaryosis (7), severe dyskaryosis (4), ?invasive (5), ?Glandular (6), and borderline nuclear changes (8).
Specimens for adult renal neoplasm could be either partial or radical nephrectomies. Renal cell carcinoma represents ~90% of renal neoplasm. Risk factors include family history (association with von Hippel–Lindau disease), smoking, obesity, and long-term renal dialysis. The commonest carcinoma is clear cell carcinoma (70–80%) with macroscopically variegated (yellow/red/white) cut surface. Prognosis depends on Fuhrman nuclear grading and TNM staging which incorporates tumour size, vascular invasion, and extrarenal extension.
Wilms tumour (nephroblastoma) is the commonest (85%) paediatric renal tumour with triphasic components: stromal, epithelial, and blastemal (small blue round cells). The tumour is WT1-positive and associated with genetic defects on chromosome 11.
• Investigations for lymphoma and leukaemia include blood film, FNA, bone marrow trephine biopsy, and core and excisional lymph node biopsies.
• Two groups of lymphomas are recognized, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), which both have different behaviours, prognosis, and treatment. Macroscopically, there is a homogeneous, white, cut surface of the enlarged lymph node.
• HL is characterized by presence of Reed–Sternberg cells which have multiple nuclei with prominent nucleoli and are positive for CD30 and CD15. The commonest subtype (75%) is nodular sclerosis.
• The majority of NHLs are of B-lymphocyte origin in which follicular lymphoma is the commonest type in adults (40%). Neoplastic cells express BCL2, CD10, and CD20. A characteristic translocation is t(14;18). Other important translocations to remember are t(11;14) in mantle zone lymphoma which express cyclin D1, and t(8;14) in Burkitt lymphoma involving the MYC gene on chromosome 8.
• During skin cut-up, you will encounter different biopsy types including punch, curetting, shave, incisional, and excisional ellipse biopsies. Try to see examples of basal cell carcinoma, squamous cell carcinoma, and melanoma which are the commonest malignant skin tumours.
• Grossly, a malignant melanoma can be a nodular or ulcerated pigmented lesion but non-pigmented melanomas also exist. If the morphology is unusual, the diagnosis can be confirmed by S100, HMB45, and Melan-A staining.
• Beware of prognostic factors as well as parameters that should be included in the pathology report. These include melanoma type, growth phase (radial/vertical), Breslow thickness, ulceration, lymphovascular invasion, regression, mitotic rate, and excision margins.
• Also keep up to date with the recent targeted therapy for melanoma. As half of the patients have changes in the BRAF gene, drugs that target this gene (e.g. vemurafenib) can be used for treatment of BRAF mutation-positive melanoma.
• Samples include urine, FNA, CSF, and serous cavities (pleural, peritoneal, and cardiac fluid).
• Pleural fluid from an elderly male with a history of asbestos exposure can confirm malignant mesothelioma which shows cellular sample containing 3D clusters of mesothelial cells with nuclear enlargement and macronucleoli.
• Urothelial carcinoma or carcinoma in situ can be diagnosed from a urine sample but correlation with cystoscopy findings is essential. Urine with BK (polyoma) virus is seen mainly in renal transplant patients.
• Thyroid FNA is useful to differentiate between benign lesions (Thy2), follicular neoplasm (Thy3), or papillary carcinoma (Thy 5). Inadequate sample is classified as Thy1 and suspicious for malignancy sample as Thy4. FNA from papillary thyroid carcinoma are usually highly cellular and composed of papillary groups with irregular nuclear membrane, nuclear overlapping, nuclear grooves and intranuclear inclusions.
• A BAL sample can differentiate between small cell carcinoma and non-small cell carcinoma (SCC or adenocarcinoma). In immunocompromised and HIV patients, a fungal (Grocott) stain of BAL can identify Pneumocystis jirovecii cysts within amorphous proteinaceous casts.
• Synovial fluid samples are useful to identify rhomboid-shaped calcium pyrophosphate crystals in pseudogout or needle-shaped uric acid crystals in gout.
• CSF results should be correlated with clinical and microbiological findings for the diagnosis of bacterial or viral meningitis.
Clinical pathology is largely based on macroscopic and microscopic visual skills, so familiarize yourself with the use of the light microscope. During your rotation in the histopathology department, you are likely to shadow a histopathology registrar. After pathology specimens get booked at the reception you will observe specimen dissection or cut-up, which involves gross examination of organs and tissues taken from patients for diagnosis, during which representative sections (tumour, polyps, resection margins, lymph nodes, etc.) are processed to slides for microscopic examination. Later, you will do examination of tissue sections under the light microscope not only for determining the type of disease, but also for characterizing its severity and extent to ensure that patients receive the appropriate treatment (e.g. determining severity in IBD and degree of hepatic fibrosis in hepatitis C). After finishing your allocated cases, you will have one-to-one teaching with a senior registrar or a consultant to discuss the cases and finalize reporting. A portion of the samples that you will examine are cytology specimens and these include pleural and ascitic fluid, urine, cervical smears, as well as breast, thyroid, salivary gland, and lymph node aspiration cytology. In addition to patient information, the histopathology report will include macroscopic and microscopic descriptions, diagnosis, and comments to clinicians.
Ancillary studies in pathology
In addition to light microscopy for morphological diagnosis, you will notice that pathologists might also use additional diagnostic techniques to assist in reaching a final diagnosis. These include some recent advances in clinical investigative science which you should understand for their clinical application. The technical aspect is generally performed by biomedical scientists and interpreted by pathologists. In addition to shadowing pathologists, try to spend some time in the pathology lab with biomedical scientists to understand the principles and clinical applications of ancillary studies, including the following:
Are very useful in liver and renal medical biopsies (e.g. reticulin, silver stain) and detection of microorganisms (e.g. periodic acid–Schiff for fungi, Gram for bacteria).
Involves the use of labelled antibodies which stain specific proteins in tissue sections (see Table 28.1). Immunohistochemistry helps to identify tumour type including the origin of metastasis (e.g. melan A in metastatic melanoma, CD45 in lymphoma, and cytokeratin in carcinoma), to determine prognosis and treatment (e.g. oestrogen receptor in breast cancer), identifications of organisms (e.g. HSV, CMV, Pneumocystis), and lymphoma subtypes (e.g. cyclin D1 and CD5 in mantle cell lymphoma).
Is used for evaluation of some inflammatory skin diseases (e.g. bullous pemphigoid and dermatitis herpetiformis) and renal biopsies for glomerular disease (e.g. lupus nephritis and IgA nephropathy) by detection of antibodies or immune complexes.
Is used for cell counting and sorting cell types in a suspension. It plays a crucial role in lymphoma and leukaemia subclassifications.
Will be available in large university hospitals. Electron microscopy is mainly used in evaluation of glomerular disease in renal biopsies.
Identifies cytogenetics for undifferentiated tumours or difficult cases, predominantly chromosomal translocations associated with sarcomas, leukaemias, and lymphomas (e.g. t(9;22) in chronic myeloid leukaemia, t(X,18)in synovial sarcoma). It is also important to test for clonality in lymphomas. FISH is used for detection of HER-2 in breast cancer. PCR plays an increasingly revolutionary role in clinical pathology, especially the diagnosis of infectious disease (viruses and Pneumocystis).
As clinical pathology highlights the diagnostic and prognostic aspects of diseases, pathology questions can be integrated within exams of other specialities, where you might be asked about laboratory investigations, serology, and pathological features. Most pathology exams are based on topics covered during clinical pathology tutorials and lectures as well as during your departmental rotation. There will be no real patients and the examiners should be consultants from different pathology disciplines. Exam questions could include MCQs, an essay, photos, and viva which are mainly problem-solving oriented. As pathological specialties are mainly visual, you should practise during your rotation to describe the gross and microscopic appearance of different specimens you see in the pathology laboratory. For instance, describing a caecal adenocarcinoma in a right hemicolectomy specimen and understanding the prognostic factors that affect patient management; these include lymph node metastasis, extramural lymphovascular invasion, and completeness of excision. Knowing the principles of tumour staging, different tumour markers, and advances in diagnostic techniques are important components of the viva.
You should also enhance your virtual skills by reviewing pathology websites. For example, http://library.med.utah.edu/WebPath provides excellent collections of microscopic and macroscopic pathology images, exam questions, and tutorials. Recently, the Royal College of Pathologists established a new eLearning project of pathology specimen podcasts ( e-pathpots.org.uk) which includes a wide range of gross appearances of diseases to support teaching medical students using virtual pots. Many thanks to the Leeds Virtual Pathology website ( http://virtualpathology.leeds.ac.uk) which provides a rich collection of virtual slides. These are high-resolution digital scans that can be viewed and navigated online using a computer-based program.