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An Overview of Histopathology

Also Known as a Biopsy or Pathology Report

What Is Histopathology?

  • How It's Performed
  • Report Components
  • Interpretation

Other Sampling Techniques

Histopathology involves using a microscope to look at human tissue to check for signs of disease. The term is derived from "histology" (meaning the study of tissues), and "pathology" (meaning the study of disease).

A histopathology report describes the findings of a specialist known as a medical pathologist . Examples include the accumulation of white blood cells seen with infections, crystallized deposits that occur with gout , granular lumps characteristic of tuberculosis or sarcoidosis , or abnormal cell formations seen with cancer .

This article explains the purpose of histopathology, what's in a histopathology report, and reasons why a histopathology test may be done. It also details how pathology results are interpreted.

In clinical practice, histopathology refers to the examination of tissues obtained by biopsy or the surgical removal of an organ. It is a form of anatomical pathology that looks specifically at tissues and organs as opposed to clinical pathology which looks at bodily fluids.

Histopathology is performed by a lab-based pathologist who, with the assistance of a medical technologist , prepares the tissues by sectioning them and placing them on a glass slide. The sample can then be exposed to dyes and other techniques to highlight, segregate, or remove cells so they are better viewed under the microscope.

Histopathology is not the same thing as cytopathology which looks at individual cells. With histopathology, the pathologist not only evaluates cell structure but also how cells are grouped.

Why Is Histopathology Important?

Without histopathology, it would be difficult, if not impossible, to diagnose many diseases. It is essential to the diagnosis of many conditions, chief of which includes cancer .

Along with a biopsy (the extraction of tissues for lab evaluation), histopathology remains the gold standard for diagnosing many solid-tumor cancers. Histopathology can differentiate benign tumors from cancerous ones and is also central to cancer staging (determining how advanced a cancer is) and cancer grading (determining how aggressive a cancer is).

Other diseases for which histopathology is central to the diagnosis include:

  • Infectious diseases like disseminated tuberculosis , tropical parasitic infections , H. pylori , and necrotizing fasciitis
  • Inflammatory diseases like sarcoidosis , Crohn's disease , ulcerative colitis , and vasculitis
  • Autoimmune diseases like celiac disease , psoriasis , scleroderma , autoimmune hepatitis , and lupus nephritis
  • Organ-specific diseases like endometriosis , uterine fibroids , and peptic ulcers

Histopathology is also important for the management of diseases. It can help monitor for organ rejection after transplant surgery or check for the response to treatment of inflammatory bowel disease (IBD) .

Histopathology also contributes to advances in our understanding of diseases, leading to the development of new treatments. It can also look for new genetic or immunological biomarkers for diseases so that they can diagnosed earlier when they are most treatable.

How Is Histopathology Performed?

Histopathology is performed by pathologists who process and cut tissue into very thin layers, called sections. Then, they stain and examine it with a microscope. Using a microscope, they can observe and document the tissue's details.

Histopathology relies on samples of tissue obtained through procedures such as endoscopy , colonoscopy , and colposcopy , or by doing surgical procedures such as a breast biopsy .

Click Play to Learn All About Histopathology

This video has been medically reviewed by Anju Goel, MD, MPH .

Frozen Section

For some diseases, a sample of the tissue can be interpreted very quickly using frozen sections (also called a cryosection) that are obtained during surgery. Frozen sections are examined immediately in the lab to provide a result within about 20 minutes.

This type of pathology is most commonly used to evaluate tumor margins during surgery so that a surgeon can decide if more tissue should be removed for the full removal of cancer. The use of frozen sections during surgery depends on the type of cancer being removed and other factors.

Lymph and Blood Cancers

Lymph nodes are often biopsied to evaluate for certain types of blood cancer and to identify metastases of solid tumors (such as breast cancer and lung cancer). A bone marrow biopsy may also be required for a definitive diagnosis of many types of blood cancers.​

Components of a Histopathology Report

Histopathology reports on surgical cancer specimens can be complex. They may include:

  • A description of the appearance of the involved tissue
  • A diagnosis
  • A synoptic report detailing the findings of the case
  • Pathologist's comments

Histopathology reports can be challenging to understand, so it's essential to go over them with a healthcare provider. Knowing which components are going to be included in your report may help you prepare for your appointment.

Interpreting the Results

Many of the pathologist's findings are used to help determine prognosis , especially in cases of cancer. Prognosis is the prediction or estimate of survival or recovery from a disease.

Prognostic indicators may include:

  • Size and severity of the disease
  • Tumor grade
  • Indications that cancer has spread and the extent of spread

Grading systems differ depending on the kind of cancer. In general, the cells are scored based on how abnormal they appear under the microscope. The more abnormal the cells look, the higher the grade.

For example, Grade 1 tumors appear nearly normal, whereas Grade 4 tumors reflect more abnormalities.

In addition to histopathology, pathologists may use other techniques to assess the presence of cancer in the tissues.

Molecular Techniques

Molecular techniques refer to the ability to analyze cells and tissues at the molecular level, which is at the level of proteins, receptors, and genes.

Pathologists diagnose cancer, such as leukemia , through a combination of techniques, including:

  • Cytochemistry : How the sampled cells take up certain stains
  • Immunophenotype : Looks for unique surface proteins
  • Karyotype : Chromosomal changes
  • Morphology : How the cells look

Immunohistochemistry

Often in lymphomas and other cancers, pathologists use immunohistochemistry to help assess the tumor type, prognosis, and treatment.

Immunohistochemistry involves using antibodies to stick to particular tags or markers outside the cancer cells. These markers that the antibodies attach to often have "CD" in their name, which stands for "cluster of differentiation." CDs identify cell phenotypes, which identify different cancers.

For example, if CD23 and CD5 are present in the cancer cells, it might support the notion that chronic lymphocytic leukemia (CLL) is a possible diagnosis.

However, these same markers are also present in other malignancies. So pathologists use this method in combination with other identifying features.

Chromosomal Studies

Pathologists may perform molecular and chromosomal studies to look at gene rearrangements and specific changes to the chromosomes. Sometimes inserted or deleted genes correlate to prognosis. Genetic changes present in a cancer tissue sample may be hereditary or acquired.

For instance, in CLL, a specific piece of a chromosome (17p) is lost. Along with the missing chromosome, a gene that helps suppress cancer is often lost.

The 17p deletion is found in about 5% to 10% of people with CLL overall. The 17p deletion CLL is a form of CLL that is harder to treat with conventional chemotherapy.

Putting It Together

Pathologists may use additional pathology techniques to diagnose cancer. For example, molecular techniques look at proteins, receptors, and genes, which help identify cancer subtypes. Immunohistochemistry looks for markers on cancer cells to narrow down what type of cancer a person has and chromosomal studies look at gene differences to develop a prognosis.

Histopathology is the study of tissue to look for disease. Pathologists perform histopathology in a lab. They examine tissue under a microscope and develop a report of their findings.

Histopathology reports can include descriptions of the tissue, diagnosis, and prognosis. In addition to evaluating the shape and structure of cells, pathologists may also use other techniques to assess and diagnose cancer.

National Cancer Institute. NCI dictionary of cancer terms.

Royal College of Pathologists. Histopathology .

Underwood JCE. More than meets the eye: the changing face of histopathology .  Histopathology. 2017;70:4–9. doi:10.1111/his.13047 

University of California Davis. Best practices in frozen section analysis .

Dogan NU, Dogan S, Favero G, Kohler C, Dursun P. The basics of sentinel lymph node biopsy: anatomical and pathophysiological considerations and clinical aspects . J Oncol. 2019;2019:3415630. doi:10.1155/2019/3415630

Tomasian A, Jennings JW.  Bone marrow aspiration and biopsy: techniques and practice implications .  Skeletal Radiol . 2022;51(1):81-88. doi:10.1007/s00256-021-03882-w

College of American Pathologists. How to read your pathology report .

Schafer KA, Eighmy J, Fikes JD, et al. Use of severity grades to characterize histopathologic changes . Toxicol Pathol . 2018;46(3):256-265. doi:10.1177/0192623318761348

Salto-Tellez M, James JA, Hamilton PW. Molecular pathology – the value of an integrative approach . Mol Oncol. 2014 Oct;8(7):1163–1168. doi:1016/j.molonc.2014.07.0211

Ho C, Rodig SJ. Immunohistochemical markers in lymphoid malignancies: Protein correlates of molecular alterations . Semin Diagn Pathol . 2015;32(5):381-91. doi:10.1053/j.semdp.2015.02.016

Shadman M.  Diagnosis and treatment of chronic lymphocytic leukemia: a review .  JAMA . 2023;329(11):918-932. doi:10.1001/jama.2023.1946

Yu L, Kim HT, Kasar S, et al. Survival of Del17p CLL depends on genomic complexity and somatic mutation . Clin Cancer Res . 2017;23(3):735-745. doi:10.1158/1078-0432.CCR-16-0594

Taylor J, Xiao W, Abdel-wahab O. Diagnosis and classification of hematologic malignancies on the basis of genetics . Blood . 2017;130(4):410-423.

By Indranil Mallick, MD  Indranil Mallick, MD, DNB, is a radiation oncologist with a special interest in lymphoma.

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A pathology report is a medical document written by a pathologist. A pathologist is a doctor who diagnoses disease by:

Explaining laboratory tests

Evaluating cells, tissues, and organs

The report gives a diagnosis based on the pathologist’s examination of a sample of tissue taken from the patient’s tumor. This sample of tissue, called a specimen, is removed during a biopsy. Learn about the various types of biopsies .

By looking at and testing the tumor tissue, the pathologist is able to find out:

If the tissue is noncancerous or cancerous. A cancerous tumor is malignant, meaning it can grow and spread to other parts of the body. A noncancerous, or benign tumor, means the tumor can grow but will not spread.

Other specific details about the tumor’s features. This information helps your doctor figure out the best treatment options.

Your doctor will receive these test results as they become available. It may take a few days to a few weeks to receive the full report. The timing depends on the testing needed. You are allowed by law to receive a copy of your pathology report. But you should expect the report to contain highly technical medical terms. Ask your doctor to explain the results in the pathology report and what they mean.

Parts of a pathology report

Different pathologists use different words to describe the same things. But most pathology reports include the sections discussed below.

Patient, doctor, and specimen

This section lists the following items:

Patient's name, birth date, and other personal information

An individual number assigned to the patient to help identify samples

The pathologist’s and oncologist’s contact information, as well as the laboratory where the sample was tested

Details about the specimen, including the type of biopsy or surgery and the type of tissue

Gross, or obvious, description

This section describes the tissue sample or tumor as seen with the naked eye. This includes the general color, weight, size, and consistency.

Microscopic description

This is the most technical section of the report. It describes what the cancer cells look like when viewed under a microscope. There are several factors noted in this section that affect diagnosis and treatment.

Whether the cancer is invasive. Tumors of many types may be noninvasive (in situ, which means “in place”) or invasive. Invasive tumors can spread to other parts of the body through a process called metastasis. Although noninvasive tumors do not spread, they may grow or develop into an invasive tumor in the future. For invasive tumors, it is important for the pathologist to note how much the tumor has grown into nearby healthy tissue.

Grade. Grade describes how the cancer cells look compared with healthy cells. In general, the pathologist is looking for differences in the size, shape, and staining features of the cells. A tumor with cells that look more like healthy cells is called "low grade" or "well differentiated." A tumor with cells that look less like healthy cells is called "high grade," "poorly differentiated," or "undifferentiated." In general, the lower the tumor’s grade, the better the prognosis. There are different methods used to assign a cancer grade for different types of cancers. Learn more about grading for specific cancer types .

How quickly cells are dividing, mitotic rate. The pathologist usually notes how many cells are dividing. This is called the mitotic rate. Tumors with fewer dividing cells are usually low grade.

Tumor margin. Another important factor is whether there are cancer cells at the margins, or edges, of the biopsy sample. A “positive” or “involved” margin means there are cancer cells in the margin. This means that it is likely that cancerous cells are still in the body.

Lymph nodes. The pathologist will also note whether the cancer has spread to nearby lymph nodes or other organs. Lymph nodes are tiny, bean-shaped organs that help fight disease. A lymph node is called “positive” when it contains cancer and “negative” when it does not. A tumor that has grown into blood or lymph vessels is more likely to have spread elsewhere. If the pathologist sees this, he or she will include it in the report.

Stage. Usually, the pathologist assigns a stage using the TNM system from the American Joint Committee on Cancer (AJCC) . This system uses 3 factors:

The size and location of the tumor (Tumor, T)

Whether cancer cells have spread to the lymph nodes located near the tumor (Node, N)

Whether the tumor has spread to other parts of the body (Metastasis, M).

Pathologic stage, along with the results of other diagnostic tests, helps determine the clinical stage of the cancer. This information guides a person’s treatment options. Learn more about the stages of cancer .

Results of other tests. The pathologist may perform special tests to identify specific genes, proteins, and other factors unique to the tumor. The results of these tests may be listed in a separate section or in a separate report. These additional tests are especially important for diagnosis because choosing the best treatment option may depend on these results.

This section provides the "bottom line." You may find this section at the beginning or the end of the report. If cancer has been diagnosed, the section may include the following:

The type of cancer, such as carcinoma or sarcoma

Tumor grade

Lymph node status

Margin status

Any other test results, such as whether the tumor has hormone receptors or other tumor markers

Synoptic report, or summary

When the tumor was removed, the pathologist will include a summary. This lists the most important results in a table. These are the items considered most important in determining a person’s treatment options and chance of recovery.

Comments section

Sometimes, a cancer may be difficult to diagnose or the development of the cancer is unclear. In these situations, the pathologist may use the comments section. Here, he or she can explain the issues and recommend other tests. This section may also include other information that can help the doctor plan treatment.

Sampling differences

Sometimes, the pathology report for a biopsy may be different from a later report for the entire tumor. This happens because the features of a tumor can sometimes vary in different areas. Your doctor will consider all of the reports to develop a treatment plan specific to you.

Questions to ask your health care team

To better understand what your pathology report means, consider asking your health care team the following questions:

What type of cancer do I have and where did it start?

How large is the tumor?

Is the cancer invasive or noninvasive?

How fast are the cancer cells growing?

What is the grade of the cancer? What does this mean?

Was the entire cancer removed? Are there signs of cancer cells at the edges of the sample?

Are there cancer cells in the lymph vessels or blood vessels?

What is the stage of the cancer? What does this mean?

Does the pathology report specify the tumor characteristics clearly? Should we get another pathologist’s opinion?

Do any tests need to be done again on another sample or in another laboratory?

Getting a second opinion

It may be helpful to talk with more than one doctor about your diagnosis and treatment plan. This is called a second opinion. It is important to get a copy of the pathology report and any other medical records.

If you choose to get a second opinion, you will want to share these with the second doctor. Some doctors work closely with their own pathologists and may want their own pathologist's opinion too. Other tests can also be done on the biopsy sample if needed. The tissue sample is kept for a long time and is available upon request. Learn more about getting a second opinion .

Related Resources

Spotlight On: Pathologists

When the Doctor Says Cancer

More Information

College of American Pathologists: How to Read Your Pathology Report

National Cancer Institute: Pathology Reports

Navigating Cancer Care

More in this section.

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Pathology Reports

What is a pathology report.

A pathology report (sometimes called a surgical pathology report) is a medical report that describes the characteristics of a tissue specimen that is taken from a patient. The pathology report is written by a pathologist , a doctor who has special training in identifying diseases by studying cells and tissues under a microscope.

A pathology report includes identifying information (such as the patient’s name, birthdate, and biopsy date) and details about where in the body the specimen is from and how it was obtained. It typically includes a gross description (a visual description of the specimen as seen by the naked eye), a microscopic description , and a final diagnosis . It may also include a section for comments by the pathologist. 

The pathology report provides the definitive cancer diagnosis. It is also used for staging (describing the extent of cancer within the body, especially whether it has spread) and to help plan treatment.

Common terms that may appear on a cancer pathology report include:

  • noninvasive
  • adenocarcinoma
  • infiltrating
  • undifferentiated
  • well-differentiated  

How is tissue obtained for examination by a pathologist?

The pathologist examines cells or tissues obtained during a biopsy (which is a procedure to remove a cell or tissue specimen for examination by a pathologist) or surgery or from bodily fluids.

A biopsy specimen can be obtained in several ways, such as by 

  • taking a tissue sample from the surface of the skin
  • using a needle inserted through the skin to withdraw tissue or fluid
  • inserting a thin, lighted tube called an endoscope through the mouth, anus , urethra , or a small incision in the skin to look at areas inside the body and remove a sample using special tools that pass through the tube

If surgery is used to remove part or all of a tumor, some or all of the removed tumor specimen will be examined by the pathologist. If the entire tumor is removed, typically the surgeon will attempt to remove some normal tissue around the tumor (known as the margin ) for examination by the pathologist to make sure that it doesn’t contain tumor cells. 

For some cancer types, especially breast cancer and melanoma, the surgeon may also remove nearby lymph nodes , called the sentinel lymph nodes , so the pathologist can see if these contain cancer cells. The Sentinel Lymph Node Biopsy fact sheet describes this procedure and its use in determining the extent, or stage , of cancer in the body.

A pathologist may also examine cells that are present in bodily fluids, such as urine, cerebrospinal fluid (the fluid around the brain and spinal cord), sputum (mucus from the lungs), peritoneal (abdominal cavity) fluid, pleural (chest cavity) fluid, cervical/vaginal smears, and bone marrow.

How does a pathologist examine tissue?

Tissue or cell specimens must be cut into very thin slices, called sections, so the pathologist can look at them under a microscope. The specimen must be processed to make it solid before it can be cut into sections. 

The most common approach used for tissue examination involves chemically “fixing” the specimen, usually with a chemical called formalin. This stabilizes the cells for further processing in an automated machine that submerges the tissue in substances that remove water and replace it with molten paraffin wax. 

Once processed, the tissue is embedded into a permanent paraffin wax block to be cut. The paraffin-embedded tissue is then sliced into very thin sections that are placed onto microscopic slides. The slides are stained with dyes to help visualize parts of the cell and structures in the tissue. This is known as histologic (tissue) examination. 

Fixed sections provide the maximum detail of the structures in a tissue sample, and they can be saved and analyzed in the future if needed. Preparing fixed sections normally takes several days. The pathologist typically sends a pathology report to the doctor within 10 days after the biopsy or surgery is performed. 

Frozen sectioning is another approach used by a pathologist for tissue examination. Frozen sections are prepared when an immediate answer about a tissue sample is needed. For example, this type of examination would be used during surgery to provide the surgeon with a rapid diagnosis for an area of abnormal tissue and the extent of the abnormal area while the patient is in the operating room. To make frozen sections, the tissue sample is rapidly frozen, cut into sections using an instrument called a cryostat, stained, and examined by a pathologist. This can be done in about 15 to 20 minutes.

Frozen sections are suitable for preparing tissue for some tests, such as immunofluorescence and immunohistochemistry . However, the fixed (permanent) section preserves more detail and is more commonly used to make a diagnosis than frozen sections.

What is the gross description on a surgical pathology report?

The gross description includes the color, weight, and size of a tissue sample as seen by the naked eye. It may also include the shape of the tissue sample and any visible abnormalities . And it will indicate the body site from where the tissue was taken from, how many samples were taken, and whether and how many lymph nodes were removed.

What is the microscopic description on a surgical pathology report?

The microscopic description in a pathology report includes information about the appearance of the cells after they have been stained with routine stains such as hematoxylin and eosin  (also known as H&E) and viewed under the microscope. H&E staining helps identify different types of cells and tissues and provides important information about the pattern and shape of cells and the structure of the tissue. With H&E staining, hematoxylin shows the ribosomes , chromatin (genetic material) within the nucleus , and some other structures in the nucleus as a deep blue-purple color. Eosin shows the cytoplasm ,  collagen , connective tissue , and other structures that surround and support the cell as an orange-pink-red color.

This description may also include the type and number of cells seen in the tissue sample, how abnormal the cells look (also called the tumor grade ), and whether there are notable cell features (such as their arrangement and behavior).

The microscopic description section will also indicate whether abnormal cells are found in the margins  (the edges of the tissue that has been removed by surgery) or in lymph nodes . Margins are described as negative (or “clean”) when the pathologist finds no cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. A margin is described as positive (or “involved”) when the pathologist finds cancer cells at the edge of the tissue, suggesting that some of the cancer has not been removed. Lymph nodes are called positive if they have cancer cells and negative if they do not. 

This description may also include the results of additional tests that were performed on the tissue. Depending on the cancer type, these may include tests that

  • measure the properties of cells in a sample, including the number of cells, percentage of live cells, cell size and shape, and the proportion of cells that have a tumor marker on their cell surface. See NCI’s Tumor Markers fact sheet for more information about tumor markers and how they are used in cancer diagnosis and treatment. 
  • investigate genetic or molecular abnormalities in specimens with the use of specific techniques. These include karyotyping, to detect aneuploidy (abnormal numbers of chromosomes ) and large translocations  (in which long pieces of chromosomes have broken off and moved to other chromosomes), as well as fluorescence in situ hybridization , to detect specific chromosomal deletions or translocations.

What is the diagnosis on a surgical pathology report?

The diagnosis section of a pathology report is the pathologist’s summary of all the findings of their visual and microscopic examination of the tissue specimen, in combination with relevant clinical information. It is in this section that the cancer type will be identified, including the tumor grade, lymph node status, margin status, and stage.

Are molecular characteristics of a tumor included on a surgical pathology report?

Certain molecular tests, sometimes called biomarker tests , are done as part of the initial pathology analysis for all cases of a given cancer type. For example, a pathology report for a patient with suspected breast cancer will include the results of testing for estrogen  and progesterone receptors  and the protein HER2/neu . The results of these tests can help identify what treatments are best for an individual patient.

A liquid biopsy —in which a sample of blood or other body fluid is tested to look for pieces of DNA that have been released from tumor cells—is another way that the molecular characteristics of a tumor may be analyzed. The findings of these additional tests may be provided in separate reports that are linked to the pathology report. 

Pathology examination is increasingly incorporating analyses of the structure and sequence of DNA extracted from fresh and fixed tissue samples to refine the cancer diagnosis through improved subtyping and stratification of tumor types and to better inform treatment.

What other information might be included on a surgical pathology report?

In the comments section of the pathology report, the pathologist may note unusual features of the sample, such as information about the cytogenetic and/or molecular characteristics of a tumor, or provide additional information. The comments section is often used by the pathologist to provide more details about the disease and its diagnosis and to recommend additional tests that might be needed. It may include relevant clinical history or test results, abnormal findings that could change a typical diagnosis, previous samples or diagnoses for the patient, and other possible diagnoses. It will also mention tests that are still in process (i.e., pending).

How will I find out what's in my surgical pathology report?

The doctor in charge of a patient’s treatment will tell the patient about the findings in the pathology report and can help the patient understand the report and what it means for their situation. A patient can also ask to discuss their report with the pathologist. 

Patients should be aware that pathology report results will often appear in the patient portal at the same time the doctor receives them. This means that patients may see their report before their doctor has had a chance to review it and discuss it with them.

Can individuals get a second opinion on their surgical pathology results?

Although the diagnosis of most cancers is straightforward, patients or their doctors may want to get a second opinion from another pathologist. Patients interested in getting a second opinion should talk with their doctor. They will need to obtain the slides and/or paraffin block from the pathologist who examined the sample or from the hospital where the biopsy or surgery was done.

Many institutions provide second opinions on pathology specimens. NCI-designated cancer centers or academic institutions sometimes provide second opinions. Patients should contact the facility in advance to determine if this service is available, the cost, and shipping instructions.

For each patient, the results of all pathology examinations and any other tests ordered by the pathologists are reviewed together by the tumor review board , a group of doctors who are experts in different specialties who plan the treatment approach for a patient.

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a report of histopathology

  • Discover pathology

Histopathology

What is histopathology.

Histopathology is the diagnosis and study of diseases of the tissues, and involves examining tissues and/or cells under a microscope. Histopathologists are responsible for making tissue diagnoses and helping clinicians manage a patient’s care.

Why is histopathology important?

Histopathologists are doctors who work closely with other clinical specialties. They can reach a diagnosis by examining a small piece of tissue from the skin, liver, kidney or other organ. This is called a biopsy.

They examine the tissue carefully under a microscope, looking for changes in cells that might explain what is causing a patient’s illness. Around 20 million histopathology slides are examined in the UK each year.

Cancer Diagnosis

Histopathologists provide a diagnostic service for cancer; they handle the cells and tissues removed from suspicious ‘lumps and bumps’, identify the nature of the abnormality and, if malignant, provide information to the clinician about the type of cancer, its grade and, for some cancers, its responsiveness to certain treatments.

With the help of sophisticated imaging techniques, biopsy tissue can now be obtained from previously inaccessible sites such as the pancreas or retroperitoneum (behind the peritoneum, the membrane lining the abdominal cavity). Tissue is then processed, usually overnight, before being examined under a microscope. In certain limited circumstances using special techniques, the specimen can be examined immediately.

With rapidly changing developments in molecular pathology, pathologists are leading the way with new techniques such as fluorescence in-situ hybridization (FISH) and polymerase chain reaction (PCR), to map the genetic material in tissues or tumours, which are essential in the management of many cancers.

Find out what a histopathologist does, by hearing from Dr Mark Howard

Find out what a histopathologist does, by hearing from Dr Mark Howard

The role of the histopathologist.

Many histopathologists specialise in specific organs such as the liver or skin, dissecting (‘cutting up’ or ‘trimming’) tissues for viewing under the microscope on a daily basis. For large specimens, such as samples of bowel or breast following surgery, these are dissected to select the most appropriate areas to examine under microscope. Histopathologists write reports on specimens, consult literature (past and current research findings), and many also have teaching and research responsibilities.

They will also attend multi-disciplinary meetings so their findings can be discussed with other clinicians. Treatments are then planned in detail and tailored to each individual patient.

Histopathologists also work directly with patients, for example, they may carry out procedures such as fine needle aspiration in head and neck or breast clinics. They increasingly have key responsibilities for cancer screening, at the moment for breast, bowel and cervical cancer, with other programmes expected in the near future.

Histopathologists also examine cells in smears, aspirates or bodily fluids (cytopathology), for example in urine or cervical smears. Other subspecialties include forensic pathology, neuropathology and paediatric pathology.

a report of histopathology

Dr Rachel Brown, Histopathologist

At my desk I do some cases at the microscope dictating reports as I go. I usually do some trimming in the morning. My areas of interest are liver/pancreas and head and neck pathology so I might be looking at a liver removed at transplantation or a partial liver resection or pancreatic resection for tumour.

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Histopathology Reporting

Guidelines for Surgical Cancer

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  • Derek C. Allen 1

Institute of Pathology, Royal Victoria Hospital, Belfast, UK

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Belfast City Hospital Histopathology Laboratory, Belfast, UK

Includes 8th edition TNM and WHO classifications of cancers

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Highlights new clinical procedures and ancillary laboratory techniques

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Table of contents (39 chapters)

Front matter, introduction.

David P. Boyle

Oesophageal Carcinoma

  • Damian McManus

Gastric Carcinoma

Ampulla of vater and head of pancreas carcinomas.

  • Paul J. Kelly

Small Intestinal Carcinoma

Colorectal carcinoma.

  • Maurice B. Loughrey

Appendiceal Lesions

  • Ciaran O’Neill

Anal Canal Neoplasia (with Comments on Pelvic Exenteration)

Gall bladder carcinoma.

  • Gerard McVeigh

Perihilar and Distal Extrahepatic Bile Duct Carcinoma

Liver carcinoma, lip and oral cavity carcinomas.

  • Séamus Napier

Oropharyngeal Carcinoma (with Comments on Nasopharynx and Hypopharynx)

Nasal cavity and paranasal sinus carcinomas, laryngeal carcinoma, salivary gland tumours.

This book is an easily comprehensible and practicable framework for standardised histopathology reports in surgical cancer. The pathological features of the common carcinomas are detailed and non-carcinomatous malignancies are also summarised. 8th edition TNM and WHO classifications of cancers are incorporated, with comments on any associated pathology, diagnostic clues and prognostic criteria supplemented visually by line diagrams.

Each chapter’s introduction gives epidemiological, clinical, investigative and treatment summary details. Other pathology includes updated immunophenotypic expression and molecular techniques. The impact of these ancillary investigations on diagnosis, and as biomarkers of prognosis and prediction of response to treatment is summarised, as is the effect of adjuvant treatments on cancers. Experience based clues are given throughout as aids to tumour typing, grading, staging, and gauging prognosis and response to treatment.

Histopathology Reporting: Guidelines for Surgical Cancer, Fourth Edition is invaluable for trainee and consultant diagnostic histopathologists all over the world, equipping the reader to produce high quality, clinically appropriate histopathology reports, and to participate in contemporary multidisciplinary team management of patients with surgical cancer.

  • TNM8 classification
  • WHO classification
  • multidisciplinary team management
  • predictive pathological factors
  • standardised histopathology reports
  • surgical cancer diagnosis
  • surgical cancer investigation
  • surgical cancer management
  • surgical cancer presentation
  • surgical cancer prognosis
  • Tumour reporting
  • Immunohistochemistry
  • Molecular pathology

Derek C. Allen

David Boyle is an NHS consultant in histopathology and a fellow of the Royal College of Pathologists. He graduated from Queen's University Belfast in 2005 and commenced training in pathology in 2007, becoming a fellow of the Royal College of Pathologists in 2011. He has worked as an NHS consultant in histopathology since 2014 and is a general pathologist with a special interest in dermatopathology and breast pathology. He has published a number of original articles and review papers.

Derek C. Allen (Belfast City Hospital, UK) is one of the authors of Histopathology Specimens: Clinical, Pathological and Laboratory Aspects, also published by Springer.

Book Title : Histopathology Reporting

Book Subtitle : Guidelines for Surgical Cancer

Editors : David P. Boyle, Derek C. Allen

DOI : https://doi.org/10.1007/978-3-030-27828-1

Publisher : Springer Cham

eBook Packages : Medicine , Medicine (R0)

Copyright Information : Springer Nature Switzerland AG 2020

Hardcover ISBN : 978-3-030-27827-4 Published: 24 March 2020

Softcover ISBN : 978-3-030-27830-4 Published: 17 April 2021

eBook ISBN : 978-3-030-27828-1 Published: 23 March 2020

Edition Number : 4

Number of Pages : XXXV, 512

Number of Illustrations : 116 b/w illustrations, 7 illustrations in colour

Topics : Pathology

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Recommendations for reporting histopathology studies: a proposal

Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands

I. D. Nagtegaal

Most published histopathology studies (describing histological characteristics of existing or new entities, existing or new markers detected by immunohistochemistry, in situ hybridization or molecular methods in tumor material often in relation to patient outcome) are retrospective and use tissue samples from a single center only. This limits the quality of the evidence provided in such a paper. A higher level of evidence, such as would be required to justify implementation in daily clinical practice, can be reached for tissue-based biomarkers by systematic review of published studies and meta-analysis of the provided data.

In such meta-analyses, only research data of sufficient quality should be used. Universally accepted criteria for the assessment of data quality do not exist. However, an essential element would be reporting at a sufficient level of detail of the key components that make up the body of evidence presented in any particular paper. This would also facilitate repetition of the experiments performed and of the relevant observations, an essential step as reproducibility is an absolute prerequisite for validation of tissue biomarkers prior to their implementation in clinical practice.

For in situ hybridization and immunohistochemistry biomarkers, the minimum information specification for in situ hybridization and immunohistochemistry experiments (MISFISHIE) guidelines have been developed to ensure that a report contains sufficient detail of the assay used [ 1 ]. MISFISHIE guidelines identify six types of information to be provided for each experiment: experimental design, biomaterials (biospecimens used) and treatments (preanalytical conditions such as fixation and embedding), reporters (antibodies and probes), staining (fluorescence or chromogenic), imaging data (how images were obtained), and image characterization (how information was extracted from the images, including quantification of relevant image elements). However, they do not focus on statistics (correlation of image-derived information with clinical data) or interpretation of the results, which are essential elements of a scientific paper.

To improve possibilities to compare results across studies involving molecular prognostic biomarkers, the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines have been developed. These are intended to facilitate evaluation of the appropriateness and quality of study design, used methods, approaches applied to data analysis, and presentation of the results [ 2 ]. The REMARK guidelines can also be used for the reporting of biomarker studies that are not strictly molecular, such as those reporting retrospective histopathological observations, although some items on the checklist will then be less applicable. Notably, the building of prognostic models, checking model assumptions, model validation, and internal validation might not be feasible.

In view of a perceived need for better standardization of retrospective histopathology studies, we have used the REMARK guidelines as a blueprint for the development of basic rules for their reporting [ 3 ]. In analogy with the REMARK guidelines, we propose a checklist of 20 items, grouped according to the generally used headings in a research paper: Introduction, Material and methods, Results, and Discussion. We have put these together in a table and will discuss each of them briefly. The intention of our commentary is to increase awareness of the need for more standardization and to stimulate discussion, in order to get to a generally accepted approach to standardized reporting of histopathological studies (Table  1 ).

Proposed items for reporting histopathology studies

FOI factor of interest, RR relative risk, OR odds ratio, CI confidence interval, HR hazard ratio, UV univariate, MV multivariate

The checklist

In order to understand the rationale (why this particular marker) and potential clinical applications (what is needed for this particular condition), a description of the marker of interest, study objectives, and a working hypotheses are necessary. Describe what is known on the biology of the marker, methods to detect and quantify the marker, and why the marker might be of clinical interest. A working hypothesis should be formulated as a rule in terms that can be tested statistically.

Describe the clinical context of the study. Describe why a particular cohort of patients was selected and the criteria used to define the cohort, which includes inclusion and exclusion criteria. Describe clinical details of the cohort in relation to potential use of the marker of interest. As an example, when the working hypothesis is that a marker might have a different prognostic value in different stages of disease, disease stage is an essential element in the description of patient data.

Treatment (neoadjuvant, adjuvant, first line, second line, etc.) is intended to alter the disease course of a patient. Different treatment modalities might not be distributed equally between groups with or without the biomarker, and this will become an important confounding factor when correlation between outcome and marker expression is looked for. Moreover, treatment might also have an influence on marker expression if the patient was treated prior to the moment the sample was taken, which will be a confounding factor in the analysis of the impact of the biomarker. When treatment information is missing, this should be specifically stated, and in studies on marker expression in relation to treatment response, such patients should be excluded.

Tissue samples used in retrospective studies are often convenience collections, which potentially run a serious risk of collection bias [ 4 ]. Authors should report why and how the specimens were collected and how the specimen was handled (primary tumor site or metastatic lesion, biopsy or resection, formalin-fixed paraffin-embedded or frozen tumor tissue). Where possible, data on preanalytical handling of specimens should also be given, in order to clarify potential confounding effects associated with sample condition [ 5 ]. When control samples are used, their origin should be stated as well as how they were selected. Control samples should fit into the experimental design based upon the working hypothesis, to avoid problems of unexpected differences between control and patient samples. Authors should report methodological variables as much as possible according to MISFISHIE guidelines [ 1 ]).

A detailed description of the criteria for assessment of the presence or absence of the biomarker at tissue level allows evaluation of potential shortcomings but also will enable future researchers to reproduce the study. Some retrospective studies on classical pathological markers tend to extract data from pathology reports, instead of rereading the slides or repeating marker expression analysis for the purpose of the investigation. This runs a risk of heterogeneity between method runs or methods applied and problems of lack of inter-individual reproducibility in reading the results. This can lead to over- or underestimation of the number of patients expressing a certain marker and might introduce selection bias [ 6 ]. For purely morphological (gross or microscopical) markers, details of specimen examination, number of slides investigated, and criteria when a marker was called positive or negative should be provided.

Visual assessment of a biomarker is an important source of variance [ 5 ]. Interpretation varies between pathologists, and biomarker data will be more robust if expression of a biomarker is scored by multiple independent observers unaware of (blinded to) the clinical parameter of interest (such as outcome). Justification of the chosen method of and criteria for (semi-)quantitative assessment should be provided in detail.

Important determinants of the reliability of study results are study design and method of patient selection. Selection of cases according to clinical or pathological parameters (for example patients selected according to age, only T4 or N0 tumors) may introduce bias; therefore, details of case selection should be reported. Stating where the patients came from might provide relevant information regarding the patient population (for example a patient population from a tertiary referral hospital might differ significantly from that of a primary care center). The time frame (when cases were recruited or diagnosis was made) should also be mentioned because therapies change over time which might affect outcome.

In many studies, outcome is the time to an event (e.g., recurrence, death), and follow-up should be long enough to make sure that events can happen. If, for example, a biomarker is associated with the risk of dissemination, follow-up should be long enough to allow this effect to be observed. Follow-up usually ends at a specific point in time (notably this date and the median follow-up time should be stated).

In histopathology studies, common endpoints include death and discovery of recurrence. Endpoints used in survival analysis are not always clearly defined. Analysis of time to death might include deaths from any cause or cancer-specific deaths. A clear distinction should be made between overall survival, disease-specific survival, and recurrence-free survival. Definition of parameters defining recurrence of disease should be clear. Recurrence might include local recurrence or distant metastasis or both. Local recurrence and distant metastases are two biologically different events, and the effect of a biomarker on each of these might be different. Lack of clearly defined endpoints may lead to misinterpretation of its association with a biomarker and preclude inclusion of a publication in a meta-analysis.

If the statistical methods used in a biomarker study are not clearly specified, it will be difficult or impossible for the reader to interpret the results or reproduce and validate the findings. Rather often the amount of detail provided in publications is marginal. Mathoulin-Pelissier et al. concluded that 68 % of the articles published in major journals reported insufficient information regarding the survival analysis [ 7 ].

Any seemingly interesting biomarker might interact with established clinical or pathological factors. Methods used to assess potential interactions with other variables should be described. The interactions are essential to evaluate whether or not found associations have independent value. All included variables should be clearly defined, and the choice of variables included in the study has to be justified (why variables included in the study were retained while others were left out).

In retrospective biomarker studies, the number of cases included in analysis is often lower than the initial number of cases included in the study. This is mainly due to missing values, such as impossibility to (re-)evaluate staining results or missing outcome data. A solution often chosen is to restrict the analyses to samples with complete data. However, this may introduce selection bias when samples with missing data are not typical for the whole study population. It is therefore necessary to state the number of patients and events included in each analysis. Only with this information is it possible to assess the reliability of reported findings.

A detailed description of patient characteristics and relevant histopathological parameters is needed to assess whether or not the patient cohort included in the study is representative for the condition under scrutiny. Obvious patient characteristics are age and gender, but parameters such as ethnicity, performance status, or medical history might be relevant. In case of cancer, characteristics of the lesion should include parameters defining TNM stage.

As stated in point 11, a new biomarker is only useful if its effect is maintained when interaction with other prognostic factors is ruled out, or if its assessment is (quantitatively or qualitatively) superior in comparison with established prognostic variables. For evaluation of clinical value, the potential interactions between a new biomarker and established prognostic variables should therefore be reported.

As mentioned above, due to missing values, the number of cases included in statistical analysis is often lower than the initial number of cases included in the study. The risk of attrition bias will increase along with the proportion of cases not included in statistical analysis [ 6 ]. To minimize attrition bias, Smith et al. proposed that at least 90 % of the selected cohort should be included in the statistical analysis [ 8 ]. Sub-analyses should be avoided because of the high risk of false-positive findings due to increasingly small patient numbers.

Establishing a biomarker’s potential association with clinical outcome is the key subject in biomarker research. In univariate analysis, the relationship between the biomarker and outcome can be assessed without adjustment for additional variables. Relative risks or odds ratios with their associated confidence intervals and p values should be given, regardless of statistical significance. Kaplan-Meier curves should be included when illustrative, but p values from log rank tests should be given regardless of statistical significance. Univariate analysis should also be performed for all other variables and presented in a summarizing table.

In multivariate analysis, the association between a biomarker and clinical outcome can be established, correcting for established prognostic variables. Authors should report which prognostic variables were included in multivariate analysis. As a rule, significant factors identified in univariate analysis should all be included. Hazard ratios with associated confidence intervals and p values should be given, regardless of statistical significance.

Within a study, significant findings are more likely to be reported than non-significant findings. In order to prevent selective reporting bias, authors should report the effects of all prognostic factors included in the multivariable analysis; not only the marker of interest or the significant findings.

Authors should critically evaluate their findings, mentioning limitations of the study and possible biases. A good discussion will allow the reader to retain a balanced perception of the importance of the results of the study.

The intention of biomarker studies is to develop new disease-associated parameters of which the contribution to clinical decision-making reaches beyond that of existing parameters included in the standard of care. A statistically significant association between a marker and disease outcome might seem promising, but authors should mention in the discussion which steps will be taken in order to eventually reach implementation of the marker in patient care.

Adherence to guidelines on reporting, whenever possible, should facilitate a clear perception by the reader of the inherent qualities of the reported study, and we presume that it might also have a positive effect on study quality, for as much as the checkpoints we propose are already used when the study is planned. The 20 checkpoints we propose speak for themselves. We paid no attention to sample size calculations, because most histopathological studies are retrospective and based upon convenience case collections that were not set up to answer specific questions well defined before the collection was started. Checking model assumptions, standardized model making and model validation is unusual in histopathology research but might become more mainstream when this is more often performed in the context of clinical trials. For a biomarker identified in a retrospective study, we consider external validation by independent groups on separate patient cohorts of much greater value than internal validation. Our checkpoints might be of help for investigators who study tissue-based biomarkers, reviewers of manuscripts, and researchers performing meta-analyses. They should ultimately support quality improvement of histopathological studies and implementation of new findings into daily practice. We welcome feedback from the scientific community to improve on and facilitate implementation of our list of checkpoints.

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This article has a correction. Please see:

  • Correction - February 01, 2015

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  • http://orcid.org/0000-0003-0887-4127 I D Nagtegaal
  • Department of Pathology , Radboud University Medical Center , Nijmegen , The Netherlands
  • Correspondence to Professor I D Nagtegaal, Department of Pathology, Radboud University Medical Center, PO Box 9101, Nijmegen 6500 HB, The Netherlands; Iris.Nagtegaal{at}radboudumc.nl

https://doi.org/10.1136/jclinpath-2014-202647

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  • CANCER RESEARCH
  • HISTOPATHOLOGY

With the increasing amount of published papers and the need for evidence-based guidelines for diagnostics and treatment, it becomes of utmost importance to assess the quality of publications. The highest degrees of evidence in medicine are based on prospectively randomised clinical trials. In histopathology, trials are virtually non-existing and prospective studies are still relatively rare. The majority of our practice is based on retrospective studies, quite often from single centres.

Higher levels of evidence can be reached by systematic reviews of the existing literature and meta-analyses, that are increasingly present in the literature ( figure 1 ). 1 These meta-analyses are also important to provide information about the prognostic value of traditional factors, against which new diagnostic tools can be compared. However, the reporting of meta-analyses varies, 2–4 limiting the possibility to assess strength and weaknesses of the reviews. Therefore, the PRISMA guidelines have been implemented for the reporting of systematic reviews and meta-analyses. 5 However the PRISMA guidelines focus on the reporting of a meta-analysis, not on the reporting of the individual studies included in the meta-analyses. The establishment of quality of publications and judgement of the risk of bias is a key element in executing a systematic review, but is considered a subjective measurement. Quality assessment scales and reporting checklists for studies have been developed; among others Quadas, 6 Newcastle-Ottawa scale 7 and REMARK. 8 For most histopathology studies these cannot be applied. The Quadas scale compares diagnostic interventions, not diagnostic criteria. The Newcastle-Ottawa scale has been developed for case-control and cohort studies. The REMARK guidelines are specifically designed for the reporting of tumour marker prognostic studies. The latter initiative comes close to what is needed for histopathology studies, however, some checklist items are only applicable on prognostic studies which assess biological molecules. Sample size calculations are rare in retrospective histopathology studies, moreover prognostic model-building, checking model assumptions, model validation and internal validation is impossible. Therefore we have adjusted the REMARK checklist to make it more suitable for retrospective histopathology studies ( box 1 ).

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Number of publications of systematic reviews and meta-analysis per year. Source: pubmed. 1

Guidelines for reporting of histopathology studies

Introduction

States the FOI, the study objectives and hypotheses

Material and Methods

Describes patient characteristics, inclusion and exclusion criteria

Describes (neoadjuvant) treatment details

Describes type of material used and number of slides examined

Specifies criteria for the FOI

Describes the number of independent (blinded) scorers

States the method of case selection, study design, hospital and time period

Describes the end of follow-up period and median follow-up time

Defines all clinical end points examined

Specifies all statistical methods

Describes how associations with other clinical/pathological factors were analysed

Describes the number of patients included in the analysis and reason for dropout

Reports patient/tumour characteristics (including FOI) with number of missing values

Describes the relation of the FOI with standard prognostic variables

>90% of initial cases included in UV/MV analysis

Reports the estimated effect (RR/OR, CI and p value provided) in UV analysis

Reports the estimated effect (HR, CI and p value provided) in MV analysis

Reports the estimated effects (HR, CI and p values provided) of other prognostic factors included in MV analysis

Interprets the results in context of the prespecified hypotheses and other relevant studies; include a discussion of limitations of the study.

Discusses implications for future research and clinical value

FOI, factor of interest; MV, multivariate; RR, relative risk, UV, univariate.

Journal editors should consider the endorsement of guidelines and standardised checklists for the reporting of histopathology studies since these studies are inherently different from clinical trials and prognostic biomarker research.

  • ↵ http://www.ncbi.nlm.nih.gov/pubmed , 2014 .
  • Needleman I ,
  • Worthington H ,
  • Berrier J ,
  • Reitman D ,
  • Liberati A ,
  • Tetzlaff J ,
  • Whiting P ,
  • Rutjes AW ,
  • Reitsma JB ,
  • ↵ ( 2013 ) http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp .
  • McShane LM ,
  • Altman DG ,
  • Sauerbrei W ,

Competing interests None.

Provenance and peer review Not commissioned; internally peer reviewed.

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  • Correction Correction N Knijn I D Nagtegaal Journal of Clinical Pathology 2015; 68 173-174 Published Online First: 20 Jan 2015. doi: 10.1136/jclinpath-2014-202647corr1

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  • Long Course Article
  • Published: 22 November 2019

Melanoma pathology reporting and staging

  • Richard A. Scolyer   ORCID: orcid.org/0000-0002-8991-0013 1 , 2 , 3 ,
  • Robert V. Rawson 1 , 2 , 3 ,
  • Jeffrey E. Gershenwald 4 ,
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Modern Pathology volume  33 ,  pages 15–24 ( 2020 ) Cite this article

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The pathological diagnosis of melanoma can be challenging. The provision of an appropriate biopsy and pertinent history can assist in establishing an accurate diagnosis and reliable estimate of prognosis. In their reports, pathologists should document both the criteria on which the diagnosis was based as well as important prognostic parameters. For melanoma, such prognostic parameters include tumor thickness, ulceration, mitotic rate, lymphovascular invasion, neurotropism, and tumor-infiltrating lymphocytes. Disease staging is important for risk stratifying melanoma patients into prognostic groups and patient management recommendations are often stage based. The 8th edition American Joint Committee on Cancer (AJCC) Melanoma Staging System was implemented in 2018 and several important changes were made. Tumor thickness and ulceration remain the key T category criteria. T1b melanomas were redefined as either ulcerated melanomas <1.0 mm thick or nonulcerated melanomas 0.8–1.0 mm thick. Although mitotic rate was removed as a T category criterion in the 8th edition, it remains a very important prognostic factor and should continue to be documented in primary melanoma pathology reports. It was also recommended in the 8th edition that tumor thickness be recorded to the nearest 0.1 mm (rather than the nearest 0.01 mm). In the future, incorporation of additional prognostic parameters beyond those utilized in the current version of the staging system into (web based) prognostic models/clinical tools will likely facilitate more personalized prognostic estimates. Evaluation of molecular markers of prognosis is an active area of current research; however, additional data are needed before it would be appropriate to recommend use of such tests in routine clinical practice.

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Introduction

One of the most important challenges clinicians face is to estimate the risk of metastasis and death for any cancer. This is important firstly, because patients want to know what is likely to happen to them and secondly, because management recommendations are principally based upon this risk. In melanoma, these include recommendations related to the definitive management of the primary tumor site such as the width of excision margins and the role of sentinel lymph node (SLN) biopsy as well as recommendations for the frequency and duration of clinical follow-up [ 1 ]. It has recently been demonstrated that targeted and immune therapies, when administered in an adjuvant setting for stage III melanoma, are associated with a 50% improvement in relapse-free survival [ 2 , 3 , 4 ]. It is therefore more important than ever that patients not only receive an accurate diagnosis but also an accurate estimate of prognosis in order to select the correct therapy.

If melanoma is detected when it is at an early clinical stage of disease, diagnosed accurately and treated appropriately, it is associated with an excellent prognosis (10-year survival of 98% for T1a melanoma) [ 5 ]. Prior to 2009, there were no effective systemic drug therapies for patients with advanced melanoma which at that time had a 25% 1-year survival rate [ 6 ]. Underpinned by improved understanding of the molecular basis of melanoma and regulation of immune system [ 7 ], new effective targeted and immune therapies have transformed the management of patients with widespread melanoma metastases. Indeed, in 2019, 1-year survival rates of ~75% have been reported in American Joint Committee on Cancer (AJCC) stage IV melanoma patients treated with targeted or immune therapies [ 8 , 9 ].

What pathologists need from clinicians to accurately diagnose end stage melanoma

Provision of an appropriate biopsy and pertinent clinical history are keys to the accurate diagnosis and prognostication of melanoma. Unless there are clinical reasons to do otherwise, it is usually recommended that an excision biopsy be performed for diagnosing lesions that are clinically suspected to be melanoma [ 10 ]. Partial biopsies, such as shave and particularly punch biopsies, that do not include the entire lesion, have been associated with an increased risk of misdiagnosis [ 11 , 12 ]. Pertinent clinical information that assists pathologists when interpreting pigmented lesions includes the age of the patient and site of the lesion. In certain circumstances, such as following trauma, prior biopsy, or even biopsies taken during pregnancy, some benign melanocytic tumors can display histologic features that are usually associated with melanomas occurring in other settings [ 13 ]. Therefore, such lesions are at risk at being overdiagnosed as melanoma if the pathologist is not aware of the clinical scenario. The duration for which the lesion has been present and any history of recent change together with the clinical diagnosis or differential diagnosis may also be of assistance to the pathologist when interpreting the biopsy. Despite widespread knowledge of the importance of the provision of pertinent clinical information on pathology request forms, and recommendations in clinical practice guidelines [ 13 ], in one recent large study, no useful clinical information whatsoever was provided in 46% of melanoma pathology request/requisition forms ( n  = 1200, de Menezes and Mar unpublished data). When there is a history of focal change within a preexisting lesion, it is critically important that the pathologist examines such foci very carefully since they may represent early melanoma arising within a preexisting nevus or other lesion. Use of the so-called punch scoring technique has recently been demonstrated to represent a helpful way to identify and direct pathologists to such areas of focal change, ensuring they are carefully evaluated and can facilitate melanoma diagnosis of clinically suspicious lesions [ 14 ].

Melanoma pathology report

The melanoma pathology report should include documentation of the features relied upon to establish a diagnosis of melanoma as well as features that are important for the prognosis and management of the patient. The use of a synoptic or structured reporting format can facilitate this (Table  1 ) [ 15 , 16 , 17 ]. The prognosis for patients with clinically localized primary melanoma is principally dependent on the tumor thickness, which is measured as described by Breslow [ 18 ]. Other important prognostic features for primary melanoma include ulceration [ 19 ], mitotic rate [ 20 ], lymphovascular invasion, tumor-infiltrating lymphocytes (TILs) [ 21 ], melanoma subtype (e.g. desmoplastic melanoma is less frequently associated with nodal metastasis and has a more favorable prognosis [ 22 , 23 ]), as well as patient characteristics such as age, gender, and anatomical site of the tumor (young patient age, female gender and melanoma arising on the extremities are each associated with a more favorable prognosis).

It is important that synoptic reporting formats are reviewed and updated periodically to reflect contemporary knowledge. Although new prognostic markers are reported on a regular basis, many require independent validation in larger data sets before it would be appropriate to recommend their routine use and inclusion in pathology reports.

8th edition AJCC melanoma staging system

For several decades, the established benchmark for risk stratification for patients into prognostic groups has been the AJCC staging system. This is updated periodically and the most recent (8th) edition became operational in 2018 [ 24 ]. The staging system is also important for eligibility, stratification, and analysis of clinical trials. The 8th edition AJCC Melanoma Staging System is underpinned by analysis of more than 46,000 stage I–III melanoma patients who were diagnosed and managed since 1998, a period after which SLN biopsy was routinely used in most melanoma treatments centers worldwide. In November 2015, the International Melanoma Pathology Study Group (IMPSG) met at the University of California, San Francisco, and considered, discussed, debated, and voted upon various pathology staging issues. The consensus recommendations from the IMPSG were subsequently taken to the AJCC melanoma expert panel and were incorporated into the 8th edition Staging System.

Similar to the staging of other cancers, melanoma staging is divided into four stages with stages I and II for clinically localized primary melanoma, stage III for patients with locoregional metastases, and stage IV for those patients with distant metastases.

AJCC T category criteria

The T category is divided into T1–T4 based on the tumor thickness. Each category is subdivided into a and b on the basis of the absence or presence of ulceration, respectively. In addition, nonulcerated tumors 0.8–1 mm thick are categorized at T1b tumors (Table  2 ).

When reporting tumor thickness, it is recommended in the 8th edition that the thickness be recorded to the nearest 0.1 mm. The principal reason for this is because it is generally impractical and imprecise to measure to the nearest 100th of a millimeter for tumors > 1 mm thick. Whilst for thinner tumors they may be measured to the nearest 100th of a millimeter, it is recommended that they be rounded up or down to the nearest 0.1 mm for recording in the pathology report to be used in the AJCC scheme. The 8th edition provides clear guidance for the application of rounding up and down. For example, any melanoma measuring 0.75–0.84 mm in thickness would be rounded to 0.8 mm and recorded as a T1b melanoma. Similarly, a melanoma measuring 1.04 mm thick would be recorded as 1.0 mm in the pathology report and designated as T1b for staging.

Data from a number of large independent data sets supported the selection of 0.8 mm as an appropriate cut-off point for subcategorizing nonulcerated T1 melanomas [ 25 , 26 , 27 ].

Mitotic rate was removed as a T1 subcategory criterion in the 8th edition. This represents a change from the 7th edition. Nevertheless, mitotic rate represents a very strong independent predictor of outcome across its dynamic range in clinically localized primary melanoma patients and should be recorded in all melanoma pathology reports (Fig.  1 ). There were a number of reasons for removing mitotic rate as a staging parameter in the 8th edition. Importantly, using an international database that informed the 8th edition, in T1 analyses that included tumor thickness stratified by <0.8 mm versus ≥ 0.8 mm −1.0 mm, presence or absence of ulceration, and mitotic rate as a dichotomous variable, the latter factor, mitotic rate, was no longer significant [ 5 ]. Concern has also been expressed that pathologists may be looking more carefully for a single mitotic figure following its introduction as a staging parameter in the 7th edition, which may have resulted in fewer melanomas being identified with zero mitotic figures than were identified in the data sets upon which its prognostic significance was originally assessed. Furthermore, it was on occasion erroneously stated that mitotic rate was only prognostically significant as a dichotomous variable (less than or greater than or equal to 1/mm 2 ) when in fact it is strongly prognostic across its full dynamic range [ 5 ]. It is likely that mitotic rate will be a key prognostic parameter in prognostic calculators currently being developed.

figure 1

Melanoma with multiple mitotic figures. High mitotic rate is an independent predictor of adverse outcome in melanoma patients

Mitotic rate should be assessed using the “hot spot” method in all T1–T4 primary melanomas [ 28 ]. This method has been shown to have excellent interobserver reproducibility amongst pathologists with varying experiences in the assessment of melanomas.

In the 8th edition, T0 designates patients in whom no evidence of a primary tumor is identified, e.g., a patient who presents with nodal metastasis and no known primary melanoma. Tis is used to designate melanoma in situ. TX is used when tumor thickness cannot be determined. The latter might occur because of perpendicular sectioning in a curettage-type or fragmented specimen (see also next section).

Challenges with measuring tumor thickness

Pathologists may be faced with a number of challenges when measuring tumor thickness. Occasionally, it can be difficult to determine whether atypical nevoid cells within the dermis represent maturing, benign-appearing melanoma cells or part of a preexisting nevus. In such instances, it may be problematic to determine the deepest dermal cell to measure the tumor thickness. Comparison of the cytological features to both the clearly invasive component as well as any associated benign nevus can assist. Nevertheless, this usually requires careful and reasoned judgment.

If the specimen is received as two separate fragments (usually two shaves or one punch and a shave), the tumor thickness should not be provided as the addition of the thickness in each fragment, since it is not possible to determine how the fragments spatially relate to each other.

When there is deep periadnexal extension of melanoma as a “tongue” of tumor that extends much more deeply than the main, more superficial part of the dermal invasive melanoma, it is not recommended that such extension be included in the measurement of tumor thickness, unless this represents the only focus on invasion. Recently published data by Dodds et al. [ 29 ] provided evidence based on outcome data that periadnexal extension should not be included in tumor thickness measurements. When periadnexal melanoma represents the only focus of invasion, tumor thickness should be measured from the middle of the adnexal structure from where it has likely risen.

Microsatellites or foci of neurotropism or lymphovascular invasion should not be included in the measurement of the Breslow thickness.

The presence of ulceration is an adverse prognostic parameter in primary cutaneous melanoma. It is important to distinguish true ulceration from separation of the epidermis from the underlying tumor as a result of sectioning or other artefactual disruption. The presence of a tissue reaction to loss of epidermis with fibrin and acute inflammation are important histopathologic hallmarks of true ulceration (Fig.  2 ). Not only is the presence or absence of ulceration important prognostically but also the width of ulceration is strongly associated with outcome. Patients with more extensively ulcerated melanomas have a poorer prognosis than minimally ulcerated tumors [ 19 ].

figure 2

a , b Ulcerated nodular melanoma. A fibrinopurulent exudate is present on the surface

Melanoma subtype

Desmoplastic melanoma is an uncommon subtype of melanoma (1–4%) characterized by the presence of spindled melanoma cells within fibrosclerotic stroma (Fig.  3a ). It often has a subtle appearance both clinical and pathological and might not be diagnosed until it is at an advanced clinical stage. Compared with other melanoma subtypes, it is associated with less frequent nodal metastasis, better overall survival and better response rates to immune therapy [ 22 , 23 , 30 ]. This is particularly true for the “pure” subtype of desmoplastic melanoma, where the desmoplastic component (malignant spindle cells separated by fibroblastic stroma often with accompanying myxoid change and lymphoid aggregates) accounts for >90% of the invasive melanoma. It typically occurs in the head and neck region in severely sun-damaged skin of elderly patients. It may be associated with a lentigo maligna in the overlying epidermis or an atypical epidermal melanocytic proliferation. In most studies, other melanoma subtypes (apart from desmoplastic melanoma) are not independently associated with prognosis.

figure 3

a Desmoplastic melanoma of pure subtype involving severely sun damaged skin. b A focus of neurotropism (intraneural invasion) is present

Neurotropism

The two major forms of neurotropism are perineural invasion and intraneural invasion (Fig.  3b ). Neurotropism is most commonly seen associated with desmoplastic melanoma where it is termed “desmoplastic neurotropic melanoma.” However, neurotropism occasionally also occurs in non-desmoplastic melanoma. Neurotropic melanoma may extend well beyond on the edge of the primary tumor. For this reason, it is associated with an increased risk of local recurrence [ 31 ]. At some, but not all, melanoma treatment centers, the presence of neurotropism instigates the application of postoperative radiotherapy to reduce the risk of local occurrence [ 31 ].

Tumor-infiltrating lymphocytes

The presence of TILs signifies that the host immune system recognizes and reacts to the tumor. As such, it is a favorable prognostic parameter in primary melanoma. Various grading schemes have been described for the quantification of TILs [ 32 ] in melanoma. In general, the more TILs that are present, the better the prognosis is for the patient [ 21 ].

As is commonly observed clinically in primary melanomas, the immune system can react against a primary melanoma and result in loss of part or all of the tumor. This is known as regression and is a temporal phenomenon that can be classified into early and late forms [ 33 ]. Early regression is characterized by immature fibrous tissue and increased vascularity, usually accompanied by a chronic inflammatory cell infiltrate. Late regression is characterized by the presence of mature dermal fibrosis usually with accompanying loss of rete ridges in the overlying epidermis. In some studies, regression has been an adverse prognostic parameter, whilst in others it has been a favorable prognostic parameter [ 34 , 35 ].

Lymphovascular invasion

The presence of tumor cells within lymphatics (or blood vessels) at or near the primary melanoma site is an adverse prognostic parameter in melanoma. The use of Immunohistochemical staining for lymphatic and/or vascular markers (such as D2-40 and CD31) accompanied by markers of melanoma cells can be useful for identifying and highlighting lymphovascular invasion (Fig.  4 ).

figure 4

Lymphatic invasion by melanoma. The melanoma cells have been stained positively with MelanA/MART1 (red chromogen) whilst the lymphatic endothelium is stained with the lymphatic marker D2-40 (brown chromogen)

Microsatellites

In the 8th edition, the definition of microsatellites was revised. It is defined as a microscopic metastasis adjacent or deep to a primary tumor site identified on pathological examination. It must be discontinuous from the primary and separate by normal stroma, without fibrosis or inflammation (Fig.  5 ). The previous minimum size and distance from the primary tumor that formed part of the 7th edition definition are not applicable in the 8th edition. It is recommended that when considering a diagnosis of the presence of microsatellites, it is often prudent to examine additional levels of the block of tissue to ensure that the microsatellite is indeed discontinuous from the primary tumor.

figure 5

Microsatellite metastasis identified in a primary melanoma wide excision specimen

AJCC N category

There are three criteria that define the N category in the 8th edition:

the presence of clinically occult regional lymph node metastases identified by sentinel lymph node (SLN) biopsy;

clinically detected regional lymph nodes (detected either via by physical examination or on radiological imaging); and

the presence of in-transit, satellites, or microsatellite metastases.

The various N categories are presented in Table  3 .

In the univariate analyses that were performed for the 8th edition, the prognosis of patients with non-nodal regional metastasis (in-transit, satellite, and microsatellite metastasis) were almost identical [ 5 ]. For this reason, these three subcategories were grouped together for staging purposes in the 8th edition. In patients with stage III melanoma, the number of locoregional metastases as well as the tumor burden strongly correlates with outcome, i.e., the various N subcategories correlate with survival. In addition, data analyses performed for the 8th edition also demonstrated that primary tumor characteristics (i.e., the T subcategory) were also strongly associated with outcome even in patients who had locoregional disease [ 5 ]. It is for this reason that both the T and N categories were combined to define the stage III groupings in the 8th edition (Table  4 ). Ten year melanoma specific survival ranges from 88% for stage IIIA to 24% for stage IIID melanoma [ 5 ].

In the 8th edition staging system, SLN biopsy is required for pathological staging of all patients whose primary melanomas is greater than 1 mm thick. Many clinical practice guidelines also recommend SLN biopsy be considered in patients with tumors 0.8–1 mm thickness when other high-risk features are present such as the presence of ulceration, a high mitotic rate, young patient age (<40), or lymphovascular invasion. SLN tumor harboring status represented the strongest predictor of outcome in patients with clinically localized primary melanoma. Furthermore, it may also be helpful in identifying some patients who may benefit from adjuvant systemic therapy.

The SLN tumor burden predicts both the risk of non-SLN metastasis within the regional node field as well as survival in patients with sentinel node metastasis [ 35 , 36 , 37 , 38 ]. Various surrogates for quantifying SLN tumor burden have been proposed, and in general, all correlate with disease outcomes. The IMPSG and the AJCC melanoma expert panel both recommend that, at a minimum, the largest dimension of the largest metastasis should be recorded in the pathology report. Other parameters that may also be useful for prognosis include the location of the metastases (subcapsular, intraparenchymal, or both), the tumor penetrative depth (centripetal thickness), and the percentage cross-sectional area of the lymph node involved by tumor. The presence of extranodal metastasis, although uncommon in SLNs, is also an adverse prognostic parameter; thus its presence or absence should be recorded in pathology reports of all regional lymph node specimens derived from melanoma cases [ 39 ].

AJCC M category

Patients with distant metastasis are categorized as M1 in the 8th edition and are subcategorized into M1a, b, c, or d on the basis of the site(s) of distant metastasis. Suffixes are added for the M category for elevated (1) or non-elevated (0) serum lactate dehydrogenase (LDH) levels (Table  5 ).

AJCC staging rules

In the 8th edition, clinical staging is defined as being based upon assessment of the initial primary tumor biopsy as well as clinical examination of regional lymph nodes. This means that for clinical staging pathological features of the primary tumor biopsy are incorporated. For pathological staging, pathological features of the definitive treatment of the primary tumor site is utilized (both the primary tumor biopsy and wide excision specimens). Pathological staging should be based on the worst features of either the primary tumor biopsy or wide excision specimen. For example, if an ulcerated T2 melanoma is identified on initial biopsy, it should be designated as cT2b. However, even if there is no ulceration present in the subsequent excision specimen, the associated primary melanoma should still be designated as pT2b. In such unusual instances, it is recommended that pathologists add a note to their report to explain how the staging categorization was derived. It is also specified in the staging system that tumor thickness measured on an initial biopsy and subsequent incision should not be added together to derive the tumor thickness. Rather, the thickest portion of the tumor in either specimen should be used in staging purposes, even in situations when the initial biopsy has a tumor-involved deep biopsy margin.

Limitations of staging

By necessity, the AJCC staging system can only take into account a limited number of prognostic parameters. Nevertheless, many additional well-established prognostic factors are not incorporated into the staging system. Incorporation of additional prognostic parameters into computerized prognostic algorithms is likely to provide more individualized and accurate prognostic estimates [ 40 ].

Prognostic estimates associated with the various AJCC staging categories are defined at the time of initial diagnosis and do not consider changes (improvements) in prognosis that may occur with survival over time in the absence of disease recurrence. The latter is known as a conditional survival estimate. For example, in one study, a patient with AJCC 8th edition stage IIID disease had a 5-year survival of 10%, however, if the patient was still alive in 5 years, they had a 50% chance of being alive 5 years later (i.e., 10 years after initial diagnosis) [ 41 ].

Molecular markers of prognosis

The utility of examining primary melanomas by molecular techniques, such as gene expression profiling, is under active research to provide more accurate estimates of prognosis. In the future, it is likely that it will be possible to integrate such data into prognostic estimates. Nevertheless, at the present time, additional data are needed before it becomes appropriate to recommend their routine use in clinical practice [ 42 ].

Conclusions

When assessing primary cutaneous melanomas, pathologists should provide a report with sufficient information to facilitate both accurate staging to occur and a reliable estimate of prognosis to be made. This is necessary to establish an evidence-based management plan and is facilitated by employing a structured pathology report. More accurate personalized predication of prognosis is likely to be possible in the future utilizing web-based or other computerized tools, the integration of additional prognostic factors and complex molecular data as well as molecular predictive and diagnostic biomarkers.

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Scolyer, R.A., Rawson, R.V., Gershenwald, J.E. et al. Melanoma pathology reporting and staging. Mod Pathol 33 (Suppl 1), 15–24 (2020). https://doi.org/10.1038/s41379-019-0402-x

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Histopathology and molecular pathology confirmed a diagnosis of atypical Caroli’s syndrome: a case report

  • Tianmin Zhou 1   na1 ,
  • Keyu Liu 2   na1 ,
  • Hao Wei 3 ,
  • Qingmei Zhong 1 ,
  • Daya Luo 4 ,
  • Wenjuan Yang 5 ,
  • Ping Zhang 1 &
  • Yingqun Xiao 1  

Diagnostic Pathology volume  19 , Article number:  36 ( 2024 ) Cite this article

Metrics details

Caroli’s syndrome is a congenital disease characterized by dilation of intrahepatic bile ducts and congenital hepatic fibrosis. It is a rare condition in clinical work. Typically, the diagnosis of this disease is confirmed through medical imaging. Here, we report a case of atypical Caroli’s syndrome in a patient who presented with recurrent upper gastrointestinal tract bleeding. The patient underwent imaging examinations, liver biopsy and whole exome sequencing. The results of the imaging examination were non-specific. However, with the aid of pathological examination, the patient was diagnosed with Caroli’s syndrome. In conclusion, for cases where the imaging presentation of Caroli’s syndrome is inconclusive, an accurate diagnosis should rely on pathology. By discussing this specific case, our aim is to enhance readers' understanding of this disease, provide valuable information that can aid in the early detection and appropriate management of Caroli’s syndrome, ultimately improving patient outcomes.

Introduction

Caroli’s disease (CD) is a rare congenital disease characterized by segmental saccular dilation of intrahepatic bile ducts without obstruction. It was first reported by Caroli et al. in 1958 [ 1 ]. The incidence of CD is approximately 1 in 1,000,000 live births [ 2 ]. It is widely recognized that CD is associated with mutations in the polycystic kidney and hepatic diseases 1 (PKHD1) gene [ 3 , 4 ]. According to the diagnostic criteria for Caroli’s disease, it is classified into two subtypes: Caroli’s disease type I, characterized by cystic segmental dilation of the bile ducts, and Caroli’s disease type II or Caroli’s syndrome (CS), which is associated with saccular alterations of the hepatic ducts, liver fibrosis, and even cirrhosis with manifestations of portal hypertension [ 5 ], as observed in our patient. CS is typically diagnosed during adolescence or before the age of 30, often coinciding with the time when patients seek medical attention due to apparent symptoms [ 6 , 7 ]. The diagnosis of typical CS is not challenging, as it can be identified through clinical symptoms and imaging techniques such as abdominal ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). Most cases of typical CS are associated with autosomal recessive polycystic kidney disease (ARPKD), which often presents with varying degrees of renal cysts. In addition, patients with unexplained hepatic fibrosis and portal hypertension may exhibit non-obstructive segmental or diffuse cystic dilation of the intrahepatic bile ducts. The most characteristic imaging finding is the “central dot sign” [ 8 ], although the presence of fibrosis in CS can sometimes obscure this sign on radiological examinations. However, the diagnosis of atypical CS can be challenging due to the absence of characteristic clinical manifestations and imaging features. In this case report, we describe the case of a young male patient with atypical CS who does not have ARPKD, polycystic liver, or the characteristic “central dot sign”. The patient's only presenting symptom is unexplained liver cirrhosis.

Case presentation

General conditions and clinical manifestations.

The 17-year-old male patient has been experiencing recurrent fatigue for 8 years and melena for the past 5 days. He has received treatment at a local hospital on multiple occasions, where a Color Doppler Ultrasound indicated liver cirrhosis and splenomegaly. He was subsequently diagnosed with liver cirrhosis following hepatitis and was treated with hemostatic drugs and fluid supplementation. However, the treatment at the local hospital failed to alleviate the symptoms of anemia. As a result, the patient sought new diagnosis and treatment at our hospital.

Upon examination, the patient's general condition was stable. The pale face observed was consistent with anemia, while no obvious signs of jaundice or Kayser-Fleischer rings were identified in either eye. Additionally, there were no signs of liver palm or spider angioma. Palpation did not reveal any superficial lymph node enlargement, abdominal mass, liver enlargement, pressing pain, or positive Blumberg sign. A firm and obtuse spleen was palpated 6 cm below the anterior rib margin using two-handed palpation. Abdominal shifting dullness was negative.

The patient denied a history of HBV infection, alcohol consumption, smoking, or exposure to schistosomiasis epidemic areas. Both parents are healthy, although the patient's younger sister and paternal grandmother have a history of liver cirrhosis.

Laboratory examination

The blood and biological tests of this patient revealed elevated levels of total bilirubin (TBiL) and serum amyloid A (SAA), as well as depressed levels of prealbumin and high-density lipoprotein (HDL). The results of hepatic enzymes were within the normal range. These findings suggest the presence of cholestasis, inflammatory reaction, and liver dysfunction.

Imaging examination

Abdominal B-mode ultrasound showed the oblique diameter of the right lobe of liver is 11.4 cm (normal 10–14 cm); the third-order biliary branches measuring 0.59 mm (normal < 0.4 mm). Glisson’s capsule was coarse. Echoes of hepatic area were uneven, and hepatic veins were not clear. The diameter of portal vein and common bile duct caliber were 13 mm (normally < 13 mm) and 4 mm (normally 6–8 mm) respectively [ 9 ]. No obvious of polycystic liver was observed (Fig.  1 ).

figure 1

USG Abdomen reveals two examinations conducted at different time prior to the current observation ( A and B ). Right portal vein (red arrowhead); Right hepatic vein (yellow arrowhead); the third-order biliary branches (green arrowhead); Right anterior lobe of the liver (SVIII)

Abdominal computer tomography (CT) measured the maximum liver diameters and showed the cranio-caudal (CC) was 15.0 cm (normal < 15 cm), anterior–posterior (AP) of right and left lob were 13.4 cm (normal 8–10 cm) and 9.3 cm (normal 6–9 cm) [ 10 ]. Importantly, no abnormal highdensity shadow or intrahepatic cyst was observed. The volume of spleen was obviously enlarged, extending into the pelvis and across the midline. The kidneys exhibited a normal morphology without evidence of polycystic kidney disease (Fig.  2 ).

figure 2

The results of CT scan. A Plane CT scan; B Delayed phase of contrast-enhanced CT; C CT scan shows giant spleen and normal kidneys

Under gastric endoscopy, it clearly showed that there were several circuitous bulges protruding into the cavity of esophagus and gastric fundus. The results showed severe esophagogastric varices. The diameter of fundus varices was about 6 mm. Red-color sign in fundus varices was positive (Fig.  3 ).

figure 3

Gastric endoscopy of Caroli’s disease shows that ( A ) 4 variceal veins in esophageal wall; B several variceal veins extending from cardia, RC + 

Pathological examination

Histological examination of liver biopsies stained with Hematoxylin–eosin (HE) revealed distinct features of the liver tissue. The portal tracts showed significant expansion of severe fibrosis, with the formation of bridging fibrosis. Infiltration of inflammatory cells and the presence of pseudolobules were observed (Fig.  4 A). Importantly, these “pseudolobules” differed from those typically associated with liver cirrhosis. The arrangement of hepatocyte plates appeared normal, without any indications of hepatocyte edema, degeneration, or cholestasis. This finding is consistent with the pathological features of congenital hepatic fibrosis reported by Ru-JiaT et al. [ 11 ]. Additionally, a large number of bile ducts within the portal tracts showed malformation and dilation, accompanied by hyperplastic cholangiocytes that showed no atypia. Notably, the dilated bile ducts showed numerous instances of cholestasis, as indicated by the presence of brown staining (Fig.  4 B).

figure 4

A Hematoxylin–eosin (H-E) stain (× 50) shows severe portal tracts fibrotic bands and “pseudolobules” (shows in black dashed circle); B HE stain (× 200): Bile ductal malformation, dilation and cholestasis (black arrowhead); The ( B ) is enlarged in black box of ( A )

The use of immunohistochemistry and many special stains of tissue specimen can help us learn more about the pathological and functional changing, contributing to make a proper diagnosis. Anti-CK7 is the antibodies used to label cholangiocytes. The immunohistochemistry of CK7 clearly showed biliary dilation and cholangiocytes hyperplasia (Fig.  5 A). In the hepatic lobule, anti-CD34 normally does not expressed in sinus endothelial cells inside of hepatic lobules except for neoangiogenesis and changes of blood composition [ 12 , 13 ]. The positive results of anti-CD34 (Fig.  5 B) showed that the interlobular vein in the portal vein dilated obviously and protruded into the hepatic parenchyma, and the interlobular vein occupied almost the whole area of the portal vein, suggesting that there may be portal hypertension, which is consistent with the clinical manifestation of the patient. We showed a normal structure of bile capillaries in hepatic lobules with anti-CEA (Fig.  5 C).

figure 5

A anti-CK7 (× 100): biliary dilation and hyperplasia; B anti-CD34 (× 100): The interlobular vein in the portal area dilated significantly and protruded into the hepatic parenchyma, and the interlobular vein almost occupied the whole portal area; C anti-CEA (× 100): normal bile canaliculi inside of hepatic lobules

The liver biopsy specimens underwent special stains including periodic acid-Schiff (PAS) stain, Masson trichrome stain, reticulin connective tissue stain, and diastase pre-treated PAS (DPAS) stain. The PAS stain allows for the visualization of intracellular glycogen storage in hepatocytes, appearing as red color under microscopy. This stain is useful in diagnosing hereditary glycogen storage diseases or ischemic injuries [ 14 ]. In this study, the hepatocytes within the hepatic lobules exhibited red staining, indicating normal glycogen storage without intracellular fading or fatty vesicles. The Masson trichrome stain highlights collagen fibers in blue and provides information on the extent of fibrosis. The reticulin connective tissue stain is used to evaluate the degree of fibrosis by labeling reticulin (type III collagen fiber) deposition [ 15 ]. Both of these connective tissue stains revealed perisinusoidal and portal tracts fibrosis, bridging fibrosis, resulting in fibrotic septa and the formation of “pseudolobules”. The D-PAS stain is employed to identify phagocytic inclusions and immunoglobulin within macrophages. In this study, neither the portal tracts nor the liver parenchyma exhibited indications of acute phagocytosis by activated macrophages or immunoglobulin globules, which are associated with drug-induced hepatitis and autoimmune liver disease (Fig.  6 ).

figure 6

A PAS staining (× 100) and ( B ) Trichrome stain (× 100) shows peri-sinus and peri-portal fibrosis; C Reticular staining (× 100) shows portal fibrosis and “pseudolobule” formation; D D-PAS (× 100)

Based on the observed interlobular bile duct malformation, dilation, cholestasis, and severe fibrosis in the patient’s clinical presentation, the diagnosis of CS was inferred in accordance with the 2022 EASL Clinical Practice Guidelines on the management of cystic liver diseases [ 16 ]. After extensive consultation with the patient, whole exome sequencing was performed to provide a thorough molecular analysis to confirm the diagnosis. This sequencing technique allowed for a detailed examination of the patient’s genetic profile, enabling the identification of potential disease-causing variants associated with CS and increasing the certainty of the diagnosis.

Whole exome sequencing

Based on the pathological results, peripheral venous blood (5 mL) was collected from the patient, his affected sister, and his healthy parents for Whole Exome Sequencing (WES), which was performed by Macro & Micro-test. The sequencing results revealed two heterozygous variants: a missense variant c.2507 T > C (p.Val836Ala) and a novel variant c.10156G > C (p.Val3386Leu). Both the patient and the sister harbored these two variants, with the former being paternal and the latter being maternal (see Table  1 ).

The patient underwent various forms of treatment to address their symptoms. This included splenic artery embolization to restore splenic function and endoscopic esophageal varix ligation to stop bleeding in the upper gastrointestinal tract. In addition, the patient received acid suppression therapy and antibiotic treatment.

Follow-up was performed by telephone interview for 2 years since the patient left hospital. No varices bleeding happened anymore. Vital signs were stable, and the patient has no discomfort.

Caroli’s syndrome (CS) is a rare congenital disease characterized by non-obstructive segmental saccular dilation of intrahepatic bile ducts [ 17 ]. It is often accompanied by congenital hepatic fibrosis (CHF), which presents as fibrosis in the portal tracts. In terms of pathogenesis, CS belongs to a disorder called ductal plate malformation (DPM), a congenital disorder caused by abnormal development of the embryonic biliary [ 18 , 19 , 20 ]. The diverse range of diseases within the DPM spectrum can present with unspecific clinical symptoms and signs, making diagnosis challenging for doctors [ 21 , 22 ]. While several intracellular pathways may contribute to the pathogenesis of CD rats, the exact pathways in humans are still being researched [ 17 ]. The etiology of CS is complex and unclear. Some cases have reported a potential link between CS and PKHD1 gene mutation. It has been confirmed that PKHD1 mutation is the primary cause of autosomal recessive polycystic kidney disease (ARPKD) [ 23 ]. The PKHD1 gene encodes fibrocystin, which is expressed on renal epithelial cells and cholangiocytes [ 24 ]. The biological function of the PKHD1 gene is not fully understood, but it is believed to be involved in cystogenesis, tube morphogenesis, cell–cell junction, cilia function, planar cell polarity, and cell proliferation [ 24 , 25 ]. The common clinical presentations of CS include upper abdominal pain, recurrent cholangitis, intrahepatic calculi, jaundice, undetermined cholestasis, portal hypertension, pancreatic damage, and spleen hyperfunction. Based on the literature, patients with CS could be easily misdiagnosed with many other hepatic diseases, such as primary sclerosing cholangitis (PSC), multidrug resistance protein 3 (MDR3) deficiency, recurrent pyogenic cholangitis, hepatic cysts, autosomal dominant polycystic liver disease (ADPKD), choledochal cysts, congenital hepatic fibrosis, biliary papillomatosis, and biliary hamartomas [ 26 , 27 , 28 ]. To make a diagnosis, doctors typically begin with imaging examinations when patients present with nonspecific clinical symptoms. When the patients with visible discomfort seek medical attention, imaging examination can usually reveal the presence of multiple dilated intrahepatic bile ducts. In most cases, imaging examinations can reveal multiple dilated intrahepatic bile ducts. The ‘central dot sign’ found on MRI and CT scan is highly specific for typical CS [ 29 ]. It is a high-dense dot in the dark background. Histologically, the dot is formed by portal veins and hepatic arteries, while the background consists of dilated intrahepatic bile ducts. However, this case does not exhibit this specific sign in the imaging examination results. Therefore, pathological examinations and gene sequencing were performed to confirm the diagnosis.

In this case report, the patient denied any history of HBV infection. The immunohistochemistry results for HBV surface antigen and core antigen were negative (figures not shown), indicating that acute or chronic hepatitis B was not present. Wilson's disease is a rare hereditary disease caused by copper accumulation, which can involve the liver and central nervous system. Liver symptoms, including jaundice, portal hypertension, and fibrosis, often occur before the age of 20, while neurological symptoms typically occur much later [ 30 , 31 ]. No Kayser-Fleischer (K-F) rings were found in the eyes, and the patient’s psychiatric condition was normal. Blood tests showed a normal level of ceruloplasmin (Table  2 ). The likelihood of hereditary Wilson's disease was low, so we did not recommend sequencing the ATP7B gene. Blood tests also showed negative serum autoantibody. Liver biopsy revealed no lymphoplasmacytic infiltration into hepatic lobules, rosette formation in hepatocytes, or interface hepatitis [ 32 ]. These results ruled out the possibility of autoimmune hepatitis. Previously known as primary biliary cirrhosis, primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of interlobular bile ducts, cholestasis, portal tracts inflammation, and fibrosis [ 33 ]. The histological features of CS can be easily distinguished from those of PBC. PBC is histologically characterized by chronic non-suppurative destructive cholangitis of the small interlobular bile ducts, resulting in chronic progressive cholestasis. In this case, microscopic observation showed no obvious bile duct damage in the portal tracts; instead, bile duct hyperplasia and dilation were observed. This suggests that the diagnosis of PBC was excluded. The diagnosis of drug-induced liver injury (DILI) should be considered after excluding other possibilities. The results of PAS-D staining did not show clusters of macrophages, and the patient had no history of drug use. Therefore, the results did not meet the criteria for a diagnosis of drug-induced hepatitis. The results of PAS staining revealed normal glycogen storage in hepatocytes, and no abnormal uncolored hepatocytes were found, indicating no steatosis. The results of anti-CD34 staining in this case suggest the presence of portal hypertension, which is consistent with the patient's clinical manifestation. The final diagnosis was based on the patient's family history of liver cirrhosis, biliary saccular dilation observed in imaging examinations, portal tracts fibrosis observed in liver biopsy, and the presence of PKHD1 mutation.

A compound heterozygous mutation of the PKHD1 gene was identified through whole exome sequencing. The results indicate that both the patient and his affected sister have two heterozygous variants: a missense variant c.2507 T > C and a novel variant c.10156G > C. We searched for the c.2507 T > C mutation on the GnomAD website, and the results suggest that this mutation is likely to be pathogenic. This finding is consistent with several Chinese articles, which suggest that it is unique to Chinese individuals [ 34 , 35 ]. However, there is no data available on the c.10156G > C mutation on the GnomAD website. We analyzed the clinical significance of this variant using polyPhen2, SIFT, MutationTaster, FATHMM, and PROVEAN. The details of this analysis are provided in Table  3 . According to the American College of Medical Genetics (ACMG) standards and guidelines for variant interpretation, the c.10156G > C mutation is considered a likely pathogenic mutation in the PKHD1 gene for this family. Additionally, we investigated the minor allele frequency (MAF) of these two mutation sites in different populations. The details are presented in Table  4 . The c.2507 T > C mutation was found to be a rare and low-frequency variant, with the MAFs of less than 5%. The c.10156G > C mutation has not been previously reported.

The PKHD1 gene encodes the fibrocystin protein (FPC), which is located in the membrane of primary cilia. These primary cilia are involved in the formation of cysts in the kidney and liver [ 36 ]. Multiple reports have demonstrated that PKHD1 mutations are responsible for autosomal recessive polycystic kidney disease (ARPKD) and Caroli syndrome (CD) [ 37 , 38 , 39 ]. To date, over 900 PKHD1 mutations have been reported, with 60% being missense mutations and 40% being protein-truncated mutations [ 34 ] Ishiko et al. conducted a minigene assay and discovered that at least one non-truncating mutation of PKHD1 is necessary for perinatal survival [ 40 ]. However, published reports indicate that the same PKHD1 mutation can be associated with different clinical presentations [ 20 , 41 ]. These findings highlight the complexity of the relationship between PKHD1 and CS. In summary, the identification of PKHD1 mutations can provide strong evidence for the diagnosis of CS. In this particular case, the PKHD1 mutation only resulted in hepatic presentations without renal disorder. This suggests that the compound heterozygous mutation could significantly contribute to the etiology of isolated Caroli syndrome. However, it is not the sole reason for the patient's clinical presentation. Additionally, environmental factors may also play a role in the pathogenesis of CS, although the mechanisms remain unclear [ 17 , 34 ]. PKHD1 mutation is the most well-known cause of CS and can be easily confirmed through next-generation sequencing (NGS). However, there may be other yet undiscovered pathological factors that contribute to the disease. Given the sequence of events, the patient will require long-term follow-up to determine whether renal symptoms will develop.

In this case report, we successfully diagnosed a case of atypical CS, despite its limited mention in the literature. Supporting our findings, previous studies have also reported cases of atypical CS. For example, XiaoYM et al. documented a series of patients with CS who exhibited atypical symptoms and imaging manifestations [ 28 ]. Although our patient did not show the typical “central sign” in ultrasound and CT, multiple cysts were observed in the liver and kidney, which contrasted with our case report. Similarly, Acioli, M.L et al. described a case of atypical CS characterized by uncommon clinical manifestations, such as the absence of non-specific abdominal pain, cholestasis, or cholangitis. However, imaging examinations still proved effective in diagnosing CS [ 42 ]. Another study conducted by Tiotia, Rahul et al. reported a patient with atypical CS who, similar to our case, did not have renal lesions. However, this patient had typical intrahepatic manifestations, such as polycystic liver and fibrosis [ 43 ].

Generally, non-invasive imaging examinations, such as ultrasound, CT, and Magnetic Resonance Imaging (MRI), are sufficient for diagnosing CS. On the other hand, invasive procedures, including Magnetic resonance cholangiopancreatography (MRCP), Endoscopic Retrograde Cholangiopancreatography (ERCP), Percutaneous Transhepatic Cholangiography (PTC), and liver biopsy, are primarily used for differential diagnosis [ 27 , 44 , 45 ]. These procedures are only performed when patients present visible symptoms and seek medical attention. Consequently, individuals with a family history of liver cirrhosis or recurrent cholangitis should be made aware of the importance of PKHD1 gene sequencing by healthcare professionals, in order to increase the early detection rate during check-ups.

Availability of data and materials

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Abbreviations

Polycystic kidney and hepatic diseases 1

  • Caroli’s syndrome

Caroli’s disease

Congenital hepatic fibrosis

Adult recessive polycystic kidney disease

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This research was funded by the General Science and Technology Projects of Jiangxi Provincial Health Commission, grant number 202211521.

This research was funded by the Science and Technology Plan Project of Nanchang, grant number 2022-KJZC-015.

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Tianmin Zhou and Keyu Liu contributed equally to this work.

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Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China

Tianmin Zhou, Qingmei Zhong, Ping Zhang & Yingqun Xiao

Queen Mary School, Nanchang University, Nanchang, 330006, China

The First Clinical Department, Nanchang University, Nanchang, 330006, China

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China

Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China

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T.Z., K.L., and Y.X. conducted a comprehensive analysis and interpretation of the patient data pertaining to anatomopathological aspects, and were responsible for the initial draft of the article. H.W. and W.Y. contributed to the literature review. D.L. conducted a thorough review of the original draft and provided valuable guidance on the writing process. Q.Z. and P.Z. provided the pathology results and collected the clinical data. All authors made significant effort in the preparation of this report.

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Zhou, T., Liu, K., Wei, H. et al. Histopathology and molecular pathology confirmed a diagnosis of atypical Caroli’s syndrome: a case report. Diagn Pathol 19 , 36 (2024). https://doi.org/10.1186/s13000-024-01462-9

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a report of histopathology

THE BIOMEDICAL SCIENTIST - Biomedical news, views and analysis

The progress of histopathology reporting

Jo Horne, Andrew Usher and Gerry van Schalkwyk discuss the progress of the histopathology reporting programme and look to the future.

a report of histopathology

It has been six years since the histopathology reporting programme started in the UK. For many years it has been clear that there are workforce issues within histopathology, with a lower than optimal fill rate of training posts and a large proportion of the pathologist workforce due to retire in the next five years.

In 2010 a working party from the Royal College of Pathologists (RCPath) and the IBMS began to develop a pilot project to seek to train a cohort of biomedical scientists to report gastrointestinal or gynaecological histopathology specimens.

These specialties were chosen as they were large volume, with gynaecology especially targeted as a pathway that cytologists could follow. This small group of histopathologists and biomedical scientists drove forward the pilot programme, by writing a curriculum based on the histopathology curriculum for medical trainees, assessing portfolios and running the practical examinations.

The first cohort of trainees began the pilot programme in September 2012, and at the end of the first year a small group of trainees sat the first ever practical competency exam at the RCPath in London, comprising of slide stations with report writing, assessment of macroscopic images and face-to-face examination by consultant histopathologist assessors.

These trainees came from diverse backgrounds, such as advanced practitioners in histological dissection, laboratory managers and consultant biomedical scientists in cytology. The first year was a success, as a number of these trainees passed their portfolios and the competency exam, and within two years of the pilot commencing, it became a fully established training programme in 2014, with the formation of a conjoint RCPath and IBMS board. 

Candidate success

Each year has seen a new influx of trainees into the reporting programme, with currently more than 50 at various stages within the programme. Some have been successful, whilst others have faced a variety of barriers precluding their success, resulting in them leaving the programme. These barriers, including management of existing roles, and a lack of support, time and backfill, were identified as part of a trainee survey and discussed in a previous article in The Biomedical Scientist.

From the original group of trainees, five attempted the first sitting of the stage C exam in 2015. The exam was run over two days in Leicester, and was mirrored on the FRCPath part two exam, but excluded frozen sections and diagnostic cytology.  The examination comprised 20 short cases, four long cases, four macros (assessment and discussion around macroscopic photographs) and two Objective Structured Practical Examinations (OSPEs), involving written and face-to-face discussion of management or theoretical issues. One candidate passed the stage C exam, and more followed within the next 12 months.

When medical trainees pass the FRCPath part two, they then undergo a period of further competency-based training within their training laboratory before being awarded their Certificate of Completion of Training (CCT), with the decision made at their Annual Review of Competence Progression (ARCP) meeting.  For scientific trainees, there is also a CCT at the end of stage D, but there is currently no formal ARCP. Additional specific structure and guidance had to be implemented for scientific trainees to be allowed to progress and for consultant histopathologists to accept the validity of the training programme, when compared to that of medical trainees. The stage D guidance for the histopathology reporting programme was written in 2016, and the two trainees who has passed the exam by this point began independent reporting.

Programme development

Another important step in programme development occurred in 2016. The examination process was formally absorbed into the RCPath examinations department. This meant examinations were set and assessed by RCPath examiners, papers were centrally marked and examinations began to run annually, in parallel with other histopathology examinations for medically qualified trainees. The stage A exam is now at the same time as the ST1 resit examination in June, while the stage C exam takes place at the same time as the autumn FRCPath part 2 exam. Trainees apply for the exam and are informed of the outcome via the RCPath website, like any other trainee. These steps have been important for the reporting programme, as although they may seem like simple practicalities, they send a clear message about validity and standardisation of the qualification.

In 2017, the first two trainees achieved their CCT and the dermatopathology pathway was introduced, with a number of new trainees choosing this route. One of these trainees is a Scientist Training Programme (STP) graduate clinical scientist, thus opening up further opportunities for scientists from all training backgrounds within histopathology departments. Another milestone was reached in 2017, as the first consultant biomedical scientist in histopathology reporting was appointed, and no doubt more will follow within the next few years.

Timeline of the histopathology Reporting Programme progress so far

  • Working party from the RCPath and IBMS begin to develop the histopathology reporting pilot
  • First cohort of scientific trainees enter the histopathology reporting pilot programme
  • First sitting of the end of stage A competency examination
  • Qualification becomes a full training programme  
  • RCPath and IBMS Conjoint Board formed
  • First sitting of the end of stage C examination  
  • First trainee passes the stage C examination  
  • Stage D independent reporting guidance written  
  • Examinations absorbed into RCPath system with central marking and ratification
  • First trainees begin formal stage D and independent reporting
  • First trainees awarded CCT
  • First consultant level post created
  • New dermatopathology module offered  
  • First STP graduate enters training programme
  • Development of new modules under consideration

Looking forward

So, where are we in 2018? One of the most important roles for those of us involved in histopathology reporting is to get out there and promote the qualification and the opportunities that it can deliver. It is now about winning the hearts and minds of the wider histopathology community, and to develop appropriate consultant level posts for successful trainees to move into after CCT, either within their existing department, or at other trusts. The qualification can provide many opportunities – for the trainee, consultants, other colleagues within the laboratory, the organisation and, most importantly, the patient.

Six years on from the start of the reporting pilot, we continue to look to the future. Histopathology is evolving, in terms of workload and new technologies, such as genomics and digital pathology. The workforce also needs to adapt and develop to meet these future needs. We need to look at the introduction of new pathways into the reporting qualification, perhaps in the long term considering a generic early qualification before specialisation into one area. But we must develop this with our colleagues within all stakeholder organisations, so that in the long term there is a clear and standardised pathway of training in histopathology reporting for any trainee wishing to specialise in this area, whether their background is as a medic or a healthcare scientist. 

Jo Horne is an Advanced Practitioner Healthcare Scientist in Cellular Pathology at Southampton General Hospital.  Andrew Usher is Cellular Pathology Laboratory Manager at Cheltenham General Hospital. Gerry van Schalkwyk is a Consultant Histopathologist at the Royal Derby Hospital.  

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