Fumarate Hydratase-Deficient Renal Cell Carcinoma: Understanding Your Pathology Report

Section Editor: Trevor Flood MD FRCPC
July 16, 2026

Fumarate hydratase-deficient renal cell carcinoma, often shortened to FH-deficient RCC, is a rare type of kidney cancer. It makes up fewer than 1 in 100 kidney cancers. It is caused by the loss of a protein called fumarate hydratase, which normally helps the cell turn food into energy. When that protein stops working, waste products build up inside the cell and switch on growth signals that should be off.

Two things make this diagnosis different from other kidney cancers. First, it tends to grow and spread earlier than most kidney cancers, including when the tumor is still small, which is why treatment is usually started promptly. Second, and just as important, a large share of people with this tumor were born with the gene change that caused it. For that reason, everyone who receives this diagnosis is offered genetic testing, and the result matters not only for you but for your close relatives.

This article will help you understand the findings in your pathology report for FH-deficient renal cell carcinoma, what each term means, and why it matters for your care. If your report or an older report calls this tumor “HLRCC-associated renal cell carcinoma” or “papillary renal cell carcinoma, type 2,” the sections below explain how those names relate to the one you have now.

What causes fumarate hydratase-deficient renal cell carcinoma?

Fumarate hydratase-deficient renal cell carcinoma, a rare kidney cancer, is caused by the loss of both working copies of a gene called FH. This gene is a tumor suppressor gene, and it carries the instructions for the fumarate hydratase protein, one step in the chain of reactions a cell uses to produce energy. When the protein is missing, a substance called fumarate builds up inside the cell. The excess fumarate does two things: it changes which genes the cell switches on and off, and it tricks the cell into behaving as though it is starved of oxygen, which turns on the signals that build new blood vessels. That false oxygen-starvation signal is the reason the drugs described later in this article work the way they do.

The important question is where the first mutation in the FH gene came from. In some people, both copies of the gene were damaged in the kidney cell itself during life, a change called somatic, which cannot be passed on to children. In many others, one damaged copy was present in every cell of the body from birth, and the second copy was lost later in a kidney cell. A large proportion of people with this tumor, in some studies the majority, fall into the second group. This is why the diagnosis cannot be treated as a purely local problem, and why genetic testing is offered to everyone rather than only to people with a family history.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome

People born with a change in one copy of the FH gene have a condition called hereditary leiomyomatosis and renal cell cancer syndrome, usually shortened to HLRCC. It is inherited in an autosomal dominant pattern, meaning a parent with the condition has a 1 in 2 chance of passing it to each child, and it affects men and women equally. It causes three main findings:

Skin lesions — Firm bumps called cutaneous leiomyomas, made of smooth muscle and growing from the tiny muscles attached to hair follicles. They usually appear on the arms, legs, trunk, or face, often starting in a person’s twenties, and are frequently painful when touched or exposed to cold. They are noncancerous, and they are often the earliest visible sign of the syndrome.
Uterine fibroids — Most women with HLRCC develop uterine leiomyomas, also called fibroids. Fibroids are very common in the general population, but in HLRCC they tend to be numerous, large, and to appear unusually early, and many women have surgery for them in their thirties.
Kidney cancer — FH-deficient renal cell carcinoma, the subject of this article. Most people with HLRCC never develop it. The lifetime risk is estimated at roughly 15%, though estimates differ between study groups, and it can occur at a much younger age than other kidney cancers.

Skin bumps and heavy early fibroids together are the combination that most often leads to the syndrome being recognized. Because men do not develop fibroids, HLRCC is more easily missed in men and is often diagnosed later.

What are the symptoms of fumarate hydratase-deficient renal cell carcinoma?

Unlike most kidney cancers, which are usually found by chance on imaging done for another reason, fumarate hydratase-deficient renal cell carcinoma more often causes symptoms by the time it is discovered, because it tends to be found at a more advanced stage. Symptoms may include:

Blood in the urine, which can make the urine look red, pink, or brown.
Pain or a dull ache in the back or the side of the abdomen.
A lump or fullness in the abdomen or side.
Weight loss that was not intended, fatigue, or fever.

The exception is people already known to have HLRCC, who have regular kidney imaging. In that situation the tumor is usually found before it causes any symptoms, which is the purpose of the screening. If the tumor has spread to another part of the body (a process called metastasis), the symptoms depend on where it has spread; the lymph nodes, bones, lungs, and liver are the most common sites.

How is the diagnosis made?

The diagnosis of fumarate hydratase-deficient renal cell carcinoma is made when a pathologist examines kidney tissue under a microscope, supported by special tests. The tumor is usually first seen as a mass in the kidney on an ultrasound, CT scan, or MRI. Tissue is most often obtained by surgery to remove the tumor, although a needle biopsy may be performed first when the cancer has already spread and a tissue diagnosis is needed before drug treatment can start.

Under the microscope, this tumor is unusual because it has no single appearance. Within one tumor, the cells may form papillae (finger-like projections), small tubes, sieve-like patterns, cysts, or solid sheets, and often several of these at once. The feature that points to the diagnosis is in the nucleus of the cell: a very large, bright red nucleolus surrounded by a clear halo, sometimes described as resembling an owl’s eye. This feature may be present in only part of the tumor, so it can be missed. Many of these tumors also grow in a way that spreads into the surrounding kidney rather than pushing it aside.

Because the appearance overlaps with other kidney cancers, a test called immunohistochemistry, which uses special stains to detect proteins inside cells, is used to confirm the diagnosis. Two stains are central. The FH stain is normally positive in all cells; in this tumor the cancer cells lose it while the normal cells around them stay positive, which is what makes the result reliable. The 2SC stain detects a substance that builds up only when fumarate hydratase is not working, and it is positive in the tumor cells. Not every case shows the expected pattern, so molecular testing of the FH gene is sometimes added when the appearance is suggestive but the stains are not clear-cut. Because these same stains also point to an inherited condition and influence drug treatment, they are discussed again in the biomarker section below. Once the diagnosis is confirmed, imaging of the chest, abdomen, and often the bones is used to look for spread.

One historical point explains a change some readers will notice. Until recently, these tumors were grouped with papillary renal cell carcinoma and called “type 2,” because they can grow in a papillary pattern. They were also called “HLRCC-associated renal cell carcinoma.” The World Health Organization now recognizes FH-deficient renal cell carcinoma as its own cancer with its own name. The current name was chosen deliberately, because a pathologist looking down the microscope can tell that fumarate hydratase is missing but cannot tell whether the gene change was inherited. Only a blood test can answer that.

Why a grade may not appear on your report

Most kidney cancers are given a grade, a number from 1 to 4 describing how abnormal the cells look, using the WHO/ISUP system based on how easily the nucleoli can be seen. That system was developed and validated for clear cell and papillary renal cell carcinoma, and it is not applied to fumarate hydratase-deficient renal cell carcinoma, so your report may not contain a grade. This is expected and is not an oversight.

The reason is that a grade would add nothing here. The very large nucleolus that defines this tumor is present in essentially every case, so grading on nucleolar appearance would place almost every tumor in the highest category. FH-deficient renal cell carcinoma is instead regarded as a high-grade cancer by definition. In its place, the stage, the tumor size, and whether the tumor has grown outside the kidney or into lymph nodes carry the information about how the tumor is likely to behave.

Tumor size

Your pathology report will state the size of the fumarate hydratase-deficient renal cell carcinoma, measured in centimeters, from the tissue removed at surgery. This measurement is more accurate than the size estimated on imaging beforehand, so the two numbers may not match exactly. Size determines part of the tumor stage (pT), and the thresholds are 4 cm, 7 cm, and 10 cm.

Size carries a different meaning in this tumor than in other kidney cancers, and the difference is worth understanding. For most kidney cancers, a small tumor can reasonably be watched. FH-deficient renal cell carcinoma can spread while it is still small, so a small size on the report is not by itself reassuring, and it is the main reason treatment teams do not use active surveillance for these tumors.

Tumor extension

Tumor extension describes whether a fumarate hydratase-deficient renal cell carcinoma has grown outside the kidney and, if so, how far. The kidney is surrounded by a layer of fat, and outside that fat is a tough envelope called Gerota’s fascia. The adrenal gland sits on top of the kidney, and the renal vein carries blood away from the kidney into the largest vein in the body, the inferior vena cava. Your pathologist examines all of these structures in the tissue removed at surgery.

The report may describe growth into the fat around the kidney (perinephric fat), into the fat in the middle of the kidney where the blood vessels enter (renal sinus fat), into the collecting system that drains urine (the pelvicalyceal system), into the renal vein or the inferior vena cava, into the adrenal gland, or through Gerota’s fascia into other organs. Because this tumor tends to grow into the surrounding kidney rather than push against it, extension outside the kidney is found more often than in other kidney cancers. It raises the tumor stage and is associated with a higher risk of the cancer returning.

Lymphovascular invasion

Lymphovascular invasion means that cells from the fumarate hydratase-deficient renal cell carcinoma are seen inside small blood vessels or lymphatic channels within or around the tumor. Blood vessels carry blood throughout the body, and lymphatic channels carry a fluid called lymph toward the lymph nodes. Tumor cells inside these vessels can be carried elsewhere, so lymphovascular invasion is associated with a higher risk of the cancer returning or spreading. It is found more often in this tumor than in other kidney cancers, which fits with its tendency to reach the lymph nodes early.

Lymphovascular invasion is not the same as growth into the renal vein, which is a large named vessel and is reported separately as part of tumor extension and stage. It does not change the pT stage on its own, but it is one of the findings your treatment team considers when deciding how closely to follow you after surgery.

Surgical margins

A margin is the cut edge of the tissue removed during surgery for fumarate hydratase-deficient renal cell carcinoma. Your pathologist examines these edges under the microscope to see whether any tumor cells reach them.

Negative margin — No tumor cells are seen at the cut edge. This suggests the whole tumor was removed and is associated with a lower risk of the cancer coming back in the same place. Your report may also state the distance from the tumor to the nearest margin, because a wider clear margin matters more in this tumor than in most kidney cancers.
Positive margin — Tumor cells are present at the cut edge. This means tumor cells may have been left behind, and it is associated with a higher risk of the cancer returning at that site. A positive margin is one of the findings the surgical and medical teams use when deciding whether more surgery or closer follow-up should be considered.

Margins carry particular weight here. For most kidney cancers, surgeons can often remove the tumor with a narrow rim of normal tissue and preserve the rest of the kidney. Because FH-deficient renal cell carcinoma grows into the surrounding kidney and can spread early, surgical teams generally aim for a wider margin of normal tissue, which may mean removing more of the kidney than would be necessary for another tumor of the same size.

Lymph nodes

Lymph nodes are small immune organs found throughout the body, including around the large blood vessels near the kidney. Cells from a fumarate hydratase-deficient renal cell carcinoma can travel through lymphatic channels and settle in a lymph node. This tumor reaches the lymph nodes far more often than other kidney cancers, and it can do so even when the tumor in the kidney is small. For that reason, and unlike the usual practice in kidney cancer surgery, removing the lymph nodes around the kidney at the same time as the tumor is often considered when this diagnosis is known or suspected before the operation.

If lymph nodes were removed, your report will state how many were examined, how many contained cancer, and the size of the largest deposit of tumor within a node. It may also state whether extranodal extension is present, which means that cancer cells inside a lymph node have broken through the outer capsule of the node into the surrounding tissue. Cancer in even one lymph node is an important finding, because it places the tumor in a higher stage group and is associated with a substantially higher risk of the cancer returning.

Examination of the non-tumor kidney

When kidney tissue is removed for fumarate hydratase-deficient renal cell carcinoma, your pathologist also examines the kidney tissue away from the tumor. Two kinds of findings may be described. The first are changes that affect how well the remaining kidney will work, such as scarring from long-standing high blood pressure or diabetes. The second are additional small tumors or cysts. In people with HLRCC, kidney cysts are common and a cancer can arise within the wall of a cyst, so any additional lesion in the surrounding kidney is examined carefully and reported. Finding more than one tumor strengthens the case for an inherited condition and may lead to a referral to a genetics clinic.

Biomarker and molecular testing

Biomarkers are features of a tumor, usually a protein or a change in a gene, that provide information beyond the diagnosis itself. In most kidney cancers, biomarker testing is optional and does not decide treatment. Fumarate hydratase-deficient renal cell carcinoma is the exception among kidney cancers: the loss of fumarate hydratase is at once the thing that defines the diagnosis, the strongest signal of an inherited condition of any kidney cancer, and a finding that shapes which drugs are considered if the cancer spreads. Testing here is not optional.

Inherited (germline) FH testing

Germline testing looks for a gene change a person was born with, using a blood or saliva sample rather than the tumor itself. A diagnosis of FH-deficient renal cell carcinoma is a reason to offer this testing to every patient, regardless of age and regardless of whether anyone in the family has had kidney cancer. This is different from other kidney cancers, where testing is reserved for people who are young, have several tumors, or have a family history. The reason is simply that the pathologist cannot tell from the tumor whether the gene change was inherited, and that so many of these tumors turn out to be.

Results are reported in one of three ways: a pathogenic (disease-causing) variant in FH, which confirms HLRCC; no variant identified, which means the gene changes happened in the tumor alone and cannot be passed on; or a variant of uncertain significance, which means a change was found but it is not yet known whether it matters. A pathogenic result changes the plan for you and for your family. It means lifelong kidney imaging for you, skin and gynecologic care for the syndrome’s other features, and it means your parents, siblings, and children can be offered testing of their own, called cascade testing, through a genetics clinic. Because kidney tumors in this syndrome can appear in childhood, testing and imaging in relatives are generally started in late childhood rather than adulthood.

What FH deficiency means for treatment

This is where the diagnosis does work that no other kidney cancer biomarker does. Because the loss of fumarate hydratase makes the tumor cell act as though it is starved of oxygen, these tumors depend heavily on two signaling pathways: one that builds blood vessels (VEGF) and one that drives growth (EGFR). Drugs that block both pathways at once, the combination of bevacizumab and erlotinib, were tested in a clinical trial in people with advanced HLRCC-associated kidney cancer. The tumor shrank in 72% of them, compared with 35% of people with papillary kidney cancer that was not FH-deficient. This is the reason establishing the diagnosis matters so much: the same treatment works roughly twice as well when fumarate hydratase is missing, and there is no way to know that without the testing described above.

Comprehensive genomic profiling (next-generation sequencing)

Next-generation sequencing reads many genes at once from the tumor tissue. In this cancer it serves two purposes. It can confirm that both copies of the FH gene are damaged when the stains leave doubt, and it can identify other changes that may open the door to a clinical trial. Reports may state which alterations were found, that no reportable alterations were identified, or that a change of uncertain significance was detected. Sequencing of the tumor alone cannot reliably tell you whether a gene change was inherited; only the germline test described above can do that.

Mismatch repair, microsatellite instability, and tumor mutational burden

These tests identify tumors that respond to immunotherapy regardless of where the cancer started, an idea called a tumor-agnostic approval. Mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) are tested by immunohistochemistry and reported as intact or retained, which is the normal result, or as deficient (dMMR) when one or more proteins are lost. The related test for microsatellite instability is reported as stable (MSS) or high (MSI-H). Tumor mutational burden counts the number of mutations in the tumor and is reported as mutations per megabase, with 10 or more considered high. These findings are uncommon in this cancer, but when present they can make a person eligible for the immunotherapy drug pembrolizumab under approvals that apply across cancer types.

You can learn more about the tests described here in our Biomarkers and Genetic Testing section.

Pathologic stage (pTNM)

The pathologic stage of a fumarate hydratase-deficient renal cell carcinoma describes how far the cancer had grown at the time of surgery. It is written using the TNM system created by the American Joint Committee on Cancer (AJCC), currently in its 8th edition, and it is the same system used for all renal cell carcinomas. T describes the size of the tumor and how far it has grown outside the kidney, N describes whether cancer is found in nearby lymph nodes, and M describes whether the cancer has spread to a distant part of the body. The letter “p” in front means the category was assigned by a pathologist after examining the tissue. The M category is almost always determined by imaging rather than by the pathologist, so it may not appear on your report at all. Because this tumor is not graded, the stage carries more weight here than in other kidney cancers.

Tumor stage (pT)

pT1a — The tumor is 4 cm or smaller and remains inside the kidney.
pT1b — The tumor is larger than 4 cm but not more than 7 cm and remains inside the kidney.
pT2a — The tumor is larger than 7 cm but not more than 10 cm and remains inside the kidney.
pT2b — The tumor is larger than 10 cm and remains inside the kidney.
pT3a — The tumor has grown into the renal vein or one of its branches, into the fat around the kidney or in the renal sinus, or into the collecting system that drains urine, but not beyond Gerota’s fascia.
pT3b — The tumor has grown into the inferior vena cava below the diaphragm.
pT3c — The tumor has grown into the inferior vena cava above the diaphragm, or into the wall of the vena cava.
pT4 — The tumor has grown beyond Gerota’s fascia, including growth into the adrenal gland on the same side.

Nodal stage (pN)

pN0 — No cancer was found in any of the lymph nodes examined.
pN1 — Cancer was found in one or more nearby lymph nodes.
pNX — No lymph nodes were removed or they could not be assessed.

What is the prognosis?

Prognosis means the expected course of a disease. Fumarate hydratase-deficient renal cell carcinoma is the most concerning of the kidney cancers described on this site, and it is more honest to say so than to soften it. It spreads earlier and more often than other kidney cancers, roughly half of people in published series have disease that has already spread when it is found, and outcomes at that stage have historically been poor. There are two important qualifications. The first is that a tumor found while it is still confined to the kidney and removed with clear margins can be cured, which is the entire rationale for screening people known to carry an FH gene change. The second is that the outcome figures in the medical literature come from people diagnosed before the treatment described above was available, and survival with that treatment has been considerably longer than in the older reports.

The features on your pathology report associated with a higher risk of the cancer returning include:

Growth outside the kidney — Involvement of the fat around the kidney, the renal sinus, the renal vein, or the vena cava.
Cancer in lymph nodes — Common in this tumor and associated with a considerably higher risk.
Lymphovascular invasion — Tumor cells within small blood or lymphatic vessels.
Positive surgical margin — Tumor cells at the cut edge of the tissue removed.
Tumor necrosis — Areas where tumor cells have died, usually because the tumor outgrew its blood supply.
Sarcomatoid change — Areas where the tumor cells are replaced by long, thin, spindle-shaped cells resembling a soft tissue cancer. Uncommon, but associated with worse outcomes when present.
Larger tumor size — Size counts toward the stage, although in this tumor a small size does not carry the reassurance it would in other kidney cancers.

What happens after the diagnosis?

Once fumarate hydratase-deficient renal cell carcinoma has been confirmed, the findings on your pathology report, particularly the stage, the margin status, and whether lymph nodes are involved, shape the next steps. This diagnosis brings in a wider team than other kidney cancers, usually including a urologist, a medical oncologist, a pathologist, a radiologist, a genetic counselor, and often a dermatologist and a gynecologist for the other features of the syndrome. Care at or in consultation with a center that sees this rare cancer regularly is worth asking about.

Surgery — Surgery is the main treatment for a tumor confined to the kidney and offers the best chance of cure. Two things differ from other kidney cancers. Treatment is generally prompt rather than watchful, even for a small tumor, and surgical teams generally aim for a wider margin of normal tissue, with removal of the surrounding lymph nodes often considered at the same time.
Treatment after surgery (adjuvant therapy) — No drug treatment given after surgery has been shown to help in this cancer. The immunotherapy options approved after kidney cancer surgery, including pembrolizumab and the pembrolizumab and belzutifan combination approved in June 2026, were studied in and approved for renal cell carcinoma with a clear cell component and do not apply here. Follow-up is by imaging, and a clinical trial may be discussed.
Treatment for cancer that has spread — The combination of bevacizumab and erlotinib, described in the biomarker section, is the option most supported by evidence in this specific cancer, and the medical oncology team will discuss whether it is appropriate. Other options used in kidney cancers other than clear cell, including cabozantinib and immunotherapy combinations, may also be considered. Clinical trials are discussed more often in this cancer than in common kidney cancers, and a trial adding immunotherapy to bevacizumab and erlotinib is under way. Chemotherapy is not effective and is not used.
Genetic assessment — A referral to a genetics clinic is part of standard care for everyone with this diagnosis, not only those with a family history. If an inherited FH change is confirmed, your relatives can be tested, and those who carry it enter a screening program.
Follow-up and screening — After surgery, imaging of the abdomen and chest continues on a schedule set by your treatment team. If HLRCC is confirmed, lifelong surveillance is recommended for you and for relatives who carry the gene change: annual MRI of the abdomen, generally beginning in late childhood, because MRI detects small tumors that other scans miss; periodic skin examination; and, for women, gynecologic care for fibroids, including a conversation about family planning at a younger age than usual.

Questions to ask your doctor

Has genetic testing been arranged for me, and when will I see a genetic counselor?
If the gene change is inherited, which of my relatives should be tested, and at what age?
How was my diagnosis confirmed, and were the FH and 2SC stains or gene testing used?
Was my tumor previously called papillary type 2 or HLRCC-associated kidney cancer?
How large was my tumor, and what was the pathologic stage (pT and pN)?
Were lymph nodes removed, and did any contain cancer?
Were the surgical margins negative or positive, and how close was the tumor to the nearest margin?
Did the tumor grow outside the kidney, into the fat, the renal sinus, or the renal vein?
Was lymphovascular invasion, necrosis, or sarcomatoid change seen?
Was more than one tumor or cyst found in my kidney?
If my cancer has spread, is bevacizumab with erlotinib an option for me, and is a clinical trial available?
Should my care be reviewed at a center that specializes in rare kidney cancers?
How often will I need imaging, and will it be MRI?
Do I need to be checked for the skin and uterine findings of this syndrome?