Cancer and a rare syndrome

When you hear the word cancer in relationship to you or your family, you may have any one of many normal reactions- fear, panic, anger and anxiety are just a few. Until you know exactly what the situation is, it can be really hard to deal with. You may feel like your life is turning upside down. Others who have not experienced this may not understand what you are going through.

It’s important to find the help you need to get you through this. On a personal level, you may want to talk to a family member, friend, religious advisor, counselor, or join a cancer support group. On a medical level, we recommend finding a doctor who will really listen to you, and seeing a genetic counselor or a geneticist.

Because the Birt-Hogg-Dubé Syndrome is so rare, you may have trouble finding a doctor who knows about kidney cysts and tumors related to BHD. Normally you’d want to go to the best specialist you can in your area. It’s important for you to know that a well trained urologist, urologic oncologist, or oncologist may not be aware that BHD kidney cancer is not necessarily treated the same way as ‘normal’, or sporadic kidney cancer. You may be the only person, or family, with BHD in your area. Even a doctor who sees many people with kidney cancer may never have met anyone with BHD. That’s why it is vital that you know as much about it as possible yourself before deciding what you want to do.

It is good to know that the kidney cancer caused by BHD in most cases is manageable and does not spread, or metastasize. People who monitor their cancer and find appropriate treatment are living pretty normal lives. In all the medical literature on BHD, there are to date only 5 reported cases of death due to BHD related kidney cancer. This means that the odds for survival are very good. The key is finding the cancer early and working with a knowledgeable doctor. Both tumors and cysts may continue to ‘pop up’ after earlier cysts and/or tumors have been treated and removed; we don’t know how to stop this growth but monitoring and treatment have been successful for many.

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Kidney Cancer

It is really important that people with BHD have their kidneys examined regularly. Kidney cysts and tumors are associated with the Birt-Hogg-Dubé Syndrome, and the tumors can be cancerous. Manifestations of BHD may be either cysts, or tumors, or both. They could be on just one kidney, or both (bilateral). They may be single, or multifocal (multiple cysts or tumors).

If you read the BHD studies that have been published over the years, you’ll see different figures for how many people with BHD will develop kidney cancer. A Dutch study presents the figure as 2%, while the most recent study from the U.S. National Institutes of Health shows 34%. This is a considerable discrepancy, and there can be several reasons for it. One can be that the people who are reflected in the studies were referred to that particular study for different reasons – maybe one center sees more cancer patients. Until we have more data on BHD, it may not be possible to know exactly what the actual percentage is.

However, one thing is very clear. Kidney cancer is a serious disease. Some families may have no history of kidney tumors. In those that do, other family members with a BHD mutation have a much higher risk of developing kidney tumors than people from BHD families with no kidney tumors. If one person in your family has kidney tumors, every other person in that family who has BHD should be vigilant and have appropriate tests or scans on a regular basis.For the families who have no known kidney tumors, the situation can be a little tricky. If every family member has been tested for BHD and there are no kidney tumors, there may be less to worry about. However, we have been in contact with many families where only a portion of the members at risk have had a test for BHD. What should you do in this case? You may not know if kidney cancer is a part of your family’s BHD. It’s quite possible to have kidney cancer and not be aware of it. We would recommend consulting with medical professionals to set up a program for having kidneys checked.

Kidney tumors related to BHD are often treated differently than kidney tumors that are not hereditary; they may also be treated differently than kidney tumors in other hereditary syndromes. It is therefore essential that you work with a doctor who is familiar with BHD or willing to learn about it.

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Symptoms of Kidney Cancer

Some people who have kidney cancer may have symptoms such as blood in the urine, flank pain (the flank is on the side of your body, between the back and the upper abdomen), pain in the lower back, high blood pressure, weight loss, fatigue, or fever. Some people experience night sweats. Edema (swelling), especially of the legs and feet, may be a factor. Since all of these symptoms may be related to other conditions or illnesses, it’s not possible to be sure you have kidney cancer just by examining the symptoms.

It’s not unusual for people with BHD to be completely unaware that they have kidney cancer at all. You may have no symptoms. This is especially true of people whose cancer is diagnosed in the early stages. Kidney cancer can sometimes lead to unusual blood and urine test results, but it’s also possible to have tests in the normal ranges and still have kidney cancer.

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Types of Kidney Cancer

Kidney cancer, or renal cell carcinoma (RCC), is not just one type of cancer. RCC is actually several different kinds of cancer which grow t different rates, have different prognoses and react differently to treatment.

Other hereditary syndromes usually have just one kind of kidney cancer as a manifestation. For example, the kidney cancer caused by the Von Hippel Lindau syndrome is always clear cell. However, with BHD, the cancer could be one of several types, or a mixture. It can be clear cell, papillary, or chromophobe. The tumor may be oncocytic; this is often described as a benign tumor but in BHD literature you may see it listed with cancers.

Hereditary kidney cancer may only constitute 5-10% of all kidney cancers; non-hereditary RCC is called sporadic. Sporadic kidney cancer can be clear cell, papillary, chromophobe, medullary, transitional cell, collecting duct; it may be oncocytic or have sarcomatoid features. It may be called unclassified or mixed. Sporadic kidney cancer occurs for reasons which are currently unknown, although it in some cases is most likely related to obesity, smoking, or exposure to certain chemicals.

This section will only deal with the types of kidney cancer that are found in the Birt-Hogg-Dubé syndrome.

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Types of Kidney Cancer Associated with BHD

Kidney cancer is the common name for renal cell carcinoma (RCC). RCC associated with the Birt-Hogg-Dubé syndrome cannot be prevented at the current time.

Oncocytomas

Oncocytomas are considered to be benign kidney tumors. However, oncocytomas can grow in places that might affect the blood flow to the kidney. They can grow inside or on the kidney. It is not possible to know if a tumor is an oncocytoma until it is analyzed by a pathology lab. The accepted practice is to remove all kidney tumors because they could be malignant. Only after a tumor is removed would you know that it is oncocytic.

This type of tumor does not metastasize, or spread, to other parts of the body. About 3% of BHD kidney tumors are classified as oncocytic.

Mixed or Hybrid Oncocytic tumors

In BHD, finding tumors that are a mixture of oncocytic and another type is common. 67% of BHD kidney tumors are like this.

Chromophobe

Chromophobe kidney cancer is often slow-growing, and does not seem to metastasize in people with BHD. About 23% of kidney tumors related to BHD are chromophobe.

Clear cell

Although clear cell is one of the most common types of renal cell carcinoma, it is not common in families with BHD. Few fatalities have been associated with BHD, but some of them were clear cell cases.

Papillary

There is not much research on papillary BHD. It is one of the two kidney cancer types (the other is clear cell) that have been associated with the 5 known BHD fatalities.

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How do I know which kind of kidney cancer I have?

Kidney cancer is perhaps most often diagnosed from CT scan, MRI, or ultrasound results. You can see if there is on or more masses on one or both kidneys on these tests. On some of them you can see thedifference between cysts and tumors. These scans will not show you what kind of kidney cancer you have, just if you have growths on your kidney.

In general, sporadic kidney tumors are malignant. For the hereditary kidney cancer related to BHD, a tumor could be a benign oncocytoma or an oncocytoma mixed with a different type of cancerous kidney tumor.

If your tumor is removed surgically, it is sent to a pathology lab for testing. The pathology result will tell you what kind of cancer you have. If the first result is not clear, you may want to ask that a section of your tumor be sent to a different lab for a second opinion.

Different family members who have BHD may have different types of kidney tumors. For example, one may have a papillary tumor and one may have an oncocytoma. You won’t be able to tell what type of RCC youhave by looking at another family member’s pathology results.

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BHD Kidney Cancer related deaths

No one likes to hear about deaths related to cancer; this is very scary for any family affected by this disease. For BHD families, it is a little different. There have been few cases reported to date. An article published in 2008 says that medical literature to date has reported five fatalities throughout the world that were associated with metastatic kidney cancer in BHD families.

Most (93%) of the kidney cancer reported in those with BHD is chromophobe, oncocytic, or hybrid oncocytic.

The metastatic kidney cancer that led to the BHD deaths was clear cell, tubullo papillary or determined to have papillary features.

This does not mean that everyone with clear cell or papillary kidney tumors is going to have their cancer metastasize, or is going to die. That has not been the case so far. However, it does mean that someone with these types of BHD related kidney cancer might want to make sure to be monitored carefully.

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Kidney Cancer Stages and Grades

If your kidney cancer is examined by a pathologist, you will be told the Stage and the Grade.

There are four stages, namely I, II, III, and IV. In Stages I and II, the cancer is confined to the kidney; it has not spread to other organs or parts of the body. These Stages would be common for Birt-Hogg-Dubé Syndrome. Stages III and IV are used to designate cases where the cancer has spread. If you are Stage I when you are diagnosed, due to the size of the tumor, your status would only be changed to III or IV if the cancer spreads outside the kidney. This is rare in BHD.

Grades are assigned a number from 1-4. Grade 1 means that the cancer is slow growing. A Grade 4 would mean that the cancer was quite aggressive, and that the prognosis would be poor compared to the lower grades.

Staging and Grading of Kidney Cancer

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Primary Kidney Cancer vs. Metastatic Kidney Cancer

It’s possible to have multiple cancerous tumors in one or both kidneys when you have BHD. In some cancers, having multiple tumors means you have metastatic disease. That’s not the case here. These tumors would all be considered primary tumors, as opposed to metastasis. You would still be classified Stage I or II , depending on the size of the tumor/s. Only if the cancer spreads would this change.

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Kidney Cysts

Kidney cysts are normally benign. They are rounded, and usually filled with fluid. As we get older, it is common to develop cysts on different organs. In most cases you would never know they are there. By the seventh decade, one third to one half of the population may have a kidney cyst. This type of cyst, usually a simple cyst, would only require treatment if it grew so big that another organ or body part might become involved. Rarely would there be a physical symptom of a kidney cyst – most often it would be discovered incidentally, during a test or scan for something else. Infrequently, a simple cyst could be painful, but it is not cancerous.

Complex cysts can potentially be malignant. A complex cyst can have a more irregular shape than a simple cyst, or other irregularities such as a thicker wall. A scan may show that a complex cyst has features that suggest cancer. Such a cyst should be carefully evaluated as it may be best to remove it.

With BHD, it is possible to have many cysts. These should be monitored regularly.

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Second Opinion on Kidney Pathology

Since kidney tumors are normally not biopsied, the type of renal cell carcinoma a patient has will be determined after a nephrectomy or partial nephrectomy, when the tumor is sent to a pathology lab to be examined. It’s important to know that rare types of renal cell carcinoma are not often seen in a typical pathology lab. There have been cases when the pathology of a BHD patient has been incorrectly identified. It may be a good idea to get a second opinion on your pathology.

You can request that a second opinion be done at the U. S. National Cancer Institute. This is at no cost to you. Your doctor or pathology lab may ask for this this second opinion – often the lab will prefer that you not arrange it yourself.

For more information, contact:

Maria J. Merino-Neumann, M.D.

Head, Surgical Pathology Section

Building 10

Room 2N212

Bethesda, MD 20892

Phone: 301-496-2441

Email: mjmerino@mail.nih.gov

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Sources

• Renal Oncocytoma Versus Chromophobe Renal Cell Carcinoma: Debate Goes On.
  Advances in Anatomic Pathology 12(3):152-153, May 2005.
  Akhtar, Mohammed MD
• Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer.
  J Med Genet 2003 Nov;40(11):820-4.
  da Silva NF, Gentle D, Hesson LB, Morton DG, Latif F, Maher ER.
• Birt-Hogg-Dubé Syndrome: Clinical and Genetic Studies of 20 Families.
  J Invest Dermatol 2007 Jul 5: 17611575 (P , S , E , B , D )

  Edward M Leter, A Karijn Koopmans, Johan J P Gille, Theo A M van Os, Gabriëlle G Vittoz, Eric F L David, Elisabeth H Jaspars, Pieter E Postmus, R Jeroen A van Moorselaar, Mikael E Craanen, Theo M Starink, Fred H Menko

• BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé Syndrome: A new series of 50 families and a review of published reports
  J Med Genet. Published Online First: 30 January 2008. doi:10.1136/jmg.2007.054304
  Jorge R Toro 1, Ming-Hui Wei, Gladys Glenn, Michael Weinreich, Ousmane Toure, Cathy Vocke, Maria L Turner, Maria Merino, Peter Pinto, Seth Steinberg, Laura Schmidt and W Marston Linehan

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