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Hastening the Road to Diagnosis
The Role of the Broad Ligament Cystadenoma in Early Detection of VHL
Editor’s introduction: This article highlights a little known benign lesion sometimes found in women with VHL. We want to share with you what is currently known, and enlist your help in learning more. If you have experienced something that sounds like this, we would appreciate your sharing your experience with us. The only way we learn is to assemble the experiences of a large number of people. Part of the problem is the widely varied terminology used to describe them. They occur among structures with names women usually do not recognize. We will explain some of this terminology and provide a list of terms you may hear.
In the VHL Handbook you will find these lesions referred to as "broad ligament cysts". In fact they are not cysts (simple fluid-filled sacs) but are cystadenomas (a benign epithelial tumor containing one or more cysts). In other words, they look more like a tumor on radiographic screening, but they are not cancer and will not invade other tissues. They do not pose a danger to the patient, but they can be helpful in diagnosing VHL. They are not all located in the broad ligament. A more appropriate name for them is adnexal papillary cystadenoma of probable mesonephric origin, or APMO (See Note 1).
More importantly, APMOs may easily be mistaken for a number of more dangerous tumors in the female reproductive tract. Labeling of an APMO as one of these more dangerous tumors might result in a recommendation for more treatment than is actually required. It is important that we learn more about APMOs.
Five women in the United States have been reported to have the unusual — and benign — APMO found to date only in women with von Hippel-Lindau disease (VHL).1 (See Figure 2.)
The good news in these small numbers is that four of the five women were diagnosed very recently, during a short six-year period beginning in 1988, so hopefully the diagnosis rate is rising.
The even better news is that accurate diagnosis of APMO in two of the patients prompted timely VHL screening and VHL diagnosis before the more typical lesions of VHL caused serious problems.
It has been known since the mid-1960’s that when the comparable epididymal cystadenoma (EC) occurs in men, it can be an important finding that may indicate that the person has VHL. Lindau himself was the first to recognize this cystadenoma in 1927 in a man already diagnosed with VHL. Important advances were made during the 1950’s and 60’s in identifying this benign cystadenoma and distinguishing it from others that occur along the male reproductive tract. Today, with routine screening and technological advances in our ability to detect small tumors, as many as 60% of men with VHL will be found to have one or more ECs.2
Until quite recently, physicians knowledgeable about VHL have not been in agreement about whether women with VHL could even have APMOs. Some doctors thought that it was an anatomical impossibility. Others believed that APMOs were occurring in women but that they were either not being reported or correctly diagnosed. In any case, APMOs were labeled "exceedingly rare" as recently as 1995 and hopes seemed slim that a finding of an APMO would assist in VHL diagnosis.
Through the late 1980s APMOs were reported only in women already diagnosed with VHL. The first two patients ever diagnosed with an APMO in the United States were women known to have VHL. But in 1990 and again in 1994, for the first time, two women were diagnosed with VHL after — and in one case because — an APMO was correctly identified.3
The route to diagnosis for these two women began with visits to their doctors for health problems that seemed to be unrelated to VHL. One woman told her physician that she had a pain in her lower right abdomen. Radiologic exam showed a calcified mass in the right pelvis. During surgery, two cystic areas were found near each of the uterine (or Fallopian) tubes. When the cystadenomas were removed and the tissue analyzed, the diagnosis was "papillary cystadenoma...highly suggestive of von Hippel-Lindau disease."4
The physician reporting on this patient writes, "The classic lesions of von Hippel-Lindau disease were clinically silent in this case." This patient was apparently experiencing none of the neurological or ocular symptoms that typically lead a physician to consider a diagnosis of VHL. Yet screening revealed pancreatic cysts and lesions of the cerebellum and kidney; renal cell carcinoma was diagnosed during follow-up surgery.
The second woman had been suffering for ten years with chronic ear problems. A year and a half after surgery for a lesion in the bony area behind her right ear (which we now understand was an endolymphatic sac tumor or ELST), a "golf-ball sized" pelvic mass was discovered during a routine physical exam. Exploratory surgery located a small tumor in the vaginal fornix, an area at the top of the vagina near the uterus. The tumor was removed and diagnosed as a "benign papillary cystadenoma." During subsequent screening, cysts of the pancreas and kidneys were found; renal cell carcinoma was later diagnosed.
The more typical lesions of VHL were not truly silent in this second patient. A "classic" cerebellar lesion had been found two years earlier, at the time the ear tumor was identified. The woman had no family history of VHL, and a diagnosis of VHL had evidently not been entertained.
Traditional guidelines for VHL diagnosis rely heavily on Central Nervous System (CNS) findings (eye, brain, spinal cord), often requiring documentation of one or more CNS hemangioblastoma in either the patient or a relative. Physicians have known since the 1960’s, however, that a different set of diagnostic criteria is necessary when an unusual cystadenoma such as the EC in men is encountered. Melmon and Rosen, in their important study of a VHL kindred, wrote in 1964, "in one of our patients...palpation of an epididymal cyst was the key to subsequent diagnosis of Lindau’s disease."5 This patient had none of the typical signs of VHL yet diagnostic screening was begun as soon as the ECs were found. Screening revealed both a CNS tumor and an eye lesion. Melmon and Rosen understood the significance of this departure from traditional diagnostic procedure. "This is the first reported case in which a diagnosis of Lindau’s disease was established before the appearance of symptoms. Decision of vigorous investigation of the patient was based on the finding of epididymal cysts and the knowledge that he had one chance in two of having inherited Lindau’s disease."6
The diagnostic guidelines developed by Melmon and Rosen remain one of the most commonly used classifications in clinical practice today. Those criteria recognize that many patients will not have symptoms from a CNS lesion and broaden the definition of VHL to include only a single major lesion of VHL in a person who has a family history of VHL. Reproductive tract cysts in men have been considered, since that time, an important presymptomatic finding, alerting physicians to begin careful screening for VHL when such cysts are found in a male patient. Could the APMO serve the same role in women?
Where do APMO's occur?
The early warning bell that sounded for men in the 1960’s has echoed for women in the early 1990’s. Reasons for the delay in activating this important warning system for women can be found buried in our anatomy, in developmental differences that begin to take shape before we are born.
The technical name for the benign reproductive tract cyst that we have been talking about is "benign papillary cystadenoma of probable mesonephric (duct) origin." This rather long diagnosis has three easy-to-understand meanings:
During the 38-week period before birth, while the embryo and fetus are developing, the mesonephric duct undergoes a lot of changes. Some parts or segments of this embryonic duct evolve into other structures that are given different names at the time of birth. Other parts "regress" or fall away.
The transformation process is different in men and in women and it is this embryological difference that becomes important as we try to understand why papillary cystadenoma has been easier to detect in men than in women. (See Figure 3.)
In men, the mesonephric duct stays intact and functional. It becomes the viable, tightly-coiled routing system upon which procreation depends and upon which a VHL diagnosis can be grounded. The duct itself becomes two ducts, the duct of epididymis and the ductus deferens. A set of small tubules, the efferent ductules, connects the head, or beginning of the epididymis to each testis. Together these structures measure over 20 feet in length and perform the important function of carrying sperm from the testes through the spermatic cord for ejaculation. Papillary cystadenoma in men are found throughout this duct system.
In women, the mesonephric duct system is a remnant system. Although it is made up of the same set of tubules and ducts that are found in men (see Figure 3), only short segments of the embryonic system, called "remnants", remain by the time a female is born. None of these segments performs any function. It is in tissue associated with these parts of the old mesonephric duct that APMOs can be found.
The first segment of the old mesonephric duct found in the adult female is called the epoophoron. The epoophoron is a cluster of eight to thirteen small tubes, each connected to a very short duct called the duct of epoophoron. In the diagram (see Figure 4) these tubules and the short duct to which they are attached look a bit like the head and bristles of a toothbrush, laying in broad ligament tissue between each uterine tube (T) and ovary (O).
All women are born with these small tubules and short duct and it is in this segment of the mesonephric duct that most APMOs have so far been found. APMOs are reported in broad ligament tissue located between the ovary and uterine tube (patient #2) and in tissue close to each uterine tube (patients #3 and #4).
The second segment of the old mesonephric duct is a longer duct called the duct of Gartner. Although it is a "duct," it does not conduct anything. In most women, only pieces of Gartner’s duct tissue remain, scattered along an almost invisible highway where the old mesonephric duct used to be.
Only the top of the Gartner’s duct is located in broad ligament tissue. The bottom end is embedded in other types of tissue. Only about 20% of adult women are estimated to have Gartner’s duct remnants. Because not all women even have such tissue remnants, fewer APMOs will be found in this segment of the old mesonephric duct.
Surgeons find mesonephric tissue remnants clustered in two "hot spots" along the Gartner’s duct : (a) along the side (or lateral) wall of the uterus close to the cervix. The round circle in the middle of Figure 4 indicates this remnant area, the second site for papillary cystadenoma.
The pathologists who examined tissue from the papillary cystadenoma found in patient #5 wrote that this APMO most likely came from a "mesonephric duct remnant." The specific location of the cystadenoma, "lateral to the posterior vaginal fornix," is an area that corresponds to this Gartner duct remnant area.
(b) along the walls of the vagina and vulva. A pair of small ovals at the bottom of Figure 4 mark this remnant area. It is not known at this time whether APMOs do not form in this area, or whether they are simply not being reported in women with VHL.
Several other infrequently reported cysts (e.g. "the Gartner’s duct cyst," the "mesonephric cyst") as well as "mesonephric remnants" also occur in this area of the reproductive tract. To date, these other mesonephric cysts and tumors do not appear to have a role in diagnosing women with VHL. (See Figure 5.) Nonetheless the variety of names by which mesonephric cysts may be called, and the difficulties in differential diagnosis, compound the problems of compiling case histories.
Careful work by radiologists and pathologists has firmly established that the reproductive tract cystadenomas that can help in diagnosing VHL occur — in both women and men — along all persisting structures and remnant tissue of the embryonic mesonephric duct system.
Changes in VHL Screening Guidelines
In 1994, two unusual cystadenomas that can herald the onset of VHL — the APMO of the female reproductive tract and the endolymphatic sac tumor (ELST), a tumor of the middle ear — were both added to a new set of screening guidelines for VHL.7
These new guidelines, developed by pathologists at the University of Virginia Health Sciences Center, suggest that "strong consideration...be given to the diagnosis of VHL" in a person who has:
(1) either the mesonephric cystadenoma or the ELST and a relative with VHL or
(2) either the mesonephric cystadenoma or the ELST and one other documented VHL lesion, if there is no relative with VHL.
Next Steps
The finding of an APMO can serve as an early warning bell, signaling both patient and doctor that a diagnosis of VHL should be considered. Yet the number of women who enter VHL screening via this route remains alarmingly low.
Hastening the road to diagnosis for a portion of women with VHL will require changes in our screening protocols, in our diagnostic and reporting procedures, and in the awareness of local-level physicians who stand in a pivotal position to make the critical care decisions that can lead to VHL diagnosis.
Equally important is the development of precise tumor identification guidelines. Clear diagnostic guidelines are still lacking. Tumor identification guidelines will need to specify sonographic appearance, histological features, and common tumor sites. These will need to be developed by consensus of gynecologists and pathologists.
Accurate diagnosis of APMOs in women currently requires:
Thus in cases where surgery is not warranted, accurate diagnosis will not be possible until better guidelines are developed.
Simple palpation and ultrasound — methods which successfully locate the majority of ECs in men — are less useful in locating and diagnosing APMOs in women. Physicians can sometimes palpate a cystic area during a routine pelvic examination. Follow-up ultrasound and abdominal CT will help pinpoint the general location of the cyst. Sonographic findings for APMOs in women to date have shown areas of "curvilinear calcifications" and masses that contain "both water attenuation and soft tissue attenuation." Radiologists caution that CT alone will not differentiate papillary cystadenoma from other types of benign and cancerous tumors that occur along a woman’s reproductive tract.
Pathology and sonographic records with clinical histories are available on at least six VHL women who have been diagnosed with APMO. An independent review would be a helpful next step in furthering our understanding of this unusual and diagnostically significant manifestation of VHL.
Women with VHL who are discussing with their physicians a cyst or tumor of the reproductive tract, should be sure to point out to the physician that benign APMOs have been found in women with VHL, and request that care be taken to differentiate an APMO from a possibly more dangerous kind of tumor, to ensure against unnecessarily aggressive treatment. We hasten to point out that this differential diagnosis is extremely difficult at this time, and may require analysis of the genes in the tumor cells. Very few hospitals in the United States can make this determination.
It will be necessary to remove the tumor and send it for an expert analysis before a final determination can be made. If appropriate, the patient and physician together might discuss the appropriateness of a "staged" approach to treatment.
Please deposit any surgically removed tissue in the VHL Tissue Bank. We are working to identify a study team to take on this research.
Tissue previously removed can also be analyzed. The pathology department will likely still have slides, or a paraffin block, that could be used to determine whether it was an APMO. This will be statistically significant in determining the prevalence of APMOs in women with VHL. With your help, we hope to see better diagnostic guidelines in the future that can be more easily applied at all hospitals.
If you are willing to contribute your own experience to such a study, please contact us at +1 617 277-5667 or info@vhl.org, or send samples directly to the Tissue Bank along with a patient history and the local pathology report.
1. Patient cases: #1: Scully et al, eds., Case 1, NEJM 298 (1978) 2:95-101; #2: Gersell et al, Papillary Cystadenoma... Am J Surg Path 12 (1988) 2:145-149 and Funk & Heiken, "Papillary Cystadenoma..." Am J Radiology (1989) 153:527-528; #3 Korn et al, "Papillary Cystadenoma..." Am J Obstet Gynecol (1990) 163: 596-598 and operative records from the diagnosing physician; #4 pathology report provided by the patient; #5: Gaffey et al, "Aggressive Papillary Tumor of Middle Ear...and Adnexal Papillary Cystadenoma", Am J Surg Path 18 (1994) 12:1254-1260. Outside the U.S., see Karsdorp "VHL: New Strategies…" Am J Med (Aug 1994), 97:158-168. The earliest reference to a possible APMO in a woman already diagnosed with VHL dates to a 1931 article published in Virchows and referenced by Melmon & Rosen (1964).
2. Choyke et al (1997) Urology 49, 6:92.6
3. Clearly in the Korn paper the APMO findings prompted VHL screening and diagnosis.
4. Information about these two patients was provided by the patients’ physicians in published reports. Women reading this article who have been diagnosed with any APMO are encouraged to contact the VHL Family Alliance and share with us their experiences.
5. Palpation means touching with pressure in order to diagnose.
6. Melmon & Rosen, "Lindau’s Disease," Am J Med (1964) 36:608-609.
7. Gaffey et al, "Aggressive Papillary Tumor…", Am J Surg Pathology (1994) 18, 12:1259. Manski et al (1997) and the June 1997 issue of the VHL Family Forum provide detailed information on the endolymphatic sac tumor. As printed in the VHL Family Forum 6:3, September 1998. For permission to reprint, please contact VHL Family Alliance, info@vhl.org.
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