All multiple endocrine neoplasias display autosomal dominant inherited patterns. Multiple endocrine neoplasia Type 1 shows nearly a complete penetrance. The prevalence in epidemiologic studies has not been done; but there have been estimates of roughly one per 200,000 people. It affects both sexes equally, shows no geographical, racial, or ethnic differences. The four Ps that medical students often learn about multiple endocrine neoplasias are as follows: Hyperparathyroidism which again shows up in 90 to 95% of patients, often the first presenting symptom, and can present late; pancreatic islet cell neoplasia presents in 75 to 80% of people; pituitary adenoma is up to 65%. The fourth P in this multiple endocrine neoplasia is autosomal dominant with high penetrance. As I read through the literature, there have also been reports of other less prevalent tumors associated with multiple endocrine neoplasias. These include foregut carcinoid tumors with the incidence of two and eight percent. The reason I bring this up is because thymic carcinomas have been associated with MEN, and they often have an aggressive malignant potential. Because of this, cervical thymectomy has been recommended at time of initial operation. Follow-ups for these malignant neoplasms include MRI and CT scans of the neck after the age of 20 and approximately about every three years. Age of onset is interesting. Multiple endocrine neoplasias happen in sporadic form as well. On average, they present 20 years earlier than their sporadic counterparts. Again, hyperparathyroidism usually presents in late adolescence, around 20; and a gastric tumor is a little bit later, 21-22. Pituitary tumors also present in this age group but, interestingly enough, the age of onset is the same as sporadic versus multiple endocrine neoplasias.

To briefly touch on the history, it was Jacob Erdheim in 1903 who first identified a possible link. He was a German pathologist who was performing an autopsy on an electrician in which he noted a pituitary tumor and other endocrine tumors. Fifty years later, Paul Warmer from Columbia University first described his classic triad of parathyroid, pancreatic, and pituitary involvement. He described it in a family of a father and four daughters. Later in the 1960s, Ballard reviewed the literature and found that in his 87 patients, hyperparathyroidism was the initial presenting symptom abnormality in 97%. Erbele and Grun later followed up with a study that reviewed the literature in the late 60s and the entire decade of the 70s and studied approximately 97 reported MEN patients and found similar results: 97% of hyperparathyroidism.

Fast forward another 50 years. The gene was finally discovered in 1997. It has been located on chromosome 11 on the 11Q13 position. It has been found to code for a protein called mennin. It is not known exactly what mennin does and studies are currently being directed at this, but overall it has been identified as a tumor suppressor gene, which basically means when normally expressed it acts as brakes on expressions of other genes, but when abnormal, the brakes are released and you get neoplasias., There have been more than 400 mutations of multiple endocrine neoplasia Type 1 gene. Alfred Knudson, in 1971, at M.D. Anderson, proposed this two-hit theory. An MEN Type 1 tends to display this as well. On the top we have a patient with MEN1. The first hit is inherited from germ line mutation and it is not until a somatic mutation, the second hit, occurs after birth that they again start expressing the release of the tumor suppressors. Thus, this is why you see presentation in MEN patients in late adolescence.

What do we, as clinicians, have to do to diagnose MEN? The clinical diagnosis that our of the three main endocrine organs, in this syndrome we have to get two of the three. Familial MEN is a prototype case of MEN Type 1 and one or more relatives with at least one major endocrine organ. In sporadic MEN there are features of MEN but no family history. That indicates the genome is germoid.

Genetic testing. Currently there is commercial genetic testing but they can only identify 75% to 77% of these mutations. Genetic testing has been limited by the fact that (1) MEN is a rare disease; (2) there is limited demand; and (3) genetic testing has not been performed that often since the patients can be followed presymptomatically. So, why get genetic testing? Genetic testing can confirm atypical presentations and identify other relatives at risk so we can start presymptomatic screening. Also, let us say a relative was at risk, we can test them for the gene mutation and if they do not have it we can stop with our screening methods.

What is the medical surveillance? Overall, the recommendations in the literature is for biochemical surveillance starting after the age of five, which includes serum parathyroid hormone and ionized calcium to check for the hyperparathyroidism; prolactin levels to check for the pituitary adenoma; and glucose and insulin levels for the pancreatic neoplasms. You could do radiographic surveillance every three to five years after the age of 20, since it is after the age of 20 when those tumors start presenting.

We deal with the parathyroids in MEN patients, but there other surgical subspecialties with whom we work. Neurosurgeons and endocrine surgeons usually manage pituitary tumors with dopamine receptor agonists. This suppresses the prolactin secretion. Here we have a pituitary tumor; this one is actually quite large and histologically staining for the prolactin levels. If they get very large and symptomatic, in which they start getting visual field defects, a transsphenoidal pituitary micro adenectomy is usually performed by Neurosurgery. Interestingly, these adenomas are rarely malignant and, in MEN1, it is very rare for them to have a malignant potential.

Moving on to our general surgeon colleagues, MEN has a poor outcome with regards to pancreatic when compared to sporadic. Overall, the goal has been medical management with these new powerful drugs, proton pump inhibitors, and H 2 blockers. They have done well for this disease and the malignancy rate is not definitively established. But the one thing to note is that insulinomas are usually multi-focal and located only in one part of the pancreas; so, for insulinomas, our general surgeon colleagues usually take them out at a convenient age. In 1987, Norton, from the National Institute of Health, performed an interesting study in which patients with MEN1 and Zollinger-Ellison syndrome had their gastric complaints better controlled when the calciums were controlled. Because of this study, the hyperparathyroidism is usually taken care of first, prior to the gastric resection. This has shown to help with needing fewer medications to control their gastric symptoms.

In our specialty, we deal with the hyperparathyroidism. Here we have normal parathyroids with lipocytes. In MEN, you get a hyperplasia, just proliferation of cells and diffuse involvement in the gland, and loss of those nice lipocytes. In all multiple endocrine neoplasias Type 1, all parathyroids should be considered abnormal. The reason is that it has been shown that any remnant parathyroids left eventually become hyperplastic. There have been several theories regarding this. Brandi, out of Italy, showed that a circulating growth factor actually stimulates these parathyroid glands. What she did was get cultured bovine parathyroids in tissue culture and subjected them to serum from patients with multiple endocrine neoplasia. In doing this, the mitogenic potential of the bovine parathyroids increased over 2,000-fold; so there is definitely a circulating factor, but it has not been definitively identified. Thakker followed up her studies in describing this as possibly a fibroblast growth factor.

Moving on to medical management versus surgical management. Veldhuis, in 1997, from the University of Virginia, published an interesting paper in which he discusses the pros and cons of both surgery and medicine treatment. He says avoiding surgery is very dangerous because you need conscientious follow-up of the signs and symptoms of hypercalcemia: neuromuscular weakness, worsening renal failure, bone degeneration, and kidney stones. The key to medical management is to avoid dehydration, avoid embolization, and avoid calcium and thiazide diuretics. He also says to be concerned with loop diuretics, even though this is a treatment for hypercalcemia, because that could dehydrate the patient and lead to an exacerbation. Overall, in 1991, a panel developed a consensus for medical management. They said to qualify for non-surgery you must have serum calcium levels that are only mildly elevated, no previous life-threatening hypercalcemia, and normal renal and bone status.

What are the indications for surgery? Why do we operate on these gentlemen and ladies? A rise in serum calcium greater than 1.6, impairment of creatinine clearance, calciuria, renal stones, and loss of bone density for same age, sex-matched individuals. These are all indications to perform surgery. So what is the prognosis to correcting the calcemia? In 1998, Burgess, a surgeon from Australia, published his data on 37 patients on whom he operated. Perioperative ionized calcium levels when dropped to approximately 1 mm per liter or less was associated with a lower recurrence rate in his study at five years. Goudet published, in 2001, the largest study of MEN1 patients. He studied over 256 patients from France and Belgium and their experience. From this study, he showed that extensive parathyroidectomy compared to lesser procedures had a 13-times higher chance of correction. Isolated MEN1 also did better as compared to familial MEN1. And, lastly, patients receiving surgery after 1985 were more likely to have hypercalcemic control. This paralleled the use of subtotal parathyroidectomy, which is 3½ glands removed at initial surgery.

The big dilemma is what is the initial operation of choice for multiple endocrine neoplasia Type 1? You have two choices: first is total parathyroidectomy with thymectomy and then immediate autograft placement. The advantage of this is a lower recurrence rate; the disadvantage is that some argue that the rates of hypoparathyroidism is higher when you do this. The second choice, subtotal parathyroidectomy, removes 3½ glands and leaves half a gland in the neck, and no transplantation is performed. With this, there is less morbidity, and an easier operation per se. The disadvantage is that there are higher recurrence rates.

Overall, there has been no randomized comparison of these two procedures in the literature. So my goal was to review the literature and find out which one should we be performing, totals or subtotals. To begin with, I wanted to address the issue of hypoparathyroidism. You submit patients to the permanent use of calcium postoperatively, more with total or subtotal. When I reviewed the trends post-surgically in the literature, Gaudet, again from France and Belgium, grouped 256 patients into three groups; before 1986, 1986 to 1990, and after 1990. He showed that an average rate of 15% was seen in each of these groups and was not specifically significant. Karimps, from UCSF, published his review of patients from 1936 to 1988. It included 42 patients but only 38 had MEN Type 1; he had a recurrence of 10%. On the side of subtotal parathyroidectomy, Dotzenrath in Germany published his work and showed a hypocalcemia rate of 12%. On the other hand, Malmaeus, in 1986, summarized the total parathyroidectomy experience, and had a rate of 27%. Overall, the significance of this is questioned so, in general, both operations given have relatively the same hypocalcemic rate.

So then we turned to, which ones are better? I reviewed all the literature and rather than go through each article I have read, I will give you the prototype article for pro total parathyroidectomy and pro subtotal parathyroidectomy. Samuel Wells is a very famous surgeon out of Duke who actually fathered the concept of total parathyroidectomy in autotransplantation. He published his work in the Annals of Surgery. He performed it on 36 patients with generalized four-gland parathyroid hyperplasia. Amazingly, he only had a 6% permanent hypoparathyroidism rate. Ninety-two percent (92%) were normal calcemic immediately after surgery and 70% remained normal calcemic two years out, with only 6% late graft failure rate. To critique this early work, he did not havethat many MEN1 patients in this article and the follow-up period was only two years. MEN usually recurs as late as 20 or 30 years down the line but typically around 10 years.

For subtotal parathyroidectomy, the supporting article I decided to use was the Arnalsteen paper out of France. He reviewed his experience from 1972 to 2001. He had 79 patients of MEN1 documented; 66% underwent subtotal parathyroidectomy and, as seen in the middle graph, the recurrence rate was 5 out of the 66, which is 8%, and his hypocalcemic rate was 13%. Those are the pros and cons.

I put all the articles in graph and chart format for us to review. I grouped them before 1986 and after 1986. I know this is a busy slide, so I will help walk everyone through it. I highlighted here those in favor of total parathyroidectomy. Wells, again, showed his recurrence rate. These are just recurrences of 30%. The problems with Wells’s article again are it short follow-up period and the fact that he did not have very many patients with MEN1. Prinz, from the United Kingdom, had 12 patients and showed a high recurrence rate with less than subtotal, which means only taking out one or two glands and subtotal 31/2 glands, 100% and 33%. Based on this he recommended use of totals. The shortcoming of this article is that only 12 patients were studied. Malmaeus, in 1986 out of Sweden, described 45 patients at five-year follow-up. Again, notice his high recurrence rate for subtotal, less than subtotals, and 33%, which is pretty good on subtotal parathyroidectomies. In the 18 patients on whom he performed total parathyroidectomies, at five years there were no recurrences. So these authors argue we should perform total parathyroidectomies.

On the other hand, Van Heerden’s study, performed at the Mayo from 1960 to 1980, showed excellent results with less than subtotal and subtotal. So here you think, “Wow, 8%! The problem with this study is that it mixed familial and non-familial MEN, and it only studied 36 patients with MEN. So the recurrence rate is different for these types of patients. That was also a critique with Van Heerden’s study. Rizzoli, in 1985, had a good study: 61 patients, five-year follow-up. This showed that with less than subtotal a rate of 66% and with subtotal a rate of 30%, which is pretty representative of what has been seen in the literature most recently. After 1986, these are the other articles. Hellman, in 1992, showed high recurrence rates, 78% and 27% and with totals, 22%. Hellman also mixes his patients and has multiple patients undergoing multiple procedures when he reports. All the most recent studies recommend subtotal parathyroidectomy. O’Riordain, out of the Mayo, showed a 16% recurrence rate. Unfortunately, only 41% of his patients had documented familial MEN Type 1. Again, remember familial MEN have a harder chance of curing. Burgess, in an Australian study, did 3½ gland subtotal parathyroidectomy and showed an average rate of 30%: very respectable. Dotzenrath, in 2001 from Germany, published his findings at five years. Subtotals showed a recurrence rate of 12%. Lastly, Arnalsteen, in 2002, published his work from France. Again, a very respectable 8% recurrence rate of subtotals, 5 out of 66.

To make it easier to summarize this, I went ahead and plotted it out. The three things I want you to get from this slide are: notice how overall after 1986 our recurrence rates have been dramatically improved. On average our recurrence rates are now 20% to 30%. The second point I would like to show is that totals are not being performed as often, only in 1992 and 1980, years in which they were studied particularly. The last point I want you to take from this graph is to notice the more aggressive procedure. Less than subtotal and the darker blue is subtotal and then the lighter turquoise color is totals. As you can see, the more aggressive the surgery, the less the chance of recurrence.

So, why are we failing at taking care of these patients and failing at controlling the hypercalcemia long-term? Kivlen had the largest study of reoperative data. He published out of the NIH from 1975 to 2000. He found that the reason for failure is that with MEN we had to know that in patients with MEN, the parathyroids should all be considered abnormal. We should identify each of them and remove at least 3½ glands. Also, Karimps, in 1992 from UCSF, found that supernumery glands or ectopic glands, are also a cause for these high recurrence rates. Again, finding the tracheoesophageal groove, anterior mediastinum in the thymus, other places in the mediastinum, retroesophageal in the carotid sheath or in the strap muscles. Again, Brandi and Friedman are talking about the serum factor that circulates in MEN patients leading to whatever gland is there eventually becoming hyperplastic.

The question is then "When do we re-operate?" It weighs heavily on us as surgeons as well as on the patients. Kivlen, as I said, had the largest study of reoperative patients from the NIH. His recommendations are:

• Confirm the diagnosis of multiple endocrine neoplasia.

• Determine if the severity of the hyperparathyroidism warrants surgical exploration.

He recommends operating only on the patients with symptoms referable to the disease. This includes significant bone demineralization, high urinary calcium levels and no other coexistent medical contraindications of surgery.

The role of sestamibi has been not been well documented in the literature. The only article that I could find is Shepherd in the year 2000. He had a prospective study of 12 patients who underwent subtotal parathyroidectomies of 3½ glands that recurred. He got scans on these 12 patients before he operated, and the scan helped the surgeon in that it identified the gland in each of the 12 cases. The advantage is that the surgeon knew exactly where the parathyroid gland was before the operation. The drawback was that when they operated on these patients, supernumery glands were found, and the sestamibi never picked those up. So, it really did not help with the first re-exploration. The outstanding value of the sestamibi scans in MEN1 is: Of these 12 patients, four recurred. They got immediate sestamibi scans within three months of the recurrence, which was three months within the initial re-operation. Sestamibis did not light up. They waited three months on these four patients and then the sestamibi finally lit up and it actually helped the surgeon out tremendously. The sestamibi helped them find those ectopic glands, and they successfully removed them in those remaining three of the four.

Now the role of intraoperative PTH. Arnalsteen, in his work in France, showed that a decrease in intraoperative PTH to a barely detectable level was associated with a cure. Now, intraoperative PTH with sporadic hyperparathyroidism is usually due to an adenoma so when you get it, it gets a dramatic drop. Tonelli, in 2000, described the drop in MEN1 as more of a stepwise decrease. With removal of the last gland you will get an average value of at least 20%. So if using interoperate PTH in these MEN1 patients, you would have a goal of at least 20% of the baseline.

In conclusion, MEN1 is a chronic disease that can be managed but not cured. MEN1 is located on MEN1 gene, 11Q13, and displays that two-hit inheritance pattern. Overall, I think the principle that I came away from this literature review is to identify all four glands in MEN1. At minimum, a subtotal resection in every case and routine transcervical thymectomy minimizes not only supernumery gland involvement but also the chance of thyroid cancer.

Case Presentation

L.G. is a 60-year-old male with previous diagnosis of MEN Type 1 syndrome manifesting as parathyroid hyperplasia, prolactinoma and peptic ulcer disease with high gastrin levels. He was referred to ENT for a follow-up evaluation of hyper-parathyroidism. At presentation; he was asymptomatic from his hypercalcemia (Ca 11.4 and alb 3.3). A recent sestamibi scan was positive for delayed washout in the right thyroid bed (lower and mid upper pole). Bone density scan indicated mild degeneration of femoral neck bilaterally. His prolactinoma was well controlled with cabergoline resulting in prolactin levels less than 100 over the past 6 months. A recent MRI of the brain showed a 9mm pituitary adenoma. His peptic ulcer disease was controlled with proton pump inhibitors. Abdominal CT was negative for any masses and liver function tests were normal.

He has no head and neck complaints. Specifically there were no complaints of diplopia, visual changes, seizures, depression, muscle weakness, mental status, renal function, or abdominal pain. The medical history was significant for prolactinoma, hyper-parathyroidism, peptic ulcer disease, and inguinal hernia. Surgically, in 1995 he underwent a total parathyroidectomy with autotransplantation to left forearm at an outside hospital. Recently this March, he had a repair of a right inguinal hernia at the VAMC. Socially, there is no history of tobacco, alcohol, or IV drug use. There is a family history of a brother with MEN I, who underwent two neck explorations with unknown outcomes.

On exam, there is no evidence of visual field deficits, rhinorrhea, or masses or lesions of the oropharynx/hypopharynx. The neck has two well-healed incisions and there are no palpable masses. Cranial nerve function is non-focal.

Labs: 3/04 - TSH 1.0,Calcium 11.4, Albumin 3.3, Alk Phos 46.0, ALT 15.0, PTH 181, Prolactin 98.3, Creatinine 1.3.

Studies: CT ABD 2/2004 – Unremarkable, no evidence mass or malignancy, 0.8cm rim of calcification within the tail of pancreas.

MRI Brain 2/2004 – Pituitary microadenoma 9mm, no increase in size from previous study 12/2001.

CT Neck 2/1998 – No thyroid pathology; no pathology noted in neck.

Sestamibi 12/2003 – Delayed planar and spect images reveal foci embedded within the lower pole right thyroid lobe and not clearly demarcated from the thyroid itself. Overall findings are more prominent when compared to previous study 12/2001.

Bone Density scan 12/03 – Mildly reduced bone density bilateral femoral neck of femur; no change from previous exam 10/2001

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