← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 127: Testicular Cancer Series, Pt 1 - Introduction
Ronak Mistry, Vivek Patel, Dan Hausrath
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- [00:00]
A
Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy. Welcome to another episode of the Fellow on Call, the hemonk podcast. We're coming at you from Rouleau University Medical Center. I'm Broenok.
- [00:23]
B
I'm Vivek.
- [00:24]
C
And I'm Dan.
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A
And on today's episode, we start a new series, this time focusing on testicular cancer.
- [00:31]
B
Excited to get into this one. You know, we just finished off our AML series. It's good to get into some of the bread and butter in oncology. And testicular cancer is such a huge success story in solid tumor oncology with just the high curates that we have. Going to be excited as we get into the treatment and everything about testicular cancer. And today we're just going to start off with the basics.
- [00:51]
C
And, you know, not that this is everything, but as far as boards are concerned, think about things that are common and curable. Testicular falls into the curable for sure.
- [01:00]
A
And as somebody that recently took their boards, I can attest that this is certainly something that felt like it came up far more disproportionately than it probably should have. But at the end of this series, hopefully all of us and all of our listeners are going to be experts in this topic. So without further ado, let's go ahead and roll that show because I think every year I ask you this question and I think it's time for our annual discussion about what our New Year's resolutions are. Vivek, what did you decide for this year?
- [01:31]
B
This year, you guys are all, especially Roanok. He talks about his gains and whatever Ronuk does in the gym. But see, what I'm trying to do is just go to the gym. So New Year's resolution, as everybody else on the planet Earth basically makes this whole commitment, I'm going to exercise more, but I used to do it all the time. I love running. So goal is to get back into all that.
- [01:51]
C
Definitely a good goal. There's a fantastic running equipment store here in East Nashville that I'd be happy to alert you to at some point. It's where I get all my shoes and running supplies at. So for me, I am trying to be a little bit more regimented about how I go through my clinical week. So I'm setting up a schedule to sort of basically block off regular amounts of time to deal with clinic related matters as opposed to just sort of dealing with it as they come through. Like obviously urgent stuff gets dealt with immediately no matter what. But instead of just trying to like respond to inbox messages all throughout the day, I'm going to block off specific things. Time to see if that improves my efficiency at all.
- [02:32]
A
I think that sounds fantastic. I think I've said things before like read more primary literature. I'm pretty sure that was mine my first year last year. I think it was maybe just reading in general. I've given up on all of those. None of them have been successful. I think something that I am going to try and do a lot more this year ideally is not look at my phone. The first thing I do when I wake up. At least not all of my emails and social media apps. And also learning to disconnect before I go to bed and not doom scrolling while I'm already in my room. It's really hard for me, but I'm trying my best. So I'm hopeful that this means better sleep and just a better outlooks for the day as we start the day. Because sometimes the news app just gives you news that you don't want to see when you first wake up in the morning. But we'll see how this goes. We'll report back in a year. And with that guys, I also want to highlight that we are recording on the eve of our third birthday. So by the time that this episode comes out, we will have been in existence for three years, which has been super exciting. We're about 125, 126 episodes in right now and this will be the next one in what will hopefully be a continued long legacy. So thank you to our listeners. Thank you for being a part of our family, whether you've been with us from the beginning or have joined along the way. And it's been a pleasure to make this podcast for you all. So with that we start a new series today on testicular cancer and I am going to turn over the floor to Vivek to kick us off with the case.
- [04:06]
B
All right, so we have a 28 year old male who presented to his primary care provider with evaluation of a painful left testicular lump. He has otherwise been doing well other than developing gynecomastia over the past several months he underwent a scrotal ultrasound that was concerning for testicular cancer with a hypoechoic mass. So that's classic to see hypoechoic mass when you do the scrotal ultrasound. He was then Referred to urology, who obtained an afp, beta, hcg, and ldh, which were all undetectable. One week later, he underwent an inguinal orchiectomy, and pathology showed a pure seminoma that measured 2.5 centimeters. And there was no evidence of lymphovascular invasion on the biopsy. So we often see patients with testicular cancer after they've been staged by urology. And before we get into the details on the initial workup and staging, let's just go through some basic, important concepts to level the playing field for germ cell tumors in general. Can one of you go through the epidemiology of testicular cancer and why you can see this present as an isolated mediastinal mass?
- [05:14]
C
Sure. And first off, you will see the terms germ cell tumor and testicular cancer are used so synonymously a lot of time. But really, we should just note that testicular cancer is a subtype of germ cell tumors. And remember that germ cells are reproductive cells that can either become eggs or sperm, and so are found in the ovaries and in testicles. For this series, we're looking just at the germ cells that arise in the testicle. There's one other key basic concept that will take us all the way back to embryology. Dig back into those memory banks into first year of med school. During embryonal development, most of the primordial germ cells migrate to the gonadal ridge, which then later develops into the ovaries and testes. There are some germ cells, though, that migrate to the thymus, where epigenetic reprogramming occurs. This means that you do have germ cells both in the testes and in the mediastinal area, just from an embryologic perspective. As a result, germ cell tumors in biological males can present in the testicle or as an isolated mediastinal mass as a primary mediastinal germ cell tumor. We broadly characterize germ cell tumors in biological males as either seminoma or non seminoma. When you look at the epidemiology of germ cell tumors in biological males from the SERE database, the peak incidence of seminoma occurs between the ages of 25 and 29, and non seminoma between 35 and 39. And we'll have a link to that data in our show. Notes. Essentially think about testicular cancer as rising sometime between 25 and 40 years old. So sort of young adulthood, Patients with cryptorchidism, so undistended testicle or family history of Testicular cancer are generally considered at higher risk, and it's not associated with obesity or smoking like so many of our other cancers. That's just sort of the basic landscape of what we're talking about.
- [07:08]
B
Yeah, Dan, I think that's really great that we went through that. And it's really important to know that, again, we're talking about biological males here, and that we find these germ cell tumors arising in the testes or in the mediastinum. So when you have that isolated mediastinal mass, that could be a germ cell tumor. And as you mentioned as well, we really think about, when we're thinking about testicular cancer, we want to break this down into seminoma versus non seminoma. These are treated differently, they have different prognosis. Important to make that distinction. Seminoma has a more favorable prognosis and has a different treatment paradigm. So, again, critical to differentiate these two through both pathologic evaluation and serum tumor markers. This is one of the few cancers that relies on tumor markers for diagnosis, prognosis, and treatment decisions. In our case, the urologist got pre orchiectomy labs with afp, beta acg, and ldh. So, Ronak, what is the role of these labs at diagnosis, and how does this help distinguish seminoma from non seminoma?
- [08:11]
A
Absolutely, Vivek. And so, after either orchiectomy or biopsy of another tumor site, the pathologist will determine if the tumor is pure seminoma, non seminoma, or a mixed germ cell tumor with components of both seminoma and non seminoma. So, again, this is what the pathologist is seeing with their eyeballs. Non seminoma will include. When we talk about non seminomas. This includes a yolk sac tumor, embryonal carcinoma, choriocarcinoma, and teratomas. And we'll discuss how each of these components matter in this episode in just a moment. Mixed germ cell tumors means that there's a component or some combination of any of these components, including part seminoma and part non seminoma. So the malignant germ cells in testicular cancer or in primary mediacinal germ cell tumors can secrete AFP alone, beta HCG alone, both or neither. We need to obtain these labs prior to orchiectomy, and then again, we want to obtain them post orchiectomy to assess the nadir. And it's critical to know that seminomas will never secrete afp. I'm going to say that again. This comes up all the time. It is critical to know that seminomas will never secrete afp. So any AFP elevation, either pre orchiectomy or post orchiectomy, means that the patient has a non seminoma. There may be a situation where the pathology report notes that the biopsy is pure seminoma. But if there is any AFP elevation, then we classify this patient as having a non seminomatous germ cell tumor, which affects our treatment planning. And this is a very, very, very common concept on board exams and research exams, and which is why I'm really emphasizing this point here. We consider AFP as truly positive if the value is above 20 and we can see some non specific fluctuations at lower values. Essentially, the labs around the time of orchiectomy is critical to help support a diagnosis of pure cell manoma if there is no AFP elevation and little beta HCG elevation. When thinking about beta HCG, very high levels in the 50,000 or more range are concerning for choriocarcinoma and possible brain metastases.
- [10:30]
B
Yeah, that's really, really great the way you broke that down and just knowing that again, any AFP means the patient has a non seminomatous germ cell tumor. And so we're going to get these values at diagnosis and then again we're going to track it to establish a nadir. It's also one of those things that these tumor markers are going to help us identify relapse. So when we're in the surveillance setting, we get these tumor markers because if they're rising, we ask why are they rising? And the big cutoff that Ronick had mentioned, the level of 20 is important. If your level is less than 20 for either AFP or Beta HCG, you should question that being real. You know, we're really looking at these absolute numbers above 20. So the other important thing is that for patients with cancer of unknown primary with a mediastinal mass, getting an AFP and a beta HCG in the blood can potentially give us a diagnosis of a primary mediastinal germ cell tumor, or let's say a metastatic germ cell tumor with significant elevations in these numbers. And this can be really helpful. This is a shout out way back to our earlier episodes. If we need to give emergent chemotherapy for patients with airway compromise or severe SVC syndrome and you have little time to get a good biopsy. So again, you see a mediastinal mass in a patient, particularly these biological male patients who are middle aged, it's very, very, very reasonable to go ahead and get an AFP and a beta HCG from the blood. So before we get to the role of the post orchiectomy tumor markers, what imaging do we need to stage these patients?
- [12:03]
C
Well, let's start with why urologists always do inguinal orchiectomy, just because this will help understand the staging and the imaging workup and everything we need to do after that. These germ cell tumors always will follow the physiologic lymph node drainage system just like any other tumor type. So they'll first go to the ipsilateral retroperitoneal nodes and then track upward toward the mediastinum and lungs. The testes are the only part of the biological male external genitalia that skip the pelvic lymph node system and and drain directly to the paraortic retroperitoneal nodes. You might think that because testicular cancer is found so close to the pelvis, that pelvic node involvement would be common, but this isn't the case, and it's purely because of the lymphatic drainage. If urologists took an approach sort of transcrotally, so cut through the scrotum, you could actually seed the scrotum with tumor cells, and that would allow access to that pelvic lymph node system. So basically, going through the scrotum would completely change the potential pattern of distribution. So it's important to kind of go through that inguinal canal. Remember that the testes actually descend down through that inguinal canal. That's part of the reason why their drainage doesn't have anything to do with pelvic node drainage. As a result, staging imaging is always ct, abdomen, pelvis to evaluate for retroperitoneal lymph node involvement, and either a chest X ray or a CT of the chest to evaluate for dissemination to the lungs and mediastinum. But remember that pelvic lymph node involvement could potentially occur if for some reason an inguinal orchiectomy approach was not taken. So that that anatomic drainage was disrupted, or a patient had prior surgery in that area, like a vasectomy or an orchidopexy for ketorchidism, which could also disrupt that normal pattern of drainage. So those are some potential anatomic considerations. But by and large, looking at the retroperitoneum, mediastinum and lungs. Right.
- [13:59]
B
That's really, really important to understand that pelvic lymph node involvement in testicular cancer is high risk disease that's disseminated disease because it should not follow that pattern. And you have these rare cases where you might have disrupted the normal anatomic drainage if you've had a procedure. So staging, we think CT abdomen, pelvis, and then consider that CT chest or chest X ray. So let's get back to our case. We have this patient who had no AFP or beta HCG elevation at initial evaluation, and the pathology after inguinal orchiectomy showed a pure seminoma. He underwent a CT chest, abdomen and pelvis, which did show evidence of enlarged retroperitoneal lymph nodes measuring 2.5 cm and 2 cm, respectively. There is no evidence of pulmonary metastasis or other distant metastatic disease. Post orchiectomy tumor markers remained undetectable.
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A
Vivek, thanks for that update. So then my question to you is, before we get into the role of post orchiectomy tumor markers, how do we stage patients with either seminoma or non seminomatous germ cell tumors?
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B
So this is actually very easy. And always remember first, in general, when we're thinking about these patients, always first distinguish seminoma or non seminoma. So that's your first branch point. When it comes to staging, it's pretty simple. There's only three stages. Every patient is curable with testicular cancer. So that's the unique thing about a solid organ tumor where we say even if it's disseminated and metastatic, we're treating for curative intent because of how good platinum agents are for testicular cancer. Stage 1 is localized disease, so that means that it's just in the testes area. Stage 2 is retroperitoneal lymph node involvement only. That's where it drains to. So if you have RP node involvement only, that's stage two. And stage three is involvement of any other area. And this is really considered distant metastatic disease. So this could be any non retroperitoneal lymph node, like the pelvic nodes, pulmonary metastasis, there's often hematogenous spread to the lungs. That's another common site. Liver mets, brain mets, and any other site that this tumor might be found. So knowing the staging is one component of treatment and the other is the nadir of the post orchiectomy tumor markers. So remember, stage one, localized stage two retroperitoneal node involvement only, Stage three, everything else.
- [16:20]
A
So in our case, our patient had a pure seminoma without tumor elevation and involvement of the retroperitoneal nodes only. And so based on what we just talked about, this patient's stage is consistent with stage two disease. He ultimately was treated with a regimen that we'll talk about in way more detail in a future episode, but he ultimately was treated with BEP times three cycles and was cured after long term follow up. So for a pure seminoma, the post orchiectomy tumor markers are not as important because the tumors don't secrete any AFP and only very little beta hcg. We still get them because they can be indicative of relapse or residual disease. But on the other hand, post orchiectomy nadirs of tumor markers are so important for non seminomas germ cell tumors. So can one of you guys go through risk stratification and the utility of tumor markers after orchiectomy and when we should be getting labs like this?
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B
The nadir of the tumor markers is key and not the markers just after orchiectomy. So that's really, really important. So basically you've got these tumors that are secreting AFP and or beta hcg, and these levels are going to rise and rise and rise and rise. Then you cut out the tumor. So you expect these levels to start to fall. And what we do is we use the nadir to help risk stratify patients and guide treatment. The whole concept of looking at AFP and Beta HCG really started in the 70s and was further refined in the 80s and the 90s when really the staging system has lasted for decades. The most important thing to understand is the half life for both beta HCG and afp, because that tells you when the nadir is going to occur. The half life of beta HCG is roughly a day or so, and the half life of AFP is closer to about a week. So for example, if you had an immediate post orchiectomy beta HCG that was 500, then we would expect it to be about 250 after a day or so, then 75 after another couple days and probably undetectable by about a week at that level. If the immediate post orchiectomy AFP was 500, then we would expect it to half at 250 after one week and then 75 after two weeks and so on and so forth. So for these patients, when you have AFP elevation, it's going to take several weeks for that to clear, and for beta ACG elevation, it'll be a little bit faster. And it's critically important that we don't rush the start of treatment and to let the values nadir because this can greatly affect the amount of chemotherapy that we give to young patients. You know, these patients are in their maybe 25, maybe 30 years old, and in general, it takes about five to eight weeks after surgery to establish the nadir of these values. The risk stratification relies on the tumor markers at the first day of chemotherapy. So again, it's really, really important to wait for that nadir. If at any point during this, you know, several week process, we're talking, you know, five, six, seven, eight weeks after surgery, the tumor markers start to rise, then that's a sign that the patient needs to begin treatment. So if there' swe expect them to continuously downtrend a nadir. But as soon as they start to rise, we've established our nadir and it's time to treat the patient.
- [19:27]
C
So the concept of the nadir in these values is really, really important. We shouldn't just rush to starting treatment. We got to be patient with these patients. To continue this discussion, let's change our case a little bit. Our patient had a baseline AFP elevation to 1500 and a beta HCG of 2,500. He underwent inguinal orchiectomy with pathology showing a non seminomatous germ cell tumor that was 15% embryonal and 85% yolk sac tumor. Staging CT of the chest, abdomen and pelvis did not show any evidence of disease elsewhere, including in the nodes. Post orchiectomy, tumor markers initially down trended, and he's now coming back six weeks post surgery, and we see that the AFP has begun to rise. It's around 250 now, and the beta HCG has risen as well, up to 200. Given the rise in these markers, a repeat CT was obtained which still did not show any evidence of disease. He's considered to have stage 1s disease. So what does that mean? What is this modifier on stage one?
- [20:28]
A
So for patients without radiographic evidence of disease, but they have rising tumor markers post orchiectomy, we have to assume that they have disseminated disease and we need to take them for treatment with chemotherapy. So again, this is interesting because unlike many other types of cancers, in the absence of symptoms and disease burden, we don't overly rely on tumor markers. But this is different, right? We're saying that if a patient does have rising tumor markers, even if we don't see evidence of disease, we have to suspect that they have disseminated disease and we should be treating them with chemotherapy. Interestingly, the stage 1s diagnosis has a similar treatment paradigm. To some stage 2 patients with retroperitoneal node involvement with or stage 3 patients who could have distant metastatic disease. And we'll talk more about that as we get into the nuances of treatment. So we here have focused on the AFP and the beta hcg, but we also get an ldh, as we said at the beginning of the episode. So can one of you talk to us a little bit about how we integrate LDH in our risk stratification for patients?
- [21:41]
B
So remember that the first step is seminoma or non seminoma. And in this case that we've updated now so we have a new patient here. That pathology report showed a non seminoma. That's a mixed germ cell tumor. Right? We have components of embryonal components of yolk sac tumor. That's pretty common to see percentages on these pathology reports unless you have a pure seminoma. So we then stage the patients as either isolated disease, stage one, RP nodes only as stage two, and and any other side of disease as stage three. After that, we use the post orchiectomy tumor markers to stratify patients prognostically as favorable, intermediate or poor risk for seminoma. We actually don't rely on tumor markers because we don't really have tumor marker elevation. And there's actually only a favorable or intermediate risk category in seminomas. And it's all defined by where the disease is. Intermediate risk is defined as any disease outside of the retroperitoneal lymph nodes or the lungs. And favorable risk is everything else. So isolated disease, retroperitoneal lymph node involvement and or lung involvement. So you can have a patient with lung mets with seminoma, and that's favorable risk disease. So seminoma is just if it's outside the lungs or retroperitoneal nodes, metastatic somewhere, that's intermediate risk. Everything else is favorable risk. For non seminoma, we use the nadir value of the AFP and beta HCG and LDH to risk stratified patients. So I always remember this with a mnemonic 1, 5 and 1.5. So 1, 5, 1.5. Intermediate risk is AFP greater than 1000, beta HCG greater than 5000, or LDH greater than 1.5 times the upper limit of normal poor risk in non seminoma is AFP greater than 10,000, beta HCG greater than 50,000, or LDH greater than 10 times the upper limit of normal. Why do I only think 1, 5, 1.5? Because intermediate and poor risk are treated the same. So if you look at all the guidelines, the way we treat these patients, intermediate and poor risk are treated identically. So if you remember 1, 5 and 1.5 for AFP greater than 1000, beta ACG greater than 5000, LDH greater than 1.5 times the upper limit of normal, that's all you really need to know when you're thinking about a recertification exam or a test or just practical knowledge for how to treat these patients, because the chemotherapy and the amount of cycles are the same. And through this series, we're really going to discuss the nuances of all of this and the chemotherapy plans. But briefly, for disseminated disease, favorable risk is treated with BEP times three cycles or EP times four cycles. Intermediate or poor risk is BEP times four cycles or VIP times four cycles. Again, we'll talk about that later. The bottom line is if you have intermediate or poor risk, you can't just give episode. You need to give either BEP for four cycles or VIP times four cycles. You can see you're adding a cycle and you're adding more chemo essentially, if you have intermediate or poor risk disease. So those are some of the really important concepts for the tumor markers. But we had mentioned brain metastasis briefly. Can one of you go through when we get an MRI for these patients?
- [24:44]
C
Sure. In short, there's only a few things that would really trigger us to go ahead and get that brain mri. So first of all, this one's pretty obvious if a patient's having neurologic symptoms. So if somebody is having new focal neurologic deficits or other concerning signs that you want to look, go ahead and get that mri. Additionally, as we referenced a little bit earlier, if the AFP is greater than 10,000 or beta HCG is greater than 5,000, the patient has extensive pulmonary involvement, any non pulmonary visceral metastases, or extensive involvement with predominant choriocarcinoma pathology. Those are also reasons to just go ahead and get that mri. The risk is high enough that there's brain mets at that point that it makes sense to do that imaging. Basically, if the patient just has a high burden of disease, really high tumor markers, non pulmonary metastases, or concerning neurologic symptoms, those are the things that should trigger you to do brain imaging. So let's go ahead and wrap this episode up with some pearls on the pathology report and how that information can influence our management. In particular, how do we think about patients with large components of embryonal histology as we've been referencing a little bit earlier in the episode. Also, how do we think about patients who have teratoma mentioned on the pathology report? That's one of those things that always stands out in your med school lectures because the teeth and hair and all that weird stuff you can find. How do these features influence our treatment planning?
- [26:09]
A
Maybe I'll start and then I'll hand it over to one of you. But some of this is really important in stage one disease, where we have the option of active surveillance after orchiectomy. So risk factors that we need to be aware of for patients that can increase the risk of relapse include things like lymphovascular invasion, invasion of the scrotum, and predominant embryonal histology. Dan, you asked about teratomas. Vivek, what is your make of teratomas? How do we think about these?
- [26:39]
B
Yeah, teratoma is one of those things that isn't really responsive to chemotherapy or radiation and requires surgery. And so when you have a patient with a non seminomatous germ cell tumor, remember, they often have components of a lot of different types of histology. Some yolk sac, maybe some of it is embryonal, maybe some of it's teratoma. And this is why patients who have undergone treatment for testicular cancer, who have non seminoma to sterm cell tumors and have any residual tumor, must undergo surgical resection because those teratomas are not gonna respond to radiation or chemotherapy. So any residual masses, they need to undergo resection. The other thing that we can see is as we're giving chemotherapy to these patients, some of them might suddenly have just massive growth of one of their tumor sites. And when we see this enlarging tumor despite giving chemotherapy, and remember, testicular cancer is exquisitely responsive to chemotherapy. We call that growing teratoma syndrome. And those patients need to go straight to surgery. So you have a patient getting chemotherapy for their testicular cancer or germ cell tumor, and there's a growing mass. Assume that's teratoma and they need to be taken to surgery. Any residual disease for non seminomatous germ cell tumor must be resected at the end of treatment.
- [27:56]
A
So a lot of really, really, really high yield points. And we'll be sure to summarize all of this in our show notes so that it's easy to follow. Again, these fundamental concepts will probably help you get the majority of questions right on any sort of board exam or in training exam. But most importantly, it's a lot of information that you're trying to analyze when you see a patient with testicular cancer in clinic. But again, these fundamentals will help you systematically walk through some of that data. So, guys, any final thoughts that you all have?
- [28:26]
C
No. I think that was a great summary. I look forward to getting into the rest of these episodes. Yep.
- [28:30]
A
Absolutely. And so, until next time, everybody. We'll see you all later.
- [28:35]
B
See you later.
- [28:36]
C
Peace.