CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Fig. 9
Pathologists should report the subtypes, she says. “Fortunately, conventional HCC is the most common subtype. Usually, the other subtypes, if present, coexist with conventional HCC. If the tumor is entirely composed of a subtype such as lymphoepithelial, the greater challenge is simply making the diagnosis of HCC and not thinking of HCC at all.”
Fibrolamellar is the one subtype that distinguishes itself in terms of clinical behavior, Dr. Richards says, because it occurs in young patients who don’t have cirrhosis. “It never occurs in the setting of cirrhosis, and that has a good prognosis. The sarcomatoid subtype is thought to have a worse prognosis.”
Dr. Richards also talked about “when the masquerader becomes the red herring.”
“That’s when sometimes you get a biopsy of a mass and it looks like HCC or what we call hepatoid and it turns out that it’s metastatic. It’s spread from another site; it’s what we call a hepatoid tumor but not a primary liver tumor.”
These hepatoid tumors may occur in multiple places, she said, presenting a list that included the lung, colon, stomach, pancreas, ovary, and other sites. “And every day you will see a case report where another case is added to the list,” she said. The tumors are “morphologically similar to HCC.” And one has to exercise caution in interpreting immunohistochemistry because all of the markers that are positive in the liver for hepatocellular carcinoma can be positive in hepatoid tumors in other settings.
Fig. 10
CDX-2, TTF-1, and PAX-8 would likely be more helpful because those are typically negative in primary liver tumors with rare exceptions, she says. “CDX-2 is an immunostain that usually indicates intestinal differentiation. TTF-1 indicates pulmonary differentiation. PAX-8 is genitourinary.”
“The important thing is to make sure to look at the H&E to see if there are any other clues,” Dr. Richards advises. “So maybe some areas are hepatoid but some areas are not; it’s more well-formed glands or has some other appearance that suggests to you that it may not be purely hepatoid. That’s one of the first clues.”
Fig. 11
These patients can also have increased serum AFP. “In fact, in many of these case reports, that’s exactly how they present.” She suggested pathologists use the site-specific markers and “go back to the bucket and put through more of the tumor. Find those features that are present in the tumor that are not hepatoid.”
Knowing the pattern of spread may help. Has there been spread to a periumbilical node, which is more common in tumors of gastric origin? “Is there also a tumor in the stomach, esophagus, or colon?”
Fig. 12
Case No. 2 involved a 54-year-old man with hepatitis C cirrhosis who had a radiologic diagnosis of HCC. The patient underwent TACE (transarterial chemoembolization) after the initial diagnosis, and then again when follow-up showed he had residual tumor. “They didn’t give us the first tumor,” Dr. Richards said. After the second TACE treatment, the patient’s AFP dropped, his CA19-9 went up, and the AFP increased again. Imaging showed a new lesion close to the treatment site, so the patient had a liver transplant. And Dr. Richards and colleagues received the explanted liver.
Dr. Richards displayed an image of a lesion that she described as “well-circumscribed, a little bit yellow on the edges” and having some hemorrhage. She also pointed out a little scarring in the center (Fig. 12). She noted that the left side of an image of the lesion under the microscope (Fig. 13) was more epithelioid-looking. On the right, “you can see a more ductular-looking lesion. In some areas,” which she notes weren’t shown, “the lesion blended a little bit more, not just that separate area, but this is a higher power of the ductular area. So this is clearly adenocarcinoma (Fig. 14). And you can see (Fig. 15) the more epithelial-looking typical steatotic-appearing hepatocellular carcinoma. So this patient had mixed hepatocellular-cholangiocarcinoma.”
Fig. 13
As for how to tell the two apart, “HCCs are not morphologically glandular—cholangiocarcinomas usually are,” she says. “HCCs are HepPar1, glypican 3, and arginase positive with membranous/canalicular polyclonal CEA. Cholangiocarcinomas are MOC31 and generally CK7 positive with cytoplasmic polyclonal CEA.”
Dr. Richards’ takeaway regarding the mixed HCC-cholangiocarcinoma: “Basically, don’t miss it, don’t miss it, don’t miss it because these lesions carry a poorer prognosis than pure HCC. They kind of pick up the worst of the two components. They have the portal and hepatic venous infiltration that HCC carries but they carry the lymph node metastatic potential of the cholangiocarcinoma.”
Diagnosing the condition preoperatively can be difficult but it does require different treatment approaches as these patients are going to fail locoregional therapy, she said. Also, once a mixed HCC-cholangiocarcinoma is diagnosed, “you are taking that patient off the transplant list” in most centers. (She noted that a limited number of centers will transplant a patient with specific types of cholangiocarcinoma.)
Fig. 14
Case No. 3 dealt with a frozen section. “I do like frozen section days,” she said. “My adrenaline is flowing but sometimes I find that on a frozen section day, I have to try extra hard to stay calm, and I will give you an example.” A 61-year-old woman who presented with painless jaundice had a pancreatic head mass. “And so she had a common bile duct brushing, which was considered ‘highly atypical cells, cannot exclude a malignancy.’” The patient was taken to the operating room to get a Whipple but the surgeon discovered a small white subcapsular liver nodule, which was sent for intraoperative consultation.
Dr. Richards pointed to an image of the frozen section which she noted had ductular proliferation. “It seems fairly circumscribed, but over on an edge (Fig. 16), there might be a suggestion that it’s a little bit infiltrative. On higher power, you can see very clearly that these are columnar cells,” she said. “They are not very atypical but they appear to be encroaching on what seems like a portal tract. Here again, you see these duct profiles [which] are varying in size. There is not a lot of atypia but when you compare it, you see there is some mucinous change also within the native ducts. But somehow the lesion appears to be kind of intermingled with the portal tract that is there.” On frozen section, the person who looked at it called it “positive for mucinous adenocarcinoma, well-differentiated.”
Fig. 15
On permanent, however, “the lesion that looked a little bit funny on the edge somehow decides to straighten up and fly right and you get this nice wedge (Fig. 17).” A CK7 was performed just to show the profiles (Fig. 18). “But you can’t really look at the profile and say, ‘Yes, it’s infiltrative.’ It seems a little bit more circumscribed and there may be a straggler here and there, but overall you could draw a line around it. And the final diagnosis on permanent was changed to bile duct adenoma or peribiliary gland hamartoma, a mucinous variant,” which is benign.
One thing to remember: When in doubt, she said, “you can’t put it back in. So if you are in the frozen section room and you’re trying to decide on the dicey call, the dicey call is to wait until the permanent comes out before you say that it’s not malignant because they will go ahead and do the Whipple. And if they go ahead and do the Whipple and on permanent it is truly metastatic, you can’t put the Whipple back. So you always have to think about the implications of your diagnosis in addition to the morphology of the lesion.”
Dr. Richards shared her general recommendations for handling liver tissue and using IHC. Every institution should have predefined protocols that separate neoplastic liver from medical liver, she said. “And neoplastic liver should never ever get up-front stains. Because you actually haven’t looked at the H&E, you don’t know what you will need to do, and here it is you’ve wasted a whole slide on a trichrome, you’ve wasted a slide on a PASD. And later on that may come back to haunt you when you need that one more immunostain.”
If Dr. Richards could devise a biopsy procedure, she’d “want one needle that went right in the lesion and one needle that went right outside the lesion.” And she’d want the specimens in two different jars. “Everything is about context, and if you know there’s cirrhosis or no cirrhosis, your differential diagnosis is going to change and how you approach the situation might change.”
The use of all stains depends on the setting, she adds. “If you have a tumor in the liver that is not morphologically distinctively liver, you are not sure where it’s from or what it represents, that’s when you want to do liver stains. First you look at the H&E and decide what you have, what question you need to answer, and then that’s when you’d do the other stains.” (See “IHC pointers—liver origin.”)
“If it’s hepatocellular carcinoma, hopefully you will see increased cell density, unpaired arteries, fatty changes in small lesions, some pseudoglandular differentiation and probably some thickened plates, and that will help you say that it’s [HCC],” she said in summing up.
“If you have a clear-cut HCC on H&E—a blind man drunk at three o’clock in the morning knows it’s HCC—you put the slide down, move on with your life, forget about the stains,” she said. “Sign it out and go on to the next case.”n
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Karen Lusky is a writer in Brentwood, Tenn. All images are courtesy of Kisha Mitchell Richards, MBBS.