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Puzzles, pearls: diagnosing interstitial lung disease

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Karen Lusky

July 2019—Most fresh blood in lung wedge biopsies is artifact, but when it’s diffuse alveolar hemorrhage, the pathologist must call the clinician because DAH patients can go downhill fast. Maxwell L. Smith, MD, a consultant in the Department of Laboratory Medicine and Pathology at Mayo Clinic Arizona and associate professor, Mayo Clinic School of Medicine, shared that pearl from one of the 10 consultation cases he and Brandon T. Larsen, MD, PhD, co-presented in their CAP18 session on diagnosing interstitial lung disease. Their discussion of two of those cases follows.

Second of two parts

A 51-year-old female had blood-tinged sputum, a sore throat, and cough in the prior few weeks. The woman’s chest x-ray displayed “sort of a symmetric, almost butterfly-shaped set of opacities,” said Dr. Larsen, a senior associate consultant in the same department at Mayo Clinic Arizona and associate professor, Mayo Clinic School of Medicine. (For this case, he was acting as the original pathologist; Dr. Smith would then enter and explain the diagnostic pitfall and how to avoid it. In the next case, they reverse roles.) Now Dr. Larsen had wedge biopsies to examine (Fig. 1). “At low power, I think the first thing that strikes me is there is a bunch of blood in the tissue, but that’s probably just from the surgeon. I don’t see fibrosis.”

At somewhat higher power, Dr. Larsen spotted a fairly fresh thrombus in a small pulmonary artery. He went on to identify other thrombi or thromboemboli, noting it was difficult to know which. “There’s definitely organizing pneumonia; I do see that. So organizing pneumonia with acute thromboemboli.” He wasn’t entirely sure “how to put all of that together,” he said, and since it was a Friday afternoon, the case had to be sent out right away. His question for a consultant: “Is there a relationship between the pulmonary artery changes and the organizing pneumonia?”

“We’ll talk about that,” Dr. Smith said. He recommended going back and looking at subtle findings on the biopsy. Hemosiderin-laden macrophages “are obscured by all that blood, but you can see these little rust-colored macrophages that are sometimes challenging to differentiate from respiratory bronchiolitis in a smoker.” (Fig. 2). Compared with smoker macrophages, hemosiderin-laden macrophages should contain larger granules with a more “refractile appearance.” Both will be iron positive, so there’s no need for an iron stain.

He noted a small amount of fibrin in the area of the organizing pneumonia and many neutrophils within the interstitium (Fig. 3). When pathologists see subtle neutrophils within what is otherwise an organizing pneumonia or acute fibrinous lung injury process, they should begin thinking about diffuse alveolar hemorrhage, Dr. Smith advises.

Showing an image of fibrin embedded with fresh red blood cells in the patient’s airspace (Fig. 4), Dr. Smith asked the audience members to imagine momentarily they are the surgeon obtaining the biopsy. And all of the blood in the airspace is related to the procedure. “Would you expect to have red blood cells embedded within fibrin? Not at all, right? Because these red blood cells embedded within the fibrin suggest that they are there when the fibrin is being formed around it.”

Dr. Smith also pointed out microvascular capillaritis, which is the lesion of diffuse alveolar hemorrhage (Fig. 5). “We call DAH a vasculitis,” he said. In an interview with CAP TODAY, Dr. Larsen noted that when most pathologists hear that clinicians are worried about vasculitis, they are looking for an obvious, inflamed large vessel, but in the lung, capillaritis is a far more frequent manifestation of that disorder, and very subtle.

The consult diagnosis was “acute and organizing diffuse alveolar hemorrhage with capillaritis.” The comment was as follows: “The differential diagnosis for DAH encompasses numerous immune-mediated diseases, including antineutrophil cytoplasmic antibody-associated vasculitis. Correlation with a complete serological workup is suggested. This patient might benefit from immune suppression and immune modulation.”

The ball is largely back in the clinicians’ court, Dr. Smith said. “They need to do the serology workup and figure out exactly what immune-mediated process it is.” The problem, though, was that Mayo Clinic didn’t receive the consult until the following Tuesday because the pathologist shipped it on Friday. And on that same Friday, the patient could not be extubated after surgery and was admitted to the ICU where she had massive hemoptysis on Saturday morning. So the clinician initiated empirical immunosuppression. The woman remained in critical condition, which Dr. Smith said is why DAH is an important diagnosis not to be missed. He also emphasized that these cases need immediate review.

What histological criteria does the pathologist have to see on the biopsy to diagnose DAH? The first, Dr. Smith said, is indication of acute lung injury. “If you do not have any lung injury, you do not have diffuse alveolar hemorrhage. I don’t care how many hemosiderin-laden macrophages you see.” The second criterion is histologic evidence of blood where it shouldn’t be in the airspaces. That can be hemosiderin-laden macrophages or fresh red blood cells. Last is evidence of microvascular injury or capillaritis (Fig. 6).

The textbooks advise looking for capillaritis and, if not present, then reporting “diffuse alveolar hemorrhage without capillaritis,” Dr. Smith continued. “But how does the blood get there? There’s microvascular injury there somewhere; you are just not seeing it. So the clue is to go to the areas of fibrin because the fibrin is telling you, ‘Hey look, there is microvascular injury here.’” That’s the reason fibrin is in the airspaces, so that’s where pathologists should focus their investigation in capillaritis.

They can be subtle, but look for neutrophils with associated enlarged and reactive-looking endothelial cells in the interstitium and in the capillary network, Dr. Smith advises. “It’s analogous to endocapillary proliferation in the glomerulus. That’s what you are looking for in the capillary network of the airspace.”

Dr. Smith presented an image and asked the audience if it was DAH (Fig. 7). “You have red blood cells. Is there any acute lung injury here? Absolutely not,” and thus it is not diffuse alveolar hemorrhage. There are no hemosiderin-laden macrophages either. He shared another image, which was DAH (Fig. 8). “Easy, right? Acute lung injury, fibrin, capillaritis, red blood cells entrapped within the fibrin, hemosiderin-laden macrophages. That’s diffuse alveolar hemorrhage.”

The next image was more challenging, he said, due to the red blood cells, hemosiderin macrophages, and “clear-cut evidence” of bleeding in the airspaces (Fig. 9). Yet there’s no definitive acute lung injury apart from perhaps slight edema within the alveolar walls. “This is one where I would keep searching because I know there is a lot of bleeding coming from somewhere. But what else can give you a lot of hemosiderin in your lung like this?” Congestive heart failure, he said. “We don’t usually get those biopsies because they can usually diagnose that clinically.”

An attendee asked about the significance of the big vessel thrombus in the patient’s case and if it is compatible with DAH. Dr. Smith replied that, in his view, organizing thrombi in pulmonary arteries is a feature seen in the setting of acute lung injury. “In addition to OP and fibrin, it is common to have organizing thrombi in the pulmonary arteries. It’s a secondary process to the acute lung injury happening,” he said, “and it is not related to the DAH.”

Dr. Smith presented another case in which a 55-year-old man had shortness of breath, cough, weight loss, and fevers for a year. The patient used antibiotics and steroids without improvement. Imaging studies revealed infiltrates and nodules more so in the right lung than the left.

In the role of the original pathologist in this case, Dr. Smith inspected a wedge biopsy of the patient’s lung at high power and identified nonspecific interstitial pneumonia, organizing pneumonia, fibrin with an eosinophil, an airway with chronic bronchiolitis, perhaps an interstitial granuloma, a vessel with perivascular infiltrates, a non-necrotizing granuloma, and a possible giant cell.

“This is all one slide of one case. Diagnosis deferred,” the original pathologist said in comments to the Mayo Clinic consulting pathologist, adding, “This biopsy shows almost all of the patterns of lung injury that have ever been described. I have no idea what to suggest in this case.” Included were the imaging studies.

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