Sidestepping pitfalls in diagnosing interstitial lung disease

The small area of neuroendocrine cell proliferation, the carcinoid tumorlet, should alert the pathologist to examine the remaining airways more closely, he advises. “In this particular case, there was profound neuroendocrine cell hyperplasia surrounding most of the small airways that were still there.” (Fig. 9). “So this is actually a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, or DIPNECH, with resulting constrictive bronchiolitis, producing a pattern of air trapping on the imaging studies that was mimicking ground glass opacities but in fact was not that.” Dr. Larsen suggests that in such a case, the pathologist might consider including a note that says, “The GGOs on the imaging studies may actually reflect mosaic attenuation of constrictive bronchiolitis, as there is no histologic correlate for ground glass opacities in the biopsy.”

The point here, Dr. Larsen tells CAP TODAY, is that the carcinoid tumorlet isn’t the main pathology. “It’s what catches the eye of the pathologist, but it’s not actually the major problem.” As for why the pathologist didn’t notice the loss of airways, Dr. Larsen says it’s easy to see something unexpected, such as the carcinoid tumorlet. “What’s harder for people to recognize is the absence of a structure that should be there but isn’t. That’s the fundamental problem here, and the bigger problem is one that relates to the overall point of our entire course, which is you can’t evaluate these things in a vacuum without clinical and imaging information.”

Dr. Larsen presented a case in which a 71-year-old male with end-stage renal disease who had a kidney transplant a week and a half earlier now had shortness of breath and swollen legs. The patient’s imaging studies resembled those of the prior case: “There’s mosaic attenuation. Maybe this is ground glass opacities, maybe it’s air trapping, one of the two—probably more likely ground glass opacities,” he speculated. The radiologist reported “extensive ground glass attenuation, focal areas of increased density and consolidation with linear opacifications in the lower lobe.” The radiologic impression was as follows: “Diffuse pulmonary edema or diffuse alveolar damage or diffuse infection or a combination of the above. Cannot exclude a chronic fibrosing process.”

Dr. Larsen viewed the biopsy at low power and said it look liked there was an alveolar filling pattern and acute lung injury. “It’s really edematous, and I see hyaline membranes, which is fantastic because now I know what the diagnosis is. Diffuse alveolar damage. Things look really reactive. I don’t think this is a tumor; I think this is just all acute and organizing diffuse alveolar damage.” (Fig. 10).

When the pathologist told the clinician he thought the patient had acute and organizing diffuse alveolar damage, the clinician replied, “No kidding. We already knew that. The patient is in the ICU on a ventilator trying to die.” The clinician said they knew the patient would have DAD because clinically there was acute respiratory distress syndrome. “The reason I did the biopsy,” the clinician said, “was so you could tell me why my patient has DAD.”

The pearl associated with this case, Dr. Smith said, is that a pathologist’s job is not complete once he or she diagnoses DAD or acute lung injury. “There’s actually a laundry list of things you need to look for in order to help identify the etiology, because that’s what the pulmonologists and clinicians and infectious disease doctors are interested in—what is causing this acute presentation with injury.”

Dr. Smith named eight features he sees frequently in the setting of acute and organizing lung injury (Fig. 11). One is edema, which is sometimes the only finding even before hyaline membranes. “All you see is edema,” he said. Others are hyaline membranes, organization, inflammatory cell infiltrates, fibrin, necrosis, and thrombi. In some cases they also see squamous metaplasia. “Then people worry about squamous cell carcinoma in situ because the squamous metaplasia is so robust in the setting of acute and organizing DAD.”

Dr. Smith recommends pathologists look for eight clues to help them discover the etiology. He refers to his mnemonic as C-BED-FISH (for the first letters of each item):

Connective tissue disease. “An acute flare in a patient with connective tissue disease will look like acute and organizing DAD,” Dr. Smith said, but features in the background suggest connective tissue disease. These are lymphoplasmacytic infiltrates, chronic pleuritis, lymphoid aggregates, chronic bronchiolitis, follicular bronchiolitis, and inflammatory cell changes.

Blood. “Features that suggest acute lung injury is related to an acute and organizing alveolar hemorrhage process are hemosiderin laden macrophages, red blood cells entrapped within fibrin, and evidence of capillaritis,” he said.
Eosinophils. Unless the patient was treated with steroids first, the criteria for acute eosinophilic pneumonia are eosinophils embedded within fibrin with reactive type II pneumocytes.

Drugs. Pathologists should look for features of drug reactions. “The common one we think about is amiodarone-induced drug toxicity where you have foamy cytoplasmic change of the pneumocytes and the macrophages in the air spaces.”

Foreign material. Someone who aspirates a lot of gastric contents might have foreign material in the lung, Dr. Smith noted, but the person can also develop an acute aspiration pneumonitis with DAD from it, and from other material too, such as chemoembolization beads.

Infection. This is the most important one to search for, Dr. Smith said, given that clinicians would treat the other conditions with steroids. “When you boil it down, that is really why they did the biopsy—to answer that one question,” he said. With input from the audience, he identified four things to look for in the setting of acute and organizing lung injury: necrosis, granulomas, viral cytopathic effect, and prominent neutrophilic inflammation. “If you have those things, you have to be super concerned about an infectious process. And you tell the clinician, ‘I don’t think I would treat that patient with steroids. Even though I can’t stain a bug with my special stains, I don’t think I would treat that patient with steroids.’”

Pathologists always have to be concerned about infection in any acute and organizing lung injury, so he advises at a minimum getting a GMS (Gomori’s methenamine silver) stain. However, “If you say it’s an acute and organizing DAD, but there’s no necrosis, no granulomas, no neutrophilic inflammation, and no viral cytopathic effect, the likelihood that that DAD is associated with infection drops,” but not to zero. “You can’t say it’s not an infection, but it drops significantly enough to say, ‘I don’t see any of these features and you want to treat with steroids, so I’d say go ahead—high dose.’”

Scarring. Patients with a background interstitial lung disease characterized by scarring may be experiencing an acute exacerbation of their idiopathic ILD.

Hypersensitivity. Many don’t think about the features of hypersensitivity in the setting of acute lung injury. Yet if someone has a “large organic antigen exposure”—such as the person who is hypersensitive to mold and cleans out a barn containing huge amounts of hay mold—he or she is going to present with an acute and organizing lung injury, Dr. Smith cautions. Features to look for are cellular interstitial infiltrates and poorly formed interstitial granulomas.

Returning to the case, Dr. Smith displayed an image of the patient’s biopsy at low and then high power, noting the pronounced foamy cytoplasmic change, both of the pneumocytes and the histiocytes that are present within the air spaces. This is what amiodarone and other drug-associated lung toxicity looks like in the setting of diffuse alveolar damage, he said, encouraging attendees to burn the image into their heads (Fig. 12).

The pathologist has to perform clinicopathologic correlation in these cases, Dr. Smith said. So he spoke with the nephrologist who said the patient’s atrial fibrillation had been treated with daily amiodarone for years. During the pre-transplant assessment, the clinicians said he should probably discontinue the drug to prepare for the transplant. “Somehow, some way, the ball got dropped, and he was actually taking amiodarone on the day he was called to get a renal transplant,” Dr. Smith said. The patient also had risk factors for amiodarone-induced lung toxicity. He was an older male who had been on a fairly high dose for years and had just undergone a major abdominal surgery for renal transplantation.

Amiodarone-induced diffuse alveolar damage was the clinicopathologic diagnosis. Dr. Smith pointed to the man’s post-treatment CT scan, which no longer showed infiltrates (Fig. 13). This is what happens, he said, when the patient has an adverse drug reaction that is treated appropriately by stopping the medication and administering high-dose steroids. “The patients do very well. It’s one of the best kinds of DAD you can have, if there is a good kind of DAD to have.”

Dr. Smith, who practiced as a general pathologist before becoming a lung pathologist, proposes how pathologists could use Dr. Leslie’s poster on pulmonary pathology patterns when they don’t have the clinical history and imaging studies for a case. “The fast thinking and the slow thinking can at least narrow down a differential diagnosis,” he tells CAP TODAY. Then the pathologist has a “handful of possibilities” and can call the clinician and say, “‘I don’t know anything about this case, but this is what I’m seeing, and I am thinking about these five possibilities. What are your thoughts?’ And that opens up a nice dialogue with your clinical colleagues.”

In Dr. Smith’s experience, often the clinicians have reviewed the patient’s imaging studies themselves and come up with a differential diagnosis. “What they are hoping for from the biopsy is some guidance as far as the diagnosis, and then how to treat their patient,” he says. Between the clinician who knows the radiology and the pathologist, “you can usually get pretty close to the actual pathologic process that is going on with the patient.”

Karen Lusky is a writer in Brentwood, Tenn. Drs. Larsen and Smith will present all 10 of their cases and pearls at CAP19, Sept. 21–25 in Orlando.