Hickam's Victims: An M&M of an MM misdiagnosis

In this case report, the authors describe the case of a 42-year-old-woman who presented with abdominal pain, rash, fever, loose stools and anorexia. Her serum eosinophil count was 2.07x10^9 (25%), and she had increased light chains - both kappa and lambda. Bone marrow biopsy showed lots of eosinophils and immature plasma cells. I will leave it to the oncology nerds to reference the report for details, but just note that the presence of both kappa and lambda is a red flag, and so are the eosinophils if you're going to call this multiple myeloma (MM). And the presenting symptoms are another red flag because they're not consistent with MM.

Nonetheless, the patient was diagnosed with MM and underwent treatment for it for seven years. The treatments included bortezomib, and she developed peripheral neuropathy. The treatment did not relieve her symptoms including asthma, rash, diarrhea, etc., and her eosinophils and kappa and lambda levels were unchanged. Never deterred, her oncologists changed her chemotherapy regimen several times, and performed over a dozen bone marrow biopsies, all showing persistent eosinophilia.

After these seven years of misdiagnosis and status iatrogenicus, she sought a second opinion, and the correct diagnosis was made: EGPA. She was treated for EGPA, and her symptoms resolved (except for the bortezomib-induced peripheral neuropathy).

One pivotal error the oncologists made was to assign a disease based on laboratory findings suggesting a disease that is an unlikely (even preposterous) explanation for the clinical presentation. This is all too common. The coronavirus is positive? The diagnosis is coronavirus, despite an incompatible clinical and radiographic picture. The PJP PCR is positive? It's PJP despite no symptoms and natural history to suggest this, and a negative 1,3-beta-D glucan. I recently conferred with a colleague talking about very odd sputum culture results, in a patient whose "pneumonia would not clear". I looked up the unfamiliar to me bugs: they are not human pathogens. Nonetheless, they are being treated. I looked at the CT: cystic disease pathognomonic of lymphangioleiomyomatosis (LAM). But it need not be microbiology results as the current case makes clear.

The next pivotal error was to ignore unusual combinations of findings, or things that should have been present but were not (e.g., clonality). I defer further discussion of this to the oncology-inclined among you.

The next pivotal error was to fail to recognize the unexpected lack of response to treatment and interpret it as evidence against the diagnosis, mandating a reappraisal.

Yet for some reason, rather than recognize this as a case of simple misdiagnosis, the authors of the report entertain the possibility that the patient has both MM and EGPA, a very odd postulate in the context of the case data (in retrospect). They state:

"This perplexing clinical course necessitates a critical reappraisal: does the presentation align with Occam’s Razor or Hickam’s Dictum?"

To be charitable, I will assume that they originally accepted the diagnosis of MM, and were tempted to apply a second (multiple) diagnosis, viz, EGPA to fully explain her symptoms. After doing some digging, they realized that the MM diagnosis was untenable and EGPA was the "unifying diagnosis". Thus, Ockham's razor (OR) triumphs: there is one diagnosis, and another erroneous diagnosis. 

Yet the authors grasp of Hickam's dictum (HD) is infirm. As we have shown, multiple diagnoses are common, and one should never be surprised when a patient with a pre-existing disease presents with another. Else we should be surprised when granddad has a cholecystectomy one year and an appendectomy the next. (The simultaneous occurrence of both might surprise us and prompt us to consider a causal link - and indeed there probably is: inflammation/infection from one extends to the other). So if she really did have MM, we should not be surprised if, seven years later, she develops another completely unrelated diagnosis.

Alas, in this case it was just careful history taking (her symptoms had been present all along, since the MM diagnosis) and confirmation of background facts that, along with a p-ANCA, led them to the correct diagnosis and debunking the MM misdiagnosis.

The cognitive forcing strategy I routinely employ to avert errors such as those in this case is PPCC:

• Problem: encapsulate the problem using a recognized diagnostic label
• Proof: show me the proof of (or evidence for) the principal or other consequential diagnoses
• Cause: explain to me what is causing the presentation, from chief complaint through labs and other findings, to the diagnosis
• Cure: what are the established treatments for this diagnosis

I'm not sure if he used this kind of cognition explicitly, but when Randy Sasich encountered one of Thomas Weiner's patients who had survived with a diagnosis of stage IV lung cancer for a decade, he was incredulous, and sought primary source confirmation of the diagnosis, which he could not find. Turns out Scot Warwick did not have lung cancer, but he did die of bleomycin lung toxicity from its treatment.

Primary source data is indispensable, but too often I find junior (and often even senior) doctors are not in possession of it while treating patients. They are satisfied with what others have done and charted before them. They trust rendered diagnoses, the last progress note or H&P, the radiologist's report or resident's preliminary read. They do not seek primary data, evaluate it themselves, or demand confirmation from expert interpreters. I warn them: you would not go to court without your exhibits to enter into evidence. You would not expect the judge, jury, or you adversaries to take what you say without evidence. And you should not be treating patients without all your pivotal exhibits ready at hand. You say the patient has a "massive pulmonary embolism" you better have seen the images and be able to describe what lobes are involved. A while back when this happened, the patient was being treated by both junior and senior docs for "massive pulmonary embolism" and when I saw the images I saw moderate burden pulmonary embolism, but massive interstitial inflammation; the patient had acute ILD from connective tissue disease.

Don't trust; just verify.