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How does a pathologist make a diagnosis?

Cryptococcal endophthalmitis

The following document and presentation were recently delivered by pathologist Alan Proia at a meeting of ophthalmologists who wished to better understand how a pathologist arrives at a particular diagnosis. The presentation is centered around an interesting paper from the Archives of Pathology and Laboratory Medicine by Brazilian pathologists Pena and Andrade-Filho, and includes specific examples from ophthalmic pathology.

The following documents are presented here with the kind permission of their author, Alan Proia, MD, PhD.

How Does a Pathologist Make a Diagnosis?¹

The objectives of this talk are: 1) to review the processes by which a pathologist makes a diagnosis; 2) the potential pitfalls in this process; and 3) to illustrate the diagnostic process using two recent cases that posed dilemmas.

In a recent paper titled “How does a pathologist make a diagnosis?” Pena and Andrade-Filho proposed a four-domain model by which pathologists render a diagnosis¹:

1. Cognitive domain: This relies on visual sensation (detection of simple properties such as brightness and color²) and uses perception (detection of objects and structures²) to interpret meaning. Pena and Andrade-Filho define the cognitive domain as involving the processes of perception, attention, memory, search, hypothesis creation, and verification.¹ Memory and search are used to collect data from the case and incorporate macroscopic and microscopic observations along with clinical and radiological findings.¹ Pena and Andrade-Filho outline these strategies used by pathologists within the cognitive domain:

1. Pattern recognition;
2. Multiple branching or arborization algorithms;
3. Exhaustive strategy (brute-force approach); and
4. Hypothetical and deductive strategy.

In reality, as an experienced pathologist, I most often rely on a, b, and d in combination, though sometimes I regress to a brute-force approach, especially with complex autopsies.

2. Communicative domain: Pena and Andrade-Filho consider communicative and cognitive skills to be of equal importance, since communication is essential to provide the clinician with arguments for the validity of a diagnosis and to render a diagnosis that will be meaningful and useful for the clinician. In my practice, I use the communicative domain as follows:

1. Uses of argument: I rarely, if ever, list the basis for a diagnosis if it is simple and expected from the clinical differential diagnosis. If I include the argumentative basis for a diagnosis, this is most often included within a note (comment) following the diagnosis. The note includes the different possible diagnoses included and the thought (cognitive) process that I used to reach my final diagnosis. If clinical data and history are essential for rendering the diagnosis, then I state this explicitly.
2. Probability: If I am unable to render a diagnosis with complete confidence, then I include an indication in a comment as to the degree of confidence that I have in my diagnosis. For example, if I receive a small or superficial biopsy, then I may not be able to render an exact diagnosis. I handle this by giving the differential diagnosis and what is needed (e.g., additional biopsy, blood tests, or radiological studies) for me to render a final diagnosis. If additional tests are required, then I will issue a supplementary report at the completion of those tests and incorporate them into a “revised” diagnosis.
3. Qualifiers: Pathologists use a variety of terms to qualify their diagnosis (“equivocators”). It seems that a favorite term of pathologists is “consistent with”, which I avoid if at all possible. Having been a member of a clinical department for many years, I realize that ophthalmologists and other clinicians want an answer; they do not want a wishy-washy “consistent with”. One way that I avoid being equivocal is to render a descriptive diagnosis and then provide the clinical-pathological correlation as part of the diagnosis or as a note. For example, I receive many pterygium resections. A common diagnosis for me is “conjunctiva with actinic elastosis, goblet cell hyperplasia, and mild chronic inflammation, histological features compatible with the clinical diagnosis of a pterygium”.
4. Rare diagnoses: As a practitioner within a large referral center, I rather often render rare diagnoses that will have little meaning to the ophthalmologist caring for the patient. In such cases, I usually add a note that places the diagnosis within the context of its frequency and I provide other information that may be helpful in caring for the patient. I also try to include a reference or two so that the clinician can readily find the information that may assist him or her.
5. Disagreement with a diagnosis rendered at another institution: In cases where I disagree with an “outside” diagnosis and it will have a major impact on patient care, then I always show the case to another pathologist and incorporate his or her name as having also reviewed the case. I also try to provide an explanation as to why I disagree with the outside diagnosis and what may have caused the confusion.
6. Telephone calls: In cases of an unexpected diagnosis that will have a major impact on treatment, I telephone the ophthalmologist. I also telephone ophthalmologists whenever I have a question about the clinical history, as illustrated by case 1 below.

3. Normative domain: The practice of pathology is driven by rules and norms. For example, these include rules to classify, stage, grade, and report tumors. Other factors within the normative domain include ethical conduct and respect for the patient, the clinician, and the referring pathologist. Within this domain, I emphasize to the pathology technicians and residents that they should handle every specimen as though it came from someone they loved. If it is not good enough for one of their family members, then it is not ready to be signed-out.

4. Medical conduct domain: The pathological diagnosis must be evaluated from the perspective of the clinician or referring pathologist. Pena and Andrade-Filho pose these questions for the pathologist to consider within the realm of medical conduct:

1. What will be the consequence of your diagnosis, i.e., how will it alter the management of the patient?
2. Should additional tests such as histochemical stains, immunohistochemical stains, or molecular testing be performed?
3. Is the pathological diagnosis clear? Does the diagnosis make the expected conduct clear?
4. Should your diagnosis be reviewed by another pathologist or are you completely certain of the diagnosis?

Pitfalls in rendering a diagnosis

There has been recent interest in trying to identify factors that can adversely affect the ability of a pathologist to render a diagnosis, i. e., do we truly see what we think we see?^{2, 3} Hamilton and coworkers list these factors that may impact the pathologist’s ability to provide an accurate diagnosis:

1. Optical illusions;
2. Varying understanding of visual clues;
3. Different spatial search strategies;
4. Variable cognitive search strategies;
5. Different weightings and combinations of factors;
6. Cognitive bias (where one observation overrides other considerations);
7. Case-based reasoning (“wallpaper matching”);
8. Variation in signal detection threshold and identification of rare events;
9. Limited processing capacity (most people can handle only seven chunks of information in our mind simultaneously);
10. Fatigue; and
11. Intuition (“gut feeling”).

To these, I would add incomplete or inaccurate clinical information.

Case presentations

Two recent cases illustrate some of the processes and pitfalls that a pathologist faces in making a diagnosis.

1. Infundibulocystic basal cell carcinoma: I received a tiny (2 x 1 x 1 mm) biopsy of skin from a 7-year-old girl with a history of multiple lid nodules and “basal nevus syndrome”. H&E stained sections showed a neoplasm that appeared to be a trichoepithelioma, though I could not completely rule out a basal cell carcinoma. The nests of tumor cells were diffusely stained using antibodies to bcl-2, while only cells in the periphery of some tumor islands expressed CD10; this pattern of staining is that expected for a basal cell carcinoma.^{4, 5} However, after speaking with the oculoplastic surgeon, I learned that this child has Gorlin syndrome (nevoid basal cell carcinoma syndrome). Patients with Gorlin syndrome develop tumors termed infundibulocystic basal cell carcinomas,^{6, 7} which have features of basal cell carcinoma with follicular differentiation, as in this case. This case illustrates the need for complete clinical information and open communication between the pathologist and ophthalmologist since “the biological behavior of infundibulocystic basal cell carcinoma, however, seems to be less aggressive than that of other clinicopathologic variants of basal cell carcinoma, because most of the lesions remain small for a long time and show little tendency to ulcerate the epidermis”.⁷

2. Mixed tumor of the choroid: A 37-year-old woman died from cerebral edema secondary to diffuse leptomeningeal oligodendrogliomatosis. At autopsy, a 2.5 x 3.0 mm tumor was seen in the left choroid, and I quickly concluded that this represented a metastatic adenocarcinoma since it did not resemble any primary tumor of the eye that I have seen or could locate in the ophthalmological literature. Despite the absence of any grossly or microscopically visible primary tumor in the body (except for the diffuse leptomeningeal oligodendrogliomatosis, which did not resemble the choroidal tumor), I undertook a large and expensive immunohistochemical evaluation of the choroidal tumor using 23 antibodies in a series of small panels to narrow my diagnostic possibilities. The immunohistochemical odyssey definitively identified the choroidal mass as a mixed tumor, a benign tumor that usually arises in salivary glands but that may occur as a soft tissue neoplasm.^8-10 Mixed tumors, myoepitheliomas, and parachordomas are rare soft tissue neoplasms, which are distinguished based on their morphology.⁹ The choroidal tumor was classified as a mixed tumor due to the presence of distinct, though rudimentary, glands as a minor component of the tumor.   I am unaware of any reports of a mixed tumor or other myoepithelial tumor arising within the choroid. This case illustrates cognitive bias since despite the appearance of the tumor in the H&E stained sections, I did not consider a mixed tumor since they had never before been identified as a primary tumor in the choroid.

References

1. Pena GP, Andrade-Filho Jde S. How does a pathologist make a diagnosis? Arch Pathol Lab Med. 2009;133:124-32.
2. Hamilton PW, van Diest PJ, Williams R, Gallagher AG. Do we see what we think we see? The complexities of morphological assessment. J Pathol. 2009.
3. Fandel TM, Pfnur M, Schafer SC et al. Do we truly see what we think we see? The role of cognitive bias in pathological interpretation. J Pathol. 2008;216:193-200.
4. Costache M, Bresch M, Boer A. Desmoplastic trichoepithelioma versus morphoeic basal cell carcinoma: a critical reappraisal of histomorphological and immunohistochemical criteria for differentiation. Histopathology. 2008;52:865-76.
5. Pham TT, Selim MA, Burchette JL, Jr., Madden J, Turner J, Herman C. CD10 expression in trichoepithelioma and basal cell carcinoma. J Cutan Pathol. 2006;33:123-8.
6. Crawford KM, Kobayashi T. Nevoid basal cell carcinoma syndrome or multiple hereditary infundibulocystic basal cell carcinoma syndrome? J Am Acad Dermatol. 2004;51:989-95.
7. Requena L, Farina MC, Robledo M et al. Multiple hereditary infundibulocystic basal cell carcinomas: a genodermatosis different from nevoid basal cell carcinoma syndrome. Arch Dermatol. 1999;135:1227-35.
8. Fletcher CDM, Unni KK, Mertens F, Editors. Pathology and Genetics of Tumours of Soft Tissue and Bone. World Health Organization Classification of Tumours. Lyon: IARC Press; 2002:198-199.
9. Hornick JL, Fletcher CD. Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol. 2003;27:1183-96.
10. Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue Tumors. Fifth Edition. Philadelphia: Mosby Elsevier; 2008:1108-1116.