On the Value of Morphology in Pathology

In an era where molecular genetics is rapidly advancing our understanding of disease, how relevant is “routine” hematoxylin and eosin (H&E) histomorphology in our training years?

Before the advent of immunohistochemistry (IHC), the study of human tissue depended largely on H&E staining and a few special stains in anatomic pathology. Now, IHC and molecular advances have completely changed the way pathology is practiced, improving our understanding of cancer and providing more precise, accurate information to the clinical care team. As our technologies evolve, does morphology still have a key role to play in modern pathology practice – and how much emphasis should pathology training place on learning histopathology as “morphologists?”

As a young trainee, I was, like many others, awestruck and amazed by the advent of ancillary techniques and their utility in surgical pathology. Indeed, they have helped us answer difficult questions, understand human disease, and open up newer approaches to disease management and drug design. In neuropathology, they have revolutionized the way we classify tumors; in hematopathology, they have helped us understand the heterogeneity, prognostication, and clinical treatments of lymphoma. No lymphoma would be signed out today without the use of IHC, flow cytometry, and other ancillary tools. In neuropathology, markers such as H3K27 are useful to ensure that pure morphological findings do not mislead us in considering a tumor “low-grade.” A positive IDH1/2 immunostain is extremely useful in distinguishing dedifferentiated chondrosarcomas with osteosarcomatous differentiation from osteosarcomas with chondroblastic differentiation – a challenge when using pure H&E evaluation. In short, these tools are undoubtedly improving the practice of our discipline. Pathology trainees are exposed to an ever-increasing pool of knowledge and expected to understand and interpret these ancillary tests. It is easy for morphological training to take a backseat – so why should we continue to pay attention to it?

Even today, morphological evaluation helps us decide the further workup of any lesion or tumor. Categorizing cells into small, medium, and large sizes can assist with suspected lymphoma. Close observation of the amount and color of cytoplasm in tumor cells, their nuclei, nucleoli, and the pattern and cellularity of the lesion support the selection of immunostains for spindle cell lesions. The presence of lymphovascular invasion in the absence of lymph node metastasis on PET imaging hints at higher risk of future metastasis. Morphological examination is still a reliable way to differentiate atrophy, atypical hyperplasia, and prostatic adenocarcinoma grade 3 + 3 on a prostate biopsy – even when immunostains are unhelpful. In many cases, a simple morphological examination still gives us key diagnostic and prognostic information.

The scenario is likely to become even more complex in years to come, as newer treatment techniques, neoadjuvant chemotherapy, and immunotherapy change the way we treat cancer. Tumor cells change with neoadjuvant chemotherapy and radiation. Newer treatment modalities may change the information we gain from ancillary stains in the future. In these cases, morphology can step in. And it’s not just about cell size and shape; morphology, in some scenarios, can yield insight into the “genotype” of various lesions. A colonic adenocarcinoma with lymphoid infiltrate raises the possibility of Lynch syndrome, whereas a type II papillary renal cell carcinoma with eosinophilic nucleoli raises the suspicion of hereditary leiomyomatosis with renal cell carcinoma. I recall an example from the WHO Classification of Soft Tissue Tumours stating that an epithelioid hemangioendothelioma consisting of well-formed vascular spaces with cells having eosinophilic cytoplasm suggests YAP1-TFE3 fusion, rather than the common WWTR1-CAMTA fusion. This understanding of morphological patterns helps “triage” further workup in the right direction, potentially improving efficiency and reducing time and cost.

Newer tests and techniques are not readily accessible to pathologists in many parts of the world. And, with the tremendous strides our knowledge of tumor genetics makes every day, it is practically impossible for even well-resourced laboratories to stay fully up to date. Not only that, but pathological assessment of intraoperative frozen sections – which relies on H&E-based assessment – is of great value to the surgical team. In short, the heterogeneity with which we describe pathological lesions may increase in the years to come – and, when it does, our morphological knowledge can help provide the best possible guidance for testing, treatment, and outcome prediction. Nowhere is this truer than in resource-poor settings, but we can all benefit from a strong understanding of morphology in our work.

As excited as I am about the newest advances in molecular pathology, ancillary tools, and IHC stains available for use, I have tried to learn just as much about morphology. No matter how much information we have at our fingertips, we cannot replace the humble morphological assessment – a foundational part of our pathology training and practice.