Micrographia 1665 – Robert Hooke Leaves His Mark on World History with a Microscope
In this article
In January 1665, a book was printed in London with the permission of the Royal Society: Micrographia. It contained drawings of a flea, a louse, and a fly's eye on a scale no one had ever seen before—and small chambers in a section of cork tissue. Robert Hooke called those chambers "cells". Three hundred and sixty years later, which treatment a cancer patient receives still depends on someone looking through a microscope and deciding what to call those cells.
This article does two things. First, it corrects six misconceptions circulating in Turkish sources about Micrographia, citing its sources—from who made Hooke's microscope to the sequence of Leeuwenhoek's and Malpighi's discoveries. Second, and more importantly, it explains what that microscope does today in oncological pathology: why cancer is still diagnosed with a microscope, how grading systems work, and what happens when two pathologists read the same slide differently.
The central tension in this article is this: the microscope remains the undisputed standard for cancer diagnosis. Yet part of what it measures is a human interpretation. In assessing atypia in breast biopsies, pathologists' agreement with the consensus diagnosis is 48% —less than half. The same pathologists' agreement for invasive carcinoma is 96%. At the extremes, the microscope is almost flawless; in the middle, it is genuinely uncertain. This is one of the least discussed problems in modern oncology.
First, Six Corrections
| Circulating statement | The correct account |
|---|---|
| "In 1665, Robert Hooke developed the compound microscope" | Hooke neither invented nor made the compound microscope himself. The instrument he used was made by London instrument maker Christopher Cock. Hooke described the optical arrangement—in his own words, "a small objective glass, a thinner eye glass, and a very deep one"—and worked on fine details by removing the middle lens. 1665 is the date of a book, not an invention. |
| "The first microscopes emerged in the Netherlands at the end of the 16th century" | Broadly correct, but the inventor is unknown, and the claim is disputed. It is attributed to Zacharias Janssen, but this claim was made by his son 35 years later, and Zacharias was probably born in 1585. His father, Hans Martens, and rival Hans Lippershey are also candidates. The earliest documented compound microscope is Cornelis Drebbel's, from 1621; Galileo made an improved version after seeing it in 1624. |
| "Hooke saw chambers in plant tissue and called them cells" | Incomplete—and the omission matters. Hooke examined a section of cork (bottle cork), and what he saw was not living cells, but the empty walls of dead plant cells. His magnification was insufficient to see their contents, and he did not recognize them as living structures. In his words, the tissue was "entirely perforated and porous, like a honeycomb"; he called them "these pores, or cells". |
| "In 1673, Leeuwenhoek described microorganisms in a drop of pond water" | The date and content do not match. 1673 was the year of his first letter, whose subjects were mold, bees, and lice. He first observed protists in 1674 ("little animalcules"). His first observation of bacteria was in 1683, in a sample from the human mouth. |
| "Leeuwenhoek's observations of capillaries were confirmed by Malpighi" | The sequence is reversed. The first person to see capillaries was Marcello Malpighi: in 1661, in a frog's lung (De pulmonibus observationes anatomicae). Leeuwenhoek was among the first to see blood flow in capillaries, but Malpighi and Swammerdam had observed these structures earlier. Leeuwenhoek's distinctive contribution was being the first to recognize that the things there were red blood cells. |
| "The Pap smear became widespread around 1943; before that, cervical cancer was a leading cause of death among US women" | 1943 is the publication date of the monograph, not the date of widespread adoption. Papanikolau first presented his work in 1928 and encountered skepticism and resistance. The method did not gain widespread acceptance until the 1940s; a comprehensive trial was conducted in the early 1950s. The statement "a leading cause of death among US women" could not be verified —at best, it should be written as "a leading cause of cancer death." |
Micrographia: Why a Book Matters So Much
| Full title | Micrographia: or Some Physiological Descriptions of Minute Bodies made by Magnifying Glasses, with Observations and Inquiries thereupon |
|---|---|
| Author | Robert Hooke, Fellow of the Royal Society |
| Publication | January 1665, London |
| Printer | Jo. Martyn and Ja. Allestry—the Royal Society's printers |
| License | Royal Society permission, dated 23 November 1664, signed by Society President Lord Brouncker |
| Microscope | Made by Christopher Cock (London); magnification of approximately 50 times. |
| Famous plates | Flea, louse, mosquito, fly's eye. The engraving of the louse, four times the size of the book, was printed as a foldout plate. |
The book was not merely a collection of drawings. In it, Hooke proposed the wave theory of light, developed from his refraction studies and vibration patterns observed in glass plates. Perhaps even more striking were fossils.
Hooke's argument about fossils was far ahead of its time. The prevailing view was that fossils were "mineral games of nature"—shapes that formed spontaneously inside stone. Hooke argued that fossilized objects such as petrified wood and ammonites were the remains of once-living organisms, turned to stone through mineral replacement. This line of reasoning paved the way for evolutionary theory and was written two centuries before Darwin.
The book's influence extended beyond academia. Samuel Pepys described it in his diary as "the most ingenious book that ever I read in my life". Micrographia was one of the first great occasions when science reached the public—and the moment it discovered the power of images in scientific persuasion.
Who Was Hooke—and Why Do We Not Know His Face?
Robert Hooke (18 July 1635, Freshwater, Isle of Wight – 3 March 1703, London) was the Royal Society's Curator of Experiments: on 11 January 1665, he was appointed for life at a salary of 80 pounds a year. His task was to prepare new experiments for the Society's meetings every week—one of the most exhausting jobs in the history of science.
No authenticated portrait of Hooke exists. There may have been a portrait by Mary Beale; this portrait was lost when Newton moved the Royal Society's headquarters in 1710. Recent suggestions that Beale's painting of an unidentified mathematician depicts Hooke are disputed.
But take care: the story that "Newton deliberately had the portrait destroyed" is widespread and unsupported by the sources —the only documented fact is that the portrait disappeared during the move. There was genuine hostility between Newton and Hooke: a priority dispute over the inverse-square form of the law of gravitation. Hooke maintained that the concept was his; Newton said that he had developed the mathematical proof independently and that intuiting a truth differed from rigorously proving it. The hostility is real; the murder of the portrait is unverified —the two must be distinguished.
The Cork Section: The Most Productive Misunderstanding in the History of Science
Hooke cut a thin slice of bottle cork and placed it under a microscope. He saw a regular honeycomb texture. In his own words: "I could extremely plainly perceive it to be all perforated and porous, much like a honey-comb, but that the pores of it were not regular." He derived their name from the Latin word for "little room," cellula, because they recalled monastic chambers, and called them "cells".
But Hooke did not see living cells. Cork is dead plant tissue; what he saw was empty cell walls. His magnification was insufficient to see cell contents, and he did not recognize these structures as the basic unit of life—what he saw was the porous structure of a material. In other words, the most fundamental concept in biology was named by looking at an empty space.
This is not a flaw but a description of how science progresses: giving the right name for the wrong reason, then spending two centuries discovering what that name means. The idea that the cell is the unit of life would come 174 years after Hooke.
The Optical Paradox: Why Did the Advanced Instrument Fall Behind?
Here lies one of the most instructive ironies in the history of science. Hooke's compound microscope—with objective and eyepiece lenses, the "advanced" one—magnified approximately 50 times. The single-lens simple microscopes handmade by Antonie van Leeuwenhoek, a cloth merchant in Delft, reached magnifications measured in surviving examples of up to 275 times.
| Hooke's compound microscope | Leeuwenhoek's simple microscope | |
|---|---|---|
| Number of lenses | Three (reduced to two for fine detail) | One |
| Magnification | ~50 times | Up to 275 times |
| Use | Relatively easy, wide field of view | Demanding; it had to be held steadily against the eye |
| Spread | Spread rapidly with the book | Leeuwenhoek did not share the secret of its manufacture |
This figure says it all: compound microscopes took approximately 150 years to reach the image quality Leeuwenhoek achieved with a single lens. The solution came in 1830: Joseph Jackson Lister, in his paper presented to the Royal Society, "On the Improvement of Achromatic Compound Microscopes," found an arrangement that, by changing the distances between lens elements, better corrected chromatic aberration and minimized spherical aberration —the law of aplanatic foci.
The lesson is this: a more complex instrument does not automatically produce a better result. Every lens is a source of error; adding lenses without learning to correct their errors does not improve the image. This principle also applies to the tendency to order more tests in oncology.
Leeuwenhoek and Malpighi: The Correct Sequence
| Year | Who | What |
|---|---|---|
| 1661 | Marcello Malpighi (1628–1694) | Capillaries, in a frog's lung. He completed the missing link in Harvey's theory of circulation. He had tried in a sheep in 1660 but failed because the structures were too small. |
| 1665 | Robert Hooke (1635–1703) | Micrographia; "cells" in a section of cork |
| 1673 | Antonie van Leeuwenhoek (1632–1723) | To the Royal Society, his first letter: mold, bees, lice |
| 1674 | Leeuwenhoek | First observations of protists —the conclusion that the moving objects were "little animalcules" |
| 1683 | Leeuwenhoek | First documented bacteria: large selenomonads in a sample from the human mouth |
| — | Leeuwenhoek | Among the first to see blood flow in capillaries; his truly distinctive contribution was recognizing the objects there as red blood cells. The exact year in which he confirmed capillaries could not be verified. |
There is also a correction to the name: "Anton Philips van Leeuwenhoek," often used in Turkish sources, is not the correct spelling. The correct form is Antonie van Leeuwenhoek; the middle name "Philips," derived from his father's name, is optional and generally omitted. He himself settled on "Antonie van Leeuwenhoek" after 1685.
From Cells to Cellular Pathology: The Chain Leading to Oncology
Hooke gave it a name. What that name meant was understood two centuries later—and when it was understood, medicine changed.
That hypothesis from 1863 remains one of oncology's most productive lines of research a hundred and sixty years later. That chronic inflammation increases cancer risk—from hepatitis to liver cancer, from Helicobacter pylori to stomach cancer, and from ulcerative colitis to colorectal cancer —is established knowledge today. The tumor microenvironment and immune-based treatments grow from the same roots. Virchow's only instrument was a microscope; by counting cells, he formed a hypothesis, and it held. Hooke gave it a name; Virchow connected that name to the concept of disease —and pathology was born.
Today: What Does the Microscope Do in the Cancer Clinic?
In the age of molecular tests, imaging, and artificial intelligence, the question arises: is cancer still diagnosed with a microscope? The National Cancer Institute's answer is a single sentence: "The pathology report provides the definitive cancer diagnosis."
| Patient identification and biopsy date |
| Where in the body the sample was taken from and how |
| Gross description —"a visual description of the sample as seen by the naked eye" |
| Microscopic description |
| Definitive diagnosis |
| Pathologist's comments |
| Tumor grade—"how abnormal the cells look" |
| Estrogen and progesterone receptor and HER2/neu results when breast cancer is suspected |
| Molecular and genetic tests (including fluorescence in situ hybridization) |
According to the NCI, the pathologist typically sends the report to the physician within 10 days after the biopsy or surgery. For details on diagnostic concepts, see our article What Is Carcinoma?.
In the Operating Room: Frozen Section
When the surgeon needs an answer during an operation, tissue is frozen, sectioned, and immediately stained. In the NCI's definition, a frozen section is prepared "when an immediate answer about a tissue sample is needed" and gives the surgeon a rapid diagnosis while the patient is on the operating table. The time required is approximately 15–20 minutes. The method was developed by Louis B. Wilson in 1905 at the Mayo Clinic at William Mayo's request.
| Use | Limitation |
|---|---|
| Assessment of surgical margins —is tumor still present at the edge of the removed tissue? | The image quality of frozen sections is lower than that of tissue fixed in formalin and embedded in paraffin. A definitive diagnosis is rarely given during surgery. A 2016 Cochrane review reported good accuracy for clearly benign or malignant tumors, but lower accuracy for borderline tumors, approximately one fifth of which were subsequently confirmed as cancer. |
| Sentinel lymph node —if positive, further lymph node dissection is performed; if benign, this procedure is avoided | |
| Rapid guiding diagnosis |
Grading Systems: Looking through a Microscope Turned into Rules
Almost all the prognostic tools most commonly used in oncology are, in fact, numerical translations of what a person sees under a microscope.
| System | Who, when | What it measures | Range |
|---|---|---|---|
| Gleason score prostate cancer |
Donald Gleason and colleagues, Minneapolis Veterans Hospital, 1960s | Patterns of glandular architecture rather than cell appearance | 2–10; converted by the 2014 ISUP Grade Groups into 1–5. |
| Nottingham (Bloom-Richardson) grade breast cancer |
Scarff-Bloom-Richardson 1957; Elston-Ellis Nottingham modification, 1991 | Three components, each scored 1–3: tubule formation, nuclear pleomorphism, mitotic count | Total 3–9: 3–5 Grade I, 6–7 Grade II, 8–9 Grade III |
| Breslow thickness melanoma |
Alexander Breslow, George Washington University, 1970 | From the granular layer of the epidermis to the deepest point of invasion, measured in millimeters. | Thresholds in AJCC staging: 1 mm, 2 mm, 4 mm |
| WHO CNS tumors 2021 glioblastoma |
World Health Organization, 5th edition (CNS5) | Morphology plus molecular alterations | Roman numerals abandoned; 1–4 in Arabic numerals |
Breslow thickness is the clearest example of how powerful a single microscopic measurement can be. The value in millimeters, measured perpendicular to the skin with an ocular micrometer, is closely associated with five-year survival: 95–100% below 1 mm, 80–96% between 1–2 mm, 60–75% between 2.1–4 mm, and approximately 50% above 4 mm. The same measurement also predicts the risk of lymph node metastasis and remains one of the cornerstones of melanoma TNM staging today. A ruler, a microscope, and a pathologist.
Immunohistochemistry: Adding Molecular Information to the Microscope
Immunohistochemistry (IHC) is still microscopy—but binding antibodies to tissue and staining it makes proteins visible that plain morphology cannot reveal. A few examples that directly determine treatment in oncology:
| Marker | How it is read | Clinical consequence |
|---|---|---|
| HER2 | 0, 1+, 2+, 3+ —according to the intensity and completeness of cell membrane staining | 3+ is considered positive. 2+ is "equivocal", and reflex in situ hybridization (FISH) is performed—because the predictive value of a 2+ score is low and interobserver variability is substantial. |
| ER / PR | Estrogen and progesterone receptor staining | The basis of the endocrine therapy decision; a standard component of a breast pathology report according to the NCI |
| PD-L1 | TPS: the percentage of viable tumor cells that stain. CPS: the number of stained tumor cells + lymphocytes + macrophages divided by the number of viable tumor cells and multiplied by 100 | TPS in the lung (thresholds of ≥1% and ≥50%); CPS in cervical, urothelial, head and neck, esophageal, and triple-negative breast cancer. 22C3 is the FDA-approved companion diagnostic clone for pembrolizumab. |
The percentage thresholds for HER2 have changed over time (ASCO/CAP updates); percentages are not provided in the table because the exact wording of the current thresholds could not be verified for this article. Ki-67 is omitted because verified data could not be obtained.
The HER2-low story alone illustrates the microscope's power today. On 5 August 2022, the FDA approved trastuzumab deruxtecan (Enhertu) for HER2-low breast cancer. HER2-low is defined as: IHC 1+ or IHC 2+/ISH negative —a subset of patients previously grouped together as "HER2-negative."
In the DESTINY-Breast04 trial (557 patients), median progression-free survival in the HR-positive cohort was 10.1 months versus 5.4 months (HR 0.51), and overall survival was 23.9 months versus 17.5 months (HR 0.64). In other words, whether a pathologist looks at an IHC slide and calls it "0" or "1+" determines whether the patient receives this drug. Two tumors that look identical on H&E take different treatment paths because of a single step in a staining score. We have discussed the expanding field of HER2-targeted treatments in our articles on HER2-mutant lung cancer and anbenitamab.
The Rarely Discussed Problem: What If Two Pathologists Read the Same Slide Differently?
A microscope is not a measuring instrument; it is an instrument for seeing. Part of what it measures is human interpretation—and the consistency of that interpretation can be measured. It has been measured.
Breast Biopsies: The B-Path Study
JAMA published a study in 2015 involving 115 pathologists, 240 breast biopsy cases, and a total of 6,900 interpretations made as the pathologists assessed the cases. Each interpretation was compared with an expert consensus diagnosis.
| Diagnostic category | Agreement | Overinterpretation | Underinterpretation |
|---|---|---|---|
| Invasive carcinoma | 96% (94–97) | — | 4% |
| Benign without atypia | 87% (85–89) | 13% | — |
| DCIS | 84% (82–86) | 3% | 13% |
| Atypia | 48% (44–52) | 17% | 35% |
| Overall | 75.3% (73.4–77.0) | — | |
Melanoma: Eight Dermatopathologists, 792 Lesions
Nature Communications published a prospective multicenter study on 17 January 2025 in which eight board-certified dermatopathologists from eight German university hospitals independently evaluated 792 lesions suspected of melanoma.
| Cases in which all eight agreed | 53.5% (424/792) |
|---|---|
| Cases with majority consensus (at least five) | 90.9% (720/792) |
| Overall Fleiss kappa | 0.701 (0.693–0.710) |
| Kappa for nevi | 0.742 |
| Kappa for invasive melanomas | 0.725 |
| Kappa for noninvasive melanomas | 0.428 (0.415–0.441) |
| Cases in which the expert panel disagreed with the local pathologist | 14.9% (118/792) |
| Cases in which the expert panel disagreed with the clinical dermatologist's impression | 33.3% (264/792) |
Both studies say the same thing, and it is worth explaining to patients: the microscope at the extremes is almost flawless—96% agreement for invasive carcinoma and kappa 0.725 for invasive melanoma. In the middle, it is genuinely uncertain —48% for atypia and kappa 0.428 for noninvasive melanoma.
The practical implication is this: requesting a second opinion on a borderline pathology result is a data-driven request, not distrust. When a report contains terms such as "atypia," "equivocal," or "could not be distinguished," having a second pathologist look at it is a step with a statistically high likelihood of changing the result. In contrast, a second opinion on a report that says "invasive carcinoma" does not provide the same degree of information. A second opinion should be sought for the right report, not every report.
Digital Pathology and Artificial Intelligence
| Date | Product | What does it do? |
|---|---|---|
| 12 April 2017 | Philips IntelliSite Pathology Solution | The first system for which the FDA permitted whole-slide imaging for primary diagnosis. It allows pathologists to read the slide not through a microscope but on a screen. In approximately 2,000 surgical pathology cases, digital interpretations were shown to be similar to glass-slide interpretations. |
| 21 September 2021 | Paige Prostate (Paige.AI) | Authorized through De Novo. In a prostate biopsy image, it marks the area most likely to contain cancer, which the pathologist then examines. |
| 10 February 2025 | Ibex Prostate Detect | 510(k) clearance. It flags tumors the pathologist may have missed, providing case- and slide-level alerts and a heat map. |
The most important detail lies in the FDA's own wording. Paige Prostate was authorized as an "adjunct"; it does not replace the pathologist, and the definitive diagnosis still requires "the professional judgment of a qualified pathologist". Its performance should also be read in this context: compared with pathologists' unaided readings, it improved cancer detection in individual slide images by an average of 7.3%, with no effect on the reading of benign slides.
And two limitations stated by the FDA itself: "Potential risks include false-negative and false-positive results", and the study "did not evaluate the effect on the final patient diagnosis, which is typically based on multiple biopsies." In other words, the regulator approved a reading aid and did not clearly demonstrate that it changed the final diagnosis. We discussed the place of artificial intelligence in medical publishing and research in our articles on JAMA's 2026 rules and Paper2Agent.
What the Microscope Cannot See: The Molecular Layer
The document that most clearly demonstrates the microscope's limit is the World Health Organization's 2021 classification of central nervous system tumors(CNS5). This classification formally acknowledges that morphology alone is insufficient.
| Condition | Previous approach | In CNS5 |
|---|---|---|
| Glioblastoma diagnosis | Microscopic evidence of necrosis and microvascular proliferation was required | These features are no longer required: the diagnosis is made if a TERT promoter mutation, EGFR amplification, or gain of chromosome 7/loss of chromosome 10 is present |
| IDH-mutant astrocytoma grading | Based on microscopic appearance | Homozygous CDKN2A/B deletion means that, regardless of the slide's appearance, it is grade 4 |
| Oligodendroglioma | Morphological diagnosis | The name itself is molecular: "oligodendroglioma, IDH-mutant, and 1p/19q-codeleted" |
| Midline glioma | — | "diffuse midline glioma, H3 K27-altered, WHO grade 4" |
The meaning of this table is that a tumor appearing low-grade under a microscope may be classified as glioblastoma because of molecular findings. Thus, the tradition of "look and describe" that began in 1665 officially reached its limit in 2021—but it was not replaced; a layer was added on top. The pathologist still looks through a microscope, but PCR and sequencing results now accompany the report. The importance of where a mutation lies within a gene is a layer of information morphology can never reveal.
Is the Electron Microscope Still Used?
Yes—with defined indications. According to the US Veterans Health Administration's diagnostic electron microscopy program, the main areas are: kidney diseases (the strongest indication; immune complexes, basement membrane abnormalities), neoplasms (determining differentiation in poorly differentiated carcinomas; distinguishing carcinoma, lymphoma, melanoma, and sarcoma), infectious diseases (agents difficult to see with light microscopy), metabolic diseases (amyloidosis, mitochondrial myopathy), and conditions of unknown cause.
Pap Smear: The Moment the Microscope Became Public Health
The microscope's largest-scale impact in medicine was in screening rather than diagnosis. Georgios Papanikolau (13 May 1883, Kymi – 19 February 1962, Miami) showed that examining cells from the cervix under a microscope could detect precancerous changes.
| 1928 | Papanikolau presents his work at a medical conference in Battle Creek, Michigan. It is met with skepticism and resistance from the medical community. |
|---|---|
| 1943 | Diagnosis of Uterine Cancer by the Vaginal Smear is published—Papanikolau and Herbert F. Traut, The Commonwealth Fund, New York. Some sources give 1942; the publication details and contemporary reviews support 1943. |
| 1940s | The method only begins to gain recognition during this period |
| Early 1950s | A comprehensive trial is conducted; widespread adoption mainly follows |
Today, screening has shifted from looking at cells to looking at viral nucleic acid—we discussed this in our articles on cervical cancer and PCR. For Papanikolau's story and details of the test, see our articles George Papanicolaou, Who Saved Millions of Women's Lives with the Pap Smear and What Does an Abnormal Pap Smear Result Mean?.
DROZDOGAN Academy Commentary
This article began as a book introduction and ended as a critique of a pathology report. The connection is no coincidence: the method Hooke began in 1665—look, describe, name—remains the basis of cancer diagnosis today. For precisely this reason, its limits must be understood.
⚡ Why it matters
Because most patients think a cancer diagnosis comes from an exact number, like a laboratory result. Yet the diagnosis is made when a person looks at a slide and writes what they see. In the National Cancer Institute's words, "the pathology report provides the definitive cancer diagnosis"; the "tumor grade" line in that report means "how abnormal the cells look". Looking is a different verb from measuring—and that difference is worth explaining to patients.
✅ The strength
The microscope still stands three hundred and sixty years later because it is almost flawless at the extremes. Pathologists' agreement with expert consensus is 96% for invasive carcinoma; kappa is 0.725 for invasive melanoma. A single microscopic measurement such as Breslow thickness is powerful enough to separate five-year survival from 95% to 50%. Frozen section gives the surgeon an answer in 15–20 minutes while the patient is on the table. No molecular test offers this speed at this cost. Being old does not mean being invalid.
⚠️ The weakness
In the middle, uncertainty is real and measured: agreement for breast atypia is 48%, and kappa for noninvasive melanoma is 0.428. The low predictive value of a HER2 2+ score and the requirement for reflex FISH are the institutional acknowledgment of the same problem— the system has installed a safety valve because it knows its own uncertainty. Artificial intelligence claims to fill this gap, but the product authorized by the FDA is an adjunct, and the regulator explicitly writes that it has not shown that it changes the final diagnosis. Finally, the WHO's 2021 CNS classification formally acknowledged that morphology alone could not establish a diagnosis.
🩺 What to tell the patient
(1) The pathology report is the definitive diagnosis, not imaging. Treatment is not planned before the report arrives, and this waiting time is not wasted. (2) The "grade" line in the report describes how cells look—it should not be confused with stage. (3) If the report includes terms such as "atypia," "borderline," or "could not be distinguished," requesting a second pathology opinion is a data-driven request; it does not provide the same amount of information for a clear report stating "invasive carcinoma." (4) Whether the HER2 score in breast cancer is 0 or 1+ currently determines access to a drug; the report can be discussed. (5) In brain tumors, a grade given before the molecular results are available is incomplete.
❓ Open questions
Does AI-assisted reading actually improve agreement between pathologists in the uncertain middle ground—atypia and borderline lesions? The FDA-approved products improve detection in prostate cancer, but the greatest need is not detection; it is classification. Second, as digital pathology spreads, obtaining a second opinion becomes technically easier—will this reduce overdiagnosis or increase it? Third, and perhaps most fundamentally, which prevails when morphology and molecular data conflict? The WHO gave the answer for gliomas in 2021 (molecular), but the question remains open for other tumor types.
Conclusion: Micrographia made a lasting contribution not through an instrument or a discovery, but through a method: magnify what cannot be seen with the naked eye, describe it carefully, draw it, and name it. Hooke had not even seen living cells while doing this—he looked at the empty walls of dead cork and gave the right name for the wrong reason. Today, oncological pathology applies a far more refined version of the same method and lives with the same structural constraint: seeing is different from measuring. No technology will invalidate the microscope, but there are layers that will not leave it alone —immunohistochemistry, molecular pathology, and perhaps artificial intelligence. The right statement is not "the microscope has fallen behind," but "the microscope no longer works alone".
Frequently Asked Questions
- Did Hooke invent the microscope?
- No. The compound microscope existed before Hooke; the earliest documented example is Cornelis Drebbel's (1621). The instrument Hooke used was also made by Christopher Cock of London. Hooke's contribution was not inventing the instrument but the book showing what could be done with it.
- Did Hooke really see cells?
- No—he saw the empty cell walls in dead cork tissue. His magnification was insufficient to see cell contents, and he did not recognize these structures as the unit of life. He gave them the name "cells" because they reminded him of monastic chambers. The idea that the cell is the basic unit of life came with Schleiden and Schwann in 1839.
- Is cancer still diagnosed with a microscope?
- Yes. In the NCI's words, "the pathology report provides the definitive cancer diagnosis." Imaging raises suspicion and blood tests provide guidance, but a definitive diagnosis requires tissue to be taken and examined by a pathologist. Molecular tests do not replace the microscope; they are added on top.
- How long does a pathology report take?
- According to the NCI, the pathologist typically sends the report to the physician within 10 days after a biopsy or surgery. If an urgent answer is needed during surgery, a frozen section is performed and the result is obtained in approximately 15–20 minutes; however, frozen sections have lower quality, and a definitive diagnosis is rarely given during surgery.
- Can two pathologists give different diagnoses for the same biopsy?
- Yes, and this has been measured. In the study in which 115 pathologists assessed 240 breast biopsies, agreement with expert consensus for invasive carcinoma was 96%, compared with 48%for atypia. In the study in which eight dermatopathologists assessed 792 lesions suspected of melanoma, all eight agreed in only 53.5% of cases. Thus, uncertainty is real and concentrated in particular diagnostic categories.
- Should I request a second pathology opinion?
- If your report includes terms such as "atypia," "borderline," "could not be distinguished," or "equivocal," a second opinion is a statistically meaningful step. A clear report stating "invasive carcinoma" does not yield the same amount of information. This is not distrust but a practice indicated by the data themselves. Discuss the decision with your treatment team.
- Are tumor grade and stage the same?
- No; they are the two concepts most often confused. Grade describes how abnormal cells look under a microscope (as in Gleason or Nottingham grading). Stage describes how far the tumor has spread. There can be different grades at the same stage, or different stages at the same grade.
- Why does the difference between HER2 "0" and "1+" matter?
- Because since 5 August 2022, the FDA has approved trastuzumab deruxtecan for HER2-low (IHC 1+ or 2+/ISH negative) breast cancer. Some patients previously grouped together as "HER2-negative" are now candidates for this drug. In the HR-positive cohort of DESTINY-Breast04, overall survival was 23.9 months versus 17.5 months. A single step in a staining score therefore changes the treatment pathway.
- Will artificial intelligence replace the pathologist?
- The current regulatory position does not allow this. Paige Prostate, authorized by the FDA in 2021, is described as an "adjunct"; a definitive diagnosis still requires "the professional judgment of a qualified pathologist." The FDA also explicitly states that the study did not evaluate the effect on the final patient diagnosis.
- Is the electron microscope still used?
- Yes, for defined indications: primarily kidney diseases, distinguishing poorly differentiated tumors, certain infectious diseases, metabolic conditions such as amyloidosis and mitochondrial diseases, and conditions of unknown cause.
Glossary
- Compound microscope
- A microscope using at least two lens groups, an objective and an eyepiece. Total magnification is the product of the lenses' powers.
- Simple microscope
- A single-lens microscope. The type Leeuwenhoek used; in his time, it provided higher resolution than the compound microscope.
- Chromatic aberration
- Color fringing caused by a lens focusing different wavelengths at different points. Largely resolved by Lister in 1830.
- Spherical aberration
- Blurring caused by rays passing through the edge and center of a lens focusing at different points.
- Histopathology
- Diagnosing disease by examining tissue under a microscope.
- Frozen section
- Freezing, sectioning, and staining tissue for a rapid diagnosis during surgery. The time required is approximately 15–20 minutes; quality is lower than in paraffin sections.
- Surgical margin
- The edge of removed tissue. Whether tumor cells are present at the margin determines whether additional surgery is needed.
- Tumor grade
- A measure of how abnormal cells look under a microscope. It is not the same as stage.
- Mitotic count
- The number of dividing cells counted in a specified number of high-power fields. One of the three components of Nottingham grade.
- Nuclear pleomorphism
- The degree of variation in the size and shape of cell nuclei.
- Breslow thickness
- In melanoma, the measurement in millimeters from the granular layer of the epidermis to the deepest point of invasion.
- Immunohistochemistry (IHC)
- Making specific proteins in tissue visible under a microscope by labeling them with antibodies.
- TPS / CPS
- Two different methods of quantifying PD-L1 staining. TPS counts only tumor cells; CPS also includes immune cells.
- Fleiss kappa
- A statistic measuring agreement among more than two observers with correction for chance. Agreement increases as it approaches 1.
- Whole-slide imaging
- Scanning a glass slide at high resolution so that it can be examined on a screen. The FDA first permitted it for primary diagnosis in 2017.
- Lymphoreticular infiltrate
- An accumulation of immune cells in tumor tissue. The finding on which Virchow based his cancer–inflammation connection in 1863.
Transparency note.
Verified: That Hooke's microscope was made by Christopher Cock and that Hooke described its three-lens arrangement in his own words; the unknown inventor of the compound microscope and Drebbel's instrument from 1621; Micrographia's January 1665 publication date, printer, Royal Society license dated 23 November 1664, and Brouncker signature; Pepys's statement; the foldout louse plate; the wave theory of light and the argument that fossils are remains of organisms; Hooke's life dates, appointment date as Curator of Experiments, and salary; the portrait's disappearance during the 1710 move; the inverse-square law dispute with Newton; that Hooke's cork observation involved dead cell walls and the "honeycomb / pores or cells" wording; Hooke's ~50 times magnification and up to 275 times in Leeuwenhoek's surviving instruments; the approximately 150-year lag of compound microscopes; Lister's 1830 achromatic work and correction of both aberrations; the content of Leeuwenhoek's first letter in 1673, protist observations in 1674, and bacterial observations in 1683; Malpighi's discovery of capillaries in a frog's lung in 1661 and Leeuwenhoek's main contribution being recognition of red blood cells; the life dates of four individuals; Schleiden and Schwann in 1839, Remak in 1852, Virchow in 1855 and 1858, and cancer–inflammation in 1863; the NCI's definition and contents of a pathology report and its 10-day timeframe; the frozen section definition, 15–20 minutes, its Wilson/Mayo origin in 1905, uses, and the 2016 Cochrane findings; founders, dates, and ranges of the Gleason, Nottingham, Breslow, and WHO CNS5 systems; Breslow survival rates; HER2 0/1+/2+/3+ categories and the rationale for reflex ISH at 2+; the HER2-low definition, FDA approval on 5 August 2022, and DESTINY-Breast04 results; PD-L1 TPS/CPS definitions, thresholds, and the 22C3 clone; B-Path (JAMA 2015) and dermatopathology (Nature Communications 2025) agreement data; regulatory decisions on Philips IntelliSite in 2017, Paige Prostate in 2021, and Ibex in 2025, together with the FDA's emphasis on their adjunctive nature and its limitation statements; WHO CNS5 molecular criteria; electron microscopy indications; Papanikolau's 1928 presentation and 1943 monograph, and cervical cancer data from the CDC and ACS CAN.
Not verified: Hooke's illumination arrangement (oil lamp, water-filled glass sphere, scotoscope)—therefore omitted from the text; the exact source of the often-quoted phrase "little boxes or cells, distinct from one another"; the lower bound of "30 times" given for Hooke's magnification; the reason compound microscopes lagged for 150 years being named as aberrations (Lister's correction of aberrations in 1830 has been verified); Leeuwenhoek's pepper-water letter from 1676 and that the 1683 sample was dental plaque; the year Leeuwenhoek confirmed capillaries; Micrographia's total number of observations ("60" could not be verified); the allegation that Newton deliberately had the portrait destroyed; that cervical cancer was a "leading cause of death" among US women before screening; whether the Papanikolau-Traut monograph was from 1942 or 1943 (1943 is better supported); current ASCO/CAP HER2 IHC percentage thresholds and ER/PR positivity thresholds; Ki-67 data of any kind (the marker is therefore omitted); interobserver kappa values for Gleason grading (no numbers are therefore provided); PD-L1 clones other than 22C3; the name of the FDA-approved companion diagnostic test for HER2-low; a complete list of FDA-approved AI pathology devices; verification of Ibex's performance figures beyond the company announcement; access to pathology services, second-opinion practices, and reimbursement in Turkey —no claims have been made on these subjects.
Source of the critiques: The assessments that "Hooke gave the right name for the wrong reason," "a more complex instrument does not automatically produce better results," "the microscope is flawless at the extremes but uncertain in the middle," "second opinions should be sought for the right report rather than every report," and "the HER2 2+ reflex ISH rule institutionalizes the system's own uncertainty" belong to this article. In contrast, the B-Path and dermatopathology agreement figures, the FDA's statements on adjunctive status and limitations, and WHO CNS5 molecular criteria are the sources' own statements.
Declaration of interests: We have no affiliation with any product, test, or company named in this article.
References
- Hooke R. Micrographia: or Some Physiological Descriptions of Minute Bodies made by Magnifying Glasses. Jo. Martyn and Ja. Allestry, London, 1665. (Full text: Project Gutenberg.)
- Lens on Leeuwenhoek. "Hooke's Microscope." lensonleeuwenhoek.net
- National Museum of Health and Medicine. Review of Hooke's microscope. medicalmuseum.health.mil
- Lister JJ. "On the Improvement of Achromatic Compound Microscopes." Presented to the Royal Society, 1830.
- Malpighi M. De pulmonibus observationes anatomicae. 1661.
- Virchow R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. Berlin, 1858.
- National Cancer Institute. "Pathology Reports" fact sheet. cancer.gov
- Gleason grading system and 2014 ISUP Grade Groups.
- Elston CW, Ellis IO. Nottingham modification, Histopathology 1991;19:403. (Original system: Bloom HJG, Richardson WW, British Journal of Cancer 1957;11:359.)
- Breslow A. Tumor thickness in melanoma, 1970.
- College of American Pathologists. "Updates in Glioma and Meningioma Classification: WHO 2021." cap.org
- U.S. Food and Drug Administration. "FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer." 5 August 2022. DESTINY-Breast04, NCT03734029.
- Elmore JG, et al. "Diagnostic Concordance Among Pathologists Interpreting Breast Biopsy Specimens." JAMA 2015;313(11):1122–1132. (B-Path)
- Study of agreement between dermatopathologists. Nature Communications 2025;16:789, 17 January 2025.
- U.S. Food and Drug Administration. "FDA allows marketing of first whole slide imaging system for digital pathology." 12 April 2017.
- U.S. Food and Drug Administration. "FDA Authorizes Software that Can Help Identify Prostate Cancer." 21 September 2021; De Novo decision summary DEN200080.
- Ibex Medical Analytics. Announcement of Prostate Detect 510(k) clearance, 10 February 2025. (Company announcement.)
- Veterans Health Administration. "Diagnostic Indications for Electron Microscopy." va.gov
- Papanicolaou GN, Traut HF. Diagnosis of Uterine Cancer by the Vaginal Smear. The Commonwealth Fund, New York, 1943.
- Centers for Disease Control and Prevention. Cervical cancer screening and mortality rates, MMWR. cdc.gov
- Frozen section: Cochrane review, 2016.
Sources
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