Assessing neoadjuvant therapy response in lung resection specimens

Amy Carpenter

July 2026—An International Association for the Study of Lung Cancer panel provided recommendations in 2020 on how to process lung cancer resection specimens and define pathologic response after neoadjuvant therapy. They were intended as guidance for clinical trials but offered as a suggestion for good clinical practice (Travis WD, et al. J Thorac Oncol. 2020;15[5]:​709–740).

Two years later, the results of the CheckMate 816 clinical trial of neoadjuvant nivolumab plus chemotherapy in resectable lung cancer began to lead to greater numbers of such cases.

“In my institution, we are seeing an increasing number of lung cancer cases that have been resected post-neoadjuvant therapy,” Mitra Mehrad, MD, said in a CAP25 session last fall on lung cancer diagnosis. She is chief of thoracic pathology and professor of pathology, microbiology, and immunology at Vanderbilt University Medical Center.

Dr. Mehrad, a member of the CAP Surgical Pathology Committee, described the proper grossing of lung resections post-therapy and how to report treatment response.

Forde, et al., reported in 2022 the CheckMate 816 findings: In patients with resectable non-small cell lung cancer, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with pathologic complete response than chemotherapy alone (Forde PM, et al. N Engl J Med. 2022;386[21]:1973–1985).

“We are the ones who need to assess for treatment response,” Dr. Mehrad said.

The first step in assessing response is the imaging to look for shrinkage, and there is often a discrepancy between radiology and histology. Changes in the inflammatory, stromal, or fibrotic components of the tumor, rather than cancer cell death, may confound the radiographic interpretation of tumor size, contributing to the inability of CT to accurately predict histopathologic response after neoadjuvant therapy.

“It’s hard for radiologists to determine whether there’s viable tumor cells in the tumor,” Dr. Mehrad said. “Is this just fibrosis? Is there still a tumor there? Especially if the tissue is inflamed, the PET scan would also be positive—or even in the setting of necrosis.”

Dr. Mehrad highlighted the important points of the 2020 IASLC recommendations:

• Always measure the tumor bed fresh because formalin fixation can change the size of the tumor, if only by a few millimeters. “Millimeters matter in staging because, especially in the lower stages, every centimeter increase in tumor size would change the staging,” she said. All of the samples must be fixed; if very necrotic, they need to be fixed longer.
• The tumor bed size determines how much tissue needs to be submitted. If the tumor bed is small ​(≤ 3 cm), the entire tumor bed should be submitted. For tumors larger than 3 cm, a 0.5-cm thick cross-section of tumor (larger one or more viable) should be made and entirely mapped and submitted. Then submit one additional section per centimeter of tumor. Representative sampling is accepted.
• Histologic sections at the periphery of the tumor should include the border of the tumor with at least 1 cm of the surrounding non-neoplastic lung parenchyma to define the edge of the tumor. “That’s where the tumor is most likely to be still active, the front edge of the tumor,” Dr. Mehrad said.
• Indicate the percentage of necrosis in the gross description.
• Always take pictures.
• If no tumor is found, more histologic sections should be submitted.

“Whoever grosses a specimen, whether it’s your trainee or PA, it is important to always check the history because specimens come in and they’re not labeled as treated,” she said, noting they won’t be photographed or mapped if treated as normal cases. At Vanderbilt, “We don’t routinely map our lung cases.”

For the specimen seen in Fig. 1, the history was not checked, she said, “so we had to go back and rebuild and it became a little challenging” to map it after the fact. In the image on the left, the tumor can be seen extending to the visceral pleura. The front edge of the tumor, with viable tumor and stromal fibrosis, can be seen in the image on the right.

In Fig. 2 is a case of squamous cell carcinoma that did not have significant pathologic response, Dr. Mehrad said, noting viable tumor, inflammatory response, and stromal fibrosis.

Post-therapy, it’s common to have necrotic tissue in the center, fibrinous material, and tumor cells in the form of single cells, she said. If cells in a specimen have no visible cytoplasm, no discernible chromatin pattern, and no visible nucleoli, they are dead and should not be counted as viable tumor cells. If the outline of the cell, the cytoplasm, and the nucleolus can be seen, it is a viable tumor cell that should be counted toward active tumor cells.

Treatment response can take various shapes, most commonly in the form of fibrosis, Dr. Mehrad said. Stromal fibrosis, elastosis, and inflammatory cells are seen in Fig. 3, and it is important not to overcall such pneumocytes as remnants of adenocarcinoma, if the case was that of a patient with adenocarcinoma. “These are just benign pneumocytes that are entrapped in the scar.”

Granulomatous reaction is seen in Fig. 4.

If there is a contiguous section of tumor with little treatment response, viable tumor and treatment are quantified by measuring the specimen histologically, Dr. Mehrad said. “But a lot of times in these cases, if there’s not much treatment response, the tumor cells are kind of scattered,” making it difficult to estimate the percentage of tumor.

IASLC recommendation No. 5 says, “Determination of the pathologic response to therapy should be made after review of all H&E slides of tumor by estimating the percentages of (1) viable tumor, (2) necrosis, and (3) stroma, which includes both fibrosis and inflammation, so these three components add up to 100%. Each component should be assessed in 10% increments unless the amount is less than 5%, in which case, an estimate of single-digit percentages should be recorded.”

For example, Dr. Mehrad said, if there is a slide with necrosis, tumor, and fibrosis, “You can say, there’s 10 percent tumor, there’s 50 percent stromal fibrosis, and then you have 40 percent necrosis. Make sure estimates are as accurate as possible.”

The pathology report should record the total number of blocks of tumor bed that were examined, Dr. Mehrad said, even if the blocks did not consist entirely of tumor but also included some uninvolved lung. The oncologist who reviews the report will have an idea how big the tumor bed was and how much of the tissue was submitted.

The same approach applies to lymph nodes. If small, they should be submitted entirely, but if the lymph node metastasis measure is larger than 2 cm, the lymph node can be bisected and the central section through the tumor can be submitted. Percentages of stromal fibrosis, viable tumor, and necrosis should be reported. A well-defined scar and/or area of tumor necrosis in the absence of identifiable viable tumor cells indicates complete pathologic response, Dr. Mehrad noted.

In Fig. 5A, viable tumor is visible; in Fig. 5B, only pools of mucin are seen. “If you have pools of mucin with no epithelial tumor cells, that doesn’t count as active tumor,” she said. “You have to have the epithelial tumor cells to call it viable tumor.”

A difficulty with lymph nodes, especially in the mediastinum, is that patients who have been smokers or have a history of exposure often have anthracosilicotic nodules, which normally cause fibrosis in the lymph nodes (Fig. 5C). Anthracosilicotic nodules often have anthracotic pigments and should not be counted toward treatment response (Fig. 5D).

“If a lesion has more than 10 percent viable tumor, that is not considered a major pathologic response,” Dr. Mehrad said. “A major pathologic response is when there is 10 percent or less of viable tumor left in the tumor bed. And the recommendation is that if you get close to 10 percent and you still haven’t put the entire tumor bed in, go back to the specimen and put in additional sections, just to be more accurate,” and always note the number of tumor bed blocks submitted.

Complete pathologic response is when there is no evidence of viable tumor cells in the tumor bed or lymph nodes (ypT0 N0), and if no tumor is seen in the initial sections and tissue from the tumor bed remains, she said, sample more tissue.

Dr. Mehrad offered the following for how to stage surgically resected lung cancers in the neoadjuvant setting:

• If possible, measure viable tumor with a ruler or microscopically.
• If not possible (multiple foci, difficult borders), provide a percentage for each component of viable tumor, tumor necrosis, and stromal fibrosis. “Once you get an average of those for the viable tumor, you multiply it by the overall size of the tumor bed to get an estimate of the size.”

For example, if the tumor bed is 8 cm and the viable tumor is 20 percent, the invasive tumor size is 1.6 cm (8 cm × 0.2). “So you stage it based on 1.6 cm, not based on 8 cm,” Dr. Mehrad said. If there is a lepidic component in the viable tumor, do not include it in the estimate when multiplying, per the eighth edition of the American Joint Committee on Cancer staging manual. “We’re only staging based on the invasive component,” she said.

• Stage viable tumor only. “If it was a tumor that was invading the chest wall and you still see a lot of fibrosis in the chest wall but no viable tumor, you shouldn’t be staging as a ypT3,” Dr. Mehrad said.
• There is no recommendation on what to do if multiple lesions are in the lung, she said, but the literature recommends reporting major pathologic response on each tumor.

Dr. Mehrad shared a few cases in which patients received neoadjuvant therapy.

Case No. 1 is that of a tumor invading the chest wall and into the rib (Fig. 6, left). Viable tumor nest glands with mucin inside can be seen (right). “So it should be staged as a T3, even though they’re kind of scattered,” she said.

The tumor in case No. 2 did not show much pathologic response (Fig. 7). Remaining tumor cells are visible. In this case, the tumor can be measured across the slide, if this is the only slide, or the gross measurement can be used, she said.

In case No. 3 (Fig. 8), “There’s a lot of stromal fibrosis and granulomatous reaction with cholesterol clefting,” Dr. Mehrad said. “That’s pretty common. All should be accounted for as stromal fibrosis when estimating the tumor bed and the percentage of viable tumor.”

In case No. 4, under the pleura is a scar type of area that looks like an apical cap, very elastotic (Fig. 9, left). It appears (right) that acinar structures are being formed, but they are entrapped airway structures and benign and should not be counted toward tumor cells, Dr. Mehrad said. “This one did have quite a bit of stromal fibrosis as a form of treatment response.”

In case No. 5 (Fig. 10), uninvolved lung and areas of necrosis are seen. In the third of the three images, “the nucleus is hyperchromatic, but the cytoplasm looks dead.” There are a few cells about which one could ask: “Should they be counted as viable tumor cells or are they just dead?”

“If you don’t see the outlines of the cytoplasm well, and if the chromatin pattern is not well visualized,” she said, “it’s best not to call these as viable tumor cells.” Eventually, this case was considered to have no viable tumor cells and complete pathologic response.

Amy Carpenter is CAP TODAY senior editor.