PATHOLOGIC FINDINGS AFTER

NEOADJUVANT CHEMOTHERAPY

Peet Nooijen, pathologist

Department of Pathology
Jeroen Bosch Hospital
Neoadjuvant chemotherapy

Firstly, downstaging of the tumor load increases the rate of breast-

conserving surgery

Secondly, neoadjuvant chemotherapy creates the opportunity to

assess in vivo the tumor response.

Furthermore, response monitoring during the chemotherapy course

may potentially create the ability to adjust the chemotherapy
regimen to the response of the primary tumor at an early stage
potentials, limitations and challenges
Potential
 Correlation with radiologic impression of the treatment response.
 (semiquantitative) Pathologic assessment of residual cancer.
 Assess the sensitivity of an individual tumour to chemotherapy in the context
of different histological and pathological variables.

Limitations
 Detection of the tumour bed in surgical specimen

Challenges
 To determine predictive and prognostic factors
 Introduction
 Chemotherapy-induced morphologic changes:
in benign breast tissue
in breast cancer.

 Complete clinical regression does not imply complete

pathologic response.

 What should be determined on pre-treatment core biopsies.

 DCIS and invasive cancer

 Grading of pathologic response?

 Complete clinical regression does not imply complete
pathologic response

In general, the histologic effects of neoadjuvant chemotherapy can

be correlated with the extent of clinical response.

However,
between 60-80% of patients considered to have a clinical complete
response have residual tumour detected by pathologists in the
surgical specimens.

On the other hand about 20% of patients with clinically suspected

residual disease have complete pathologic response after
microscopic examination.
Changes in benign breast tissue

Atrophy of the terminal ductal lobular units (TDLU)

 This includes reduction of the lobular acini, lobular sclerosis

and the attenuation of the ductal/lobular epithelium.

 The attenuation of the epithelial lining make the myoepithelial

cells appear prominent.

 Sometimes scatered atypical epithelial cells with enlarged

hyperchromatic nuclei and vacuolated cytoplasm.

 No mitotic activity
Lobular sclerosis and the attenuation of the
ductal/lobular epithelium
Attenuation of the epithelium makes the
myoepithelial cells appear prominent
Epithelial cells with enlarged hyperchromatic
nuclei and vacuolated cytoplasm.
Epithelial cells with enlarged hyperchromatic
nuclei and vacuolated cytoplasm.
 Changes in breast cancer
 The histologic changes in the tumour are often due to the
combined effect of multiple chemotherapeutic agents.

 Not all breast cancers respond in the same way.

 Complete pathologic response rates vary between approximately

60% and 2%.

 Good response in the breast usually exhibit decreased evidence

of axillary disease manifested by smaller metastases in fewer
lymph nodes in the axillary dissection.
The main morphologic manifestation of treatment effect is
a decrease of tumour cellularity.

Early after treatment residual degenerated and infarcted necrotic

invasive carcinoma may be recognized.
Later on, the degenerated invasive carcinoma is absorbed. Healed
sites of previous infiltrating carcinoma may be appreciated by
fibrosis and stromal edema. These fibromyxoid areas contain
patchy lymphocytes and histiocytes.

Grossly, the tumour bed appears as a poorly defined fibrotic area

or simply fibrotic streaks. (Sometimes no gross lesion/ tumour bed
is seen)
Decrease of tumour cellularity.
 The use of a radio opaque clip is advised to identify tumour
bed in surgical specimen.
 The sampling method and number of blocks taken vary among
institutions and are dependent on the size of the specimen and
the size of the lesion. In general, the previous tumour bed
should be sampled extensively, additional or entire sampling is
necessary if the initial sections don’t show microscopic residual
tumor.
 Cytokeratin immunostaining is essential for the detection of
minimal residual carcinoma in the breast and lymph nodes.
When tumour is extensively sampled and no tumour cells are
identified, this is termed complete pathologic response.
Specimens containing residual tumour cells with signs of
regression in the tumourbed (fibrosis, lymphocytic infiltrate) are
labeled as partial pathologic response.

If residual cells are present, they may be seen as infiltrating cords

and nests, or sparce and singly dispersed cells mimicking
histiocytes.
Residual tumor cells may show marked retraction artefacts in the
fibrous stroma mimicking lymphovascular invasion.

Most common chemotherapy effects include nuclear

hyperchromasia, nuclear pleomorphism and vacuolization of the
cytoplasm.
Residual tumor cells may show marked retraction artefacts in the
fibrous stroma mimicking lymphovascular invasion.
Singly dispersed tumour cells mimicking histiocytes.
Nuclear hyperchromasia, nuclear pleomorphism and
vacuolization of the cytoplasm.
The tumour bed appears as a poorly defined fibrotic /
fibromyxoid area
 DCIS ?

There is histological evidence that foci of intraductal

carcinoma and lymphatic tumour emboli are
relatively more resistant to neoadjuvant treatment
than invasive carcinoma is.

The determination of pCR is restricted to invasive

carcinoma. DCIS is not included.
Response predicting factors
The Relevance of Breast Cancer Subtypes in the Outcome
of Neoadjuvant Chemotherapy
M. E. Straver, et al, Ann Surg Oncol. 2010

A consecutive series of 254 patients with operable breast cancer

treated with neoadjuvant chemotherapy was analyzed.
 Tumors were classified according to their receptor status in
estrogen receptor (ER)-positive tumors (HER2-negative), triple-
negative tumors, and HER2-positive tumors.
 The type of surgery feasible prior to neoadjuvant chemotherapy
was compared with the actual surgery performed
Response predicting factors
The Relevance of Breast Cancer Subtypes in the Outcome of Neoadjuvant
Chemotherapy
M. E. Straver, et al, Ann Surg Oncol. 2010
 ER- receptor positive disease have a low likelihood of achieving
a pCR
 HER2-positive patients showed a both a high pCR rate as well
as a significant increase in breast-conserving surgery
 HER2-positive tumors that are ER-positive are less
chemosensitive than HER2-positive tumors that are ER-
negatives.
 Triple-negative tumors showed a higher pCR rate and a slightly
lower increase in breast conserving surgery compared with the
other subtypes
Imaging and breast cancer subtype
Magnetic resonance imaging response monitoring of breast cancer during
neoadjuvant chemotherapy: relevance of breast cancer subtype.
Loo et al. J clin. Oncol. 2011

MRI during NAC to monitor response is effective in triple-

negative or HER2-positive disease but is inaccurate in ER-
positive/HER2-negative breast cancer.
Response predicting factors

• tumour size
• HER-2/neu positivity
• “basal” phenotype
• ductal histology (lobular less response)
• ER negativity
• Tumour grade III
 What should be determined on pre-treatment
core biopsies ?

Histologic diagnosis
 tumour type,
 histologic grade,
 ER, PR and Her2/neu status
 the presence of in-situ lesions (DCIS)
Grading of pathologic response? and how?
(EUSOMA, Pinder et al.)
In breast tissue specimen:
 Complete pathologic reponse, either no residual carcinoma or
no residual invasive carcinoma but DCIS present.
 Partial response to therapy
Near complete response = Minimal residual disease
(< 10% tumour remaining),
Evidence of response
but 10-50 % remaining tumour cells.
>50% tumour cellularity remains evident, although some
features of response are present.
 No evidence of response
When compared with the previous core biopsy sample.
 Grading of pathologic response
In post-neoadjuvant lymph node samples:

1. No evidence of metastatic disease and no evidence of

changes in the lymph node.
2. Metastatic tumour not detected but evidence of response
(fibrosis)
3. Metastatic disease present but also evidence of response
(fibrosis)
4. Metastatic disease present without evidence of response.

In case of discrepancy in response the most unfavourable

category must be chosen.
 Summary
What is special for the pathologist in the evaluation
of specimen following neoadjuvant therapy?

 Determination of predictive/prognostic factors on the pre-

treatment core biopsy.
 Gross detection of tumourbed in breast specimen can be very
difficult. Detection clips are strongly advised.
 Therapy related morphological changes in benign beast tissue
and breast cancer.
 Assessment of response (Breast and lymph nodes),
cytokeratin immunostaining can be essential.
 Semiquantitative grading of the pathologic response.
 Gratefully acknowledged for their
contribution
Dr. J. Wesseling
Het Nederlands Kanker Instituut - Antoni van Leeuwenhoek
Ziekenhuis, Amsterdam

Prof. Dr. P.J van Diest

Department of Pathology
University Medical Center Utrecht

References:
Rosens’s Breast Pathology, chapter 41, pathologic effects of therapy. PP Rosen. Lippincott-Raven, 2009.

F. Fan. Evaluation and reporting of breast cancer after neoadjuvant chemotherapy. OPJ, 2009, 3, 58-63 .