Breast Carcinoma vs. Pulmonary Adenocarcinoma

Some authors have estimated that 4-9% of patients with breast carcinoma will eventually develop second pulmonary carcinomas. As a result, many pathologists have been faced with the problem of trying to determine whether a particular lung carcinoma represents metastatic breast carcinoma or a new primary pulmonary adenocarcinoma. This month, we will briefly review antibodies that may be useful in addressing this differential diagnostic problem.

 GCDFP-15 (gross cystic disease fluid protein-15): This marker has good specificity for breast carcinoma, although its sensitivity is not high, as only about 50% of breast carcinomas express this marker. Another potential problem with this marker (particularly when dealing with small biopsy specimens) is that it is often expressed in a focal fashion, occasionally in only a very small percentage of tumor cells. Therefore, the possibility of sampling error must always be kept in mind when dealing with small biopsy specimens stained for this marker. Although I have seen it very rarely expressed in lung carcinoma (<1% of cases), reactivity with this marker supports breast origin over lung origin.

TTF-1 (thyroid transcription factor-1) and PE-10 (surfactant protein A): These two antibodies are wellknown for their ability to serve as markers of pulmonary origin. Only nuclear reactivity with TTF-1 should be assessed, and TTF-1 stains roughly 75% of pulmonary adenocarcinomas. The sensitivity of PE-10 (a cytoplasmic antigen) is substantially less, and from my experience I would estimate that about 30-40% of pulmonary adenocarcinomas express PE-10. It is also important to keep in mind that thyroid carcinoma may express both of these markers (particularly TTF-1), so metastatic thyroid carcinoma to the lung is a potential diagnostic trap. In this situation, identification of reactivity with monoclonal CEA can provide additional support for a primary pulmonary origin, since substantial CEA reactivity is very uncommon in papillary and follicular carcinomas of the thyroid. (Parenthetically, medullary carcinoma of the thyroid characteristically expresses strong and diffuse CEA). I have never personally observed expression of TTF-1 in a breast carcinoma.

Villin: Villin is a marker that is expressed in a very high percentage of GI and related (pancreatic, bile duct, etc.) adenocarcinomas, but it is also expressed in a subpopulation of pulmonary adenocarcinomas. Since it is extremely uncommon for breast carcinoma to show substantial villin immunoreactivity, identification of this marker in a tumor provides evidence against a breast primary origin.

H&E sections (top left and top right) of a lung tumor biopsy from a 65
year-old female with a prior history of ER negative, PR negative invasive
ductal breast carcinoma. Original slides on the breast tumor
were not available for comparison. The villin immunostain (bottom
left) was strongly positive, rendering breast origin highly unlikely.
Pulmonary origin was confirmed by positivity for TTF-1 (bottom middle)
and PE-10 (bottom right).

Estrogen and Progesterone Receptors: It is wellknown that estrogen and progesterone receptors are expressed in the majority of breast carcinomas. Although past conventional wisdom dictated that lung adenocarcinoma was always negative for ER, it is important to realize that a small but significant percentage (probably THE FOCUS Immunohistochemistry H&E sections (top left and top right) of a lung tumor biopsy from a 65 year-old female with a prior history of ER negative, PR negative invasive ductal breast carcinoma. Original slides on the breast tumor were not available for comparison. The villin immunostain (bottom left) was strongly positive, rendering breast origin highly unlikely. Pulmonary origin was confirmed by positivity for TTF-1 (bottom middle) and PE-10 (bottom right). GCDFP-15 about 5-10%) of lung adenocarcinomas do indeed express estrogen receptors (at least when using the 1D5
antibody), and I have seen expression of ER in unequivocal lung adenocarcinomas on multiple occasions. In most instances it is expressed in a "low-level" fashion in lung adenocarcinoma, with a subpopulation of tumor cells showing weak to moderate reactivity. However, on a few occasions I have observed strong reactivity in lung tumors, including several from male patients. When employing the 6F11 clone, Dabbs et al have reported ER positivity in 67% of lung adenocarcinomas! I have not personally observed significant expression of progesterone receptors in lung adenocarcinoma. Obviously, it is always helpful if one is aware of the ER and PR status of the original breast tumor when dealing with potential second primary carcinomas in patients with a prior history of breast carcinoma.

Immunostains on lung FNA cell block from a female smoker with
prior breast carcinoma. The ER immunostain (left) showed moderate
positivity, but the TTF-1 immunostain (right) was strongly positive.
Further history indicated that this patient had a small tubular
carcinoma with no regional node metastases, that was morphologically
different from the lung tumor. This case represented a primary
pulmonary adenocarcinoma that expressed ER. Obviously,
relying on a single ER immunostain to work up this case may have
led to an erroneous diagnosis, underscoring the importance of appropriate
panels of immunostains in working up such cases.

BCL-2: Alsabeh et al published a paper in 1996 calling attention to the potential application of BCL-2 immunostaining to this differential diagnostic problem. In a series of 208 breast carcinomas, 79.3% of the breast tumors expressed BCL-2, in contrast to only 5.6% of 54 lung adenocarcinomas. As such, immunoreactivity with BCL-2 supports breast over lung primary origin.

HBME-1: Miettinen and Kovatich found that HBME- 1 showed significant expression in only 9% (3 of 34 cases) of invasive ductal carcinomas examined, whereas this marker showed significant expression in 45% (23 of 51 cases) of lung adenocarcinomas. As such, expression of HBME-1 favors lung primary over breast primary.

S100 Protein and CEA: Some authors report S100 reactivity in 15-30% of breast carcinomas, but only rarely in lung adenocarcinoma. In addition, others report that CEA may also be useful in this situation, in that strong diffuse expression of CEA is more common in lung carcinoma than breast carcinoma. However, in my practice I have not been impressed with utility of CEA for distinguishing lung from breast carcinoma.

SUMMARY: In summary, I think the combination of TTF-1, GCDFP-15, villin, ER, and PR represents a useful initial panel to attempt to distinguish breast carcinoma from pulmonary carcinoma (keeping in mind that some lung carcinomas may show expression of ER). If the initial battery of immunostains is not diagnostic, other markers such as PE-10, BCL-2, HBME-1, and S100 protein would be reasonable markers to consider.

1. Miettinen M, Kovatich AJ: HBME-1. A Monoclonal Antibody Useful in the Differential Diagnosis of Mesothelioma, Adenocarcinoma, and Bone Tumors. Applied Immunohistochemistry 3(2): 115-122, 1995.
2. Alsabeh R, Wilson CS, Ahn CW, et al: Expression of BCL-2 by Breast Cancer: A Possible Diagnostic Application. Modern Pathology 9(4):439-444, 1996.
3. Raab SS, Berg LC, Swanson PE, Wick MR: Adenocarcinoma in the Lung in Patients with Breast Cancer. A Prospective Analysis of the Discriminatory Value of Immunostains. American Journal of Clinical Pathology 100:27-35, 1993.
4. Wick MR, Lillemoe TJ, Copland GT et al: Gross Cystic Disease Fluid Protein-15 as a Marker for Breast Cancer: Immunohistochemical Analysis of 690 Human Neoplasms and Comparison with Alpha-Lactalbumin. Human Pathology 20 (3):281-287, 1989.
5. Kaufman O, Dietel M: Thyroid Transcription Factor-1 is the superior immunohistochemical marker for pulmonary adenocarcinomas and large cell carcinomas compared to surfactant proteins A and B. Histopathology 36:8-16, 2000.
6. Dabbs DJ, Liu Y, Raab SS et al: Immunohistochemical Detection of Estrogen Receptor in Pulmonary Adenocarcinomas is Dependent Upon the Antibody Used. Modern Pathology 13 (3):208A, abstract #1227, 2000.
7. Bejarano PA, Baugman RP, Biddinger PW et al: Surfactant Proteins and Thyroid Transcription Factor-1 in Pulmonary and Breast Carcinomas. Modern Pathology 9(4):445-452, 1996.
8. Nicholson AG. McCormick CJ, Shimasato Y et al: The Value of PE-10 (SP-A, Lung), a Monoclonal Antibody against Pulmonary Surfactant, in Distinguishing Primary and Metastatic Lung Tumours. Histopathology 27(1):57-60, 1995.


Breast Core needle biopsy procedure

Patients undergo breast core biopsy generally due to one of the 3 main reasons:

1) Presence of a mass or mass-like lesion either clinically palpable or diagnosed on imaging.
2) Presence of suspicious calcifications on screening mammography.
3) Nipple discharge or skin/nipple changes.

Advantages of breast core needle biospy over Fine needle aspiration cytology (FNAC) are as follows:

•Most cases can be definitely categorised
•Provides architectural information
•Microcalcifications can be directly visualised

The biopsy techniques and imaging modalities used by radiologists vary and is generally dependent on the type of lesion, most suitable method for visualization, and patient related factors.
• Calcifications are most obvious on screening mammograms and are amenable to stereotactic core biopsy.
• A mass lesion is generally best seen under ultrasound (US) guidance

Imaging modality used for biopsy are :-
• Stereotactic
• Ultrasound (US)
• Magnetic Resonance Imaging (MRI)

Stereotactic breast core needle biopsy :
–Uses X-ray imaging for localizing and targeting a lesion
– Calcifications and masses visualized on a mammogram can be biopsied
– Patient is placed in prone or upright position
– Generally performed using a Vaccume Assited Device (VAD)
– Needle gauges range from 7-14 depending on the lesion biopsied

Not all mammographically detected lesions/changes are biopsied. Radiologists use a method of scoring called Breast Imaging and Radiologists Scoring (BI-RADS) system to assess if the lesion identified on imaging requires a biopsy. Any lesion with a score of 4 is biopsied.

Ultrasound (US) guided core biopsy offers several advantages over stereotactic biopsy.
1. US is a real time procedure, i.e. it is possible to follow the motion of the biopsy needle as it moves through the breast tissue.
2. Since it does not require breast compression, US guided core biopsy procedure may be more comfortable to the patient.
3. US guided biopsy is faster, cheaper, avoids ionizing radiation and allows biopsy of areas hard to reach (under the arm or close to the chest wall) via stereotactic biopsy.

Ultrasound guded biopsy

Some difficult to see lesions are generally more obvious under magnetic resonance imaging (MRI). MRI is also used in some high risk patients to detect early lesions. Some breast centers have also started using bilateral breast MRI after the diagnosis of invasive cancer to exclude the possibility of multifocal disease, although the significance of this practice is currently debated. MRI guided core biopsies are more cumbersome than other methods and requires administration of gadolinium and therefore cannot be performed in pregnant patients.

Type of biopsy devices used for biopsy-

– Automated large core (ALC)
– Vacuum assisted device (VAD)
– Total removal device (TRD)

The type of biopsy devices used may also vary by the type of imaging technique employed to perform the procedure. The vacuum assisted devices (VAD) have largely replaced automated large core (ALC) devices for stereotactic and MRI guided biopsies, but ALC devices are still used for US guided core biopsies. ALC with 14-gauge needle or a VAD with 7-14 gauge needle can be used in an US guided core biopsy A VAD offer several advantages over ALC devices. VAD allows single insertion of the needle to obtain large amount of tissue which results in more accurate diagnosis and less false negatives. To further reduce the underestimation of disease, total removal devices (TRD) have recently been introduced that can be used under stereotactic or US guidance. This biopsy system requires an 8 mm skin incision and removes an intact portion of breast tissue preserving the architecture of the lesion. More experience is required for its diagnostic and therapeutic use.

Breast Biopsy -video


Microcystic adenocarcinoma of the prostate-pseudobenign carcinoma

Reference :

Microcystic Adenocarcinoma of the Prostate: A Variant of Pseudohyperplastic and Atrophic Patterns : Yaskiv, Oksana et al.
The American Journal of Surgical Pathology: April 2010 - Volume 34 - Issue 4 - pp 556-561

Do you see anything in this prostate that's worrisome for malignancy?
dilated glands admixed with small acini in a nodule
I don't, at least not at this power, and yet this is an example of "microcystic" adenocarcinoma of the prostate. Higher power will show clear-cut cytologic features of malignancy.
If this doesn't concern you about the risk of scanning prostate slides at 4x, it should!

Microcystic adenocarcinoma with dilated and crowded glands displaying a predominantly flat lining layer

Microcystic adenocarcinoma with jumbled arrangement of dilated malignant glands.

Microcystic adenocarcinoma with atrophic features.

Dilated malignant glands with adjacent usual small acinar adenocarcinoma glands for size reference

Numerous crystalloids in dilated glands of microcystic adenocarcinoma.

Nuclear atypia with prominent nucleoli in the lining layer of 2 microcystic adenocarcinoma glands.

Microcystic adenocarcinoma extending into periprostatic adipose tissue, along with several small acinar adenocarcinoma glands.

Overerexpression of α-methylacyl CoA racemase in microcystic adenocarcinoma, with luminal accentuation. No basal cells are detected with this p63/AMACR cocktail immunohistochemical stain.

Overexpression of AMACR with granular cytoplasmic signal in microcystic adenocarcinoma gland with basal cell absence (right). Internal control benign atrophic glands on left show basal cell presence, with p63 marker, and lack of AMACR staining.

Basal cell absence in microcystic adenocarcinoma (left) compared with benign atrophic glands with basal cells (right), as assessed with 34βE12 immunostain.

Microcystic adenocarcinoma in needle biopsy tissue
Reference :
Microcystic Adenocarcinoma of the Prostate: A Variant of Pseudohyperplastic and Atrophic Patterns : Yaskiv, Oksana et al.The American Journal of Surgical Pathology: April 2010 - Volume 34 - Issue 4 - pp 556-561

Cystic glandular dilatation is a common finding in benign prostatic tissues, being identified in benign prostatic hyperplasia (BPH) in the transition zone and as cystic atrophy in the peripheral zone. Diagnostic awareness that acinar prostatic adenocarcinoma may exhibit cystic dilatation is important to avoid underdiagnosis of prostatic adenocarcinoma.

Cystic change in adenocarcinoma of the prostate is unusual and may be confused with benign cystic atrophy.Microcystic adenocarcinoma of the prostate is a distinctive histomorphologic presentation of prostatic adenocarcinoma that is deceptively benign-looking at low magnifications.

Detection of intraluminal crystalloids or wispy blue mucin at low magnification, immunostains for α-methylacyl CoA racemase, and basal cells, and a search for adjacent usual small acinar adenocarcinoma are helpful diagnostic aids. Diagnostic awareness of this growth pattern of prostatic carcinoma is important to avoid underdiagnosis of adenocarcinoma of the prostate.


High Grade Prostatic Intraepithelial Neoplasia (HGPIN)

High Grade Prostatic Intraepithelial Neoplasia (HGPIN):
Common questions asked about HGPIN are :
-How do we as pathologists make these diagnoses?
-What do they mean for the patient in terms of cancer risk?
-What is/are the optimal strategies for follow-up so that if cancer does eventually develop it is caught at an early, curable stage?

Pathology criteria for diagnosis of HGPIN:

-Architecturally benign acini/ducts lined by atypical cells.
-These cells show large nuclei and prominent nucleoli (cytologic features of carcinoma).
-Generally at least 10% of the luminal cells should show these features to make the diagnosis.

Diagnosis of HGPIN has been shown to be reproducible. Low grade prostatic intraepithelial neoplasia has poor reproducibility (even among experts), ill defined diagnostic criteria, and no true clinical relevance. It is for these reasons that I do not personally diagnose LGPIN.

Risk of subsequent cancer:

-In previous studies the risk of carcinoma on follow-up biopsy for a HGPIN diagnosis has been reported to be as high as 50%, however, when the data is based on series with increased case numbers, this decrease to around 25%.

-Number of cores with high grade PIN predicts risk of subsequent cancer (1 core-30%, 3 cores-40%, 4+ cores-75%).In addition, morphologic patterns of HGPIN (i.e. flat, tufted, micropapillary, cribriform) have not been shown to be predictive of subsequent carcinoma.

Follow up strategy for patients with HGPIN:

Although there have been several follow-up strategies for patients with a diagnosis of HGPIN, many recommend re-biopsy within 3-6 months. One protocol includes biopsies at 3-6 months for 2 years, followed by yearly biopsies for life.
In a recent study, recommendation was made that in the absence of other clinical indicators worrisome for cancer, men do not need a routine repeat biopsy within a year following a HGPIN diagnosis. As the natural history of HGPIN in any given patient is not known, the decision to take additional biopsies past 1 year is best made on a patient by patient basis with a frank discussion between the physician and patient.

Various studies have shown that in patients with prior diagnosis of HGPIN, cancer is often diagnosed in adjacent sites and even within the contralateral lobe. It is for this reason that when re-biopsy is performed for HGPIN sampling should be concentrated in the region of the previous HGPIN with the rest of the gland sampled so as not to miss small foci of cancer. Specimens should be meticulously labeled as to site (in addition to patient identification) and optimally no more than 2 cores should be submitted per container.


1. HGPIN is characterized by architecturally benign glands lined by cells which are morphologically similar to prostate cancer, and is the putative precursor of prostate cancer.

2. Unlike HGPIN the diagnosis of LGPIN is not reproducible and carries no clinical significance.

3. While earlier reports described the risk of cancer following a diagnosis of HGPIN as high as 50%, more current reviews suggest that the risk may be much lower.

4. Men with a diagnosis of HGPIN (especially those with HGPIN focally) may not need re-biopsy for up to one year after initial diagnosis. Repeat biopsies should concentrate on the area of previous HGPIN, but also include sampling of the entire gland.
(Thanks to Dr.Dharam Ramnani for allowing to use the above images for this site.)
1. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. The Journal of Urology 2006; 175: 820-834.
2. Bishara T, Ramnani DM, Epstein JI. High grade prostatic intraepithelial neoplasia on needle biopsy risk of cancer on repeat biopsy related to number of involved cores and morphologic pattern. The American Journal of Surgical Pathology 2004; 28: 629-633.
3. Bostwick DG, Qian J. High-grade prostatic intraepithelial neoplasia. Modern Pathology 2004; 17: 360-379.

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