Mimics of Prostate Cancer –


Atrophy

• looks suspicious for adenocarcinoma at first glance.
• the nuclei are small and hyperchromatic.
• No prominent nucleoli are seen.
• Some glands are lined by obviously benign flattened atrophic epithelium.
• The immunostain for high molecular weight cytokeratin can be helpful in distinguishing between atrophy (fragmented basal cell layer) from atrophic variant of prostatic adenocarcinoma (no basal cell layer). 

Atypical adenomatous hyperplasia

• It may show the infiltrative architecture of cancer,
• lacks the cytologic features such as prominent nucleoli.
• The immunostain for high mol. wt. Cytokeratin will show fragmented basal cell layer in most cases.

Post-Atrophic Hyperplasia

• Post-atrophic hyperplasia architecturally mimics adenocarcinoma
• lacks the cytologic features.
• In difficult cases, the immunostain for high mol. wt. cytokeratin can be performed which would show at least a few basal cells in post-atrophic hyperplasia.

Sclerosing Adenosis

• small glands with infiltrative growth pattern in a cellular spindled stroma.
• The plump spindle cells in the stroma are nicely seen here.
• The lining acinar epithelial cells lack cytologic atypia – no significant nuclear or nucleolar enlargement is seen
• Myoepithelial differentiation in basal cells of the acini of Sclerosing adenosis is illustrated with the immunostain for muscle specific actin.

Cowper's Glands

•  They have a lobular configuration and are often associated with skeletal muscle fibers
• The glands are lined by goblet cells distended with mucin.
•  The small hyperchromatic nuclei are pushed to the periphery. 
• Sometimes ducts lined by cuboidal cells are present in the center of the lobules.

Mucinous Metaplasia

•  Mucinous metaplasia is seen in about 1% of prostates. 
• It may occasionally resemble prostatic adenocarcinoma. However, it lacks prominent nucleoli and the does not show immunoreactivity for PSA and PAP. 
• The cells are positive for PAS, mucicarmine and Alcian blue.

Prostatic xanthoma

• Prostatic xanthoma is an uncommon benign lesion that may mimic high-grade prostatic adenocarcinoma. 
• It consists of lipid-laden macrophages that may be arranged in small circumscribed nodules or infiltrating cords extending into the stroma 
•  diffusely positive for CD68 (shown here), and negative for CAM5.2, PSA, and PSAP.

Thanks to Dr.Dharam Ramnani for the images.

Protocol for Synpotic reporting of Breast  excision specimen with diagnosis of  Ductal Carcinoma In Situ (DCIS) of the Breast

Protocol applies to DCIS without invasive carcinoma or microinvasion.
The complete pathology report should include following parameters.

Specimen type.

• ___ Partial breast
• ___ Total breast (including nipple and skin)
• ___ Other (specify): 
• ___ Not specified

Procedure 

• ___ Excision without wire-guided localization
• ___ Excision with wire-guided localization
• ___ Total mastectomy (including nipple and skin)
• ___ Other (specify): ____________________________
• ___ Not specified

Lymph Node Sampling (select all that apply) 

• ___ No lymph nodes present
• ___ Sentinel lymph node(s)
• ___ Axillary dissection (partial or complete dissection)
• ___ Lymph nodes present within the breast specimen (ie, intramammary lymph nodes)
• ___ Other lymph nodes (eg, supraclavicular or location not identified)
•             Specify location, if provided:  _________________________

Specimen Integrity

• ___ Single intact specimen (margins can be evaluated)
• ___ Multiple designated specimens (eg, main excisions and identified margins)
• ___ Fragmented (margins cannot be evaluated with certainty)
• ___ Other (specify):  __________________________________

Specimen Size (for excisions less than total mastectomy)

Greatest dimension: ___ cm

*Additional dimensions: ___ x ___ cm

___ Cannot be determined

Specimen Laterality

• ___ Right
• ___ Left
• ___ Not specified

*Tumor Site (select all that apply)

• ___ Upper outer quadrant
• ___ Lower outer quadrant
• ___ Upper inner quadrant
• ___ Lower inner quadrant
• ___ Central
• ___ Nipple
• Position: ____  o’clock
• ___ Other (specify):  _____________________
• ___ Not specified

Size (Extent) of DCIS  ( Click here for more info about measuring size of DCIS)

• Estimated size (extent) of DCIS (greatest dimension using gross and microscopic evaluation): at least ___ cm
• *Additional dimensions ___ x ___ cm
• *Number of blocks with DCIS: ___
• *Number of blocks examined: ___
• Note: The size (extent) of DCIS is an estimation of the volume of breast tissue occupied by DCIS.

Histologic Type 

• ___ Ductal carcinoma in situ.  Classified as Tis (DCIS) or Tis (Paget)

*Architectural Patterns (select all that apply) 

• ___ Comedo
• ___ Paget disease (DCIS involving nipple skin)
• ___ Cribriform
• ___ Micropapillary
• ___ Papillary
• ___ Solid
• ___ Other (specify:  ___________________)

Nuclear Grade 

• ___ Grade I (low)
• ___ Grade II (intermediate)
• ___ Grade III (high)

Necrosis 

• ___ Not identified
• ___ Present, focal (small foci or single cell necrosis)
• ___ Present, central (expansive “comedo” necrosis)

Margins (select all that apply) 

___ Margins cannot be assessed

___ Margin(s) uninvolved by DCIS

            Distance from closest margin: ___ mm

            *Specify margins:

                  *Distance from superior margin: ___ mm

                  *Distance from inferior margin:    ___ mm

                  *Distance from medial margin:     ___ mm

                  *Distance from lateral margin:      ___ mm

                  *Distance from anterior margin:   ___ mm

                  *Distance from posterior margin: ___ mm

                  *Distance from other specified margin: ___ mm

                       *Designation of margin:  ______________________

___ Margin(s) positive for DCIS

            *Specify which margin(s) and extent of involvement:

                  *___ Superior margin

                        *___ Focal

                        *___ Minimal/moderate

                        *___ Extensive

                  *___ Inferior margin

                        *___ Focal

                        *___ Minimal/moderate

                        *___ Extensive

                  *___ Medial margin

                        *___ Focal

                        *___ Minimal/moderate

                        *___ Extensive

                  *___ Lateral margin

                        *___ Focal

                        *___ Minimal/moderate

                        *___ Extensive

                  *___ Anterior margin

                        *___ Focal

                        *___ Minimal/moderate

                        *___ Extensive

                  *___ Posterior margin

                        *___ Focal

                        *___ Minimal/moderate

                        *___ Extensive

*Treatment Effect: Response to Presurgical (Neoadjuvant) Therapy

• *___ No known presurgical therapy
• *___ No definite response to presurgical therapy
• *___ Probable or definite response to presurgical therapy

Lymph Nodes (required only if lymph nodes are present in the specimen) 

• Number of sentinel nodes examined:  ____
• Total number of nodes examined (sentinel and nonsentinel):  ____
• Number of lymph nodes with macrometastases (>0.2 cm):  ____
• Number of lymph nodes with micrometastases (>0.2 mm to 0.2 cm and/or >200 cells):  ____
• Number of lymph nodes with isolated tumor cells (<0.2 mm and ≤200 cells):  ____
• Size of largest metastatic deposit (if present):  ____

Note:  The sentinel node is usually the first involved lymph node.  In the unusual situation in which a sentinel node is not involved by metastatic carcinoma, but a nonsentinel node is involved, this information should be included in a note.

 

*Extranodal extension:

• *___ Present
• *___ Not identified
• *___ Indeterminate

*Method of Evaluation of Sentinel Lymph Nodes (select all that apply)

• *___ Hematoxylin and eosin (H&E), 1 level
• *___ H&E, multiple levels
• *___ Immunohistochemistry
• * ___ Sentinel lymph node biopsy not performed
• *___ Other (specify): _______________________

Pathologic Staging (pTNM) 

TNM Descriptors (required only if applicable) (select all that apply)

• ___ r (recurrent)
• ___ y (post-treatment)

Primary Tumor (pT)

• ___ pTis (DCIS):   Ductal carcinoma in situ
• ___ pTis (Paget):   Paget disease of the nipple not associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma.

Note: If there has been a prior core needle biopsy, the pathologic findings from the core, if available, should be incorporated in the T classification.  If invasive carcinoma or microinvasion were present on the core, the protocol for invasive carcinomas of the breast¹ should be used and should incorporate this information.

Regional Lymph Nodes (pN) (choose a category based on lymph nodes received with the specimen; immunohistochemistry and/or molecular studies are not required)

Note: If internal mammary lymph nodes, infraclavicular nodes, or supraclavicular lymph nodes are included in the specimen, consult the AJCC Staging Manual for additional lymph node categories.

Modifier (required only if applicable)

___ (sn)              Only sentinel node(s) evaluated.  If 6 or more sentinel nodes and/or nonsentinel nodes are removed, this modifier should not be used.

Category (pN)

___ pNX:            Regional lymph nodes cannot be assessed (eg, previously removed, or not removed for pathologic study)

___ pN0:            No regional lymph node metastasis identified histologically

Note: Isolated tumor cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section.^#   ITCs may be detected by routine histology or by immunohistochemical (IHC) methods.  Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated.

___ pN0 (i-):       No regional lymph node metastases histologically, negative IHC

___ pN0 (i+):      Malignant cells in regional lymph node(s) no greater than 0.2 mm and no more than 200 cells (detected by H&E or IHC including ITC)

___ pN0 (mol-):  No regional lymph node metastases histologically, negative molecular findings (reverse transcriptase polymerase chain reaction [RT-PCR])

___ pN0 (mol+): Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC

___ pN1mi:        Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 2.0 mm).

___ pN1a:          Metastases in 1 to 3 axillary lymph nodes, at least 1 metastasis greater than 2.0 mm

___ pN2a:          Metastases in 4 to 9 axillary lymph nodes (at least 1 tumor deposit greater than 2.0 mm)

___ pN3a:          Metastases in 10 or more axillary lymph nodes (at least 1 tumor deposit greater than 2.0 mm)

^# Approximately 1000 tumor cells are contained in a 3-dimensional 0.2-mm cluster.  Thus, if more than 200 individual tumor cells are identified as single dispersed tumor cells or as a nearly confluent elliptical or spherical focus in a single histologic section of a lymph node, there is a high probability that more than 1000 cells are present in the lymph node.  In these situations, the node should be classified as containing a micrometastasis (pN1mi).  Cells in different lymph node cross-sections or longitudinal sections or levels of the block are not added together; the 200 cells must be in a single node profile even if the node has been thinly sectioned into multiple slices.  It is recognized that there is substantial overlap between the upper limit of the ITC and the lower limit of the micrometastasis categories due to inherent limitations in pathologic nodal evaluation and detection of minimal tumor burden in lymph nodes.  Thus, the threshold of 200 cells in a single cross-section is a guideline to help pathologists distinguish between these 2 categories.  The pathologist should use judgment regarding whether it is likely that the cluster of cells represents a true micrometastasis or is simply a small group of isolated tumor cells.

Distant Metastasis (M) 

___ Not applicable

___ cM0(i+):   No clinical or radiographic evidence of distant metastasis, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastasis

___ pM1:      Distant detectable metastasis as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm

Note: The presence of distant metastases in a case of DCIS would be very unusual.  Additional sampling to identify invasive carcinoma in the breast or additional history to document a prior or synchronous invasive carcinoma is advised in the evaluation of such cases.

*Additional Pathologic Findings 

*Specify: ____________________________

*Ancillary Studies

*Estrogen Receptor (results of special studies performed on this specimen or a prior core needle biopsy) 

*___ Immunoreactive tumor cells present

*___ No immunoreactive tumor cells present

*___ Pending

*___ Not performed

*___ Other (specify):  _____________________

*Name of antibody: ___________________

*Name of vendor: ___________________

*Type of fixative: ________________

*Progesterone Receptor (results of special studies performed on this specimen or a prior core needle biopsy) 

*___ Immunoreactive tumor cells present

*___ No immunoreactive tumor cells present

*___ Pending

*___ Not performed

*___ Other (specify):  _____________________

*Name of antibody: ___________________

*Name of vendor: ___________________

*Type of fixative: ________________

*Microcalcifications (select all that apply) 

• ___ Not identified
• ___ Present in DCIS
• ___ Present in non-neoplastic tissue
• ___ Present in both DCIS and non-neoplastic tissue

*Clinical History (select all that apply) 

The current clinical/radiologic breast findings for which this surgery is performed include:

*___ Palpable mass

*___ Radiologic finding

            *___ Mass or architectural distortion

            *___ Calcifications

            *___ Other (specify):  _________________________

*___ Nipple discharge

*___ Other (specify):  ____________________

*___ Prior history of breast cancer

*Specify site, diagnosis, and prior treatment:  ______________________

*___ Prior neoadjuvant treatment for this diagnosis of DCIS

*Specify type:  ______________________

*Comment(s)

For specimens with a known diagnosis of DCIS (eg, by prior core needle biopsy) it is highly recommended that the entire specimen is examined using serial sequential sampling to exclude the possibility of invasion, to completely evaluate the margins, and to aid in determining extent.  If an entire excisional specimen or grossly evident lesion is not examined microscopically, it is helpful to note the approximate percentage of the specimen or lesion that has been examined.


Ref. College of American pathologist.

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.

REFERENCES:
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.