114: Paget’s Disease

Question 1

What is the peak incidence age range for Mammary Paget’s Disease (MPD)?

Answer 1

The peak incidence for MPD is between 50 to 60 years.

Question 2

What are the common clinical features of Extramammary Paget’s Disease (EMPD)?

Answer 2

Common clinical features of EMPD include well-defined, moist, erythematous, scaly plaques usually involving apocrine gland-bearing skin, with the vulva being the most affected area (65% of EMPD cases).

Question 3

What is the most reported symptom in both MPD and EMPD?

Answer 3

The most reported symptom in both MPD and EMPD is pruritus.

Question 4

What are the two contrasting theories regarding the etiology of Mammary Paget’s Disease?

Answer 4

The two contrasting theories regarding the etiology of Mammary Paget’s Disease are: 1. Epidermotropic theory: Malignant Paget cells arise from an underlying breast adenocarcinoma and extend into the epidermis via lactiferous ducts. 2. Transformation theory: Epidermal keratinocytes on the nipple transform into malignant Paget cells that are distinct from any underlying breast carcinoma.

Question 5

What percentage of EMPD cases are associated with underlying malignancies?

Answer 5

Only 20% to 30% of EMPD cases are associated with underlying malignancies.

Question 6

What is the significance of the findings related to noncutaneous manifestations in patients with Mammary Paget’s Disease?

Answer 6

About half of patients with MPD present with a palpable underlying breast mass, and among these, 50-66% have axillary lymph node metastases, indicating a significant association with breast cancer progression.

Question 7

How does the clinical presentation of EMPD differ from that of MPD?

Answer 7

EMPD typically presents as well-defined, moist, erythematous, scaly plaques in apocrine gland-bearing areas, while MPD presents as unilateral, erythematous, scaly plaques involving the nipple and/or areola.

Question 8

What are the clinical features of ectopic EMPD, and where can it occur?

Answer 8

Ectopic EMPD presents as well-defined, moist, erythematous, scaly plaques in areas relatively free of apocrine glands, such as the chest, abdomen, thigh, eyelids, face, and external auditory canal.

Question 9

What is the significance of HER2/neu overexpression in Mammary Paget’s Disease?

Answer 9

HER2/neu overexpression is often seen in both Paget cells and the underlying ductal carcinoma, supporting the epidermotropic theory of pathogenesis.

Question 10

What are the common clinical symptoms of Mammary Paget’s Disease?

Answer 10

Common symptoms include erythematous, scaly plaques on the nipple and areola, pruritus, pain, bleeding, burning sensation, and serosanguinous discharge.

Question 11

What are the clinical features of Mammary Paget’s Disease in advanced stages?

Answer 11

Advanced MPD may present with nipple and areola retraction, ulceration, weeping, crusting, and nipple erosion.

Question 12

What are the key diagnostic requirements for confirming Mammary Paget’s Disease (MPD)?

Answer 12

To confirm MPD, the following diagnostic requirements must be met: 1. High index of suspicion is necessary. 2. A full-thickness punch, wedge, or excisional biopsy of the skin is required for histopathologic confirmation. 3. Bilateral mammography is mandatory in all cases, with biopsy of any detectable breast mass. 4. MRI may be used in patients with biopsy-proven MPD and negative mammogram to help identify occult breast malignancy.

Question 13

What imaging studies are recommended for patients with biopsy-proven Mammary Paget’s Disease (MPD)?

Answer 13

Bilateral mammography is required in all cases, with biopsy of any detectable breast mass. Additionally, MRI may be used in patients with biopsy-proven MPD and negative mammogram to help identify occult breast malignancy.

Question 14

What are the first-line studies recommended for evaluating underlying malignancy in patients with Extramammary Paget’s Disease (EMPD)?

Answer 14

First-line studies for evaluating underlying malignancy in patients with EMPD include colonoscopy, cystoscopy, pelvic examination with Papanicolaou test, and colposcopy.

Question 15

How does the level of carcinoembryonic antigen (CEA) relate to Extramammary Paget’s Disease (EMPD)?

Answer 15

Elevated carcinoembryonic antigen (CEA) levels are associated with a greater risk of death from EMPD, and the level of CEA parallels the disease course.

Question 16

What histopathological features are characteristic of intraepidermal adenocarcinoma in EMPD and MPD?

Answer 16

Intraepidermal adenocarcinoma of EMPD and MPD is characterized by groups, clusters, or single cells within the epidermis showing nuclear enlargement with atypia, prominent nucleoli, and well-defined ample cytoplasm, with absent intercellular bridges.

Question 17

What immunohistochemical markers are sensitive for confirming the diagnosis of MPD and EMPD?

Answer 17

CK7 and CAM 5.2 are sensitive immunohistochemical markers for both MPD and EMPD, helping to distinguish them from pagetoid squamous cell carcinoma (SCC).

Question 18

What is the role of MUC expression in the diagnosis of MPD and EMPD?

Answer 18

MUC expression is useful in the diagnosis of both MPD and EMPD, with MUC1 being positive in both, while MUC2 may be expressed in cases of secondary EMPD with an associated underlying colorectal adenocarcinoma.

Question 19

What is the significance of elevated carcinoembryonic antigen (CEA) levels in patients with Extramammary Paget’s Disease (EMPD)?

Answer 19

Elevated CEA levels in patients with EMPD indicate a greater risk of death from EMPD and the level of CEA parallels the disease course.

Question 20

What is the significance of CK7 and CAM 5.2 in diagnosing EMPD?

Answer 20

CK7 and CAM 5.2 are sensitive markers for EMPD and MPD, helping to distinguish them from pagetoid SCC.

Question 21

What is the significance of a full-thickness punch, wedge, or excisional biopsy in the diagnosis of Mammary Paget’s Disease (MPD)?

Answer 21

A full-thickness punch, wedge, or excisional biopsy of the skin is necessary to confirm the diagnosis of Mammary Paget’s Disease (MPD).

Question 22

A 55-year-old woman presents with a unilateral, erythematous, scaly plaque involving the nipple and areola. What is the most likely diagnosis, and what diagnostic steps should be taken?

Answer 22

The most likely diagnosis is Mammary Paget’s Disease (MPD). Diagnostic steps include a punch, wedge, or excisional biopsy of the lesional skin and bilateral mammography to detect any underlying breast mass.

Question 23

A patient with EMPD has elevated serum CEA levels. What does this indicate, and how should the disease course be monitored?

Answer 23

Elevated serum CEA levels in EMPD indicate a greater risk of death and may parallel the disease course. For patients with a history of metastatic disease and elevated serum CEA, trending the serum CEA values over time can be useful for disease surveillance.

Question 24

What malignancies should be considered in a 70-year-old man presenting with erythematous, scaly plaques in the perianal region?

Answer 24

Perianal EMPD is associated with colorectal cancer. Recommended diagnostic tests include colonoscopy, cystoscopy, and pelvic examination with Papanicolaou test and colposcopy.

Question 25

What are the histopathologic features of Paget cells in EMPD and MPD?

Answer 25

Paget cells are intraepidermal adenocarcinoma cells with nuclear enlargement, atypia, prominent nucleoli, and well-defined cytoplasm. They may extend into hair follicles and sweat gland ducts, showing a 'pagetoid' appearance.

Question 26

What is the significance of MUC5AC expression in EMPD?

Answer 26

MUC5AC is more commonly expressed in invasive and metastatic EMPD than in noninvasive EMPD.

Question 27

What are the histopathologic differences between primary and secondary EMPD?

Answer 27

Primary EMPD is CK7+/CK20− and often GCDFP-15 positive, while secondary EMPD is CK20+ and may express MUC2 if associated with colorectal adenocarcinoma.

Question 28

What is the clinical significance of MUC1 expression in EMPD?

Answer 28

MUC1 is commonly expressed in both MPD and EMPD, aiding in diagnosis.

Question 29

What is the role of PET-CT in the evaluation of EMPD?

Answer 29

PET-CT is used in invasive EMPD to evaluate lymph node involvement and metastasis, though it does not detect microscopic metastases.

Question 30

What is the standard diagnostic procedure for Extramammary Paget's Disease (EMPD)?

Answer 30

The standard diagnostic procedure includes a **lesional biopsy** of the skin for histopathologic confirmation.

Question 31

What imaging study is required in all cases of suspected breast malignancy?

Answer 31

**Bilateral mammography** is required in all cases, with biopsy of any detectable breast mass.

Question 32

When is MRI used in the context of breast malignancy?

Answer 32

**MRI** may be used in patients with biopsy-proven MPD and negative mammogram to help identify occult breast malignancy, although there is potential for false negatives and positives.

Question 33

What do elevated carcinoembryonic antigen (CEA) levels indicate in patients with EMPD?

Answer 33

Elevated CEA levels in patients with EMPD indicate a **greater risk of death** from EMPD and that the level of CEA **parallels the disease course**, suggesting its potential use as a prognostic marker.

Question 34

How does the mucin content in EMPD differ from that in MPD?

Answer 34

Paget cells in EMPD have a greater amount of **intracellular mucopolysaccharides** compared to MPD, which can be significant in distinguishing between the two conditions during histopathological examination.

Question 35

What are the first-line studies recommended for evaluating underlying malignancy in EMPD?

Answer 35

The first-line studies recommended for evaluating underlying malignancy in EMPD include: 1. **Colonoscopy** 2. **Cystoscopy** 3. In female patients: - **Pelvic examination** with Papanicolaou test - **Colposcopy**

Question 36

What immunohistochemical markers are sensitive for both Mammary and Extramammary Paget's Disease?

Answer 36

The sensitive immunohistochemical markers for both MPD and EMPD include: - **CK7** - **CAM 5.2** (anticytokeratin) ## Footnote These markers help in distinguishing Paget's Disease from pagetoid squamous cell carcinoma (SCC), although they are not completely specific.

Question 37

What factors influence the prognosis of Mammary Paget's Disease (MPD)?

Answer 37

Prognosis depends on the presence or absence of: - Clinically palpable breast mass - Advanced disease tendency - Lymph node metastases (57-63%) - Invasive and multifocal ductal carcinoma - 5-year overall survival rates: 35-43% with palpable mass vs. 75-93% without palpable mass.

Question 38

What are the risk factors associated with a worse prognosis in Primary EMPD?

Answer 38

Risk factors that appear to carry a worse prognosis include: 1. Lymphovascular invasion 2. Increasing depth of tumor invasion 3. Dermal invasion greater than 1 mm 4. Lymph node metastases (indicates very poor prognosis) 5. Elevated serum CEA levels (not all patients with metastatic disease have elevated CEA).

Question 39

What is the standard management approach for Mammary Paget's Disease (MPD)?

Answer 39

The standard management approach includes: - Mastectomy for clinically palpable breast mass - Breast-conserving therapy (BCT) plus radiotherapy in select cases - Sentinel lymph node biopsy (SLNB) for patients without clinically pathologic nodes - Axillary lymph node dissection if lymph node biopsy confirms metastatic disease.

Question 40

How does the prognosis of Secondary EMPD compare to Primary EMPD?

Answer 40

Secondary EMPD generally has a worse prognosis than primary EMPD, as it is caused by an underlying adnexal carcinoma or visceral malignancy. The prognosis depends on the prognosis of the underlying cancer.

Question 41

What is the significance of serum CEA levels in the prognosis of Secondary EMPD?

Answer 41

In Secondary EMPD, elevated serum CEA levels can indicate metastatic disease. Monitoring serum CEA values over time may be useful for surveillance of the disease, especially in patients with a history of metastatic disease and elevated CEA levels.

Question 42

What are the key risk factors associated with a worse prognosis in Primary EMPD?

Answer 42

Key risk factors for worse prognosis in Primary EMPD include: - Lymphovascular invasion - Increasing depth of tumor invasion - Dermal invasion greater than 1 mm - Lymph node metastases, which significantly reduce overall survival (5-year survival rates ranging from 0 to approximately 20%).

Question 43

How does the management of Mammary Paget's Disease differ based on the presence of a clinically palpable breast mass?

Answer 43

Management strategies for Mammary Paget's Disease include: - **Mastectomy** as the standard of care for palpable breast mass. - **Breast-conserving therapy (BCT)** plus radiotherapy for select cases, especially when mammography is negative and no palpable mass is present. - **Sentinel lymph node biopsy (SLNB)** is recommended for patients with underlying invasive ductal carcinoma (IDCA) without clinically pathologic nodes.

Question 44

What is the clinical significance of elevated 5a-reductase in EMPD?

Answer 44

Elevated 5a-reductase is more common in invasive EMPD and may contribute to disease invasiveness through autocrine androgen synthesis.

Question 45

What is the role of breast-conserving therapy in Mammary Paget's Disease?

Answer 45

Breast-conserving therapy, combined with radiotherapy, is used in select cases of MPD with excellent results and low recurrence rates.

Question 46

What are the common differential diagnoses for EMPD?

Answer 46

Differential diagnoses include melanoma, pagetoid SCC, and other dermatoses presenting with erythematous, scaly plaques.

Question 47

What is the standard treatment for extramammary Paget's disease (EMPD)?

Answer 47

The standard treatment for EMPD is **surgery**, specifically wide-local excision. However, local recurrences are common, even when wide excision margins are used, with recurrence rates ranging from 30% to 60%.

Question 48

What are the benefits of intraoperative frozen-section analysis during surgery for EMPD?

Answer 48

Intraoperative frozen-section analysis can help reduce recurrences in some studies by providing immediate feedback on the surgical margins, thus aiding in ensuring complete excision of the tumor.

Question 49

What systemic chemotherapy options are available for invasive and metastatic EMPD?

Answer 49

Systemic chemotherapy options include: 1. Combination of low-dose 5-FU and cisplatin 2. Combination of 5-FU, carboplatin/cisplatin, mitomycin C, epirubicin, and vincristine 3. Docetaxel 4. Combination of trastuzumab, docetaxel, and carboplatin followed by lapatinib.

Question 50

What is the significance of Mohs micrographic surgery in treating EMPD?

Answer 50

Mohs micrographic surgery improves cure rates and allows for tissue sparing of critical genitourinary anatomic structures. The recurrence rates for primary EMPD are 16% to 28%, and 50% for recurrent EMPD.

Question 51

What is the role of photodynamic therapy in the treatment of EMPD?

Answer 51

Photodynamic therapy is used as an adjuvant to chemoradiotherapy, as a neoadjuvant prior to surgery, and as a primary modality with reasonable success in treating EMPD.

Question 52

What are the recommended surgical approaches for managing EMPD?

Answer 52

The standard surgical treatment for EMPD includes: 1. **Wide-local excision** - Local recurrences are common, even with wide excision margins (30-60%). 2. **Mohs micrographic surgery** - Improves cure rates and spares critical genitourinary structures. Recurrence rates are 16% to 28% for primary EMPD and 50% for recurrent EMPD.

Question 53

What is the role of topical chemotherapy and immunomodulators in the treatment of EMPD?

Answer 53

Topical chemotherapy and immunomodulators include: - **5-FU**: Used as a neoadjuvant modality prior to surgery to delineate clinical margins. Not proven to be reliably curative due to limited drug penetration. - **Imiquimod**: Can achieve clinical and histologic clearance in some cases.

Question 54

What is the significance of sentinel lymph node biopsy (SLNB) in the management of EMPD?

Answer 54

SLNB may be beneficial for prognosis and management, particularly for patients with increased risk of metastatic disease, such as those with invasive disease or elevated serum CEA levels.

Question 55

What is the role of 5-FU in the treatment of EMPD?

Answer 55

5-FU is used as a neoadjuvant modality prior to surgery to delineate clinical margins and for early postoperative detection of recurrence. However, it is not a reliably curative agent.

Question 56

What is the role of sentinel lymph node biopsy (SLNB) in the management of EMPD?

Answer 56

SLNB may be beneficial for prognosis and management in patients with increased risk of metastatic disease, such as those with invasive disease or elevated serum CEA levels.

Question 57

What is the role of 5-FU in the treatment of EMPD?

Answer 57

5-FU is used as a neoadjuvant modality prior to surgery to delineate clinical margins and for early postoperative detection of recurrence. However, it is not a reliably curative agent due to limited drug penetration.

Question 58

What are the treatment options for recurrent EMPD?

Answer 58

Treatment options include Mohs micrographic surgery, radiotherapy, topical agents like imiquimod, and systemic chemotherapy for invasive or metastatic disease.

Question 59

What is the role of imiquimod in the treatment of EMPD?

Answer 59

Imiquimod has shown clinical and histologic clearance in some cases of primary and recurrent EMPD. Patients with recurrences who declined further surgery chose to retreat with imiquimod.

Question 60

What is the role of photodynamic therapy in EMPD?

Answer 60

Photodynamic therapy is used as an adjuvant to chemoradiotherapy, neoadjuvant prior to surgery, or as a primary modality with reasonable success.

Question 61

What are the recurrence rates for EMPD after wide excision surgery?

Answer 61

Recurrence rates are 30-60% even with wide excision margins.

Question 62

What is the role of systemic chemotherapy in EMPD?

Answer 62

Systemic chemotherapy is used for invasive and metastatic EMPD. Regimens include combinations of 5-FU, cisplatin, carboplatin, mitomycin C, epirubicin, vincristine, docetaxel, and trastuzumab.

Question 63

What is the role of Mohs micrographic surgery in EMPD?

Answer 63

Mohs micrographic surgery improves cure rates and spares critical genitourinary structures. It also allows for complete peripheral and deep margin mapping.

Question 64

What are the surgical treatment options for patients with extramammary Paget's disease (EMPD) and how do they impact recurrence rates?

Answer 64

Surgical treatment for EMPD includes: 1. Wide-local excision: Local recurrences are common (30-60%). 2. Mohs micrographic surgery: Improves cure rates and spares critical genitourinary structures. Recurrence rates are 16% to 28% for primary EMPD and 50% for recurrent EMPD. 3. Intraoperative techniques: Frozen-section analysis can reduce recurrences. Multiple scouting biopsies help delineate disease extent. CK7 immunostaining during surgery aids in tumor margin delineation. 4. Sentinel lymph node biopsy (SLNB): Beneficial for prognosis and management in high-risk cases.

Question 65

How does radiotherapy serve as a treatment option for extramammary Paget's disease (EMPD)?

Answer 65

Radiotherapy is indicated for: - Poor surgical candidates: Those who cannot undergo extensive surgery. - Patients concerned about genitourinary function: It helps mitigate risks associated with extensive surgical procedures. - Local recurrences: It can be beneficial as an adjuvant therapy after surgery or for patients with a high risk of recurrence.

Question 66

What are the roles of topical chemotherapy and immunomodulators in the management of EMPD?

Answer 66

Topical chemotherapy and immunomodulators include: 1. 5-FU: Used as a neoadjuvant modality to delineate clinical margins. Aids in early postoperative detection of recurrence but is not reliably curative due to limited drug penetration. 2. Imiquimod: Can achieve clinical and histologic clearance in some cases. Patients with recurrences may choose to retreat with imiquimod instead of further surgery, as they did not progress to invasive disease.

Question 67

What is the significance of photodynamic therapy in the treatment of EMPD?

Answer 67

Photodynamic therapy is used as: - An adjuvant to chemoradiotherapy. - A neoadjuvant treatment prior to surgery. - A primary modality for treatment, showing reasonable success in managing EMPD.

Question 68

What systemic chemotherapy regimens are reported for invasive and metastatic EMPD?

Answer 68

Systemic chemotherapy options include: 1. Combination of low-dose 5-FU and cisplatin. 2. Combination of 5-FU, carboplatin/cisplatin, mitomycin C, epirubicin, and vincristine. 3. Docetaxel. 4. Combination of trastuzumab, docetaxel, and carboplatin followed by lapatinib. These regimens are limited in reports but are considered for invasive and metastatic disease.

Question 69

What are the immunohistochemistry markers used to differentiate between Mammary Paget's Disease (MPD) and Extramammary Paget's Disease (EMPD)?

Answer 69

The following immunohistochemistry markers are used: | Marker | MPD | 1° EMPD | 2° EMPD | |--------|-----|----------|----------| | S100 | - | - | + | | CK7 | + | + | + | | CAM 5.2| + | + | + | | CEA | + | + | + | | CK20 | - | + | + | | EMA | + | + | + | | GCDPF-15| + | + | + | | MUC1 | + | + | + | | MUC2 | - | + | + | | HER2/NEU| +/-| +/- | +/- |

Question 70

What immunohistochemistry markers are typically positive in Mammary Paget's Disease (MPD) and how do they compare to those in primary and secondary Extramammary Paget's Disease (EMPD)?

Answer 70

The immunohistochemistry markers for MPD typically show the following positivity: | Marker | MPD | 1° EMPD | 2° EMPD | |---------|-----|---------|---------| | S100 | - | - | - | | CK7 | + | + | + | | CAM 5.2 | + | + | + | | CEA | + | + | + | | CK20 | - | + | + | | EMA | + | + | + | | GCDPF-15| + | + | + | | MUC1 | + | + | + | | MUC2 | - | + | + | | HER2/NEU| +/- | +/- | +/- |

Question 71

How does the expression of MUC1 and MUC2 differ between Mammary Paget's Disease (MPD) and Extramammary Paget's Disease (EMPD)?

Answer 71

In Mammary Paget's Disease (MPD), MUC1 is typically positive, while MUC2 is negative. In contrast, both primary and secondary Extramammary Paget's Disease (EMPD) show positive expression for both MUC1 and MUC2. This indicates a significant difference in mucin core protein expression between these conditions, which can aid in differential diagnosis.

Question 72

What immunohistochemistry markers are typically positive in Mammary Paget's Disease (MPD) compared to primary and secondary Extramammary Paget's Disease (EMPD)?

Answer 72

In Mammary Paget's Disease (MPD), the following markers are typically positive: | Marker | MPD | 1° EMPD | 2° EMPD | |--------|-----|----------|----------| | S100 | - | - | - | | CK7 | + | + | + | | CAM 5.2| + | + | + | | CEA | + | + | + | | CK20 | - | + | + | | EMA | + | + | + | | GCDPF-15| + | + | + | | MUC1 | + | + | + | | MUC2 | - | + | + | | HER2/NEU| +/-| +/- | +/- |

Question 73

How do the immunohistochemistry markers differ between primary and secondary EMPD in terms of positivity for MUC1 and MUC2?

Answer 73

In terms of positivity for MUC1 and MUC2: | Marker | 1° EMPD | 2° EMPD | |--------|----------|----------| | MUC1 | + | + | | MUC2 | + | - | This indicates that while both primary and secondary EMPD show positivity for MUC1, only primary EMPD shows positivity for MUC2.