Paget's disease if Nipple- Review

Clinical:

Approximately 1%–3% of women with adenocarcinoma of the breast have Paget disease. Clinically-Paget disease has common dermatitis-like appearance, as originally described in 1874, when Sir James Paget recorded that such lesions may resemble “ordinary chronic eczema” or present as nipple erosion or ulceration. Paget disease often has a deceptively banal clinical morphology but should lead the list of differential diagnoses when evaluating unilateral lesions of the nipple–areola complex in adults.

Paget disease presenting with nipple erosion. 

Most women with the histopathologic finding of Paget disease have a clinical abnormality of the nipple. However, in at least 10% of affected patients, Paget disease is found incidentally, during microscopic examination of mastectomy specimens.

Underlying invasive ductal carcinoma or DCIS, detected in more than 90% of patients with Paget disease, is multifocal in about 50% of cases and does not necessarily occur near or contiguous with the nipple–areola complex.

In addition, because of the practice shift from mastectomy to breast-conserving surgery, a patient whose nipple–areola complex was spared during surgery may present with Paget disease or epidermotropic metastatic breast cancer to the nipple after diagnosis and treatment of primary breast cancer.

Histopathology:

Paget disease is characterized by intraepidermal infiltration with large cells that have abundant pale cytoplasm and hyperchromatic nuclei often with prominent nucleoli.

Potential histopathologic pitfalls include pronounced epidermal hyperplasia or denuded epithelium, sometimes mandating additional biopsy. The latter is particularly problematic when Paget cells completely separate from surrounding keratinocytes. Although this phenomenon has been described as acantholysis, Paget disease cells do not have intercellular connections with keratinocytes; they instead are tucked individually or in clusters between normal epithelial cells.

When the appearance of acantholysis is pronounced, pemphigus may be included in the differential diagnosis. Large acantholytic-like Paget disease cells  may mimic the cytopathic effect of herpes simplex or varicella-zoster infection, particularly when their nucleoli are inconspicuous.

Large, rounded, “acantholytic” cells in Paget disease of the nipple

Intraepidermal clefting and stromal inflammation in Paget disease of the nipple

Infiltration of epithelium by pale cells and stromal inflammation in Paget disease involving the areola

 Immunohistochemical stains often are necessary to confirm the diagnosis of Paget disease because the differential diagnosis may include SCC in situ, malignant melanoma in situ, and rarely other entities such as Langerhans cell histiocytosis.

Pigmented Paget disease and pigmented epidermotropic metastatic breast cancer have been reported. In contrast with melanoma, pigmented Paget disease usually is negative for S100, Melan A, and HMB-45.

In contrast with SCC in situ, Paget disease cells typically express low–molecular-weight keratins 7 and CAM 5.2 but not keratin 20 or high–molecular-weight keratins.

Paget disease tends to be estrogen- and progesterone-receptor negative and androgen-receptor positive, especially in patients with high-grade underlying ductal carcinoma.

HER2 overexpression often is a feature of cases associated with underlying ductal carcinoma.

Immunohistochemical stain for keratin 7 highlights epithelial infiltration with Paget disease cells

Immunohistochemical stain for Cam 5.2 highlights epithelial infiltration with Paget disease cells.

HER2 expression in Paget disease.

  

The histopathologic differential diagnosis also should include benign conditions characterized by pale-clear intraepidermal cells; these include pagetoid dyskeratosis, thought to be due to chronic irritation of the nipples, and clear-cell papulosis, a rare eruption affecting children that manifests as hypopigmented macules, mainly along milk lines.

These 2 disorders of large pale cells usually are distinguishable from Paget disease morphologically. Both are characterized by pale cells with limited (if any) pleomorphism; these cells tend to be larger than surrounding keratinocytes and are distributed singly or in small clusters set neatly in an otherwise normal-appearing epidermis, without discohesion. The clear cells of pagetoid dyskeratosis are positive for high–molecular-weight keratins, rather than low–molecular-weight keratins. Clear-cell papulosis typically has a profile similar to that of Paget disease, including expression of keratin 7, CAM5.2, and lack of staining for estrogen receptor, but appears to be negative for HER2.

REFERENCES

1. Ackerman AB, Kessler G, Gyorfi T, et al. Contrary view: the breast is not an organ per se, but a distinctive region of skin and subcutaneous tissue. Am J Dermatopathol. 2007; 29: 211–218.

2. Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development. 2000; 127: 2269–2282.

3. Sternlicht MD. Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res. 2006; 8: 201.

4. De Giorgi V, Grazzini M, Alfaioli B, et al. Cutaneous manifestations of breast carcinoma. Dermatol Ther. 2010; 23: 581–589.

5. Aftab K, Idrees R. Nipple adenoma of breast: a masquerader of malignancy. J Coll Physicians Surg Pak. 2010; 20: 472–474.

Role of Excisional lymph node biopsy, Core needle biopsy and FNAC in Lymphoma diagnosis

The newly developed and more sophisticated techniques for analysis of lymphoma cells have provided us with the tools necessary for precise classification of non-Hodgkin’s lymphoma. Nonetheless, routine histologic studies remain the gold standard for diagnosis. 

Excisional Biopsy

A well-processed hematoxylin and eosin (H&E) stained section of an excised lymph node is the mainstay of pathologic diagnosis. Most often, the diagnosis of difficult lesions relies heavily on a careful assessment of the underlying architecture. Lymphoma diagnoses are much less about cytologic detail and far more about altered architecture. For example, follicular small-cleaved cell lymphoma (FSC) is characterized by an abundance of neoplastic lymphoid follicles containing monomorphous small-cleaved lymphocytes. The individual cells themselves, however, are otherwise typical small cleaved lymphocytes seen in the benign follicles of reactive lymph nodes.

The loss of normal nodal architecture that accompanies an infiltrate is of paramount importance in making a diagnosis. An incisional lymph node provides only a glimpse of the architecture, making interpretation difficult. Our surgical colleagues must be instructed to biopsy the most clinically significant site, and whenever possible, to remove an intact lymph node for pathological processing. The tissue should be delivered fresh to pathology at an appropriate time of the day in order to maximize the material for lymphoma protocol studies.

Many hematopathologists prefer to triage the material using imprint preparations, whereby a fresh cut surface of the node is touched onto glass slides for Romanowsky staining. Experienced pathologists are able to make a good approximation of the disease process based on the touch prep morphology, thus resulting in the efficient ordering of additional tests.

When the size of the tissue is limiting, the first priority must be to process the material routinely for fixation and H&E sections. Properly fixed specimens can be used for regular histologic examination, paraffin(Drug information on paraffin) section immunoperoxidase staining, and depending on the fixative, for gene rearrangement studies by polymerase chain reaction (PCR). Although B5 is the optimal fixative for routine lymphoid histology and is preferred for immunoperoxidase studies, it precludes PCR studies in most laboratories. Formalin fixation is preferred when the biopsy is small because all of the above studies, including PCR, can be performed.

Diagnosing Disease at Extranodal Sites—Approximately 30% to 35% of cases of non-Hodgkin’s lymphoma in adults present primarily at extranodal sites. Much less is known about the molecular mechanisms involved in these disorders in comparison to node-based disease. Therefore, it is important to remember to process extranodal biopsy material for lymphoma protocol studies whenever there is a suspicion of a hematolymphoid neoplasm.

Molecular genetic and cytogenetic data from gastric and pulmonary resection specimens have enormous potential to provide insights into the pathogenesis of mucosal-associated lymphoid tissue (MALT) lymphomas but, unfortunately, lymphoma protocol is frequently overlooked in this setting. Nonetheless, examination of a well-processed H&E section from an excisional biopsy by an experienced hematopathologist will be sufficient to establish a diagnosis in the majority of cases.

Needle-Core Biopsy & FNAC

Needle-core biopsies have a role in lymphoma pathology, although it remains limited.The use of 14 to 22 gauge needles under ultrasound or radiological guidance to establish a diagnosis of non-Hodgkin’s lymphoma is problematic because of technical difficulties with biopsy crush artifact, inadequate sampling, and the usual vagaries of lymphoma pathology. Although this technique has advantages over fine-needle aspiration (FNA), it should be used judiciously as a diagnostic tool for patients with suspected non-Hodgkin’s lymphoma.

Needle-core biopsies do allow a minimal assessment of architecture in addition to immunostaining procedures, but interpretation can be problematic in cases of T-cell rich B-cell lymphoma, angioimmunoblastic-type peripheral T-cell lymphoma, or MALT lymphoma where much of the lymphoid infiltrate is reactive.

A careful review of most excisional lymph node biopsies demonstrates marked cytologic and architectural variation throughout the section, underscoring the complexity of non-Hodgkin’s lymphoma diagnoses in what would otherwise be considered routine circumstances.

Needle-core biopsies are unable to detect this variability, leading to the possibility of incorrect diagnoses in many cases. Although recent studies have recommended increased use of these techniques, patient selection and failure to provide convincing evidence that the “right treatment” decision was made in the majority of cases hamper their interpretation. Also, many of these studies included patients with an established diagnosis of either non-Hodgkin’s lymphoma or Hodgkin’s disease—an approach that differs significantly from a diagnostic procedure.

In managing ill patients or those with significant comorbid disease who are unable to tolerate an invasive surgical procedure, needle-core biopsies offer a better alternative to FNA for the diagnosis of intra-abdominal or thoracic disease. Ideally, two or three cores should be obtained with one core routinely processed for histology and the remainder used for lineage and clonality studies. In this setting, cautious interpretation of the biopsy by an experienced hematopathologist and integration of the results of the ancillary studies should allow a reasonable treatment decision to be made in most cases.