Invasive Micropapillary Carcinoma of the Breast


  • Breast carcinoma with a prominent (pseudo) micropapillary pattern

Diagnostic Criteria

  • Numerous small pseudo-papillary clusters of cells
    • No fibrovascular cores
    • Frequent central lumen formation in clusters
    • Peripherally located nuclei frequently bulge out with knobby appearance, "the hedgehog" tumor
  • Clusters surrounded by clear spaces
    • One or only a few clusters per space
    • Scant mucin rarely detectable in spaces
  • Spaces surrounded by loose fibrocollagenous stroma
  • Frequent high nuclear grade reported in some series
  • Frequently has abundant eosinophilic cytoplasm
  • Frequent lymphatic involvement
  • Occasional psammoma bodies
  • Associated DCIS may be of various types
  • Pattern may be predominant or focal
    • No clinical difference between predominant and focal cases
    • No reported cutoff for minimal significant amount of pattern
    • Report such cases as mixed
  • Frequently mixed with infiltrating ductal carcinoma
    • Rarely mixed with other type


  • Incidence
    • Pure about 1%
    • Mixed about 4-7%
  • Frequent local recurrence (70-90%)
  • Poor prognosis
    • Approximate 40% dead of disease in three years
    • Not independent of stage
      • Linked to high incidence of nodal involvement
  • Rare cases reported in males

Grading / Staging / Report

  • Bloom-Scarff-Richardson grading scheme is most widely used
  • Total score and each of the three components should be reported
  • Based on invasive area only
Tubule formationScore
>75% tubules1
10-75% tubules2
<10 span="" tubules="">3

Nuclear pleomorphism (most anaplastic area)Score
Small, regular, uniform nuclei, uniform chromatin1
Moderate varibility in size and shape, vesicular, with visible nucleoli2
Marked variation, vesicular, often with multiple nucleoli3

Mitotic figure count per 10 40x fields (depends on area of field, see key below)Score
0.096 mm20.12 mm20.16 mm20.27 mm20.31 mm2
  • Olympus BX50, BX40 or BH2 or AO or Nikon with 15x eyepiece: 0.096 mm2
  • AO with 10x eyepiece: 0.12 mm2
  • Nikon or Olympus with 10x eyepiece: 0.16 mm2
  • Leitz Ortholux: 0.27 mm2
  • Leitz Diaplan: 0.31 mm2
  • Mitotic count figures based on original data presented for Leitz Ortholux by Elston and Ellis 1991, with modifications based on pubished and measured areas of view
  • Evaluate regions of most active growth, usually in cellular areas at periphery
  • We employ strict criteria for identification of mitotic figures
Sum of above three componentsOverall grade
3-5 pointsGrade I (well differentiated)
6-7 pointsGrade II (moderately differentiated)
8-9 pointsGrade III (poorly differentiated)
  • Micropapillary carcinoma is associated with frequent lymph node metastases
    • Seen even with primary tumors <1 cm="" span="">
    • Seen even with mixed tumors with small micropapillary component
    • Nodal involvement is frequently by micrometastases
  • TNM staging is the most widely used scheme for breast carcinomas but is not universally employed
  • Critical staging criteria for regional lymph nodes
    • Isolated tumor cell clusters
      • Usually identified by immunohistochemistry
        • Term also applies if cells identified by close examination of H&E stain
      • No cluster may be greater than 0.2 mm
      • Multiple such clusters may be present in the same or other nodes
    • Micrometastasis
      • Greater than 0.2 mm, none greater than 2.0 mm
    • Metastasis
      • At least one carcinoma focus over 2.0 mm
        • If one node qualifies as >2.0 mm, count all other nodes even with smaller foci as involved
      • Critical numbers of involved nodes: 1-3, 4-9 and 10 and over
    • Note extranodal extension
  • Excisions: the following are important elements that must be addressed in the report for infiltrative breast carcinomas
    • Grade
      • Total score and individual components
    • Size of neoplasm
      • Give 3 dimensions or greatest dimension
      • Critical cutoffs occur at 0.5 cm and at 2 cm
    • Margins of resection
      • Measure and report the actual distance of both invasive and in situ carcinoma
    • Angiolymphatic invasion
      • Indicate if confined to tumor mass, outside tumor mass or in dermis
    • (Extensive DCIS is not currently felt to be a significant predictor of behavior)
    • Results of special studies performed for diagnosis
    • Results of prognostic special studies performed
      • ER, PR, Proliferation marker, Her2neu
      • If studies were performed on a prior specimen, refer to that report and give results
  • Needle or core biopsies
    • Provisional grade may be given but may defer to excision for definitive grade
    • Presence of absence of angiolymphatic invasion
    • Results of special studies performed for diagnosis
    • Results of prognostic special studies if performed
      • ER, PR, Proliferation marker, Her2neu
      • State if studies are deferred for a later excision specimen
  • Regional lymph nodes
    • Report findings as described above


Paget's disease if Nipple- Review


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.

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.


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.

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Interesting Case

Clinical History:

53 years male,History of hypertension and tachycardia,MRI abdomen:-Left adrenal mass:- size 5.8 cm Right renal mass:- size-3.0cm Microscopic examination of the renal mass showed vascular tumor with diffuse sheets of clear cells having Fuhrman grade III nuclei. There was no evidence of necrosis within the tumor. There was no evidence of extraparenchymal invasion.
Gross examination of the left adrenal gland revealed cortically centered, solid and multinodular mass measuring 6.5 x 6.0 x 5.0 cm and weighing 122 grams. The tumor was encapsulated but showed evidence of extraparenchymal penetration. The tumor had golden brown cut surface with areas of hemorrhage and necrosis. The partial nephrectomy showed 3.0cm x 3.0cm x 3.0 cm yellow solid mass which did not invade into the perinephric adipose tissue.
Microscopically, the adrenal mass had predominant diffuse sheets and focal trabecular arrangements. The former pattern was present in about third of tumor. The cells had clear cytoplasm and round to ovoid nuclei with conspicuous nucleoli. Mitotic rate was 9/50 HPF and included atypical forms. Gross necrosis and capsular invasion were documented microscopically. There was no evidence of lymphovascular invasion. Considering the above mentioned features, a Weiss histopathologic score2 of 7/9 was applied.


The differential diagnosis included Renal Cell Carcinoma (RCC) with contralateral adrenal metastasis, Adrenocortical carcinoma (ACC) with contralateral renal metastasis, synchronous RCC and ACC or synchronous RCC and adrenocortical adenoma. A panel of immunohistochemical stains was performed to sort out the diagnosis. Adrenal tumor demonstrated strong Vimentin positivity and is negative for CK7, CK20, E1/AE3, EMA, Synaptophysin and S100.Renal cell carcinoma was positive for CK7, AE1/AE3, EMA (weak) and Vimentin. It was negative for CK20, Synaptophysin and S100. The difference of immunoprofile between the two tumors documented that they originated from two different primaries.

Final Diagnosis:

The diagnosis of synchronous RCC and ACC rather than metastasis influences the prognosis.


The longest disease free interval after removal of contralateral adrenal metastasis was 12.1 years8 and the longest crude survival was 14.3 years. In contrast non metastazing RCC has an excellent prognosis if no metastasis developed.