Painless upper outer quadrant lump in left breast (single, hard, mobile, non-tender, irregular, measuring 4 × 3 cm) without axillary lymphadenopathy and without family history. Fine needle aspiration (FNA) showed findings shown in Figure 1.

Figure 1:: (a) Tight clusters and morules of tumor cells against a clean background (Pap stain; ×10). (b) Cell clusters in papillary configurations, with many dissociated tumor cells (Pap stain; ×20). (c) Papillary structures with well-defined outline and without true fibrovascular core (Pap stain; ×40). (d) Round to oval tumor cells with distinct cell margins, moderate amount of pale cytoplasm, eccentrically placed round to pleomorphic nuclei with coarse chromatin and inconspicuous nucleoli (Pap stain; ×40) (Breast lump, FNA direct smear).

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Q1: What is the interpretation?

Papillary neoplasm of breast

Papillary carcinoma of the breast

Invasive micropapillary carcinoma of the breast

Metastasis of papillary carcinoma to the breast.

Answer: (c) Invasive micropapillary carcinoma of the breast (IMPC)

The reports mentioning histopathological features are available in the reviewed literature; however, reports explaining the cytology of IMPC are scarce. The commonly observed features are richly cellular smears displaying angulated, three-dimensional cohesive clusters of ductal epithelial cells, and numerous dissociated cells with intact cytoplasm in a clean background [Figure 1a and b].[1-4] These aggregates show papilloid configuration meaning thereby that they lack a true fibrovascular core and possess smooth round to angulated contours [Figure 1c]. The tumor cells show a moderate amount of pale cytoplasm, high nucleocytoplasmic ratio, irregular nuclear membrane, fine to coarse chromatin, and inconspicuous nucleoli [Figure 1d]. Occasional mitosis is noted. Bare bipolar nuclei, cyst macrophages, and necrotic material were not observed in the smears examined. These distinctive cytomorphological features favor a cytodiagnosis of ductal carcinoma with the possibility of micropapillary subtype. Now, the certainty with which specific diagnosis of IMPC could be offered prospectively on cytology which is less commonly observed; and in most times, it is a retrospective diagnosis after correlating cytohistologic features.[1] This is because there exists a a list of differentials which can come to the mind of a cytopathologist that includes ranging from benign to malignant papillary lesions. In malignant category, it can either be primary or metastatic papillary carcinoma in of breast.[2-4]

The distinction of benign and malignant papillary neoplasms of the breast is essential from a management point of view; however, the cytologic diagnostic criteria are not sufficient to arrive at a definitive diagnosis in papillary lesions of the breast and show significant error due to overlapping features. The presence of increased cellularity, cellular atypia, long slender papillae, discohesive tumor cells with marked nuclear atypia, and absence of bare bipolar nuclei favor a malignant papillary lesion over the benign

Invasive papillary carcinoma reveals ramifying papillae having true fibrovascular core lined by columnar cells with hyperchromatic and pleomorphic nuclei. The background also shows many cyst macrophages, presence of necrosis, and hemorrhage[2]

In contrast to this, IMPC displays cohesive and angulated cell clusters, tumor morules, and papilloid aggregates lacking a true fibrovascular core and marked cell dissociation. These cells are round to cuboidal with pale cytoplasm and centrally placed pleomorphic nuclei against a clean background[1,3,4]

The metastatic papillary carcinoma to breast also needs to be ruled out as the line of management is different. Detailed clinical workup for ovarian, endometrial, or thyroid papillary carcinoma could help to exclude the possibility of metastatic disease. In situations of dilemma, an immunohistochemical such as gross cystic disease fluid protein-15 or mammaglobin a sensitive and specific marker for further confirming the diagnosis of primary breast carcinoma.[2,3]

Question 2: IMPC is seen to be commonly associated with which subtype of invasive breast carcinoma?

Medullary carcinoma breast

Tubular carcinoma

Secretory carcinoma

Mucinous carcinoma

Answer: (d) Mucinous carcinoma.[5]

Question 3: The smears from IMPC can also show features such as

Psammoma bodies

Apocrine cytology

Focal mucin deposition

All of the above

Answer: (d) All of the above.[5]

Question 4: IMPC an uncommon variant shows aggressive behavior because of

Hematogenous spread

Lymphatic spread

Pagetoid spread

None of the above

Answer: (b) Lymphatic spread.

The patient subsequently underwent a modified radical mastectomy of left breast with ipsilateral axillary lymph node dissection. The specimen received measured 50 × 30 × 30 cm, and the cut surface revealed an irregular, firm, yellowish, and gritty tumor of size 5 × 4 × 3 cm situated in the upper and outer quadrant. A total of 15 lymph nodes were dissected from the left axilla. Multiple sections examined from mass revealed an infiltrating tumor composed of small hollow and morula-like clusters of malignant epithelial cells surrounded by distinctly clear space and separated by thin fibrous septa [Figure 2]. The papilloid clusters were deficient in the central fibrovascular core and at places revealed tubules with the central lumina. The tumor cells displayed reverse polarity or inside out phenomenon characteristic feature of IMPC seen on histology only [Figure 3].[5] The lining epithelial cells were cuboidal with scant pale cytoplasm and round nuclei oriented toward the luminal surface. Nuclear pleomorphism was evident and mitotic figures were <5/10 hpf. The DCIS component, vascular invasion, nipple involvement, and skin infiltration were not evident in the surrounding breast parenchyma. Histopathology exhibited a pure IMPC (Grade I) without any associated component of conventional invasive breast carcinoma (IBC) or mucinous carcinoma and with evidence of metastasis in six out of 15 axillary lymph nodes.

Figure 2:: Tumor aggregates without fibrovascular core surrounded by large empty spaces and separated by thin septa (HP: H&E stain; ×5).

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Figure 3:: Tumor cells in nests and tubules with central lumina displaying reverse polarity and separated by thin fibrous septa. The cells reveal nuclear pleomorphism and coarse chromatin with inconspicuous nucleoli (HP: H&E stain; ×40).

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Detailed further workup also excluded primary ovarian, endometrial, thyroid, and renal malignancy. The patient underwent post-operative radiotherapy and chemotherapy. There is no evidence of relapse to date.

Pure IMPC is a rare variant of IBC constituting 0.9–2%.[5] This tumor type has received much attention in recent times not only because of its characteristic pathologic appearance, high Ki-67 proliferation index, but also more frequent HER-2/Neu overexpression, high incidence of lymph node metastasis, and aggressive biological behavior.[5,6] Positron emission tomography scan shows a high maximum standardized uptake value, which is an apparent feature of IMPC due to its frequent lymphovascular invasion and lymph node metastasis hence might be helpful in the early detection of IMPC.[7] The carcinomas with a micropapillary component reflect aggressive behavior, with a 5-year survival rate significantly lower than IBC -No special type (IBCNST) of the corresponding grade.[8,9] IMPC occurs as a pure form or maybe a component of IBC-NST or in combination with mucinous carcinoma. In IBC-NST, EMA is expressed on the luminal surface of the cell membrane; however, in IMPC, it is expressed in stroma-facing surface indicating reverse polarity. Furthermore, the expression of basolateral adhesive protein (E-cadherin) is mutually exclusive with EMA substantiating reverse polarity. In vitro studies revealed that increased expression of EMA on cell membrane facing toward stroma and simultaneous reduced expression of adhesion molecules might be responsible for the detachment of the cells from the stroma. Gene expression profiling reveals that IMPC is mostly luminal type breast carcinomas.[5]

As a consequence of increasing awareness, timely diagnoses, and appropriate management of this rare variant; the 5-year overall survival of these patients has recently been improved and the treatment of choice is radical mastectomy with postoperative radiotherapy and chemotherapy.[9]

Histopathology shows characteristic micropapillae lying within clear spaces and separated by a thin fibrocollagenous stroma, thus exhibiting inside-out phenomenon a diagnostic hallmark of IMPC.[10] Fine-needle aspiration cytology being simple and easy, office procedure is utilized as a first-line investigation in an initial assessment of almost every palpable breast lump. Hence, it is imperative to identify prototype cytological features for early detection of this rare variant, as specific diagnosis mandates identifying a group of patients with a poor outcome. The consistent cytologic appearance of IMPC is unique to reveal high cellularity, angulated clusters, morules of tumor cells and papilloid aggregates lacking a fibrovascular core, and marked cell dissociation exhibiting high-grade nuclear features against a clean background. These appear to be the most reliable cytological features as quoted in earlier reports that should raise suspicion of IMPC.[3,4]

To sum up the precise, cytodiagnosis of invasive IMPC can be offered with certainty if one carefully looks for the indicators such as angulated papilloid cell clusters with anatomical borders and lacking a fibrovascular core, tumor morules, and plenty of dissociated malignant cells in a clean background.