Fine-Needle Cytological Characteristics of Carcinoma Breast with Medullary or Medullary-like Features Masquerading as Dendritic Reticulum Cell Sarcoma: An Attempt to Explore the Reasons for Erroneous Cytologic Interpretation.

BACKGROUND: Infiltration of tumors by dendritic reticulum cells (DRC) reflects the host immune defense mechanism. We observed three breast carcinomas cases with dense tumor-infiltrating DRC and lymphocytes in fine-needle aspiration (FNA) smears, leading to cytodiagnosis or differential diagnosis of dendritic reticulum cell sarcoma (DRCS). An attempt was made to find out the reason behind such an erroneous interpretation.
MATERIALS AND METHODS: Between 2009 and 2014, two cases were diagnosed as DRCS of the female breast by FNA cytology and in one case possibility of DRCS was considered along with medullary breast carcinoma (MBC). We compare and contrast the cytomorphological features of these three cases with those of nine cytologically diagnosed MBC.
RESULTS: Cases diagnosed as DRCS or MBC showed singly dispersed tumor cells, nuclear pleomorphism, bare nuclei, prominent nucleoli, and presence of lymphocytes. There was no significant difference between the two groups for discohesive clusters, syncytial clusters, plasma cells, neutrophils, foamy histiocytes, and necrosis. However, there was significant difference for presence of cohesive clusters (0% DRCS and 100% MBC, P = 0.00485), severe degree (+++) of pleomorphism (100% DRCS vs. 11.1% MBC, P = 0.01818), +++ DRC (P = 0.04697), and DRC with ++ to +++ enlarged nuclei (P = 0.03333), and pleomorphic nuclei (P = 0.00833). Two of the three cytologically diagnosed DRCS cases proved to be MBC or MBC-like and one as invasive ductal carcinoma. Six of nine cytologically diagnosed MBC cases with histology proved to be invasive breast carcinomas.
CONCLUSION: Criteria for cytodiagnosis MBC need a fresh look. Cases with numerous dendritic cells possibly represent MBC. Copyright:

INTRODUCTION

Medullary breast carcinoma (MBC) is an invasive breast carcinoma type, characterized by a predominantly (>75%) syncytial growth pattern, microscopically complete circumscribed state, moderate to marked mononuclear stromal infiltration, absence of microglandular features and intraductal components, and moderate or marked nuclear pleomorphism; whereas the diagnosis of typical medullary breast carcinoma (TMBC) requires all five of above criteria, atypical medullary breast carcinoma (AMBC) deviates slightly from TMBC, by requiring all of the criteria except one (>75% syncytial growth pattern).[1] Dendritic cells (DCs) or antigen-presenting cells are a heterogeneous group of nonlymphoid non-phagocytic elements grouped under the generic designation of immune accessory cells of lymphoid and nonlymphoid organs.[2] In lymph nodes, these nonlymphoid accessory cells are classified as follicular dendritic cells (FDCs) or dendritic reticulum cells (DRC), interdigitating dendritic cells (IDCs), and fibroblastic reticular cells (FBRCs).[3] DCs are known to infiltrate the tumors, which reflects the host immune defense mechanism; the more DCs infiltrate the tumor, the better the prognosis.[4] Quantitative assessment of tumor-infiltrating dendritic cells (TIDC) has been correlated to prognosis in a variety of human neoplasms including breast cancer.[5] DCs too can undergo a neoplastic transformation; however, neoplasms derived from FDCs are uncommon.[367] and those of IDC origin are even rarer.[38] These reticulum cell neoplasms occur primarily in lymph nodes[69] but can occur in extranodal sites including breast.[28] During a period of 5 years, we observed three peculiar cases of breast tumors with dense and atypical DCs as well as lymphoplasmacytic infiltration in fine-needle aspiration (FNA) smears, leading to the erroneous initial cytodiagnostic label or differential diagnosis of dendritic reticulum cell sarcoma (DRCS) of the breast but these cases proved to be invasive breast carcinoma, two of them being MBC or MBC-like. On the other hand, six of nine cytologically diagnosed MBC cases with available histology proved to be invasive breast carcinomas. We have made an attempt to find out the reason behind such erroneous interpretations during routine cytodiagnosis.

MATERIALS AND METHODS

Between 2009 and 2014, two cases were diagnosed as DRCS of the female breast by FNA cytology and in one case the possibility of DRCS was considered along with medullary carcinoma of the breast. During the same period, nine cases were cytologically diagnosed as medullary carcinoma of the breast. The age of these 12 cytologically diagnosed cases ranged from 25 to 65 years with a median of 35.5 years [Table 1]. The left breast was affected in eight cases and the right breast in four. The various cytomorphologic parameters assessed during the review of the smears included cellularity, cohesive clusters, discohesive clusters, syncytial clusters, singly dispersed cells, nuclear pleomorphism, prominent nucleoli, DRCs with or without pleomorphism, presence of necrosis, and other infiltrating cells such as lymphocytes, plasma cells, foamy histiocytes, and neutrophils. Parameters like cellularity, discohesive clusters, nuclear pleomorphism, bare nuclei, DRC with enlarged/pleomorphic nuclei, and lymphocytes were also assessed semi-quantitatively in a sliding scale of − (absent), ± (occasional), + (mild/minimal), ++ (moderate) and +++ (excessive/marked). Immunocytochemical (ICC) studies were performed in all the three cytologically diagnosed DRCS cases and one of the nine MC cases. Results of histopathological examination were available for all three cytologically diagnosed DRCS cases and six of nine MBC cases. The DRCS and MBC cases were compared in respect of various cytomorphological features. Fisher's exact test was utilized to find out the statistical significance.

Table 1

Clinical features, cytodiagnosis, and histopathological diagnosis in cytologically diagnosed dendritic cell tumors and medullary breast carcinoma (MBC)

Age in years/sex	Side	Location	Size	Initial cytodiagnosis	Reviewed cytodiagnosis	Histopathological diagnosis
34F	Left	9 O’clock	4 × 2 cm	IDRCS	DRCS	MBC
32F	Left	Upper-outer Q	2.5 × 2.5 cm	DRCS/MBC	DRCS/MBC	MBC
65F	Right	6 O’clock	2 × 1.5 cm	DRCS	DRCS	Inv. ductal ca.
25 F	Left	10-12 O’clock	4 × 3 cm	MBC	MBC	-
37 F	Left	3 O’clock	3 × 2 cm	MBC	MBC	Duct cell ca.
31F	Left	12 O’clock	-	MBC	MBC	-
60F	Left	3 O’clock	5 × 5 cm	MBC	MBC.	Inv ductal ca.
44F	Right	Upper-outer Q.	4 × 3 cm	MBC	MBC	Inv ductal ca.
32F	Left	7 O’clock	4 × 3 cm	MBC	MBC.	Inv ductal ca.
44F	Left	11 O’clock	-	MBC.	MBC	Inv ductal ca.
44F	Right	9 O’clock	2 × 2 cm	MBC	MBC	Inv ductal ca.
33F	Right	4-6 O’clock	5 × 3 cm	MBC	MBC	-

DRCS: dendritic reticulum cell sarcoma; IDRCS: interdigitating reticulum cell sarcoma; Inv: invasive; Ca: carcinoma; Q: quadrant

RESULTS

DRCS Case 1: A 34-year-old woman presented to the surgical outpatient department of our hospital complaining of a left breast mass of 10 days duration. Breast examination revealed a mass in the left breast at 9 o'clock position, which was 4 × 2 cm, and hard with an irregular border. Ultrasonogram, however, revealed two masses in the left breast measuring 2.5 cm × 1.4 cm and 0.5 cm × 0.2 cm at 9 O'clock and 12 O'clock, respectively. FNA smears from the left breast mass at 9 O'clock position showed numerous pleomorphic tumor cells in occasional syncytial clusters [Figure 1a] but mostly in singly dispersed form and as bare nuclei, intermingled with mature lymphocytes [Figure 1b]. The tumor cells had abundant cytoplasm and many DC processes [Figure 1c]. Cytomorphology was suspicious of an interdigitating dendritic reticulum cell sarcoma (IDRCS). ICC staining performed on FNA smears revealed a positive reaction for CD68 [Figure 1d], vimentin [Figure 1e], and leukocyte common antigen (LCA) [Figure 1f] in pleomorphic cells with dendritic processes. There was a weak positive reaction for S-100 protein in scattered inflammatory cells [Figure 1g] and a positive reaction for epithelial membrane antigen (EMA) was observed in occasional to a small group of pleomorphic cells [Figure 1h]. A few cells showed weak positivity for CD3 and CD30 but no positive reaction was observed for CD15 and CD 20. Following cytodiagnosis, multiple core biopsies of the breast mass were performed and the final histopathological diagnosis, reported from another laboratory was medullary-like high-grade mammary carcinoma. Immunohistochemical studies revealed 30% ER-positive cells, the strong and diffuse positive reaction for pan CK, CK6, and CK HMW. Ki67 labeling index was 70%. The negative reaction was observed for PR, Her-2, CD35, S100, GCDFP, and p63.

Figure 1

Fine-needle aspiration (FNA) smears from a 4 × 2 cm, irregular and hard-left breast mass close to areola in a 34-year-old woman, which was noticed 10 days back (Case no: 1). Ultrasonogram revealed a 2.5 × 1.4 cm lobulate hypoechoic mass at 9 O'clock position. The histopathological diagnosis of core biopsy was high-grade medullary-like carcinoma. (a) FNA smears show numerous pleomorphic tumor cells in occasional syncytial clusters but a few single dispersed intermingled with mature lymphocytes (Papanicolaou × 400). (b) Mostly bare nuclei with prominent nucleoli, a sprinkling of lymphocytes and a few dendritic cells with cytoplasmic processes are appreciated. (MGG × 400). (c) A mixture of bare nuclei, cells with dendritic cytoplasmic processes having pleomorphic nuclei and prominent nucleoli and scattered lymphocytes (Papanicolaou × 400). (d) Positive reaction for CD68 in pleomorphic cells (×400). (e) Vimentin positivity in pleomorphic cells and cells with dendritic processes (×400). (f) Dendritic cells are positive for leukocyte common antigen (LCA) (×400). (g) Scattered dendritic cells are positive for S100 (×400). (h) Occasional and a small group (inset) pleomorphic cells were positive for EMA (×400)

DRCS Case 2: FNA was performed on a 2.5 cm × 2.5 cm swelling situated in the upper-outer quadrant of the left breast in a 32-year-old woman. The smears were hypercellular and showed predominantly singly scattered pleomorphic cells, mostly as bare nuclei along with numerous plasma cells and lymphocytes [Figure 2a]. The occasional discohesive clusters of neoplastic cells with intact cytoplasm, dendritic processes, and prominent nucleoli were also observed [Figure 2b]. The possibilities considered as a part of cytodiagnosis were 1) high-grade carcinoma with lymphocytic infiltration (medullary type) and 2) DRCS. Histopathological examination and immunohistochemical studies were advised for definitive characterization. In the meantime, immunohistochemical studies performed on cell-block sections revealed focal positive reaction for CD35 [Figure 2c]. Occasional cells were positive for CK [Figure 2d]. A large number of cells were positive for LCA [Figure 2e] and vimentin [Figure 2f]. Many scattered CD68 positive cells with dendritic cytoplasmic processes were present [Figure 2g], and occasional cells were positive for PR [Figure 2h]. The cells were negative for CD21, CD23, and ER. The histopathological diagnosis of segmentectomy and sentinel node biopsy was triple-negative invasive medullary left breast cancer (G3, pT2, pN0, L0, V0, and R0).

Figure 2

FNA smears from a 2.5 cm mass in the upper and outer quadrant of the left breast in a 32-year-old woman (Case No: 2). Cytodiagnostic possibilities were (1) high-grade carcinoma with lymphocytic infiltration (medullary-type) and (2) dendritic reticulum cell sarcoma (DRCS). The histopathological diagnosis segmentectomy specimen was medullary (triple-negative) carcinoma. (a) Pleomorphic bare nuclei intermingled with lymphocytes and plasma cells (MGG × 400). (b) The bare nuclei have prominent nucleoli. A few cells have faint ill-defined cytoplasm. The background shows lymphocytes (Papanicolaou × 400). (c) Occasional groups of cells were positive for CD35 (×400). (d) Occasional cells were positive for CK (×400). (e) Large number of cells, mostly inflammatory cells were positive for LCA (×400). (f) Groups of cells were positive for vimentin (×400). (g) Scattered cells with dendritic cell processes were positive for CD68 (×400). (h) Occasional nuclei showed a positive reaction for PR (original magnification × 400)

DRCS Case 3: A 65-year-old woman presented with a right retro areolar round mass at 6'O clock position measuring 2 cm × 1.5 cm and another mass at the right axillary tail. FNA smears from the retro areolar mass were cellular and showed numerous singly dissociated atypical nuclei having prominent nucleoli intermingled with a few DCs [Figure 3a]. Scattered lymphocytes were present between these large atypical nuclei. Occasional cells with intact cytoplasm and prominent dendritic cytoplasmic processes containing enlarged atypical nuclei were observed in between the atypical bare nuclei [Figure 3b]. The DCs and rare large abnormal cells with enlarged nuclei and prominent nucleoli were positive for LCA [Figure 3c], CD68 [Figure 3d], vimentin [Figure 3e], and S100 protein [Figure 3f]. Staining for ER was noncontributory. FNA smears from the right axillary tail mass contained scanty cells with abundant vacuolated cytoplasm. Cytodiagnosis was highly suggestive of DRC sarcoma. However, the core biopsy revealed a grade-III invasive mammary carcinoma showing dense inflammatory cell infiltration in between the islands of tumor cells. The tumor cells were positive for ER in 80% cells, PR in 1% cells, pan-CK, and Her-2-neu. Ki67 proliferation marker showed high proliferation, approximately 60%. The inflammatory cells were positive for LCA, CD68 and S100 protein.

Figure 3

A 65-year-old woman presented with a right retro areolar round mass at 6'O clock position measuring 2 cm × 1.5 cm and another mass at the right axillary tail. Cytodiagnosis was highly suggestive of DRCS. The core biopsy revealed a grade-III invasive mammary carcinoma showing dense inflammatory cell infiltration. (a) FNA smears from the retro areolar mass were cellular and showed numerous singly dissociated atypical nuclei having prominent nucleoli intermingled with a few dendritic cells (Papanicolaou × 400). (b) Occasional cells with intact cytoplasm and prominent dendritic cytoplasmic processes containing enlarged atypical nuclei were observed in between the atypical bare nuclei (Papanicolaou × 1000). (c) The dendritic cells were positive for LCA (×400) and rare large abnormal cells with enlarging nuclei and prominent nucleoli (inset) were also [positive for LCA (×1000). (d) Dendritic cells including those with prominent nucleoli were positive for CD68 (×1000). (e) Dendritic cells and atypical cells were positive for vimentin (×1000). (f) Dendritic cells and atypical cells were positive for S100 (×1000)

MBC: The presenting features of nine female patients with cytologically diagnosed (routine as well as reviewed FNA cytodiagnoses) MBCs and the histopathological diagnoses have been displayed in Table 1. The age ranged from 25 to 60 years with a median of 37 years. The tumors were located in the left and right breasts in six and three cases, respectively. The upper quadrants, lower quadrants, and the junction of the upper and lower quadrants were involved in four, two, and three cases, respectively. The sizes ranged from 2 cm to 5 cm in maximum dimensions. The histopathological reports available in six cases proved them to be invasive ductal carcinoma.

As seen in Tables 2 and 3, the MBC cases were cytomorphologically characterized by low (+) cellularity in one case, moderate (++) cellularity in three and high (+++) cellularity in five. Cohesive clusters of neoplastic cells were present in all MBC cases. Minimal (+) number of cohesive clusters of neoplastic cells were present in three cases, moderate (++) number in five and excessive in one case. Dyscohesive clusters were present in 8 (88.9%) cases of MBC, which included minimal (+), moderate (++) and excessive (+++) numbers in two, five, and one case, respectively. Syncytial clusters were present in four cases, which were either of minimal or moderate degree (two cases each). Singly dispersed carcinoma cells were present in all cases, their extent being mild (+), moderate (++), and excessive (+++) in two, six, and one case, respectively. Pleomorphic bare nuclei were present in all cases. These pleomorphic bare nuclei were occasional (±), minimal (+), moderate (++) and excessive (+++) in two, two, one, and four cases, respectively. Nuclear pleomorphism was a moderate degree in eight (88.9%) cases and marked in one case. Prominent nucleoli were present in all cases, which was +, ++, and +++ in two, six, and one case, respectively. In addition, lymphocytes were present in all cases, being of mild (+), and moderate (++) degree in three and six cases, respectively. Plasma cells (± to ++), neutrophils (+ to ++) and foamy histiocytes (± to +) were observed in five, four, and five cases, respectively. DCs were present in seven (77.8%) cases; their number was minimal (+) in two and moderate in five cases. DRC in MBC had enlarged and pleomorphic nuclei in five cases, each. Overall cells appearing to be neoplastic and had DC processes in six (66.7%) cases, which included occasional (±), minimal number (+), and a moderate number in two cases each. Tumor necrosis was a feature in three (33.3%) cases.

Table 2

Morphological features of cytologically diagnosed dendritic cell tumors of the breast and medullary breast carcinoma (MBC)

Sr. No and FNA cytodiagnosis	Cellularity	Cohesive clusters	Discohesive clusters	Syncytial clusters	Single cells	Dendritic Process in Cells	Bare nuclei	Nuclear pleomorphism	Prom. nucleoli
1. DRCS	+++	-	±	±	++	++	+++	+++	+++
2. DRCS/MBC	+++	-	-	-	++	++	+++	+++	+
3. DRCS	++	-	+	+	+	++	++	+++	+++
4. MBC	++	+	++	−	++	−	+++	++	+
5. MBC	+++	++	++	−	+++	±	+++	++	++
6. MBC	+	++	−	+	±	−	±	++	+++
7. MBC	++	+	+	−	+	++	+	++	++
8. MBC	++	++	++	+	++	++	+	++	++
9. MBC	+++	++	+	++	++	+	+++	++	++
10. MBC	+++	++	+++	−	++	−	++	++	++
11. MBC	+++	+++	++	−	++	+	±	++	+
12. MBC	+++	+	++	++	++	±	+++	+++	++

− (absent), ± (occasional), + (mild/minimal), ++ (moderate) and +++ (excessive/marked).

Table 3

Cytomophology of dendritic reticulum cell sarcoma (DRCS) of breast and medullary breast carcinoma (MBC) in respect of inflammatory cell component and necrosis

Cyto diagnosis	Lymphocytes	Plasma cells	Neutrophils	Foamy histiocytes	DRC	DRC with enlarged nuclei	Pleomorphic DRC	Necrosis
1. DRCS	+++	+	−	−	+++	+++	+++	−
2. DRCS/MBC	++	++	−	+	+++	++	++	−
3. DRCS	++	−	−	−	++	++	++	−
4. MBC.	+	−	−	−	−	(NA)	(NA)	+++
5. MBC	++	±	+	±	++	−	−	−
6. MBC	+	−	−	−	−	(NA)	(NA)	−
7. MBC	++	++	−	−	++	+	+	−
8. MBC	++	+	−	−	++	++	+	+
9. MBC	++	+	++	+	++	+	+	±
10. MBC	++	−	+	+	++	+	+	−
11. MBC	++	+	−	±	+	+	+	−
12. MBC	+	−	+	+	+	−	−	−

− (absent), ± (occasional), + (mild/minimal), ++ (moderate) and +++ (excessive/marked), NA=Not applicable

Only one of the nine cytologically diagnosed medullary MBC had ICC studies. FNA was attempted under ultrasound-guidance from a 5 cm × 5 cm cystic mass situated at 3 O'clock position in the left breast in this 60-year-old woman. 12 ml of brownish turbid fluid mixed with blood was aspirated. Smears prepared from it showed pleomorphic malignant cells with prominent nucleoli in groups as well as singly dispersed form [Figure 4a]. The groups of malignant cells were infiltrated by lymphocytes. The background contained foamy histiocytes and DCs. Whereas the DCs had DC processes, the other inflammatory cells that surrounded the malignant cells included reactive lymphoid cells, neutrophils, and plasma cells. Dendritic cytoplasmic processes were not limited to DRCs only but were observed in occasional pleomorphic malignant cells with prominent nucleoli [Figure 4b]. Cytodiagnosis was MBC. ICC studies performed on smears prepared from the aspirated cyst fluid revealed positive reaction of the neoplastic cells for EMA [Figure 4c], pan-CK [Figure 4d], S100 [Figure 4i] and CD35 (weak) but negative for LCA [Figure 4e], vimentin [Figure 4f], CD68 [Figure 4g] and CD21. The background inflammatory cells were positive for LCA [Figure 4e], vimentin [Figure 4f], CD68 [Figure 4h], and S100 [Figure 4j]. The needle core biopsy of the breast mass was highly suspicious of invasive ductal carcinoma with predominantly lymphoplasmacytic infiltration. The immunohistochemical stains were noncontributory.

Figure 4

A 60-year-old woman was subjected to FNA under ultrasound-guidance from a 5 × 5 cm cystic mass situated at 3 O'clock position in the left breast. Cytodiagnosis was medullary carcinoma of the breast. The needle core biopsy of the breast mass was highly suspicious of invasive ductal carcinoma with predominantly lymphoplasmacytic infiltration. (a) Smears prepared from it showed pleomorphic malignant cells with prominent nucleoli in groups as well as a singly dispersed form (MGG × 400). (b) The groups of malignant cells were infiltrated by lymphocytes. Occasional malignant cells also displayed dendritic processes (Papanicolaou × 400). (c) The neoplastic cells were positive for epithelial membrane antigen (×400). (d) The neoplastic cells were positive for pan-CK (×400). (e) Inflammatory cells were positive for LCA but the neoplastic cells were negative (×400). (f) Inflammatory cells were positive for vimentin but neoplastic cells were negative (×400). (g) The neoplastic cells were negative for CD68 but a few inflammatory cells were positive (×400). (h) Most inflammatory cells, likely to be histiocytes, are positive for CD68 (×400). (i) The neoplastic cells were positive for S100 (×400). (j) The inflammatory cells, likely to be histiocytes, were positive for CD68 (×400)

Cytologically diagnosed DRCS (three cases) vs. medullary carcinomas (nine cases) of breast [Table 4]: Two cases diagnosed as DRCS and five cases of MBC showed high (+++) cellularity (P = 1.00000). In respect of cohesive clusters of malignant cells, there was significant difference between DRCS (none, 0%) and MBC (nine cases, 100%, P = 0.00455). However, there was no significant difference between the two groups for discohesive clusters (66.7% in DRCS vs. 88.9% in MBC, P = 1.00000) and syncytial clusters (66.7% vs. 44.4%, P = 1.00000). Even moderate (++) to excessive (+++) number of discohesive clusters were taken into consideration, no significant difference was observed (0% vs. 66.7%, P = 0.18182). All cases in both groups contained singly dispersed cells (P = 1.00000). All cases in both groups had pleomorphic nuclei with prominent nucleoli. However, there was significant difference in terms of severe degree (+++) of pleomorphism (100% in DRCS vs. 11.1% in MBC, P = 0.01818). There also was no significant difference between DRCS and MBC in respect of presence of bare nuclei (100% in both groups, P = 1.00000), +++ bare nuclei (66.7% vs. 44.4%, P = 1.00000) and prominent nucleoli (100% in both groups, P = 1.00000), or +++ prominent nucleoli (33.3% vs. 11.1%, P = 1.00000). All cases of DRCS and seven (77.8%) MBC cases contained DRCs (P = 1.00000). However, there was significant difference between DRCS and MBC in respect of excessive (+++) number of DRC (66.7% vs. 0%, P = 0.04697) and DRC with moderate (++) to marked (+++) pleomorphic nuclei (100% vs. 0%, P = 0.00833). All cases of DRCS and MBC contained lymphocytes and there was no significant difference between the two groups when moderate (++) to excessive (+++) degree of lymphocytic infiltration was taken into consideration (100% vs. 66.7%, P = 0.50909). There was also no significant difference between DRCS and MBC in respect of presence of plasma cells (66.7% vs. 55.6%, P = 1.00000), neutrophils (0% vs. 44.4%, P = 0.49091), foamy histiocytes (33.3% vs. 55.6%, P = 1.00000), and necrosis (0% vs. 33.3%, P = 0.50909).

Table 4

Comparison of morphological features between cytologically diagnosed dendritic reticulum cell sarcoma (DRCS) and medullary carcinoma (MC) of the breast

Parameters	DRCS (3 cases)	MC (9 Cases)	P
High (+++) cellularity	2	5	1.00000
Cohesive clusters of neoplastic cells	0	9	0.00455
Discohesive clusters of neoplastic cells	2	8	1.00000
++ to +++ discohesive clusters	0	6	0.18182
Syncytial clusters of neoplastic cells	2	4	1.00000
Single dispersed tumor cells	3	9	1.00000
Nuclear pleomorphism	3	9	1.00000
Severe degree (+++) of nuclear pleomorphism	3	1	0.01818
Presence of bare nuclei	3	9	1.00000
Excessive (+++) number of bare nuclei	2	4	1.00000
Prominent nucleoli	3	9	1.00000
Presence of +++ degree of prominent nucleoli	1	1	1.00000
Dendritic reticulum cells (DRC)	3	7	1.00000
+++ DRC	2	0	0.04697
DRC with ++ to +++ pleomorphic nuclei	3	0/7	0.00833
Lymphocytes	3	9	1.00000
++ to +++ lymphocytes	3	6	0.50909
Plasma cells	2	5	1.00000
Neutrophils	0	4	0.49091
Foamy histiocytes	1	5	1.00000
Necrosis	0	3	0.50909

Discussion: Overall MBC comprises 3–6% of all breast cancer subtypes.[10] The frequency of MBC was 3.3% of 3,246 breast carcinomas in a report by Zangouri et al.[11] Histologic features of medullary carcinoma include a multinodular pattern as well as areas of geographic necrosis in a tumor composed of sheets of very atypical cells with multiple nucleoli, smudged cells, and atypical mitotic figures; a tumor lacking boundaries between the tumor cells and showing an intimate mixture of lymphocytes and plasma cells.[12] Kleer[12] also defined medullary-like carcinoma as an invasive carcinoma with some, but not all, histologic features of medullary carcinomas. The FNA cytologic picture of MBC is characterized by cellular smears composed of highly atypical epithelial tumor cells in loosely cohesive sheets and lying singly, admixed with polymorphous lymphocytes, plasma cells, and neutrophils.[13] In an FNA cytologic study of four special types of breast cancer, Haji et al.[14] observed that lymphomononuclear cell infiltration in a significantly higher number of cases than in papillary, mucinous, and apocrine carcinomas of breast (P < 0.0001). Further, moderate to marked nuclear pleomorphism and nuclear irregularity were significantly higher than those of mucinous carcinoma and papillary carcinoma. Based on histological and immunohistochemical studies, Romaniuk et al.[15] concluded that invasive ductal carcinoma and MBC are completely independent and different types of malignancy in the breast. Zangouri et al.[11] observed that MBC patients predominantly had triple-negative breast cancer with less invasiveness as compared to rest of invasive ductal carcinoma (P < 0.001), and MBC group had had a significant association with a higher histological grade (P < 0.001) as well as negative estrogen receptor (P < 0.001), progesterone receptor (P < 0.001), and HER-2 (P = 0.004). In the present study, we observed that there is a subgroup of breast neoplasms having some characteristics of medullary carcinoma, but certain cytomorphological features so as to be misdiagnosed as follicular DC tumors of the breast.

Whereas malignant neoplasms showing follicular DC differentiation are uncommon,[6] interdigitating DC tumor (IDCT) is an extremely rare malignancy.[8] A review of the literature by us for the period 1988–2014 revealed 143 reports on DC tumors (FDCS, IDRCS, and FRCS), mostly based on single case reports but there were 10 or more cases in eight studies.[616171819202122] As has been observed in these studies on FDCS cases, the predominant site of involvement was lymph nodes. In some recent reports, the rarity of extranodal FDCS/tumors[223] and interdigitating cell sarcoma/tumors (IDCS/Ts)[2] has been highlighted. A review of the literature shows that during a period of 15 years (1999–2013) DC tumors of the breast have been reported in nine cases from eight studies.[28242526272829] FDCS and IDCS are generally diagnosed based on histopathological features, supported by immunohistochemical or both immunohistochemical and ultrastructural studies. Histopathologically, FDCS is composed of oval to spindle cells with eosinophilic cytoplasm arranged in sheets, fascicles, whorls, sometimes admixed with foci showing a storiform pattern growth.[36716] The tumor cells have a variable amount (scant to abundant) of eosinophilic cytoplasm with ill-defined border and oval to spindle-shaped nuclei with thin nuclear membrane, fine chromatin, and small basophilic nucleoli.[6791630] The mitotic activity varies from scattered/low to high.[6730] The neoplastic cells are characteristically intermingled with mature lymphocytes and at places, the perivascular cuff of lymphocytes are present[671623]

FNA cytology of cases reported that FDCS or IDRCS showed dissociated as well as loosely cohesive or syncytial clusters of large, spindle to oval, and polygonal tumor cells with high nuclear-cytoplasmic ratio, round to oval vesicular nuclei with prominent nucleoli and increased mitotic activity; binucleated cells and cells with lobulated nuclei were also seen and the neoplastic cells were intimately admixed with mature lymphocytes.[313233] The various diagnostic possibilities considered prior to histopathology, based on these cytologic features were high-grade lymphoid neoplasms like anaplastic large cell lymphoma, metastatic carcinoma and poorly differentiated tumor favoring mesenchymal origin. All the above features were of DC tumors present in our case, and in addition, there was not only dense infiltration by benign-looking DCs, a variable number of pleomorphic cells with enlarged nuclei and prominent nucleoli had also DC processes, which prompted us to suspect FDCS/IDRCS on FNA smears.

Whether it is cytology or histopathology, diagnosis of reticulum cell sarcoma is not an easy diagnosis. According to Domínguez-Malagón et al.,[34] follicular DCS is a tumor of recent description and characterization; it is often under-diagnosed because it is easily confused with other entities. Because the tumor shows cohesive growth and a sharp interface with the fibrous stroma, they could also be mistaken for carcinoma, sarcoma, or melanoma.[35] According to Guiter et al.,[33] the differential diagnosis of follicular DC tumor (FDCT) is broad and includes other tumors characterized by an admixture of large neoplastic cells and small mature lymphocytes, such as thymomas, lymphoepithelial-like carcinomas, and interdigitating reticulum cell tumors. It may not be possible to diagnose FDCT based on FNA material without the use of ICC and electron microscopic studies. CD21, CD23, and CD35 are important ICC/IHC parameters for FDCT. Unfortunately in our cases, the ICC studies were not adequate.

There are only a few reports of FNA cytology diagnosis of DC tumors at various sites, and these include only one case of FDC occurring in the breast and that too was cytologically diagnosed as a case with poorly differentiated malignant cells, probably epithelial.[25] Among the nine cases of DC tumors of breast reported in the literature, there was one case a collision or metaplastic tumor comprising FDCS and PD carcinoma.[27] One of the IDCS cases had also a history of invasive breast carcinoma.[29] These observations raise the possibility of our cases being a combination of FDCS and breast carcinoma where the FDCS component was sampled by FNA. However, considering the histopathology report as gold-standard, it appears that FNA cytology misdiagnosed these cases. An analysis of cytological, histopathological, and immunocyto/histochemical features was necessary to find out the reasons behind the limitations of FNA cytology. Among our three cytologically diagnosed DRCS of the breast, medullary carcinoma was an alternative possibility in one. Whereas histopathological examination proved to be MBC in two and it was invasive breast carcinoma in one. We tried to differentiate the cases diagnosed as DRCS from MBC based on cytologic features to find out what could have prompted us to misdiagnose the invasive breast cancers, especially MBC as DRCS. All cases diagnosed as DRCS or MBC showed singly dispersed tumor cells, nuclear pleomorphism, bare nuclei, prominent nucleoli, and presence of lymphocytes. There was no significant difference between the two groups for discohesive clusters (P = 1.00000), syncytial clusters (P = 1.00000), and necrosis (P = 0.50909). There was also no significant difference between the two groups in respect to infiltrating plasma cells (P = 1.00000), neutrophils (P = 0.49091), and foamy histiocytes (P = 1.00000). However, there was significant difference for the presence of cohesive clusters (0% DRCS and 100% MC, P = 0.00485), severe degree (+++) of pleomorphism (100% DRCS vs. 11.1% MC, P = 0.01818), +++ DRC (P = 0.04697), and DRC with ++ to +++ enlarged nuclei (P = 0.03333) and pleomorphic nuclei (P = 0.00833). Thus, there were considerable similarities between cytologically diagnosed MBC and DRCS cases of the breast in respect of many parameters, but significant difference in some important cytomorphological features, may explain why medullary or medullary-like carcinoma with DRC infiltration can lead to an erroneous FNA cytodiagnosis of DRCS. As regards cytologically diagnosed MBC cases, they were invasive duct cell carcinomas as per histopathology reports available in six cases but could not be categorized as MBC. Therefore, FNA cytodiagnosis of MBC does not merely depend upon the presence of a lymphoplasmacytic infiltrate in pleomorphic breast tumors; these cases should satisfy all cytomorphological features and ICC parameters.

It is known that Langerhans cells (LCs), a form of DCs, may play an important role in tumor immunity and good prognostic outcome, as patients with dense infiltration of LCs in the tumor tissue survive significantly longer than those without such infiltration.[36] As regards, cytodiagnosis of DRCS of the breast, this possibility should be considered when there is dense DC infiltration along with atypical cells with dendritic processes, and lymphoplasmacytic infiltrate in a pleomorphic breast neoplasm with numerous bare nuclei. However, it should be kept in mind that DRCS of the breast is an extremely rare entity. Presence of a large number of DCs or LCs with DC processes in a pleomorphic malignant tumor of the breast with lymphoplasmacytic infiltrate could be indeed an MBC, which has a good prognostic outcome. In such situations, appropriate ICC parameters for both MBC and DRCS should be applied on FNA material to rule out one possibility and confirm the other.

Declaration of patient consent

The authors certify that verbal informed consent was taken before carrying out the procedure of FNA. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.