Introduction

Breast Cancer is the most common cancer diagnosed in women, accounting for 1 in 10 cases of cancer diagnosed every year. Breast tissue is prone to develop benign and malignant changes. GLOBOCAN 2020 reports breast cancer as the most common cancer worldwide and fifth most common, death causing cancer globally.1

Recent studies from India suggest that Breast Cancer is the leading cause of cancer death in women surpassing the previous widely recognised Cervical Cancer as the leading cause with age adjusted rate as high as 25.8 per 100,000 women and mortality 12.7 per 100,000 women.2

Spindle cell lesions of the breast include a diverse group of entities sharing common histopathological features. These rare lesions mimic clinically and radiographically the common benign lesions of the breast (eg, fibroadenomas) or may appear falsely malignant. Spindle cell lesions often pose a challenge to the diagnosing clinician because of the vast differential diagnoses, the rarity of these lesions and the histological similarities.

Figure 1

According to (Charu et al., 2017)3 spindle cell lesions can be categorised as under.

Fine Needle Aspiration Cytology (FNAC) can be helpful in the diagnosis of these breast lesions by combining its results with clinical and radiological features. An important adjunct could be to determine if these lesions have only spindle cells or if other components such as epithelial cells are present. Whether the lesions appear bland or pleomorphic on FNAC, the diagnostic accuracy of these lesions and thus the patient outcomes can be improved. 4, 5

Immunohistochemistry is a good diagnostic tool for the diagnosis of bland appearing spindle cell lesions. As no immunohistochemistry marker is completely sensitive and specific, it would be appropriate to conclude that using a panel of antibodies would yield the best results. Interpretation of the results of immunohistochemistry should take into account the cytological features of the lesion as well. A suspected spindle cell carcinoma should be tested using a panel of antibodies against epithelial markers: both low and high molecular weight cytokeratin. 4, 6

The diagnostic challenges that these lesions pose due to diversity of the features on cytomorphology with focal nature of the diagnostic and prognostic histochemical properties, we aimed to conduct this study to profile these rare lesions of the breast and correlate the cyto-histopathological features on FNAC with immunohistochemical characteristics to determine its efficacy.

Materials and Methods

The present study entitled, “A Clinical, Cyto-Histopathological and Immunohistochemical study of Spindle Cell Lesions of Breast” included 260 patients, suffering from spindle cell lesions of the breast, attending the outpatient and in-patient services of the Department of Surgery at Jawaharlal Nehru Medical College & Hospital (JNMCH), Aligarh Muslim University, Aligarh. The cytological and histopathological examinations were carried out in the Department of Pathology, (JNMCH). Relevant clinical history and examination findings were also recorded. Three years of retrospective cases and two years of prospective cases i.e. total 5 years cases were included in this study.

Results

Total number cases of breast lesions received in the Department of Pathology during 5 year study period were 15,270 out of which 9700 cases were of Histopathology and 5570 were of Cytopathology. Among 15,270 cases, a total number of 15,010 (98.29%) cases belonged to “non spindle cell lesions” which were excluded from the study and the remaining cases i.e., 260 (1.7%) cases diagnosed as spindle cell lesions of breast constituted the study group. Of the total 260 cases, 105 cases were of cytopathology and 220 cases were of histopathology and cases common to both i.e., those cases which had cyto-histopathological correlation were 65 cases (20%). Of the 260 cases of breast spindle cell lesions, all patients were female and no case was found in the male sex. Out of 260 cases the most common clinical complaint was breast lump in 240 cases (92.3%) followed by pain and mastalgia in 104 cases (40%) (Table 1).

Out of 105 cases received in cytopathology, 70 (66.7%) cases were diagnosed as benign spindle cell lesions, whereas 25 (23.8%) cases were malignant and 10 (9.52%) cases were inconclusive for any opinion (Table 2).

Whereas Out of 220 cases received in histopathology, 148 cases (67.3%) fell broadly into benign category whereas 42 (19.1%) cases were diagnosed as malignant spindle cell lesions, followed by 30 (13.6%) cases wherein the diagnosis rendered was either a borderline spindle cell malignancy or a low grade malignancy (Table 2).

In our study, highest incidence of Spindle cell lesions of breast on cytopathology was observed in age group of 40-49 years with total 52 cases (49.52%) (35 cases were benign, 15 cases were malignant and 02 cases were inconclusive) followed by age group of 30-39 years with total 30 (28.5%) cases (22 cases were benign, 02 were malignant and 06 were inconclusive). No spindle cell malignancy cases was found in the age group of <20 years (Table 3).

Of 105 cases, a diagnosis of spindle cell lesion of breast was rendered in 65 cases (62%) on cytology favouring a “benign spindle cell lesion” in 40 cases (38%) and a “malignant spindle cell lesion” in 25 cases (24%). In rest 30 cases (28.5%) cytological diagnosis was a “benign phyllodes tumor”. In 10 cases cytological findings were inconclusive for any opinion (Table 4).

In our study, highest incidence of Spindle cell lesions of breast diagnosed on Histopathology was observed in age group of 40-49 years with total 74 cases (33.6%) (55 cases were benign, 11 cases were malignant and 8 cases were of borderline category) followed by age 30-39 years with total 51 cases (23.1%) (40 cases were benign, 05 malignant and 06 borderline lesions). Least number of cases i.e., 13 cases falling in benign category were found in <20 years of age with no observed malignant and borderline malignant lesions in this age group (Table 5).

Out of 220 histopathologically diagnosed cases, benign phyllodes tumor was the most common entity comprising of 85 cases (38.6%). Other tumors in benign category were 15 cases (6.8%) of PASH, 13 cases (6%) of Myofibroblastoma, 12 cases (5.4%) of Nodular Fasciitis and 10 cases (4.54%) of desmoid type fibromatosis and 4 cases (1.81%) of Inflammatory myofibroblastic tumor. Borderline phyllodes tumor was the most common entity in intermediate category with total 30 cases (13.7%). In malignant category malignant phyllodes tumor was the most common tumor accounting for 25 cases (11.4%) followed by metaplastic carcinoma with total 13 cases (6%) and myxofibrosarcoma 3 cases (1.36%). Less common entities encountered were DFSP, neurofibroma, schwannoma and spindle cell lipoma (Table 6).

Figure 2

A: FNA smear showing cellular stromal fragments and sheets of benign spindle cells favouring a cytological diagnosis of benign spindle cell tumor/ Benign phyllodes tumor. (H&E 20x); B,C: H&E sections of Benign Phyllodes Tumor showing proliferation of stromal spindle cells and myxoid changes in stroma. Mitosis and necrosis were absent. (10x and 20x)

Figure 3

A,B: Corresponding H&E section of Malignant Phyllodes Tumor showing sheets & papillae of atypical spindle cells with oval / round vesicular to hyperchromatic nuclei, prominent nucleoli and moderate eosinophilic cytoplasm. Mitosis was also present frequently. (H&E 10x and 40x)

Figure 4

A,B: FNA smear of Benign spindle cell lesion of breast showing bland oval to spindlecells lying singly and in loose clusters of fat mixed myxoid background. (H&E 20x); B,C: Corresponding H&E section of Myofibroblastoma showing tumor cells composed of spindle to oval cells arranged in short haphazardly intersecting fascicles of spindle shaped cells separated by band of eosinophilic collagen. (H&E 10x and 40x); D,E: Cytoplasmic positivity of both SMA and Vimentin in tumor cells of Myofibroblastoma (IHC 40x); F,G: Myofibroblastoma Pan Ck and CD34 negative in tumor cells. (IHC X 20X)

Figure 5

A: FNA smear of Nodular Fasciitis showing cluster of bland appearing spindle cells along with mild lymphocytic infiltrate in background. (H&E 20x); B,C: Corresponding H&E section of Nodular Fasciitis showing bland spindle to oval cells arranged in short fascicles to storiform pattern (feathery growth). (H&E 10x and 20x); D,E: Corresponding H&E section of Nodular Fasciitis showing bland oval to stellate cells arranged in short fascicles to storiform pattern (feathery growth) along with areas of haemorrhage and lymphocytic infiltrate in background. Mitosis and necrosis were absent. (H&E 10x and 20x); F: Nodular Fasciitis SMA positive (cytoplasmic staining). (IHC X 20x)

Figure 6

A: FNA smear of Desmoid Type Fibromatosis Breast showing isolated plump fibroblasts without atypia, along with heterogeneous population of lymphocytes, and a few stromal fragments in a proteinaceous background. (H&E 20x); B,C: Corresponding H&E section of Desmoid Type Fibromatosis Breast showing long sweeping fascicles of bland spindle cells aligned parallel to one another. The fascicles were variably cellular with an infiltrative margin and absence of any epithelial neoplastic component. Background showed inflammatory infiltrate.(H&E 10x and 20x);

Figure 7

A: FNA smear of Metaplastic Carcinoma of Breast showing sheet of pleomorphic spindle cells in a myxoid background. (H&E 40 x); B,C: Metaplastic Carcinoma corresponding section from tumor area showing proliferation of atypical spindle cells with moderate cytological atypia, coarse granular chromatin with prominent nucleoli and eosinophilic cytoplasm with interlacing trabeculae of osteoid differentiation. (H&E 20x); D,E: H&E section Metaplastic Carcinoma of Breast showing atypical spindle cells in a myxoid background along with osseous differentiation, areas of necrosis and mitosis of 5-10/10hpf. (H&E 40x); F,G: Metaplastic Carcinoma Vimentin positive and focally CYTOKERATIN positive in malignant spindle cell. (IHC 40x and 20 x)

Figure 8

A,B: Myxofibrosarcoma of Breast Corresponding H& E section showing pleomorphic spindle shaped cells with pseudo lipoblasts and condensation of cells around vessels. (H&E 20x); C,D: Myxofibrosarcoma of Breast CD34 - Cytoplasmic Positivity (IHC X 10x) and SMA - Diffuse strong cytoplasmic positivity. (IHC 20x)

Figure 9

A,B: H&E sections of Neurofibroma Breast showing benign appearing spindle cells arranged in form of bundles and fascicles with intervening collagen. (H&E 20x, and 40x)

Figure 10

A,B: H&E of Schwannoma of Breast showing two architectural patterns in variable proportions: Antoni A areas composed of compact, elongated cells with nuclear palisading (Verocay bodies) and Antoni B areas is less cellular. The tumor area composed of densely packed spindled cells arranged in intersecting fascicles along with hyalinized blood vessels and variable lymphoid aggregates. (H&E 20x)

Discussion

Based on the spectrum of differentiation, morphological, immunohistochemical and molecular characteristics, WHO, 2019 has categorised breast lesions and tumors into various subtypes. With varying tumor characteristics, spindle cell tumors represent a different category of breast lesions.8 An algorithmic approach is suggested for the diagnosis of different entities and the following parameters should be clearly evaluated: (1) cellular structures, (2) existence and degree of atypia, (3) growth pattern, (4) mitotic figures, (5) clinical and radiological characteristics. 9, 10

The main objective of this study was to analyse benign and malignant spindle cell lesions and tumors of the breast in terms of clinical profile and to ascertain a cytopathological and histopathological correlation with special emphasis on cyto-histomorphological and immunohistochemical characteristics of these lesions.

Our study was a 5 year retrospective and prospective study of 260 patients that were diagnosed with a breast spindle cell lesion or a neoplasm. Fine needle aspiration cytology was performed and as per routine laboratory protocol, the surgically resected specimens and biopsies were processed. Various basic immunohistochemical markers such as broad spectrum Cytokeratins, S100, CD34, SMA, Desmin, Vimentin and Ki-67 were applied as per the need of the case. Whenever required, lineage specific or specific IHC markers were used to arrive at a final diagnosis.

In our study, the age of presentation for spindle neoplasms in the breast exhibited a broad spectrum, ranging from under 20 to over 60 years. Notably, the 40-49 age group emerged as the most common age range, with 48.46% of cases falling into this category. This age trend is consistent with previous research by Unal et al. in (2015),11 as well as studies by Abd El All12 and Lekshmi et al,13 which reported median ages of 46.2 and 50.37 years, respectively, for spindle cell breast lesions. Benign tumors were predominantly observed in the 40-49 age group in our study, with only 3% occurring in individuals aged 60 and above. Conversely, malignant spindle cell neoplasms primarily affected patients between 40-49 years, constituting 10% of cases. Notably, the lowest incidence of malignant spindle cell neoplasms was observed in individuals under 30 years of age, accounting for less than 1% of total spindle cell malignancies. These findings closely align with the observations made by Lakhani et al. (2012),8 who noted that malignant metaplastic carcinomas are more frequently diagnosed in patients over the age of 50. This reinforces the importance of age-related considerations in understanding and managing spindle neoplasms of the breast.

The vast majority of patients (92.3%) in our study reported the presence of a palpable lump or mass in the breast as their primary complaint. This observation is in line with the findings of Ünal et al. in (2015),11 where palpable masses were the predominant complaint, and only patients with Angiosarcoma reported pain. A retrospective study by Blanco et al in (1999)14 further supported our results, with all patients presenting with palpable breast lumps of varying sizes. Additionally, our study identified other complaints, such as mastalgia (pain) in 40% of cases, lymphadenopathy in 30.7%, ulceration or fungating mass in 20.7%, nipple discharge in 16.1%, and nipple retraction in 7.6% of cases. These findings highlight the diverse clinical presentations of breast spindle cell neoplasms, with Lekshmi et al (2017)13 noting that the majority of cases present as painless masses, while one-third of cases report pain.

In our study, we analysed a total of 220 histopathological cases, comprising 190 resected lumpectomy/mastectomy specimens and 30 small/core needle biopsies. The spindle cell tumors were categorized into three main groups, with 148 cases classified as benign tumors, 42 as malignant tumors, and 30 as atypical/borderline tumors. Notably, our findings revealed a higher prevalence of benign tumors compared to malignant ones. This pattern is consistent with the observations made by Abd El all in 2006, further underscoring the predominance of benign spindle cell neoplasms in both studies.12 Understanding the distribution of these tumor types is crucial for accurate diagnosis and effective treatment strategies.

Within our study, Phyllodes tumors were the most prevalent, accounting for 63.63% of all cases. This category included 38.36% of benign Phyllodes tumors, 13.6% of borderline Phyllodes tumors, and 11.36% of malignant Phyllodes tumors (Figure 2, Figure 3). Our findings align with Tan et al.'s (2016) 15 study, where Phyllodes tumors were graded as benign, borderline, or malignant based on histomorphological characteristics. Additionally, research by Chaney et al (2000).16 Cheng et al., (2006)17 & WHO (2019),7 respectively, also supported our observations, showing that benign Phyllodes tumors were the most frequent, accounting for a significant portion of cases, while borderline and malignant Phyllodes tumors constituted smaller proportions. This consistency underscores the prevalence of benign Phyllodes tumors in our study and in the broader literature.

Mesenchymal tumors were the second most common subgroup in our study comprising a total of 67 cases (30.45%). In our study, myofibroblastoma exhibited characteristic microscopic features, with tumor cells arranged in intersecting fascicles of spindle-shaped cells separated by collagen bands. Immunohistochemistry revealed positivity for SMA and Vimentin, while Pan cytokeratin and S100 were negative (Figure 4). These findings closely align with the observations of Magro et al in 2018, underscoring the consistency in the histopathological and immunohistochemical characteristics of myofibroblastoma. 18

Cases of Nodular fasciitis on cytology showed plump fibroblasts with pale cytoplasm, uniform vesicular nuclei and small nucleoli in addition to infrequent giant cells and other inflammatory cells which was in accordance with a study by Michelow et al., 2019.5 H&E sections showed spindle to oval cells arranged in short fascicles along with Extravasated erythrocytes and scattered lymphocytes (Figure 5). On applying IHC SMA was positive which was similar with the study of Rakha et al., 2016.5

Rakha et al (2016) and Michleow et al (2019) reported that fibromatosis of the breast accounted for 0.2% of primary breast lesions, which closely matches our findings of 0.1% of total breast lesions. 5, 6 The age range of patients with mammary fibromatosis in their studies, spanning from 13 to 80 years with a median age of 25 years, aligned with our observations. In our study, cases of Desmoid type Fibromatosis exhibited characteristic features on FNAC, including bland spindle cells in a hypocellular stromal background. Histopathologically, the lesion comprised fascicles of spindle cells and lymphocytes at the lesion edge (Figure 6). Immunohistochemistry results showed positive staining for β-catenin and SMA, while CD34 was negative, consistent with the findings of Lee et al. (2007). 19 These similarities highlight the diagnostic consistency of fibromatosis across studies.

In our study, cases of metaplastic breast carcinoma exhibited cellular FNAC smears with pleomorphic spindle cells showing increased N: C ratio, hyperchromasia, and high mitotic activity. Osseous differentiation was observed in the background, along with necrotic and myxoid areas in some cases. The cytological diagnosis was malignant spindle cell lesion, warranting further histopathological examination. Histologically, we observed atypical spindle cells with prominent nucleoli, eosinophilic cytoplasm, and osteoid differentiation in 5 cases (Figure 7). Similar findings were reported by Charu et al. (2017), 3 showing atypical nuclei in spindle cells and high mitotic activity on FNAC, along with pleomorphic cells histologically. Abd El All (2006) 12 noted Vimentin, CK, SMA, S100, and CD10 positivity in spindle cells and negative Desmin and CD34. Our study exhibited comparable findings with Vimentin, CK5/6, and p63 positivity, focal Pan Ck positivity, and negativity for CD34, S100, CD117, SMA, Desmin, with a high Ki-67 index. These consistent features emphasize the diagnostic and immunohistochemical characteristics of metaplastic breast carcinoma.

The FNA of a myxofibrosarcoma revealed variable cellularity with a myxoid granular background. Tumor cells were large, with round to spindled shapes and nuclear pleomorphism. H&E staining showed pleomorphic spindle-shaped cells with pseudo lipoblasts and a curvilinear arrangement around vessels (Figure 8). Immunohistochemistry with SMA and CD34 displayed strong cytoplasmic positivity, while Ki67 was high and S100, Desmin were negative, consistent with Klopčič et al. (2009). 20

Among tumors of neural origin, in our study we encountered a total of 6 cases of Schwannoma and Neurofibroma, collectively accounting for less than 1% of primary breast tumors. These findings closely align with Hasebe et al.'s study in Japan, where neurilemmomas accounted for only 0.2% of benign intra-mammary tumors.21 On FNAC, both Schwannoma and Neurofibroma exhibited elongated, bland spindle cells with pointed ends and indistinct cytoplasm (Figure 9, Figure 10), consistent with the observations of Bellezza et al in 2007 22 and Soni et al in 2014. 23 These consistent features emphasize the rare but characteristic histopathological patterns of these neural tumors in the breast.

Conclusion

Spindle cell lesions in the breast are relatively rare, accounting for only 1.7% of cases. Diagnosing them through histopathology alone can be challenging due to morphological overlap. A comprehensive approach that considers clinical characteristics, cyto-histological parameters, and immunohistochemistry is essential for accurate diagnosis, risk assessment, and treatment planning. While defining features may not be present for each entity, a practical diagnostic algorithm that stratifies these lesions and employs a targeted immunohistochemical panel is crucial. In some cases, molecular and genetics studies may also be necessary to guide treatment decisions in recent years.

Source of Funding

None.

Conflict of Interest

None.