Diagnostic and management challenges in a partially infarcted borderline phyllodes tumor in an adolescent female: A case report and review of literature

Abstract

BACKGROUND

Fibroadenomas (FA) and phyllodes tumors (PT) are fibroepithelial neoplasms and are difficult to differentiate radiographically and histologically. We present a partially infarcted borderline PT in an adolescent with rapid tumor enlargement within 24 hours. Tumor infarction made the diagnostic work-up difficult. Complete surgical excision is the standard of care for PTs. There is controversy regarding margin re-excision for borderline PTs. In this report, we discuss the diagnostic challenges of PT and the evolving concept of margin status on PT recurrence rate.

CASE SUMMARY

A 14-year-old healthy female with no medical history presented with a painful right breast mass with no nipple discharge, trauma, or skin findings. The mass showed rapid enlargement over 24 hours, prompting a workup with ultrasound and core needle biopsy. The initial biopsy was limited due to large areas of infarction. Based on the scant viable tissue and considering the patient’s age, the mass was favored to be a juvenile FA. The patient underwent excision of the mass. Final pathology confirmed a borderline PT with positive surgical margins. The patient underwent margin re-excision, which did not show any residual tumor. At the 6-month post-op visit, there was a mass-forming lesion on the breast ultrasound. Subsequent core needle biopsy showed benign breast parenchyma with scar formation. The primary goal of evaluation in pediatric breast masses is to do no harm. However, rapidly growing and symptomatic masses require a more extensive work-up including biopsy and surgical excision. We present a rapidly growing breast mass in a 14-year-old female which was diagnosed as a borderline PT on her excision specimen. The mass rapidly enlarged over 24 hours. The initial biopsy pathology was limited due to a large area of infarction. The patient underwent excision of the mass. Final pathology confirmed a borderline PT that extended into the surgical margin, resulting in an additional re-excision procedure. Accurate diagnosis prior to surgical intervention is crucial to avoid additional procedures. Although histological morphology remains the gold standard for diagnosis, immunohistochemistry and molecular studies have recently shown to improve the accuracy of diagnosis of PTs. Long-term clinical and pathologic follow-up of PTs in adolescent patients should be collectively studied to examine whether our current diagnostic criteria for PT can reliably predict tumor behavior in this age group.

CONCLUSION

Accurate diagnosis of PTs requires surgical excision. Tumor infarction may lead to rapid tumor enlargement, hindering the correct diagnosis. More research is needed on margin status and recurrence rate, especially in adolescent patients, to help establish the best possible care for this age group.

Key Words: Borderline phyllodes tumor; Adolescent breast tumor; Infarction; Diagnostic challenge; Local recurrence; Surgical margins; Case report

Core Tip: The primary goal of evaluation in pediatric breast masses is to do no harm. However, rapidly growing and symptomatic masses require a more extensive work-up, including biopsy and surgical excision. We present a rapidly growing breast mass in a 14-year-old female, which was diagnosed as a borderline phyllodes tumor (PT) on her excision specimen. The mass rapidly enlarged over 24 hours. The initial biopsy pathology was limited due to a large area of infarction. The patient underwent excision of the mass. Final pathology confirmed a borderline PT that extended into the surgical margin, resulting in an additional re-excision procedure. Accurate diagnosis prior to surgical intervention is crucial to avoid additional procedures. Although histological morphology remains the gold standard for diagnosis, immunohistochemistry and molecular studies have recently shown to improve the accuracy of diagnosis of PTs. Long-term clinical and pathologic follow-up of PTs in adolescent patients should be collectively studied to examine whether our current diagnostic criteria for PT can reliably predict tumor behavior in this age group.

INTRODUCTION

Breast masses in adolescents include both benign and malignant entities[1]. Most pediatric breast masses are benign entities such as fibroadenomas (FA), which constitute up to 90% of breast masses in adolescents[1]. FAs are typically present in late adolescence as smooth or multinodular lesions. They are slow growing and hormone responsive, which may result in rapid growth during puberty[1]. Breast cancer constitutes less than 0.02% of breast masses in adolescents with phyllodes tumors (PT) accounting for less than 1% of those malignant breast masses[1,2]. PTs typically present as rapidly enlarging masses[1,2]. PTs are further graded histologically into benign, borderline, and malignant forms[3]. An accurate diagnosis of FAs from PTs on a core needle biopsy can sometimes be challenging due to tumor heterogeneity[3]. Since PTs and FAs are both fibroepithelial neoplasms of the breast, there are overlapping microscopic features between juvenile or cellular variants of FAs and benign PTs as well as among different grades of PTs[3].

In this case report, we present a rapidly enlarging, infarcted breast mass in a 14-year-old female. Considering that most pediatric breast masses are benign, the primary goal of management is to do no harm. However, rapidly growing, symptomatic breast masses with limited definitive imaging features warrant more extensive work-up, including biopsy and resection. The rapidly enlarging breast mass was initially diagnosed as an infarcted fibroepithelial neoplasm, most likely a juvenile FA. The final diagnosis was a borderline PT on the excision specimen. The rarity of this tumor in adolescents, spontaneous infarction, and microscopic overlapping features with FAs posed diagnostic and management challenges in our case[4-8]. Spontaneous infarction of PTs has only been described during pregnancy and the postpartum period but not in the adolescent population[9,10]. The standard treatment for malignant PTs is complete surgical excision with negative margins, but excision with negative margins is controversial for benign and borderline PTs[3]. The aims of the case report include a discussion of therapeutic intervention for borderline PTs in adolescence and diagnostic challenges of infarcted fibroepithelial neoplasms of the breast.

CASE PRESENTATION

Chief complaints

Painful right breast mass.

History of present illness

A 14-year-old healthy female with no medical history presented with a painful right breast mass (Table 1). Over-the-counter analgesics, heat, and ice packs initially helped. She reported no nipple discharge, trauma, or skin changes. The patient underwent an initial breast ultrasound. The patient re-presented with rapid enlargement over 24 hours, prompting a more extensive diagnostic work-up.

Table 1 A detailed treatment timeline table including diagnostic work-up, therapeutic intervention, follow-up, and outcomes.

May 22, 2024 Initial evaluation	Clinical presentation of a painful right breast mass measuring 4.8 cm by ultrasound
May 23, 2024 Follow-up with rapid breast enlargement	Repeat ultrasound demonstrated a 5.5 cm solid mass with a new cystic component measuring 2.5 cm
	Core needle biopsy showed infarcted fibroepithelial neoplasm, favoring a juvenile fibroadenoma
	Conservative management was trialed
June 27, 2024 Initial excision and final tumor diagnosis	Pathologic diagnosis of the surgical specimen: Borderline phyllodes tumor extending to the surgical margins
August 15, 2024 Re-excision of surgical margins	The multidisciplinary team recommended margin re-excision based on NCCN guidelines
	Final pathology showed no residual tumor
August 21, 2024 1-week follow-up after re-excision	Smooth recovery from surgery without complications
December 3, 2024 6-month follow-up	The ultrasound showed a 1.0 cm × 0.8 cm × 0.8 cm mass forming lesion adjacent to the prior surgical site
	Core needle biopsy demonstrated benign breast parenchyma with post-surgical changes

History of past illness

The patient has no past medical history.

Personal and family history

The patient has no personal history of cancer or relevant family history.

Physical examination

After the rapid enlargement, a clinical exam at the office demonstrated a mobile, tender right breast mass measuring approximately 6 cm × 7 cm.

Laboratory examinations

After rapid enlargement, an ultrasound-guided core needle biopsy of the mass was performed. The biopsy consisted predominantly of infarcted tissue with scant viable breast cores that showed a fibroepithelial lesion (Figure 1A). The stromal cellularity was moderately increased without marked cytologic atypia, stromal overgrowth, or malignant heterologous element (Figure 1B). The pathology evaluation was limited by the presence of a large area of infarction. Therefore, a definitive classification of the fibroepithelial lesion could not be completed. The fine needle aspiration demonstrated necroinflammatory debris and no malignant cells. Based on the patient’s age and the limited microscopic findings from the biopsy, a juvenile FA was favored.

Figure 1 Breast biopsy. A: The whole slide view showed tissue cores composed predominantly of infarcted tissue (green arrows) admixed with scant viable breast tissue (blue arrows); B: Viable breast tissue showed a fibroepithelial lesion with increased stromal cellularity (H&E, 10 ×).

Imaging examinations

On the initial ultrasound, the breast mass measured approximately 4.1 cm × 4.8 cm × 2.7 cm (Figure 2). The subsequent ultrasound demonstrated a 5.3 cm × 2.9 cm × 5.5 cm solid mass with a new separate cystic component measuring 2.4 cm × 1.5 cm × 2.5 cm (Figure 3).

Figure 2 Initial breast ultrasound. The radial (left) and anti-radial (right) scanning patterns showed a solid circumscribed oval mass in the right breast measuring 4.1 cm × 4.8 cm × 2.7 cm, suggestive of a fibroepithelial lesion, likely a benign fibroadenoma vs phyllodes tumor.

Figure 3 Repeat breast ultrasound two days after the initial presentation. The radial (left) and anti-radial (right) scanning patterns showed enlargement of the mass to 5.3 cm × 2.9 cm × 5.5 cm and new cystic spaces with a peripheral cystic area measuring 2.4 cm. The rapid enlargement and development of cystic components suggest interval growth and necrosis, which raises the differential diagnosis of fibroepithelial lesion likely phyllodes tumor.

FINAL DIAGNOSIS

Partially infarcted borderline phyllodes tumor.

TREATMENT

With the preoperative diagnosis of juvenile FA with infarction, the patient underwent right breast excisional biopsy due to rapid enlargement for the local mass symptoms and the diagnostic uncertainty associated with an infarcted fibroepithelial lesion. The surgery had no complications, and the patient was discharged the same day.

OUTCOME AND FOLLOW-UP

The gross specimen consisted of a tan-white nodule measuring 2.3 cm with a well-circumscribed border (Figures 4A and B). A portion of the nodule showed areas of yellow discoloration with hemorrhage, consistent with infarction. The histologic examination showed a partially infarcted fibroepithelial lesion with a predominant pericanalicular growth pattern and focal papillary fronds growing into a cystic space (Figure 5A). While the tumor border was well-circumscribed on gross examination, a microscopic permeative border was appreciated (Figure 5B). The stroma demonstrated increased stromal cellularity accompanied by mild periductal condensation (Figure 5C). The stromal cells appeared plump with mild to moderate cytological atypia and increased mitotic activity (Figure 5D). Multiple sets of ten high-power fields (HPFs) were evaluated, and the mitotic counts ranged from 1 to 15 per 10 HPFs with an average count of 6 per 10 HPFs. While infarction was present in the tumor, significantly increased mitotic activity was observed in viable tumor away from the infarcted site. No stromal overgrowth, marked cytologic atypia, or malignant heterologous elements were identified. P53 and p16 immunohistochemistry stains were also performed to help more objectively determine the grading of this PT. The stromal cells showed wild-type (non-mutated) expression of p53 (Figure 5E) and normal patchy expression of p16 (Figure 5F). Both histology and immunohistochemistry did not show overtly malignant features, and the fibroepithelial lesion was best classified as a borderline PT. The borderline PT extended to the inked surgical margin.

Figure 4 The gross appearance of the excision specimen. A: A nodular fibrofatty tissue measuring 3.1 cm × 3 cm × 2.8 cm was received for pathologic evaluation; B: Serial sectioning of the specimen showed a well-circumscribed tan-white nodule measuring 23 cm in greatest dimension (yellow arrows). A portion of the nodule demonstrated areas of yellow discoloration with hemorrhage, consistent with infarction (blue arrows).

Figure 5 Microscopic features of the fibroepithelial lesion in the excision specimen. A: Low magnification view showed a fibroepithelial neoplasm with focal papillary fronds growing into a cystic space (blue arrows). The tumor border was predominantly well-circumscribed with foci of stromal cells infiltrating the surrounding adipose tissue (yellow arrows), indicative of a microscopic permeative border. The glands displayed predominantly a pericanalicular growth pattern. Necrotic tissue consistent with infarction (top right) was also identified, corresponding to the gross tumor appearance. (H&E, 1 ×) B: Low magnification demonstrated increased stromal cellularity and permeative tumor border indicated by yellow arrows (H&E, 2 ×). C: Higher magnification showed increased stromal cellularity with mild periductal condensation (H&E, 10 ×). D: Plump stromal cells displayed mild to moderate cytologic atypia with three mitotic figures (green arrows) identified in one high-power field (H&E, 20 ×). E: p53 stain shows wild-type expression in the stromal cells (IHC, 10 ×). F: p16 stain shows normal patchy expression in the stromal cells (IHC, 10 ×).

The final pathology confirmed a borderline PT. Given the uncertainty of local recurrence for the borderline PT in an adolescent, a multidisciplinary consensus was made to consider re-excision to achieve negative margins. Genetic testing, radiation therapy, and chemotherapy were not felt to be necessary at this time. The re-excision was performed without complications one month later. Final pathology revealed no residual tumor.

At the patient’s 1-month follow-up, there was no recurrence of symptoms or new breast masses. At the 6-months follow-up, a routine breast ultrasound showed a 1.0 cm × 0.8 cm × 0.8 cm mass close to the prior surgical site. The differential at the time was recurrent PT vs surgical changes. An ultrasound-guided core needle biopsy demonstrated benign breast parenchyma with suture granulomas and scar, which was consistent with post-surgical changes.

DISCUSSION

A rapidly enlarging breast mass is a rare occurrence in an adolescent female. Once delineated as solid, FAs are the most common entity in adolescents while PTs are more common in older women with an average age of presentation estimated between 35 to 42 years[1,11-13]. The rarity of this tumor in adolescents poses diagnostic and treatment challenges in this age group[4]. PTs are particularly difficult to differentiate from FAs on imaging studies since both can appear as well-circumscribed, hypoechoic solid masses[1,14,15]. Histologic differentiation between PTs and FAs can also be challenging as the two entities have comparable histological characteristics[7]. Due to the large amount of infarction in the PT from this case, it was difficult to definitively classify the fibroepithelial neoplasm on the biopsy material. While the stroma cellularity was increased, no significant mitotic activity was appreciated in the scant viable stroma. Even if mitotic figures were appreciated, their significance is difficult to determine as the adjacent infarction can also increase mitotic activity. The degree of stromal cellularity was deemed to still be appropriate for a juvenile or cellular fibroadenoma based on the patient’s age and was favored at the time of evaluating the biopsy.

The subsequent surgical excision allowed microscopic examination of the entire tumor composition as well as its border. A microscopic permeative border, mild to moderate cytologic atypia in well-preserved stromal cells, and significantly increased mitotic activity away from the infarction site were appreciated in addition to increased stromal cellularity on the excision specimen. These histologic features met the diagnostic criteria of a borderline PT, which could not have been discerned in the prior limited and largely infarcted biopsy sample. Infarction of the PT in this case certainly hindered the initial pathology evaluation as infarction can lead to significant changes in tissue morphology, and accurate diagnosis always needs to be made in viable tissue[10]. The discordance between initial and final pathologic interpretation in this case demonstrated the challenge in diagnosing PTs, especially when infarction is present. Accurate tumor classification and grading for PTs cannot always be achieved solely based on the imaging studies and core needle biopsies, which is consistent with the conclusion drawn from many other literature studies[1,7-8,16-19].

Due to a significant difference in clinical management, immunohistochemical and molecular methods that can help differentiate PTs from FAs and determine grading for PTs have been investigated. On-going investigations of MED12 mutations in PTs have shown correlations with improved disease-free survival and utility in the diagnosis of PTs from other spindle cell neoplasms[14]. TERT promoter mutations, rarely present in FAs, serve as a potential avenue to differentiate PTs from FAs[14]. Immunohistochemical expression including p16, p53, CD117 (c-kit) protein, Ki67, and epithelial pRb scores have shown to improve grading accuracy of PTs and association with disease-free survival and recurrence of disease[20-23]. Furthermore, some studies have shown that stromal expression of p16 and p53 significantly correlates with tumor grade in PT[20-22]. Therefore, in our case, p16 and p53 immunohistochemical stains were utilized to more objectively grade the PT.

Newer research has examined the possibility of biochemical fingerprints and tumor metabolism via Raman spectroscopy for precise diagnosis of PT over FA[24]. Estimated area under the curve (AUC) was up to 97.45% and 95.61% for benign FA and small-size PTs, respectively[24]. Compared to current diagnostic tools including ultrasound and CNB, the Raman model has higher accuracy and AUC[24]. However, the study had a small population (n = 204), and the use of spectroscopy in diagnosis may result in advertent barriers due to cost and availability[24]. While there is ongoing development of ancillary testing to help improve diagnostic accuracy and grading of PTs, histologic morphology remains the gold standard in the current practice. There is a continuous discussion to refine current World Health Organization diagnostic recommendations for grading PTs[25].

There have been few reports of borderline PTs in adolescents with no known reports of partially infarcted borderline PTs in this age group[4,6,8]. Two cases of spontaneous infarction of PTs have previously been described during the pregnancy and the postpartum period[9,10]. In this case, it is difficult to determine the definitive cause of tumor infarction. Rapid tumor growth and increased metabolic demands in puberty may have resulted in spontaneous infarction[8,10-11]. Microscopically, the borderline PT in our case showed significantly increased mitotic activity (up to 15 per HPFs), indicative of increased tumor proliferation, which could lead to tumor infarction. The tumor infarction also likely contributed to rapid tumor enlargement due to hemorrhagic necrosis and inflammation of the tissue. Magnetic resonance imaging may be useful in differentiating benign tumors from malignant tumors with infarction but is limited in differentiating PTs from FAs[15].

In addition to the diagnostic challenges encountered in radiology and pathology, surgical management is also an important topic of discussion in this case. Negative surgical margins are not recommended for FAs and benign PTs, but 1 cm surgical margins on local excision are recommended in borderline and malignant subtypes due to the risk of recurrence[1,5,26,27]. The estimated recurrence rate is 7.1% for benign PTs, 16.7% for borderline PTs, and 25.1% for malignant PTs[28]. While previous studies have found associations between margin status and recurrence for all PT subtypes, recent meta-analyses have challenged the consequence of re-excision to wider margins for benign and borderline PTs[27,29-31]. Rosenburg et al[32] looked at re-excision of negative margins for benign PTs, noting that a wider margin was not associated with a lower risk of local recurrence[32]. A 2023 study of 439 PTs looked at 5-year disease-free survival (DFS) between margin-negative and margin-involved cases[33]. 5-year DFS was not associated with margin involvement but was influenced by large tumor size (> 5 cm) and infiltrative tumor border, suggesting a limited association between recurrence and margin status. Tan et al[34] also concluded that the complete excision of benign and borderline PTs without adequate surgical margins may be acceptable. Cowan et al[35] found the recurrence rates for benign and borderline PTs are extremely low, and there is no significant difference in recurrence rates between patients with positive or negative margins. All these studies imply that local excision without wide surgical margins may be sufficient for treating benign and borderline PTs. However, given the preponderance of benign over borderline PTs in these studies and the NCCN guidelines for margin width, accepting positive margins in our case of a borderline PT was difficult. In addition, while re-excision may have significant psychosocial repercussions in an adolescent patient, observation of a borderline PT with uncertain biological behavior may cause as much stress and anxiety to patients and their family[36]. Therefore, in this case, the multidisciplinary team still recommended re-excision of the margin. While close clinical and radiological follow-up may be a potential management option for borderline PTs with positive surgical margins, more scientific data needs to be collected to study the biological behavior of borderline PTs in adolescent patients and the risk factors associated with tumor recurrence to establish best treatment guidelines for this age group.

CONCLUSION

The rapid enlargement of a painful solid breast mass may be explained by tumor infarction, resulting in necrosis and edema of the tissue. Initial diagnostic work-up that demonstrates large areas of infarction may warrant additional testing to more accurately classify fibroepithelial neoplasms, to identify PTs, and to improve surgical planning. When infarction is suspected at presentation or on imaging studies, core biopsy samples should attempt to target the area away from the infarction and in the viable component of the lesion. Excisional biopsies may still be required to definitively diagnose and accurately grade PTs. The current standard of care recommended by NCCN guidelines for borderline PTs is complete excision with a 1 cm negative margin. However, recent scientific data has challenged this practice. PTs are rare in adolescent patients, so more long-term clinical follow-up and pathology data need to be collectively studied in this age group to examine risk factors associated with PTs recurrence, including histologic features and margin status. Understanding risks of recurrence may help refine our diagnostic criteria for PTs and tailor our management guidelines for treating PTs in the adolescent population.

ACKNOWLEDGEMENTS

Dr. Kamaljeet Singh, provided pathologic consultation on both the patient’s breast biopsy and excision specimen.