1. DS Ross,1 DD Giri,1 MM Akram,1 JP Catalano,1
Fibroepithelial Lesions in the Breast of Adolescent Females: A Clinicopathological Profile of 53 Cases
DS Ross,1 DD Giri,1 MM Akram,1 JP Catalano,1
KJ Van Zee,2 E Brogi1
1Department of Pathology, Memorial Sloan-Kettering Cancer Center, NYC, NY
2Department of Surgery, Memorial Sloan-Kettering Cancer Center, NYC, NY

2. Background Fibroepithelial lesions (FELs):
Most common breast abnormality in adolescent females (< 18 years-old)
Referred to as:
Fetal fibroadenoma
Tubular adenoma
Cellular fibroadenoma
Hamartoma
Juvenile fibroadenoma
Cystosarcoma phyllodes
Giant fibroadenoma
Phyllodes tumor
Fibroadenoma variant
Fibroepithelial lesions are the most common breast abnormality in adolescent females, defined as 18 years old and younger.
Various terminology has been used in the literature to describe these lesions, including fetal, cellular, juvenile, giant and variant fibroadenomas, tubular adenoma, hamartoma, cystosarcoma phyllodes and phyllodes tumor.

3. Study Aims
Investigate the morphology and clinical behavior of FELs in adolescents
Standardize the diagnostic terms used for FELs in adolescents based upon histologic criteria
The aims of this study are to:
Investigate the morphology and clinical behavior of FELs in adolescents AND
Simplify and standardize the diagnostic terms based upon histologic criteria

4. Study Design (1) Search of MSKCC pathology database
Age < 18 years-old
Excision or mastectomy between
Diagnosis of any fibroepithelial lesion
7 FELs from a prior series were also included ( )
Barrio AV et al. Ann Surg Oncol 2007
We performed a retrospective search of our pathology database to identify patients 18 years old and younger that underwent an excision or mastectomy from 1992 to 2011 and had a diagnosis of any fibroepithelial lesion
7 fibroepithelial lesions in patients from the same age group that were part of a previously published series were also included.

5. Study Design (2) 3 pathologists reviewed all available slides
Features noted:
Gross & microscopic size
Stromal cellularity
Borders / margin status
Nuclear pleomorphism
Growth pattern
Epithelial hyperplasia
Stromal overgrowth
Stromal cell mitoses
3 pathologists reviewed all available slides and the histologic features were noted, including gross and microscopic size, borders and margin status, growth pattern, stromal overgrowth, stromal cellularity, nuclear pleomorphism, epithelial hyperplasia and stromal cell mitoses
Smooth muscle actin was performed on available tissue to further characterize the stromal elements
Smooth muscle actin-α (1A4, DAKO) staining performed on available tissue

6. Study Design (3)
Patient information and clinical follow-up obtained from e-medical records
Age at presentation
Age at menarche
Race
Laterality
Family history
Patient information and clinical follow-up were obtained from electronic medical records including age at presentation, age at menarche, race, laterality and family history

7. Patient Population (1) FELs N=53 Patients N=47 F Solitary FEL 42
Multiple FEL 5
3 ipsilateral 1
2 ipsilateral 2
bilateral
Race
N=23
White 16
African-American 7
Our patient population consisted of 47 females 18 years old or younger, with a total of 53 fibroepithelial lesions.
42 pts had solitary FELs
5 pts had multiple FELs including 1 pt with 3 ipsilateral FELs, 2 with 2 ipsilateral FELs and 2 pts with bilateral FELs
The race information was available for 23 patients with 16 White, 7 African American patients
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47 patients (pts) with 52 FELs
42 pts with 1 FEL
1 pt with 3 FELs in same breast
2 pt with 2 FELs in same breast
2 pts with bilateral FELs

8. Patient Population (1) FELs N=53 Patients N=47 F Solitary FEL 42
Multiple FEL 5
3 ipsilateral 1
2 ipsilateral 2
bilateral
Race
N=23
White 16
African-American 7
Our patient population consisted of 47 females 18 years old or younger, with a total of 53 fibroepithelial lesions.
42 pts had solitary FELs
5 pts had multiple FELs including 1 pt with 3 ipsilateral FELs, 2 with 2 ipsilateral FELs and 2 pts with bilateral FELs
The race information was available for 23 patients with 16 White, 7 African American patients
___________________________________
47 patients (pts) with 52 FELs
42 pts with 1 FEL
1 pt with 3 FELs in same breast
2 pt with 2 FELs in same breast
2 pts with bilateral FELs
Age (years)
Mean Age at Diagnosis
15.4 (10-18)
Mean Age for Menarche*
- Median time from Menarche to Dx**
12.0 (10-14)
48 mo
*Information available for 26 patients
**1 patient presented 12 mo prior to menarche

9. Family History of Breast CA
Patient Population (2)
Laterality
N=53
Right 33
Left 20
Presentation of FEL
N = 42
Palpable Mass 41
Ultrasound 1*
33 tumors were in the right breast and 20 in the left
41 out of 42 FELs for which presentation information was available had presented as a palpable mass. The remaining 1 FEL was initially detected on ultrasound in a pt with an ipsilateral FEL.
13 patients had a family history of breast carcinoma
Patients
Family History of Breast CA 13
*Pt undergoing US for ipsilateral FEL

10. 53 Fibroepithelial Lesions
We classified the 53 FELs based on morphologic criteria. This pie chart shows the breakdown of our cases:
Juvenile FA were the most common lesion
I will now review the findings for each subgroup of FELs

11. Malignant Phyllodes Tumor (8%), Low Grade N=1,High Grade N=3
Gross size*: 4 & 25cm
Infiltrative borders**
Stromal overgrowth
All high grade tumors
Malignant phyllodes tumors represented 8% of all cases, and consisted of 1 low grade and 3 high grade lesions
The gross size was available for 2 high grade tumors which measured 4 and 25 cm
The borders were infiltrative in all cases that could be assessed
Each high grade tumor showed stromal overgrowth
*Gross size available for 2 cases
**Borders assessable in 2 case

12. Malignant Phyllodes Tumor (8%), Low Grade N=1,High Grade N=3
Increased stromal cellularity
Moderate-marked stromal nuclear atypia
Mean mitotic count / 10 HPF:
Low grade: 10
High grade: 17 (12-20)
Increased stromal cellularity was seen in all cases.
The low grade tumor showed moderate nuclear atypia and the high grade tumor showed marked nuclear atypia, as shown here.
The mitotic count for the low grade lesion was 10 and the mean mitotic count for the high grade tumors was 17 with a range of 12 to 20
Based on our review, malignant PT in adolescents were morphologically indistinguishable from the same tumor type in adults although we noticed a relatively high mitotic activity in the single case of low grade phyllodes tumor.

13. Benign Phyllodes Tumor, N=15 (28%)
Mean gross size*: 4 cm (1-13 cm)
Borders**:
Circumscribed: 11/14 (79%)
Infiltrative: 3/14 (21%)
Stromal overgrowth: 13% (2/15)
Growth pattern
Intracanalicular: 10/15 (67%)
Pericanalicular: 5/15 (33%)
There were 15 cases of benign phyllodes tumor, representing 28% of all cases.
The mean gross size was 4 cm with a range of 1 to 13 cm
79% of cases showed circumscribed borders and the rest showed an infiltrative border
Stromal overgrowth was present in 13% of cases
The growth pattern was intracanalicular in 2/3s of cases, as shown in this picture, and pericanalicular in 1/3 of cases
*Gross size available for 11 cases
**Borders assessable in 14 cases

14. Benign Phyllodes Tumor, N=15 (28%)
Increased stromal cellularity
Mild-moderate stromal nuclear atypia
Epithelial hyperplasia: 7/15 (47%)
Mean mitotic count / 10 HPF: 3.1 (1-7)
Increased stromal cellularity and mild to moderate nuclear atypia were seen in all cases

15. Benign Phyllodes Tumor, N=15 (28%)
Increased stromal cellularity
Mild-moderate stromal nuclear atypia
Epithelial hyperplasia: 7/15 (47%)
Mean mitotic count / 10 HPF: 3.1 (1-7)
Epithelial hyperplasia was identified in 47% of cases

16. Benign Phyllodes Tumor, N=15 (28%)
Increased stromal cellularity
Mild-moderate stromal nuclear atypia
Epithelial hyperplasia: 7/15 (47%)
Mean mitotic count / 10 HPF: 3.1 (1-7)
The mean mitotic count was 3 with a range of 1 to 7
Based on our review, BPT in adolescents were morphologically indistinguishable from the same tumors in adults. However, the mean mitotic activity in these tumors was higher than the adult counterpart.

17. Usual Fibroadenoma, N=11 (21%)
Mean gross size: 2.6 cm ( cm)
Circumscribed borders
Growth pattern
Intracanalicular: 10/11 (91%)
Pericanalicular: 1/11 (9%)
There were 11 cases of usual fibroadenoma, amounting to 1/5th of all cases
The mean gross size was 2.6 cm
All cases showed circumscribed borders
The growth pattern was intracanalicular in most cases, as shown in this picture, and pericanalicular in only 1 case

18. Usual Fibroadenoma, N=11 (21%)
Increased stromal cellularity: 3/11 (27%)
No stromal nuclear atypia
Epithelial hyperplasia: 2/11 (18%)
Mean mitotic count / 10 HPF: 1.3 (0-6)
6 mit / 10 HPF in pt pregnant 1y before; FA w/ focal lactational changes
Mean mitotic count w/o above pt is 0.8
Increased stromal cellularity was seen in 27% of cases and there was no nuclear atypia

19. Usual Fibroadenoma, N=11 (21%)
Increased stromal cellularity: 3/11 (27%)
No stromal nuclear atypia
Epithelial hyperplasia: 2/11 (18%)
Mean mitotic count / 10 HPF: 1.3 (0-6)
6 mit / 10 HPF in pt pregnant 1y before; FA w/ focal lactational changes
Mean mitotic count w/o above pt is 0.8
Epithelial hyperplasia was noted in 2 cases.

20. Usual Fibroadenoma, N=11 (21%)
Increased stromal cellularity: 3/11 (27%)
No stromal nuclear atypia
Epithelial hyperplasia: 2/11 (18%)
Mean mitotic count / 10 HPF: 1.3 (0-6)
6 mit / 10 HPF in pt pregnant 1y before; FA w/ focal lactational changes
Mean mitotic count w/o above pt is 0.8
The mean mitotic count was 1 with a range of 0 to 6
The patient with 6 mitoses had given birth 11 months prior to excision and the fibroadenoma showed focal lactational changes
If we were to exclude this pt the mean mitotic count is nearly 1
In the cases reviewed usual FA in adolescents were morphologically indistinguishable from the same tumor type in adults. However, the mitotic activity, although minimal, was higher than typically seen in adult fibroadenomas.

21. Juvenile Fibroadenoma, N=23 (43%)
Mean gross size*: 3.1 cm (0.5-7 cm)
Circumscribed borders
Growth pattern
Pericanalicular
Floridly glandular
Retention of lobular structure
In our case series there were 23 cases showing distinctive morphology that we classified as juvenile fibroadenoma.
The mean gross size was 3.1 cm
All cases showed circumscribed borders
The growth pattern could be regarded as pericanalicular but it is more accurate to say that these tumors were characterized by increased glands and the retention of lobular architecture as shown in this low power picture
Although at low magnification these lesions may resemble an adenosis tumor or tubular adenoma…..
______________________________________________________
(The gross size for 1 case was not available)
*Gross size available for 22 cases

22. Juvenile Fibroadenoma, N=23 (43%)
Increased stromal cellularity: 14/23 (61%)
No stromal nuclear atypia
Epithelial hyperplasia: 7/23 (30%)
Mean mitotic count / 10 HPF: 1.8 (0-7)
on closer examination all showed expanded stroma that was composed of bland myofibroblasts in a fascicular arrangement.
Stromal cellularity was increased in 61% of cases and there was no nuclear atypia.
Most cases showed no distinction between intralobular and extralobular stroma, and uniform cell density was present throughout.

23. Juvenile Fibroadenoma, N=23 (43%)
Increased stromal cellularity: 14/23 (61%)
No stromal nuclear atypia
Epithelial hyperplasia: 7/23 (30%)
Mean mitotic count / 10 HPF: 1.8 (0-7)
Epithelial hyperplasia, predominantly of gynecomastoid / micropapillary type was seen in 30% of cases, as shown here

24. Juvenile Fibroadenoma, N=23 (43%)
Increased stromal cellularity: 14/23 (61%)
No stromal nuclear atypia
Epithelial hyperplasia: 7/23 (30%)
Mean mitotic count / 10 HPF: 1.8 (0-7)
The mean mitotic count was 1.8 with a range of 0 to 7

25. Juvenile Fibroadenoma, N=23 (43%)
A distinctive feature in the juvenile fibroadenoma were bundles of collagen admixed with the stromal proliferation.
Many of the stromal cells showed positive staining for smooth muscle actin but the staining pattern was also observed in other FELs.
SMAα

26. Juvenile Fibroadenoma
A distinctive type of FA
Collagenized and cellular stroma
Pericanalicular growth pattern
Lobular arrangement
+/- Florid ductal hyperplasia
In summary the morphologic features of juvenile fibroadenoma were collagenized and cellular stroma, pericanalicular growth pattern, lobular arrangement of glands, and plus or minus florid ductal hyperplasia. These features allowed reproducible diagnosis of juvenile fibroadenoma in this series.

27. Juvenile Fibroadenoma: Variation in Morphology
Other tumors in this series showed features of a juvenile fibroadenoma with a slight variation in morphology.
These tumors had well circumscribed borders, a pericanalicular growth pattern and cellular and collagenous stroma, similar to what I described in juvenile fibroadenomas, however they consistently showed areas of stromal expansion throughout the lesion.

28. Fibroadenoma Variant Characterized by collagenous and cellular stroma
“…related to FAs in structure and composition but show sufficient difference to raise problems in precise dx and classification”
Differential dx often includes a phyllodes tumor
This morphology is reminiscent of a lesion introduced by Dr. Azzopardi in 1979 termed fibroadenoma variant.
This term describes a fibroepithelial lesion composed of collagenous and cellular stroma that is related to a fibroadenoma in structure and composition but shows sufficient difference to raise problems in precise classification.
This lesion can sometimes be problematic b/c the differential diagnosis often includes a phyllodes tumor as I will discuss.
__________________________________________________________
STROMA The characteristics of the stroma of fa variants differentiate these tumors from fa. Like fa variants, PT typically have a cellular stroma that shows varying levels of collagen deposition; however the stroma of msot PT contains myxoid ground substances as well as collgen. Furthermore, most PT do not have the abundant glands arranged in complex formations seen in fa variants.
Azzopardi, 1979

29. Juvenile Fibroadenoma,
Variant Pattern (N=8/23)
On the left is the image from Dr. Azzopardi’s book compared to the picture I previously showed.
The stroma shows a cellular yet collagenized fibrous quality throughout.
This pattern was seen in 8 of the 23 juvenile fibroadenomas.
Problems in Breast Pathology, Azzopardi, 1979
Case from our series

30. Juvenile Fibroadenoma:
Variant Pattern & Intratumoral Heterogeneity (N=4/23)
Out of these 8 cases with a variant pattern, 4 showed intratumoral heterogeneity.
Intratumoral heterogeneity might cause confusion with a benign phyllodes tumor in these young patients.

31. Juvenile Fibroadenoma:
Variant Pattern & Intratumoral Heterogeneity (N=4/23)
On higher power of these lesions you can see the border between compact glands, similar to what I showed in the juvenile fibroadenoma, adjacent to an area with a cellular and collagenous stromal component, similar to the variant pattern.
The pericanalicular pattern and lack of nuclear atypia are features that should help a pathologist classify this lesion as a juvenile fibroadenoma with these variant features.

32. Distinguishing Features
Juvenile Fibroadenoma
Benign Phyllodes Tumor
This variant of juvenile fa may raise the differential dx of phyllodes tumor however a few morphologic features allow distinction between the 2.
The juvenile fa variant shows a pericanalicular pattern with uniform stromal cellularity throughout and the lack of leaf like fronds which are characteristic of phyllodes tumors

33. Distinguishing Features
Juvenile Fibroadenoma
Benign Phyllodes Tumor
On closer examination the distinction can be more subtle and rests upon benign cytology and evident collagen bundles in the juvenile fibroadenoma but not in a phyllodes tumor

34. Distinguishing Features
Juvenile Fibroadenoma
Benign Phyllodes Tumor
Mitotic activity would not help in this differential b/c as I showed juvenile fa can also have considerable mitotic activity in this age group.
Mean Mitotic Count: 1.8 (0-7)
Mean Mitotic Count: 3.1 (1-7)

35. Original Diagnosis
This bar graph shows the breakdown of the 53 study cases according to the original diagnosis. Initially these cases had been categorized into 9 different subgroups.

36. Reclassification
Using stricter morphologic criteria, we classified the same tumors into just 5 subgroups achieving our goal to standarize the diagnostic terminology

37. Follow-Up 37 patients (41 FELs) Mean follow-up: 40 months
From less than a month to 278 months
Follow-up was available for 37 pts with 41 FELs
The mean overall follow-up was 40 months (3 years 4 months) with a range of less than 1 month to 278 months (23 years)

38. Increased Stromal Cellularity
2 Recurrent Cases
Information for index FEL
Months to Recur.
Gross Size (cm)
Borders
Increased Stromal Cellularity
Mitotic count per 10 HPF
Stromal atypia
BPT
12.2
8.5
Infiltrative
Yes 4
Mild
LGMPT 18
N/A 10
Moderate
Local recurrence was reported in 2 of the 53 cases.
The benign phyllodes tumor recurred approximately 1 year after initial excision.
The low grade malignant phyllodes tumor recurred a year and a half after initial excision.

39. 1992-2011: 46 Consecutive Fibroepithelial Lesions
To determine the incidence of FEL in this young age population, we focused only on the 46 consecutive lesions obtained between 1992 to 2011.
The breakdown was similar to what I just described for all 53 cases in this series with juvenile fibroadenomas comprising 46% of all cases

40. Conclusions FEL in adolescents Benign in two-thirds of cases
Juvenile FA 46%, Usual FA 24%
In conclusion….
Fibroepithelial lesions in adolescents are benign in 2/3s of cases and consist of juvenile fibroadenomas in nearly half of the cases and usual fibroadenoma in one fourth.
Mitoses are common in FELs from females 18 years old and younger, and can even be substantial, up to 7 mitoses per 10 HPF, in juvenile Fas. It is important to be aware of this finding because in adults increased mitotic activity is a feature of high grade fibroepithelial lesions.
Juvenile fibroadenoma is the most common lesion in this case series and is characterized by a floridly glandular lobular architecture, collagenous stroma and pericanalicular growth pattern.
Variant morphologies characterized by stromal expansion and intratumoral heterogeneity, such as in the fibroadenoma variant described by Azzopardi, can be seen in these tumors.
Awareness of the morphologic features of this lesion is important to avoid overdiagnosis of phyllodes tumors in adolescents which can lead to additional surgery and carries the risk of disrupting the developing breast bud.
______________________________________
Our results provide a useful reference to pathologists and clinicians treating adolescents with FELs.

41. Conclusions FEL in adolescents Benign in two-thirds of cases
Juvenile FA 46%, Usual FA 24%
Frequent stromal mitoses
In conclusion….
Fibroepithelial lesions in adolescents are benign in 2/3s of cases and consist of juvenile fibroadenomas in nearly half of the cases and usual fibroadenoma in one fourth.
Mitoses are common in FELs from females 18 years old and younger, and can even be substantial, up to 7 mitoses per 10 HPF, in juvenile Fas. It is important to be aware of this finding because in adults increased mitotic activity is a feature of high grade fibroepithelial lesions.
Juvenile fibroadenoma is the most common lesion in this case series and is characterized by a floridly glandular lobular architecture, collagenous stroma and pericanalicular growth pattern.
Variant morphologies characterized by stromal expansion and intratumoral heterogeneity, such as in the fibroadenoma variant described by Azzopardi, can be seen in these tumors.
Awareness of the morphologic features of this lesion is important to avoid overdiagnosis of phyllodes tumors in adolescents which can lead to additional surgery and carries the risk of disrupting the developing breast bud.
______________________________________
Our results provide a useful reference to pathologists and clinicians treating adolescents with FELs.

42. Conclusions FEL in adolescents Juvenile FA is the most common FEL
Benign in two-thirds of cases
Juvenile FA 46%, Usual FA 24%
Frequent stromal mitoses
Juvenile FA is the most common FEL
Distinctive morphology
In conclusion….
Fibroepithelial lesions in adolescents are benign in 2/3s of cases and consist of juvenile fibroadenomas in nearly half of the cases and usual fibroadenoma in one fourth.
Mitoses are common in FELs from females 18 years old and younger, and can even be substantial, up to 7 mitoses per 10 HPF, in juvenile Fas. It is important to be aware of this finding because in adults increased mitotic activity is a feature of high grade fibroepithelial lesions.
Juvenile fibroadenoma is the most common lesion in this case series and is characterized by a floridly glandular lobular architecture, collagenous stroma and pericanalicular growth pattern.
Variant morphologies characterized by stromal expansion and intratumoral heterogeneity, such as in the fibroadenoma variant described by Azzopardi, can be seen in these tumors.
Awareness of the morphologic features of this lesion is important to avoid overdiagnosis of phyllodes tumors in adolescents which can lead to additional surgery and carries the risk of disrupting the developing breast bud.
______________________________________
Our results provide a useful reference to pathologists and clinicians treating adolescents with FELs.

43. Conclusions FEL in adolescents Juvenile FA is the most common FEL
Benign in two-thirds of cases
Juvenile FA 46%, Usual FA 24%
Frequent stromal mitoses
Juvenile FA is the most common FEL
Distinctive morphology
+/- Stromal expansion and intratumoral heterogeneity (fibroadenoma variant)
In conclusion….
Fibroepithelial lesions in adolescents are benign in 2/3s of cases and consist of juvenile fibroadenomas in nearly half of the cases and usual fibroadenoma in one fourth.
Mitoses are common in FELs from females 18 years old and younger, and can even be substantial, up to 7 mitoses per 10 HPF, in juvenile Fas. It is important to be aware of this finding because in adults increased mitotic activity is a feature of high grade fibroepithelial lesions.
Juvenile fibroadenoma is the most common lesion in this case series and is characterized by a floridly glandular lobular architecture, collagenous stroma and pericanalicular growth pattern.
Variant morphologies characterized by stromal expansion and intratumoral heterogeneity, such as in the fibroadenoma variant described by Azzopardi, can be seen in these tumors.
Awareness of the morphologic features of this lesion is important to avoid overdiagnosis of phyllodes tumors in adolescents which can lead to additional surgery and carries the risk of disrupting the developing breast bud.
______________________________________
Our results provide a useful reference to pathologists and clinicians treating adolescents with FELs.

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