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Anastomosing squamoid adenoma: clinicopathological analysis of three cases of a novel sweat ductal adnexal tumour with distinctive histopathological features
Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka, JapanDepartment of Pathology, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Tokyo, JapanDepartment of Pathology, Itabashi Central Clinical Laboratory, Tokyo, JapanDepartment of Anatomic Pathology, Tokyo Medical University, Tokyo, JapanDepartment of Diagnostic Pathology, Shizuoka Cancer Center Hospital, Sunto, JapanDepartment of Clinical Laboratory and Diagnostic Pathology, Osaka National Hospital, Osaka, JapanDepartment of Dermatology, Hyogo Cancer Center, Akashi, JapanDepartment of Dermato-oncology/Dermatology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan
There are numerous tumour types in the sweat ductoglandular appendageal group of cutaneous adnexal tumours. Nevertheless, new tumour types, including secretory carcinoma,
have been recently proposed and established. Herein, we present three cases of a sweat ductal tumour with novel, characteristic histopathological features of anastomosing epithelial growth accompanied by a surrounding and intermixed lymphocytic infiltrate. This study aimed to thoroughly investigate them and illustrate why we believe that this represents a new tumour entity.
The study was approved by the research ethics committee of Osaka International Cancer Institute, Osaka, Japan (reference number: 21179). Three cases (Cases 1–3) with similar histopathological features were retrieved from the author's (KG) consultation files (2020–2021). In Case 1, a subcutaneous nodule with over 20 years history was found in the right eyebrow area of a 53-year-old woman. The lesion exhibited a skin-colored appearance with a diameter of approximately 1 cm. She felt no pain. The past medical history included breast cancer (invasive ductal carcinoma) 18 months previously. The patient in Case 2 was a 41-year-old woman who had a 12 mm subcutaneous nodule on her scalp. This had been thought to be a benign cyst clinically and she remembers first noticing it 10–15 years previously. Case 3 was a 31-year-old woman who also had a 12 mm subcutaneous nodule on her scalp. This had been present for at least 5 years and she felt it had increased in size slowly over that time. In addition, 16 years had now elapsed since it was resected. All these patients have been followed clinically and none have known evidence of recurrence or metastasis to date (follow-up duration: 6 months in Case 1, 16 years in Case 2, 4 years in Case 3). The clinical courses before surgery were over 20 years in Case 1, 10–15 years in Case 2, and at least 5 years in Case 3.
All tumours showed similar histopathological features (Fig. 1). They were well-circumscribed subcutaneous tumours without circumferential fibrous capsule formation (Fig. 1A,F,K). A prominent lymphoid cuff was present at the periphery of the tumours as well as prominent lymphoid stroma within the tumours (Fig. 1A,F,K). These tumours exhibited an anastomosing epithelial network (Fig. 1B,D,G,I,L,N). A few small ductal and dilated cystic structures were distributed within the tumour nests (Fig. 1B,C,G,H,L,M,N). Most inner side tumour cells had a spindled/fusiform eosinophilic cytoplasm with keratinization, similar to the squamoid changes seen in squamoid eccrine duct carcinoma. The squamoid change was seen in all cases with varying degrees, and was most prominent in Case 3 (Fig. 1L,M). The tumour cells had oval nuclei with one or two small nucleoli. Nuclear chromatin was heterogeneously distributed but not increased. No nuclear atypia was observed (Fig. 1D,E,I,J,M). Mitotic figures were not observed in the tumour cells. No peripheral palisading of the tumour cells resembling follicular germinative cells was confirmed (Fig. 1D,E,I,J,M). An infiltrate of mainly lymphocytes, with fewer plasma cells, and eosinophils was observed in the tumour stroma (Fig. 1E,H,J,M–O). The tumour stroma was fibrotic, but neither hyalinising nor sclerosing changes were noted (Fig. 1D,E,I,J,O).
Fig. 1Histopathological findings of Cases 1 (A–E), 2 (F–J), and 3 (K–O). (A) Circumscribed tumour with lymphoid cuff in Case 1. (B) Anastomosing/reticulated network of tumour cells. (C) Beautiful ductal structures. (D) Marked squamoid change in the tumour cells. (E) No nuclear atypia in the tumour cells. (F) Subcutaneous circumscribed tumour with lymphoid cuff in Case 2. (G) Cystic and ductal structures showing anastomosing/reticulated growth pattern. (H) Ductal formation. (I) Anastomosis of squamoid tumour cells. (J) Squamoid tumour cells with no nuclear atypia. (K) Subcutaneous circumscribed tumour with lymphoid cuff in Case 3. (L) Cystic and ductal structures showing anastomosing/reticulated growth pattern. (M) Ductal structure with marked squamoid change. (N) Partial fibrous capsule formation. (O) Prominent fibrotic stromal change with an infiltrate of mixed inflammatory cells.
The immunoprofile in all cases is summarised in Table 1 [expression of all the immunohistochemical markers other than Ki-67 and YAP1 was graded into four categories: negative (−), focally positive (+, 1–30% of the targeted tumour components), partially positive (++, 31–70%), and diffusely positive (+++, 71–100%)]. The peripheral layer tumour cells expressed CK5/6 and p63 but not CK7, CK19, BerEP4, CEA, and EMA (Fig. 2A–I). In contrast, the inner side tumour cells were positive for CK7, CK19, BerEP4, CEA, and EMA but negative for CK5/6 and p63 (Fig. 2A–I). CEA and EMA also highlighted the luminal surface within the tumour nests (Fig. 2H,I). In Case 3 with marked squamoid change, the peripheral layer tumour cells expressing CK5/6 and p63 were more prominent than the inner side tumour cells expressing CK7, CK19, and BerEP4 (Fig. 2E). GATA3 expression was limited (Fig. 2J). However, CK20, c-kit, ER, GCDFP15, mammaglobin, α-SMA, SOX10, BRAF, NUT, and PLAG1 were completely negative for these tumour cells. Nuclear YAP1 immunoexpression was observed in <5% of tumour cells in two tested cases. The Ki-67 labeling index was ≤10% in all tumours (Fig. 2K). In situ hybridisation for EBER was performed in all cases, with negative results. Moreover, MAML2 break-apart FISH revealed no split signals in any case (Fig. 2L).
Table 1Immunohistochemical findings of three cases
Case 1
Case 2
Case 3
CK5/6
+++ (P)
+++ (P)
+++ (B)
CK7
+++ (I)
+++ (I)
+ (I)
CK19
+++ (I)
+++ (I)
+ (I)
CK20
−
−
−
BerEP4
+ (I)
++ (I)
+ (I)
c-kit
−
−
−
CEA
+++ (L), ++ (I)
+++ (L), ++ (I)
ND
EMA
++ (L), ++ (I)
++ (L), ++ (I)
ND
ER
−
−
−
GATA3
++ (I)
+ (I)
+ (I)
GCDFP15
−
−
ND
Mammaglobin
−
−
ND
P63
+++ (P)
+++ (P)
+++ (B)
α-SMA
−
−
−
SOX10
−
−
ND
BRAF
−
−
ND
MYB
+ (B)
−
−
NUT
−
−
ND
PLAG1
−
−
ND
YAP1
<5%
<5%
ND
Ki-67
10%
5%
5%
α-SMA, α-smooth muscle action; B, on both tumour cells; CEA, carcinoembryonic antigen; CK, cytokeratin; EMA, epithelial membrane antigen; ER, oestrogen receptor; GCDFP15, gross cystic disease fluid protein 15; I, on the inner side tumour cells; L, on the luminal surface; ND, not done; P, on the peripheral layer tumour cells; PLAG1, pleomorphic adenoma gene 1; YAP1, yes-associated protein 1.
Fig. 2Immunohistochemical and molecular findings. (A) Cytokeratin 19 highlighting the anastomosing structure. (B) Diffuse staining of cytokeratin 19 on the inner side tumour cells. (C) Cytokeratin 5/6 clarifying the anastomosing structure. (D) Diffuse expression of cytokeratin 5/6 on the outer side tumour cells. (E) Only a few inner side tumour cells expressing cytokeratin 7 in Case 3. (F) Diffuse p63 immunoreactivity on the outer side tumour cells. (G) BerEP4 with the immunoexpression on the inner side tumour cells. (H) Carcinoembryonic antigen highlighting the luminal surface and inner side tumour cells. (I) Epithelial membrane antigen clarifying the luminal surface and inner side tumour cells. (J) Limited GATA3 expression. (K) Low index of Ki-67 labeling. (L) No split signal in break-apart fluorescence in situ hybridisation for MAML2 gene.
We present the investigation of three cases of a sweat ductal tumour with distinctive histopathological features, which to the best of our knowledge have not been previously reported. All tumours developed as a well-demarcated subcutaneous nodule on the upper part of the head in young or middle-aged women. Histopathologically, anastomosing structures composed of peripheral layer tumour cells expressing CK5/6 and p63 and inner side tumour cells expressing CK7, CK19, BerEP4, CEA, and EMA were characteristic of the tumours. Squamoid change (squamous metaplasia) was present in all cases. Intriguingly, all cases had a striking lymphocytic infiltrate which was most prominent peripherally and associated with fibrosis.
These well-circumscribed tumours have no nuclear atypia and no mitotic activity. Taken together with the uneventful clinical course ranging from approximately 5 to over 20 years, a benign biological behaviour seems likely. The two population layers composed of ductoglandular and peripheral cells and ductal lumen highlighted by CEA and EMA are consonant with a sweat ductoglandular adnexal tumour rather than a follicular or sebaceous adnexal tumour. These tumours may exhibit sweat ductal differentiation, owing to the lack of a myoepithelial component implied by the lack of SOX10 and α-SMA staining, and the lack of eccrine glandular differentiation implied by the lack of SOX10.
Immunohistochemistry for CD117 (KIT) is effective in distinguishing cutaneous adnexal tumors with apocrine/eccrine or sebaceous differentiation from other epithelial tumors of the skin.
Immunohistochemistry for CD117 (KIT) is effective in distinguishing cutaneous adnexal tumors with apocrine/eccrine or sebaceous differentiation from other epithelial tumors of the skin.
and could explain this finding. The p63 positivity is interesting. Some of the positivity can be explained by the squamoid morphology, but the rimming p63-positive tumour cells have the character of poroid cells. Poroid cells, which are located outside sweat ducts, express p63 but do not express SOX10 or SMA.
Given these novel findings, serious consideration was given to the differential diagnosis. Case 3 was originally biopsied in 2006 and has been seen in consultation by a variety of senior dermatopathologists who have been unable to categorise it. Squamous cell carcinoma, including lymphoepithelioma-like carcinoma of the skin, is the most important differential diagnosis; however, the present cases have ductal differentiation and lack atypia.
Cribriform carcinoma can also be accompanied by a lymphoid cuff but does not exhibit anastomosis of squamoid tumour cells or two population layers of p63-positive peripheral cells and p63-negative inner side cells.
Primary cutaneous cribriform apocrine carcinoma: a clinicopathologic and immunohistochemical study of 26 cases of an under-recognized cutaneous adnexal neoplasm.
Adenoid cystic carcinoma is composed of c-kit-positive ductoglandular epithelial and SOX10-positive myoepithelial cells and does not have an inflammatory stroma.
MYB translocations in both myoepithelial and ductoglandular epithelial cells in adenoid cystic carcinoma: a histopathologic and genetic reappraisal in six primary cutaneous cases.
Two of the three cases expressed extremely limited YAP1 expression, which does not suggest YAP1 fusion, but similar limited expression of YAP1 can be seen in the normal epidermal keratinocytes and other cancers.
Hidradenoma does not demonstrate an anastomosing/reticulated tumour structure or the lymphocytic infiltrate, and MAML2 translocation seems to be a constant feature.
Tubular adenoma also does not show an anastomosing/reticulated tumour structure, and the BRAF V600E mutation is frequently present in this tumour. Apocrine mixed tumour of the skin is characteristic of the proliferation of myoepithelial tumour cells with SOX10, α-SMA, and PLAG1 immunoexpression. Eccrine mixed tumour is composed of numerous small monolayered ductal structures with round lumina and myxohyalinised and cartilaginous stroma but not anastomosing ductal structures nor lymphoid stroma. Cutaneous lymphadenoma is a benign trichoblastoma-like tumour with Reed–Sternberg-like cells but does not show sweat ductoglandular differentiation. In addition, lymphoid aggregates in the tumour nests are seen in cutaneous lymphadenoma but not in our cases.
All tumours in the present study were noted in the upper part of the head of young to middle-aged women, although it remains unknown whether the clinical findings are characteristic of this tumour type. Additional reports will likely further define the clinicopathological characteristics.
In this study, we investigate three cases of a sweat ductal tumour with distinctive histopathological features. Based on the characteristic histopathological features, we believe these should be designated as a distinct entity and propose the label ‘anastomosing squamoid adenoma’. Hopefully, this will encourage others to identify further cases of this unusual tumour.
Data availability statement
The datasets generated and analysed during the present study are available from the corresponding author on reasonable request and IRB approval but are not publicly available due to privacy or ethical restrictions.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose.
References
Kastnerova L.
Luzar B.
Goto K.
et al.
Secretory carcinoma of the skin: report of 6 cases, including a case with a novel NFIX-PKN1 translocation.
Immunohistochemistry for CD117 (KIT) is effective in distinguishing cutaneous adnexal tumors with apocrine/eccrine or sebaceous differentiation from other epithelial tumors of the skin.
Primary cutaneous cribriform apocrine carcinoma: a clinicopathologic and immunohistochemical study of 26 cases of an under-recognized cutaneous adnexal neoplasm.
MYB translocations in both myoepithelial and ductoglandular epithelial cells in adenoid cystic carcinoma: a histopathologic and genetic reappraisal in six primary cutaneous cases.
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