Clinical, Histopathological and Immunohistochemical Aspects of Digital Papillary Adenocarcinoma: A Case Report and Literature Review
Sergen YAGCI1, Aysen TERZI1, Abbas ALBAYATI2, Ahmet Cagrý UYSAL2
1Department of Pathology, Baþkent University Faculty of Medicine, ANKARA, TURKEY
2Department of Plastic and Reconstructive Surgery, Baþkent University Faculty of Medicine, ANKARA, TURKEY
Keywords: Malignant eccrine tumor, Digital papillary adenocarcinoma, Mohs Micrographic Surgery
Digital papillary adenocarcinoma (DPA) is a rare malignant eccrine tumor. A 62-year-old female presented with a subcutaneous nodular
1.5cm-mass in the thumb. Macroscopically, a poorly circumscribed mass containing cystic and solid components was observed. Microscopically,
epithelial neoplasm consisting of tubular-cystic structures with back-to-back arrangements was observed. The lining epithelium was composed
of cuboidal/columnar cells with mild atypia, with micropapillary extensions. Immunohistochemistry revealed double-layered neoplastic
epithelium containing two different types of cells: basaloid/myoepithelial and luminal. We recommend two out of vimentin, HMWCK, and
D2-40 for myoepithelial/basaloid cells, also CK7 and EMA for luminal/columnar cells. As the tumor had infiltrated the surgical margins, the
patient underwent axillary sentinel lymph node (SLN) dissection and re-excision with Mohs micrographic surgery (MMS). Two additional MMS
stages were required due to suspicious surgical margin positivity in the frozen sections. The operation was continued despite the risk of loss of
function. Upon examination of the permanent sections, we observed no tumors in the suspected positive foci. Additionally, no tumor was found
in the surgical margins. No metastasis was detected in the sentinel lymph node. We have reached 300 reported cases of DPA in the literature. We
discussed the histopathological and intraoperative diagnostic pitfalls of DPA with a literature review and our experience.
Digital papillary adenocarcinoma (DPA) is a rare malignant
tumor of the sweat glands that often presents as a solitary
painless mass on the digits or toes with an incidence
of 0.08 per 1 000 000 people/year (1) and was originally
described by Helwig (2) in 1984. The male/female ratio
was reported 4:1 (1). It is most frequently diagnosed in the
sixth to eighth decades but adolescents may also be affected
(3). Most tumors exhibit nodular and cystic growth patterns
with a median diameter of 1.7 cm. Due to its slow
growth and non-specific symptoms and signs, the diagnosis
is often missed or delayed. The tumor has a frequently
inconspicuous clinical course but significant potential for
recurrence and metastasis. The overall local recurrence rate
has been reported as 30%. However, after adequate surgical
treatment with re-excision or amputation, this rate may be
decreased to 5%. The rate of distant metastases has been
reported to be 14-26% regardless of treatment or the presence
of local recurrence (4,5). The recommended treatment
is surgical with clear resection of the margins. There is a
possibility of proximal amputation in case of muscle and bone invasion (4,5). Because of the difficulty of its differential
diagnosis from metastatic adenocarcinoma, this process
is problematic for the pathologist (6). Here, we aimed
to discuss the case of DPA with the diagnostic pitfalls and
review the literature.
A 62-year-old female presented with a painless swelling in
the thumb. Clinically, it was thought to be a ganglion cyst or
vascular lesion on initial physical examination. A subcutaneous
nodular mass with a diameter of 1.5 cm was detected
in the proximal phalanx (Figure 1A
). Magnetic resonance
imaging (MRI) showed a cystic lesion, thought to be compatible
with infectious processes, and the surgeon excised
the lesion. Macroscopically, a partially well-circumscribed
but mostly infiltrative mass containing cystic and solid
components was observed (Figure 1B
). Microscopically, an
epithelial neoplasm was observed in the solid component,
some of which consisted of cribriform, back-to-back tubular
structures (Figures 2A
). The lining epithelium
of the cystic component was composed of a single row of flattened mild atypical cells, sometimes containing doublelayered
cuboidal/columnar cells with mild atypia, with
micropapillary extensions to the lumen (Figure 2B
). A rare
mitotic figure was seen. No necrosis, lymphovascular or
perineural invasion was observed. Histochemical staining
showed focal intracytoplasmic mucin in neoplastic cells.
Immunohistochemistry revealed that the bilayer neoplastic
epithelium contained two distinct cell types: basaloid/
myoepithelial and luminal (Figures 2E and 2F). Tumor
cells were cytokeratin AE1/AE3, MOC31, BEREP4 positive,
but S100 and CEA were negative. Luminal cells were
CK7 and EMA positive; basaloid/myoepithelial cells were
vimentin, p63, HMWCK, D2-40, and calponin positive.
We observed sparse mitotic figures and calculated the
Ki-67 index as 15% in the highest areas. No atypical mitosis
or necrosis was observed. The tumor was infiltrating the
surrounding adipose tissue and was present in the deep
surgical margins. We reported histomorphological and
immunohistochemical findings consistent with DPA. We
suggested re-excision if metastatic adenocarcinoma was
excluded clinically and radiologically. No involvement was
found in any other focus on PET/CT. Re-excision was performed
with axillary sentinel lymph node (SLN) dissection
and MMS. We did not detect SLN metastases. During the
MMS procedure for re-excision, intraoperative examination
revealed suspicious tumor foci at the surgical margins
by the pathologist. Two additional MMS steps were then
performed to ensure negative surgical margins. We noticed
that there was no tumor in the suspected positive foci in the
permanent sections (Figure 2D). There was no tumor in the
surgical margins. Our patient was recurrence-free after 30
months of postoperative follow-up.
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|Figure 1: A subcutaneous nodular 1.5cm-mass in the thumb. No ulceration or color change (A and B).
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|Figure 2: A) An epithelial neoplasm was observed in the solid component, some of which consisted of cribriform, back-to-back tubular
structures (hematoxylin and eosin x50). B) The lining epithelium of the cystic component was composed of a single row of flattened mild
atypical cells; sometimes it contained double-layered cuboidal/columnar cells with mild atypia, with micropapillary extensions to the
lumen (hematoxylin and eosin x100). C) Epithelial cells with mild atypia form solid sheeting, focally (hematoxylin and eosin x200). D)
Suspicious positivity was noted in frozen sections. It was noticed that there was no tumor in the suspicious positive foci in the permanent
sections (hematoxylin and eosin x200). Immunohistochemistry revealed that the bilayer neoplastic epithelium contained two distinct
cell types; basaloid/myoepithelial and luminal. Luminal cells were CK7 positive (E, x200); basaloid/myoepithelial cells were HMWCK
positive (F, x100).
Kao et al. first defined the cases as adenoma and adenocarcinoma
in their 57 cases of DPA, in 1987 (7). Duke et al.
described 67 cases (50 of adenoma, 17 of adenocarcinoma),
6 cases with metastases, and three of these cases were found
to have histopathological criteria previously defined as adenoma
by Kao and colleagues. The results showed that only
DPA terminology should be used (4).
We have found that 300 cases have been reported in the
PubMed using the search terms ‘aggressive DPA’, ‘DPA’,
and ‘aggressive digital papillary adenoma’ as of April 2023.
The male/female ratio was 3.86 (174:45). The median age
was 51 years (range, 14-96). The tumor was mostly localized
on the hand, especially on the fingers (mostly third
finger). On the feet, it was mostly localized on the big toe.
Localization was mostly on the volar surface of the hands
or feet and distal fingers or toes.
DPA is a diagnostic challenging tumor, and treatment is
often delayed due to misdiagnosis (8). Metastatic adenocarcinoma
and benign adnexal tumors are the two main
entities that cause difficulties in the histopathological differential
diagnosis. Typical histopathological features of DPA
are multinodular, solid, and cystic development, but pure
solid cases have also been reported (4). In addition to papillary
projections protruding into the cystic lumen, tubular
structures surrounded by an outer neoplastic myoepithelial
layer and an inner low columnar/cuboid epithelium, with
back-to-back arrangements were also observed, which are
typical features of DPA. Suchak et al. suggested that the
presence of tumor-associated myoepithelial cells should
not be interpreted as benign but rather a clinical or histo-pathological evaluation for the primary adnexal origin of
the tumor (5). DPA is defined as a poorly circumscribed
tumor involving the dermis and subcutis (4). Since metastatic
adenocarcinoma is the first line in the histopathological
differential diagnosis, immunohistochemical revealing
of the different phenotypes of the myoepithelial layer and
columnar epithelium was valuable in our case.
Cases presented in the literature have been evaluated with
a wide variety of immunohistochemical panels, and there
is no recommendation for an optimal diagnostic panel for
DPA. Therefore, we also reviewed the immunohistochemical
markers used for differential diagnosis of DPA in the
literature and showed that most of them in Table I. We
created a mini-panel recommendation for using the DPA
diagnosis. We found it helpful to apply two of three markers
for myoepithelial/basaloid cells vimentin, HMWCK,
and D2-40. In our experience, other myoepithelial cell
markers such as S100 did not stain any neoplastic cells, and p63 stained myoepithelial/basaloid cells selectively but not
all of them. The most useful luminal/columnar cell markers
were CK7 and EMA. MOC31 and BerEP4 are positive in
most carcinomas; both were positive in our case and not
helpful to distinguish DPA from metastatic adenocarcinomas.
The p53 nuclear positivity of the tumor was less than
10%, which helped us to lower the probability of metastatic
carcinoma. Since p53 can also show diffuse positivity in
benign adnexal tumors, it did not help us in the differential
diagnosis of DPA from benign skin adnexal tumors. However,
the Ki-67 proliferation index can be a useful marker,
as it may indicate a significant focal increase in DPA. Wide
excision or digital amputation with or without SLND followed
by close, long-term follow-up is the recommended
treatment method of DPA (5). Six cases of Mohs micrographic
surgery (MMS) have been reported in the current
literature. (4,8-11). MMS offers the advantage of achieving
histologic margin clearance and functional preservation
(9). In our experience, two additional MMS stages were
required due to suspicious positivity, unlike the previously
reported 6 DPA cases that underwent MMS. Although the
diagnosis is known preoperatively, suspicious positivity
was noted in frozen sections because of the innocent histomorphology
of DPA. The operation was advanced despite
the risk of loss of function. In contrast, the residual tumor
was only in a microscopic focus in the permanent sections.
It was noticed that there was no tumor in the suspicious
positive foci in the permanent sections. Additionally, no
metastasis was detected in serial sections in the sentinel
lymph node, which showed a 3.5 cm fatty change, in our
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|Table I: Immunohistochemistry was applied to 111 cases,
including our case*. The statistics of the immunohistochemical
analysis applied in the literature are shown in the table.
Sentinel lymph node procedure was applied to 48 cases
reported, and metastasis was observed in 6 cases (13%)
(4,12-14). Disease-related death was reported in 6 cases
(3.3%) (4,14-18), 37 patients (19.5%) showed local recurrence,
and 26 patients (13.7%) had distant metastasis in the
reported 190 patients with follow-up, in the current literature.
According to these data, the event-free survival rate
was 76.8% during the mean 57 months of follow-up. Our
patient was recurrence-free after 30 months of postoperative
DPA has a silent clinical course and innocent histomorphology.
Careful histopathological examination and clinical
correlation are essential in the differential diagnosis,
since there are various diagnoses from benign skin-appendix
tumors to metastatic adenocarcinoma. These tumors
are often unrecognized because of their rarity so being
aware of this entity is essential for both pathologists and
Conflict of Interest
The authors declare that they have no conflicts of interest.
Concept: SY, AT, Design: SY, Data collection or processing: SY, AT,
AA, ACU, Analysis or Interpretation: SY, AT, AA, ACU, Literature
search: SY, Writing: SY, AT, Approval: SY, AT, AA, ACU.
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