Digital Papillary Adenocarcinoma Research Articles

Is it time for international consensus clinical guidance development for digital papillary adenocarcinoma? : reply to Joshi et al.

Is it time for international consensus clinical guidance development for digital papillary adenocarcinoma? : reply to Joshi et al.

Digital Papillary Adenocarcinoma: Uncommon Malignancy of Sweat Glands - Two Rare Cases

Abstract Digital papillary adenocarcinoma (DPA) is a very rare malignant tumor of the sweat glands originally described by Helwig in 1979.It often presents as a solitary painless mass, commonly found on the volar surface of the fingers and toes and the adjacent skin of the palms and soles. Materials and Methods: Two rare cases of DPA in 43- and 48-year-old male patients who presented with swelling finger were included over period of one year study in a tertiary care hospital. Results: Our study had two cases with male patient of age 48 year and 43 year old. Both presented with swelling and a mass lesion left middle finger, past 8 years and nodule in proximal phalangeal region of left index finger for 15 years respectively. On histomorphology and immunohistochemistry both were diagnosed as DPA. Conclusion: DPA is a rare adnexal tumor which generally present for months to years before the patient seeks medical attention. Careful evaluation with early surgical removal and accurate histological diagnosis is must when managing patients with DPA as these can be aggressive and even result in metastasis..

Epidemiology, survival, and risk of subsequent primary malignancies in patients with digital papillary adenocarcinoma: a retrospective study of 213 patients in the Surveillance, Epidemiology, and End Results (SEER) Program.

Digital papillary adenocarcinoma (DPAc) is a rare, aggressive cutaneous malignancy of sweat gland derivation. Herein, we conduct a retrospective study of 213 DPAc patients using the 17 registries of the Surveillance, Epidemiology, and End Results (SEER) program. We estimate the incidence of DPAc to be 0.11 per million persons per year, with the incidence rising over the past two decades. Our study shows DPAc to most commonly afflict White males, typically in their 40s-60s. We note a 5-year disease-specific survival of 98.3% and 5-year overall survival of 95.7%. We also show advanced age to be associated with more aggressive disease and identify tumor size as an independent risk factor impacting disease-specific survival. Our results also suggest that patients with DPAc have an elevated risk of developing subsequent primary malignancies, with males being at increased risk of developing lung/bronchial neoplasms and females being at increased risk of developing breast cancer.

A rare tumour – metastatic digital papillary adenocarcinoma: literature review, clinical case of successful therapy

Digital papillary adenocarcinoma (DPA ) is a rare malignant neoplasm of sweat glands, which was first described by Helwig in 1979 and then classified by Kao in 1987. This disease most often occurs in men aged 50–70 years and is characterized by a relatively favorable prognosis. In most cases, radical excision of the tumor leads to cure. However, 14–47 % of patients develop distant metastases with predominant lung involvement (70 %). The study of etiology and pathogenesis of this rare cancer and its molecular genetic profile seems to be interesting. Currently, there is no clear approach to the treatment of metastatic DPA , but sporadic cases of using chemotherapy have been reported. Aim of the study: to analyze current data on the pathogenesis of DPA , diagnostic features and treatment methods used, as well as to present the first clinical case of treatment of disseminated digital carcinoma with immune checkpoint inhibitors described in scientific literature. Material and Methods. A search of available literature published in Medline, Pubmed, etc. databases from 1984 to 2023 was performed, 21 sources were included in this review. Clinical Case Description. We present a rare case of metastatic digital papillary carcinoma in a 23-year-old male with disease manifestation at the age of 14 years. Lack of vigilance and awareness of oncologists and morphologists did not allow timely diagnosis of malignancy, even in case of 3 local recurrences of the disease. Only biopsy of a metastatic lung nodule with histological and IHC examination (of archival and new material) made it possible to make a correct diagnosis. This case revealed 2 potential targets that could be used for disease control: androgen receptor positive expression and PD -L1 expression with CPS =20. The use of immune response checkpoint inhibitors (ipilimumab + nivolumab) resulted in partial response followed by stable disease.

Digital Papillary Adenocarcinoma: The Detection of Low-Risk Human Papillomaviruses and the BRAF p.V600E Mutation in a Subset of Cases.

Digital papillary adenocarcinoma (DPA) is a rare malignant neoplasm which arises from the sweat glands and has metastatic potential. DPA exhibits a wide range of architectural features and exhibits low-grade to high-grade features, so distinguishing DPA from benign skin neoplasms, including acral hidradenoma, poses significant diagnostic challenges. The recent literature suggests a strong association between DPA and human papillomavirus (HPV) 42, a low-risk HPV (LR-HPV) subtype, and a possible association between DPA and BRAF p.V600E. To explore these associations, we assessed the utility of in situ hybridization (ISH) for LR-HPV (types 6, 11, 40, 42, 43, 44) and immunohistochemistry (IHC) for BRAF p.V600E in diagnosing DPA and distinguishing DPA from acral hidradenoma. With institutional review board approval, we retrospectively identified 15 specimens of DPA (from 13 patients) and 3 cases of acral hidradenoma. Of the 13 DPA cases, 6 were negative for LR-HPV and BRAF p.V600E; 6 were positive for only LR-HPV; and 1 was positive for only BRAF p.V600E but negative for LR-HPV. All three cases of acral hidradenoma were negative for LR-HPV and BRAF p.V600E. As our sample size is limited, larger studies are needed to assess the value of detecting LR-HPV and BRAF p.V600E in the distinction of DPA and acral hidradenoma. However, our findings indicate a stronger association of DPA with LR-HPV than with BRAF p.V600E.

Ancillary immunohistochemical and molecular testing in the classification of cutaneous sweat gland/duct neoplasms: A validation study with emphasis on histomorphologic correlation and pathological diagnosis

Sweat gland neoplasms represent a challenging area of dermatopathology, as they are relatively uncommon and often histopathologically complex. Recent studies have uncovered distinct immunohistochemical and molecular profiles in several sweat gland neoplasms, including digital papillary adenocarcinoma (DPA), papillary eccrine adenoma/tubular apocrine adenoma (PEA/TAA), poroid family tumors (PFT)/porocarcinoma, and clear cell hidradenoma (CCH)/clear cell hidradenocarcinoma (CCHCa). To further evaluate the diagnostic utility of ancillary studies in various sweat gland neoplasms, we performed an independent validation study in a cohort of patients with acral and non-acral tumors (9 DPA, 8 PEA/TAA, 13 PFT, 5 porocarcinoma, 23 CCH, 7 CCHCa, 6 sweat gland carcinoma not otherwise specified). p63 immunohistochemistry (IHC) demonstrated a myoepithelial pattern in 8/8 DPA and 4 of 4 tested PEA/TAA cases, and showed a ductal pattern in all tested PFT/porocarcinoma and CCH/CCHCa cases (42/42). All PEA/TAA (8/8) cases were positive for BRAF V600E IHC. 5 of 12 tested PFT and 5/5 porocarcinoma cases showed either positive staining with NUT IHC or harbored YAP1::NUTM1 fusion gene by RNA sequencing. MAML2 fluorescence in situ hybridization (FISH) was positive in all CCH and CCHCa cases (23/23 and 7/7, respectively). Our results further support the usefulness of appropriate ancillary studies in precise classification of sweat gland tumors, which may be routinely applied in diagnostic pathology practice when morphologic evaluation is in doubt.

National epidemiology of digital papillary adenocarcinoma in England 2013-2020: a population-based registry study.

Digital papillary adenocarcinoma (DPA), formerly known as aggressive DPA, is a rare adnexal cancer of sweat gland differentiation with metastatic potential. DPA epidemiology and patient outcome data are a prerequisite to develop diagnostic and therapeutic guidance, which is lacking for this rare cancer. To report the incidence, patient demographics and treatment of patients with DPA in England from 1 January 2013 to 31 December 2020 using national cancer registry data. DPA diagnoses in England during 2013-2020 were identified from the National Cancer Registration Dataset using morphology and behaviour codes. These were registered from routinely collected pathology reports and cancer outcomes and services datasets. The 2013 European age-standardised incidence rates (EASRs) were calculated. In total, 36 DPA (7 in females and 29 in males) were diagnosed. The median age at diagnosis for the cohort was 54 years (interquartile range 46-64). The most frequently affected sites were upper limbs (81%). All patients in the cohort received surgical excisions. The European age-standardised incidence rate (EASRs) was 0.10 [95% confidence interval (CI) 0.07-0.14] per 1,000,000 person-years (PY)]. This study reports the incidence and variation of DPA in England between 2013 and 2020. DPA was more common in older men and predominantly affected the upper limbs. This supports the need to develop a national policy for the reporting and management of DPA as well as clinical guideline development.

Nectin-4 expression in a subset of cutaneous adnexal carcinomas: A potential target for therapy with enfortumab vedotin.

Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4 that is used to treat urothelial carcinoma. Nectin-4 is inherently expressed in the skin and adnexal structures. Since therapeutic options for cutaneous adnexal carcinomas are limited, we sought to evaluate Nectin-4 expression in adnexal carcinomas and benign adnexal neoplasms to identify tumors that are potentially targetable with EV. Eight sebaceous carcinomas (seven periocular and one lymph node metastasis), eight digital papillary adenocarcinomas, seven squamoid eccrine ductal carcinomas, eight poromas, eight trichilemmomas, and seven sebaceous adenomas were subjected to immunohistochemical staining for anti-Nectin-4 antibody. H-scores for Nectin-4 expression were calculated. Benign adnexal neoplasms had a significantly lower mean (±SD) Nectin-4 H-score (142.6 ± 39.1) than did the adnexal carcinomas (198 ± 90.8; p = 0.006). Nectin-4 was expressed in 91% (21/23) of adnexal carcinomas. Sebaceous carcinomas frequently exhibited high expression of Nectin-4 (88% [7/8]), with a mean (±SD) H-score (258.1 ± 58.4) significantly higher than those for digital papillary adenocarcinomas (197.5 ± 52.5; p = 0.035) and squamoid eccrine ductal carcinomas (131.4 ± 114.1; p = 0.031). Sebaceous carcinomas also had significantly higher H-scores than did sebaceous adenomas (186.4 ± 25.0; p = 0.013). Increased Nectin-4 expression in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, reveals that EV is a potential therapeutic option for these tumors.

NUT Expression Is of Diagnostic Utility in the Distinction of Digital Papillary Carcinoma From Poroid Hidradenoma.

The distinction between digital papillary adenocarcinoma (DPAC) and benign cutaneous adnexal tumors is clinically important and can be challenging. Poroid hidradenoma frequently occurs at acral sites and can show a number of histological features, which overlap with digital papillary adenocarcinoma. Recent work has shown that YAP1-NUTM1 fusions are frequent in poroid hidradenoma and are associated with nuclear protein in testis (NUT) expression by immunohistochemistry. We evaluated the expression of NUT-1 by immunohistochemistry in 4 cases of DPAC and 4 cases of poroid hidradenoma. Three of 4 cases of poroid hidradenoma showed strong NUT-1 expression, with no staining in any of the cases of DPAC. These results suggest that NUT-1 immunohistochemistry may be a useful additional tool in evaluating this differential diagnosis.

Digital Papillary Adenocarcinoma in Nonacral Skin: Clinicopathologic and Genetic Characterization of 5 Cases.

Digital papillary adenocarcinoma (DPA) is a rare sweat gland neoplasm that has exceptionally been reported outside acral locations. Recently, human papillomavirus 42 was identified as the main oncogenic driver of DPA. Herein, we report 5 tumors arising in extra-acral locations predominantly in the female anogenital skin. Four patients were female and 1 patient was male. The mean age at the diagnosis time was 65 years (range: 55 to 82y). Tumors were located on the vulva (n=3), perianal area (n=1), and forearm (n=1). Histologically, all tumors were lobular and mainly solid and composed of sheets of cells with rare focal papillae and frequent glandular structures in a "back-to-back" pattern and lined by atypical basophilic cells. Immunohistochemistry showed diffuse positivity for SOX10. Epithelial membrane antigen and carcinoembryonic antigen highlighted the luminal cells and staining for p63 and p40 revealed a consistent and continuous myoepithelial component around glandular structures. Follow-up was available in 3 cases (mean duration: 12mo [range: 8 to 16mo]). One patient developed local recurrence and 1 experienced regional lymph node metastases. HPV Capture Next-generation sequencing revealed the presence of the HPV42 genome in all samples. Viral reads distributions were compatible in the 5 cases with an episomal nature of the viral genome, with a recurrent deletion in the E1 and/or E2 open reading frames. In conclusion, this study demonstrates that digital DPA may rarely present in nonacral locations mainly in the female anogenital area, usually with a more solid pattern as compared with those cases presenting on the digits and it is also associated with HPV42.

Sweat Gland Tumors Arising on Acral Sites: A Molecular Survey.

Recurrent oncogenic drivers have been identified in a variety of sweat gland tumors. Recently, integration of human papillomavirus type 42 (HPV42) has been reported in digital papillary adenocarcinoma (DPA). The main objectives of the present study were (i) to provide an overview of the prevalence of previously identified oncogenic drivers in acral sweat gland tumors and (ii) to genetically characterize tumors in which no recurrent genetic alteration has been identified yet. Cases of acral sweat gland tumors were identified from the database of the French network CARADERM. After histologic review, the presence of previously identified genetic alterations was investigated in the entire cohort (n=79) using a combination of immunohistochemistry and targeted DNA and RNA sequencing. Tumor entities with no recurrent genetic alterations were submitted to whole-transcriptome sequencing. CRTC1::MAML2 fusion was identified in cases of hidradenoma and hidradenocarcinoma (n=9/12 and n=9/12). A p.V600E mutation of BRAF was observed in all cases of tubular adenoma (n=4). YAP1:MAML2 and YAP1::NUTM1 fusions were observed in poroid tumors (n=15/25). ETV6::NTRK3 and TRPS1::PLAG1 fusion transcripts were identified in secretory carcinoma (n=1/1) and cutaneous mixed tumors (n=3/4), respectively. The HPV42 genome was detected in most cases of DPA (n=10/11) and in 1 adnexal adenocarcinoma not otherwise specified. Finally, whole-transcriptome analysis revealed BRD3::NUTM1 or NSD3::NUTM1 fusions in 2 cases of NUT adnexal carcinoma and NCOA4::RET and CCDC6::RET fusion transcripts in 2 cystadenoma/hidrocystoma-like tumors. Our study confirms distinctive cytogenetic abnormalities in a wide number of acral adnexal neoplasms and supports the use of molecular analysis as a valuable aid in the diagnosis of these rare and often difficult to diagnose group of neoplasms.

DP24 A case of digital papillary adenocarcinoma linked to human papillomavirus-42

Abstract A 60-year-old man with known stage-4 non-small cell lung cancer (NSCLC) and previous right-thumb hidradenoma presented with a 5-month history of a growing vascular lesion on his right great toe. Histology revealed a digital papillary adenocarcinoma (DPA) and positive quantitative polymerase chain reaction (qPCR) for human papilloma virus (HPV)-42 (courtesy of Thomas Wiesner’s research team in Austria). Review of previous histology for the lung and thumb lesions showed histological features consistent with DPA. He re-presented after 2 years with metastatic DPA in his right posterior calf. Following wide local excision (WLE), this locally reoccurred, requiring further excision. Aside from chemotherapy for NSCLC, he was not immunosuppressed and had no history of HPV-related disease. Digital papillary adenocarcinoma is a rare and aggressive neoplasm of sweat glands. Despite being a low-grade tumour, the rates of metastases and reoccurrence are high. Distant metastases are common and can present years after initial presentation. Distant metastases without lymph node spread have been reported. The annual incidence in the USA is ~0.08 cases per 1 000 000, typically presenting in men aged 50–70 years as a solitary lesion on the digits. It can invade muscle, tendons and bone. Owing to its rarity, misdiagnosis and treatment delay are common (Kobayashi T, Hiura A, Oishi K et al. Aggressive digital papillary adenocarcinoma with multiple organ metastases: a case report and review of the literature. Am J Dermatopathol 2016; 38:910–14). Studies show a link between HPV-42 and DPA, with qPCR detecting HPV-42 in known DPA cases (HPV-42 negative in hidradenoma). Human papilloma virus-42 was previously unknown to be oncogenic, and HPV vaccines do not target HPV-42 (Leiendecker L, Neumann T, Jung PS et al. Human papillomavirus 42 drives digital papillary adenocarcinoma and elicits a germ cell-like program conserved in HPV-positive cancers. Cancer Discov 2022; 13:70–84). There are no clear management guidelines and no drug therapy for DPA. Case studies have shown chemotherapy to be ineffective. Management is surgical with either amputation or WLE to avoid reoccurrence or metastases (Leiendecker et al.). Clinical suspicion for DPA should be high given its aggressive nature with regular long-term follow-up to detect reoccurrence or metastases early. More research is required on the epidemiology of this rare tumour in the UK and Europe and on treatment strategy beyond surgical resection, targeting the link between HPV-42 and DPA.

Acral BRAF‐mutated tubular adenoma should be distinguished from HPV42‐related digital papillary adenocarcinoma

Acral <i>BRAF</i>‐mutated tubular adenoma should be distinguished from <scp>HPV42</scp>‐related digital papillary adenocarcinoma

Two distinct pathogenic pathways of digital papillary adenocarcinoma - BRAF mutation or low-risk HPV infection.

Digital papillary adenocarcinoma (DPA) is a rare neoplasm that can exhibit local recurrence and distant metastasis. We present a series of eight cases of DPA showing two distinct clinical presentations, morphologies, immunophenotypes, and molecular features. Four cases were characterized by painless, slow-growing nodules located on the digits. The lesions were small, well-defined, and confined in the dermis. Histopathologically, these tumors were composed of glandular structures lined by cuboidal epithelium with luminal papillary infoldings. Only rare mitotic figures and minimal squamoid differentiation were present, and cellular necrosis was absent. All four cases were positive for the BRAF V600E immunohistochemistry but negative for p16, low-risk and high-risk HPV in situ hybridization (ISH). In contrast, the remaining four cases were characterized by painful, rapidly growing masses on the digits. These four lesions were located in the deep dermis and consisted of a solid, tightly packed papillary architecture lined by atypical epithelioid cells with inconspicuous nucleoli. Cellular necrosis, numerous mitotic figures, and prominent squamoid differentiation were seen. All cases were negative for the BRAF V600E IHC. However, they showed strong, patchy to diffuse reactivity for p16 and were positive for low-risk HPV ISH and negative for high-risk HPV ISH. Our findings suggest that the current classification of DPA encompasses tumors that show two discrete pathogenic pathways - BRAF mutation or low-risk HPV infection. DPAs with low-risk HPV infection exhibit aggressive clinical features, high-grade morphology, marked squamoid differentiation, and wild-type BRAF. DPAs with BRAF V600E have less aggressive clinical features, low-grade morphologic findings, mild to absent squamoid differentiation, and negative HPV infection.

Regional recurrence of digital papillary carcinoma in ipsilateral axillary lymph nodes 12 years after digital amputation – a case report

Digital papillary adenocarcinoma (DPA) is a rare malignant adnexal tumour that affects 0.08 per 1,000,000 people/year.1 It often presents as a solitary painless mass in the digital extremities where eccrine sweat glands are abundant. It is reported to have a recurrence rate of 50% and 14% rate of metastasis.2 Due to its rarity and vague clinical presentation, it has frequently been misdiagnosed as a benign adnexal tumour, pyogenic granuloma and ganglion cyst. We report a rare case of regional recurrence of DPA in an ipsilateral axillary node of a 66- year-old male, 12 years after a right ring finger distal phalanx amputation.

Human Papillomavirus 42 Drives Digital Papillary Adenocarcinoma and Elicits a Germ Cell-like Program Conserved in HPV-Positive Cancers.

We identify HPV42 as a uniform driver of DPA and add a new member to the short list of tumorigenic viruses in humans. We discover that all oncogenic HPVs evoke a germ cell-like transcriptional program with important implications for detecting, diagnosing, and treating all HPV-driven cancers. See related commentary by Starrett et al., p. 17. This article is highlighted in the In This Issue feature, p. 1.

Association of HPV42 with digital papillary adenocarcinoma and the use of in situ hybridization for its distinction from acral hidradenoma and diagnosis at non-acral sites

AbstractDigital papillary adenocarcinoma (DPAC) is a rare tumor of sweat gland origin that preferentially affects the digits and has the potential to metastasize. Its tumor diagnosis can be difficult. Well-differentiated variants of DPAC can be confused with a benign sweat gland tumor, in particular nodular hidradenoma. With the recent detection of HPV42 DNA in DPAC by next-generation sequence analysis, we reasoned that this association could be used for diagnostic purposes. To this end, we performed in situ hybridization for HPV42 on 10 tumors diagnosed as DPAC as well as 30 sweat gland tumors of various histology types, including 8 acral hidradenomas. All DPAC were positive for HPV42. Positive hybridization signals for HPV42 were seen in both primary and metastatic DPACs. All other tumors and normal tissues were negative. This study confirms the association of HPV42 with the tumor cells of DPAC through in situ hybridization. The positive test result in all lesions of DPAC and lack of detection of HPV42 in any of the acral hidradenomas or other sweat gland tumors examined in this series is encouraging for the potential diagnostic utility of the assay. As documented by two scrotal tumors of DPAC, the in situ hybridization test for HPV42 can also help support the rare occurrence of this tumor at a non-acral site.

Defining Novel DNA Virus-Tumor Associations and Genomic Correlates Using Prospective Clinical Tumor/Normal Matched Sequencing Data

This study is the largest analysis of DNA viruses in solid tumors with associated genomics. To achieve this, a novel method for discovery of DNA viruses from matched tumor/normal next-generation sequencing samples was developed and validated. This method performed comparably to reference methods for the detection of high-risk (HR) human papilloma virus (HPV) (area under the receiver operating characteristic curve=0.953). After virus identification in 48,148 consecutives samples from 42,846 unique patients, novel virus tumor associations were established by segregating tumor types to determine whether each DNA virus was enriched in each of the tumor types compared with the remaining cohort. All firmly established solid tumor-virus associations (eg, HR HPV in cervical cancer) were confirmed, and the novel associations discovered included: human herpes virus 6 in neuroblastoma, human herpes virus 7 in esophagogastric cancer, and HPV42 in digital papillary adenocarcinoma. Theseassociations were confirmed in an independent validation cohort. HR HPV- and Epstein-Barr virus-associated tumors showed newly discovered genomic associations, including a lower tumor mutation burden. The study demonstrated the ability to study the role of DNA viruses in human cancer from clinical genomics data and established the largest cohort that can be utilized as a validation set for future discovery efforts.

A Case of Skin Metastasis of Digital Papillary Adenocarcinoma with Clinical Appearance of Hard Edema

A Case of Skin Metastasis of Digital Papillary Adenocarcinoma with Clinical Appearance of Hard Edema

Malignant Cutaneous Adnexal Tumors and Role of SLNB

Malignant cutaneous adnexal tumors (MCATs) are rare and their natural history is poorly understood. Available literature indicates aggressive behavior with a significant risk of metastasis. Retrospective review of our institutional surgical oncology databases was performed for patients diagnosed with MCATs (2001-2020). We hypothesized that most patients have a low risk of lymph node involvement, recurrence, and death. Kaplan-Meier statistical analysis was used to assess risk of recurrence and 5-year survival. We identified 41 patients diagnosed with MCATs (median age 59 years, 68% were men). Most patients had long-standing cutaneous lesions (median 24 months) and no palpable adenopathy. Most patients had stage I or II disease (98%). Primary tumors were treated with wide local excision (n= 28 [68%]), Mohs surgery (n= 5 [12%]), or amputation (n= 8 [19%]). Of 25 patients who underwent SLNB (61%), 1 had lymphatic metastasis. These include apocrine carcinoma (1 of 3), digital papillary adenocarcinoma (0 of 8), porocarcinoma (0 of 4), and additional MCAT sub-types (0 of 10). Three patients (7%) had disease recurrence at a median interval of 3.6 years (interquartile range 1.5 to 4.4 years). Five patients (12%) died at a median interval of 7 years (interquartile range 6.7 to 9.2 years), but only 1 patient was known to have succumbed to MCAT. Overall 5-year survival rate was 96% (95% CI, 75% to 99%). Despite the historical impression that MCATs have a high metastatic potential, most patients have low recurrence rates and excellent 5-year survival rates. Lymphatic disease identified after SLNB in early-stage tumors is rare and the value of this staging procedure in MCAT remains unclear.