Introduction

There is a peculiar group of rare neoplasms which tend to occur in adults on the acral parts, in particular the fingers, toes and adjacent skin of the palms and soles, as an isolated solid or solid and cystic mass. Termed aggressive digital papillary adenoma or adenocarcinoma, this lesion presents as a tumefactive nodule on a digit and invades the adjacent soft tissue, but rarely ulcerates. Since the year 2000, the approach taken by pathologists to such neoplasms has undergone a radical change, reflecting novel publications in the peer-reviewed medical literature that in turn reflect the reported experience of national reference centers that deal with patients who develop these rare neoplasms.

Histopathology

The entity termed ‘aggressive digital papillary eccrine adenoma and adenocarcinoma’ first appeared in the English language medical literature in 1984.¹⁸³ Papillary eccrine neoplasms in other anatomic locations were recognized prior to their identification in digits and other acral parts.^{184, 185, 186, 187} The papillary digital eccrine adenomas and adenocarcinomas typically manifest features of eccrine differentiation by virtue of showing intracytoplasmic lumina and common luminal margins (Figures 15 and 16). The neoplasm is divergent morphologically from the typical eccrine spiradenoma or eccrine acrospiroma and other allied benign eccrine adnexal neoplasms by virtue of showing a papillary or micropapillary architecture cognate to that of in-situ papillary carcinomas of ductal structures of the human breast.^{186, 188, 189, 190, 191, 192, 193, 194, 195, 196} In particular, these neoplasms tend to manifest areas of micropapillary projections protruding into cystically dilated luminal spaces; these micropapillary structures lack fibrovascular cores. The micropapillae comprise tufts of banal or variably atypical low columnar epithelium, sometimes showing apocrine differentiation. This constellation of findings is reminiscent of the intraductal papillomas, atypical papillomas and papillary carcinomas seen in breast ducts. Such areas may merge to form complex sheets of cells associated with stromal invasion. A subset of digital papillary eccrine neoplasms is capable of provoking distant metastatic spread with significant patient morbidity and mortality. Predicting which of these digital eccrine neoplasms belong to the subset having a metastatic potential is extremely difficult. The so-called low-grade ‘aggressive digital papillary adenoma’ is distinguished from the ‘high-grade adenocarcinoma’ by virtue of the latter showing greater pleomorphism, mitoses and necrosis. Notwithstanding the foregoing, criteria distinguishing benign from malignant eccrine neoplasms have been elusive in the literature. Currently, all such digital eccrine papillary neoplasms are lumped together and are held to have a metastatic potential, albeit the said potential is apparently greater in the more floridly atypical and mitotically active forms. Thus, the term ‘aggressive digital papillary adenoma’ favored in an earlier era seems soon to be abandoned. Earlier textbooks in the discipline,¹⁹⁷ and some subspecialty textbooks of skin adnexal neoplasia,¹⁵¹ distinguish papillary eccrine adenoma of acral parts from malignant papillary eccrine tumors. In earlier works, most such neoplasms were held to represent adenomas¹⁵¹ lacking the capacity to generate distant metastases and/or mortality. However, even prior to 1990, it was recognized that ‘at least 40% of recurrent lesions have regional lymph node and/or pulmonary metastases’.¹⁵¹ The challenge of differentiating benign from malignant variants of these tumors is further clouded by the recognized capacity of histologically banal eccrine neoplasms to transform into cancers.¹⁹⁸ The concept of progressive transformation of benign to malignant proliferations of epithelial and other cell types has long been recognized in other tissues in humans and in animals. It is thus possible, indeed even likely, that some cases of otherwise indolent digital papillary eccrine adenoma undergo malignant transformation as well.

Figure 15.

Eccrine digital papillary adenocarcinoma. The low-power morphology of digital papillary eccrine carcinoma (a) is cognate to that of ductal carcinoma in situ of the breast. Within nests of neoplastic columnar epithelia are areas of confluent necrosis (b).

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Figure 16.

Eccrine digital papillary adenocarcinoma. The neoplastic columnar epithelia form papillary tufts and buds projecting into the dilated lumina of pre-existing eccrine structures. Due to the degree of cytologic atypia, a tumor with this architectural pattern in the breast would be considered an intermediate-grade cribriform/papillary carcinoma despite the abundant intraluminal necrosis.

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It is now recognized that histologic criteria do not reliably distinguish benign (adenoma) from malignant (adenocarcinoma) in acral digital papillary eccrine adnexal neoplasms.¹⁹⁹ Duke's paper specifically addresses and refutes the work of Kao et al,²⁰⁰ who felt that criteria existed to distinguish aggressive digital papillary adenoma from aggressive digital papillary adenocarcinoma histologically. In the hands of Kao et al, poor gland differentiation, necrosis, cytologic atypia, mitotic rates and invasion of soft tissue, bone or blood vessels were features that distinguished adenocarcinoma from adenoma. Despite the foregoing, the concept of papillary eccrine adenoma has persisted into the common era.^{201, 202, 203}

Management

Management of the aggressive digital papillary adenoma and adenocarcinoma remains a controversial issue, with some authors advising digital amputation.¹⁸⁰ In addition to high local recurrence, some 50% of tumors manifest distant metastases, typically to lungs and lymph nodes. As with acral melanomas, amputation at or above the nearest joint is one recommended strategy for local control.^{180, 181, 182} In part because of the rarity of these tumors, modern surgical approaches such as sentinel lymphadenectomy that are commonplace for melanomas are reportable as isolated cases when applied to the digital papillary eccrine tumors.^{204, 205} Currently, the use of aggressive local surgical extirpation is generally advised for any digital papillary eccrine neoplasm as the ‘originally proposed criteria for distinguishing benign (adenoma) and malignant (adenocarcinoma) do not necessarily predict biological behaviour’.²⁰⁵

Differential Diagnosis

Differential diagnostic considerations include the microcystic adnexal carcinoma, hidradenoma papilliferum, syringocystadenoma papilliferum and the nipple adenoma. Microcystic adnexal carcinoma shows thin vertically and haphazardly oriented columns of variably atypical epithelia surmounted by keratinizing microcysts with a granular cell lining internally. It therefore lacks the architectural organization of the papillary eccrine and apocrine neoplasms and also does not show apocrine differentiation. Stromal desmoplasia is frequent in the microcystic adnexal carcinoma and is not seen in the digital papillary neoplasms of benign character. In contrast, the digital papillary adenocarcinomas of increasing dedifferentiation show irregularly shaped and sized nests associated with pronounced stromal fibroplasia, in concert with abundant endolumenal necrosis, overt nuclear anaplasia and mitotic activity. These large tubulopapillary structures are thus strikingly different and simultaneously more cytologically atypical than the microcystic adnexal carcinoma, and should be easily distinguished even at scanning magnification. As mentioned above, they have more in common morphologically with in-situ ductal breast carcinoma than with the indolent or low-grade eccrine neoplasms. Hidradenoma papilliferum typically seen in areas of high apocrine gland concentration, such as the vulva, perineum and the axillae, exhibits large structures with a rounded peripheral contour containing papillary proliferations of apocrine epithelium lacking cytologic atypia, necrosis or mitotic activity. The syringocystadenoma typically opens to the epidermal surface, as seen in the setting of an underlying nevus sebaceus, and manifests banal apocrine epithelium admixed with cuboidal cells covering fibrovascular stromal cores which are rich in plasma cells. The nipple adenoma may also open to the epidermal surface to form the so-called ‘erosive adenoma’, and is morphologically similar to syringocystadenoma papilliferum. Furthermore, the hidradenoma papilliferum is confined, in the great majority of cases, to women. As mentioned above, the distinction of a benign eccrine papillary neoplasm from one with a metastatic potential is extremely difficult and, in the view of some authorities, impossible.