Polydactylous Squamous Cell Carcinoma of the Nail Unit: A Structured Review of the Literature.

Squamous cell carcinoma of the nail unit (SCCNU) is a rare neoplastic condition that involves multiple digits (polydactylous SCCNU) in only 3.9% of cases. Here, we report a case of polydactylous SCCNU and perform a comprehensive review of MEDLINE and Embase to collate 44 cases of polydactylous SCCNU reported to date. Polydactylous patients were younger on average (48 to 61-63 years) and had a longer diagnostic delay (44 vs 35.1 months) compared with reported monodactylous cases. Human papillomavirus (HPV) positivity was observed in 49% of cases, and the most common serotypes noted were 16 (25.8%), 73 (16.1%), 58 (9.7%), 18 (6.5%), and 33 (6.5%). Twenty percent of the cases were in immunosuppressed individuals who had a statistically significant lower age at diagnosis (39.33 years vs 51.12 years; P = .01) and diagnostic delay (2.50 months vs 132.46 months, P = .04). Patients with HPV positivity had a lower age at diagnosis (43.74 years vs 53.29 years, P = .04). Environmental exposures noted to be associated with polydactylous disease included X-rays, paint/solvents, soluble oils, and stagnant water. This comprehensive literature review serves to characterize polydactylous SCCNU and distinguish the differences in its characteristics to improve diagnosis and clinical recognition.

Nail changes in autoimmune blistering disorders: A case-control study.

BACKGROUND: Pemphigus and pemphigoid disorders produce blistering cutaneous lesions. Earlier case reports state that nail involvement is uncommon in these autoimmune blistering disorders. AIMS AND OBJECTIVES: To study nail changes in autoimmune blistering disorders. METHODS: A case-control study was conducted where 40 cases and 40 controls were evaluated for nail changes. RESULTS: Nail changes were seen in 72.5% of cases and 17.5% of controls. The most common nail findings were paronychia and onychorrhexis. LIMITATIONS: Small sample size; short study duration; nail biopsy could not be done. CONCLUSION: Our findings indicate that the inflammatory nature of the blistering cutaneous disease is often reflected conspicuously in the nails.

Nail unit squamous cell carcinoma in people with immunosuppression.

BACKGROUND: Nail unit squamous cell carcinoma (NUSCC) is uncommon and diagnosis is often initially incorrect or delayed. Immunosuppression appears important in the clinical behaviour of NUSCCs. OBJECTIVES: To highlight the frequency and nature of immunosuppression in a case series of patients with NUSCC, and identify the distinguishing characteristics in this subgroup. MATERIALS AND METHODS: Clinical, photographic and histological details were reviewed for all patients with NUSCC, over a 16-year period in a university dermatology department. RESULTS: Forty-three patients were identified and seven (16%) were immunosuppressed. Patients with immunosuppression presented at a younger age (mean 52 vs. 63 years, P = 0.08) and sooner (mean 9 vs. 65 months, P < 0.001) than immunocompetent patients, and had a higher frequency of polydactylous disease [four of seven (57%) vs. two of 36 (6%), P < 0.001], relapse at the same site [two of seven (29%) vs. 0], and recurrent disease at other sites [four of seven (57%) vs. 0]. CONCLUSIONS: Immunosuppression plays a role in the development and clinical behaviour of NUSCCs. Clinicians should have a low threshold for early biopsy of nail dystrophies, particularly in those with immunosuppression. These patients are at higher risk of relapse and recurrent disease and therefore require prolonged follow-up.

Superficial acral fibromyxoma: a clinicopathological and immunohistochemical analysis of 12 cases of a distinctive soft tissue tumor with a predilection for the fingers and toes.

AIM: Superficial acral fibromyxoma (SAFM) is a rare soft tissue tumor, recently delineated and documentated as a separate entity. We report 12 cases of SAFM observed in our department from June 2004 to June 2010 and highlight pathological features and differential diagnosis. METHODS: Radiographic examination of the affected digit was performed in all patients. All the tumors were surgically excised under local anesthesia. Follow-up was made every 6-8 months for a maximum period of five years. RESULTS: The patients consisted of 8 men and 4 women, age range 28-76 years (mean 51), presenting with a solitary mass or nodule located in the toes and fingers. Histologically the lesions were well circumscribed dermal nodules composed of stellate and spindle cells, arranged in a myxoid matrix. Very low grade atypia and a few mitotic figures were found in only one case. Neoplastic cells showed immunoreactivity for CD34 (12 patients). In contrast focally positive or negative staining was shown for the epithelial membrane antigen (EMA) and CD 99. Actin, S100 protein, HMB45 and cytokeratin were negative. In three cases marked hyperkeratosis and acanthosis of the epidermis was present. Pathological analysis confirmed the diagnosis of superficial acral fibromyxoma. No recurrences were observed even in a long term, 2-5 year follow-up. CONCLUSION: Complete surgical excision of the tumors and a careful follow-up is suggested, despite the benign course previously reported.

Evaluation of nail disease in psoriatic arthritis by using a modified nail psoriasis severity score index.

BACKGROUND: The Classification of Psoriatic Arthritis Study Group published new criteria for classifying psoriatic arthritis (PsA) which included nail psoriasis. Our aim was to clarify the clinical importance of nail disease in PsA patients. METHODS: We investigated the types and severity of nail disease by using the modified nail psoriasis severity score index (mNAPSI) in 23 PsA patients and 23 patients with uncomplicated psoriasis. We analyzed the relationships of mNAPSI with nail fold psoriasis, psoriasis area and severity index score, swollen and/or tender joint counts, distal interphalangeal (DIP) joint disease, acute phase reactants and the score on the Japanese version of the standard health assessment questionnaire. RESULTS: The mNAPSI in 23 PsA patients was higher than that of controls (4.8 ± 5.3 vs. 2.3 ± 3.7, P < 0.05). The severity of fingernail disease in PsA patients was significantly associated with DIP joint disease (8.6 ± 5.9 vs. 3.1 ± 3.3, P < 0.05) and nail fold psoriasis (6.7 ± 5.2 vs. 3.5 ± 5.2, P < 0.05). There were no correlations between the mNAPSI and other systemic involvements. CONCLUSIONS: The nail involvement and prolonged nail bed psoriasis were common in PsA patients. Nail fold psoriasis and DIP joint arthritis were associated with nail involvement in PsA patients. Nail psoriasis would be related to the Koebner phenomenon and local inflammatory DIP joint arthritis in PsA patients, and we suggested that nail involvement in PsA was among the disorders indicative of distal phalanx enthesitis.

Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease.

The traditional model for psoriasis and psoriatic arthritis (PsA) is that autoimmunity directed against a common skin and joint autoantigen leads to chronic autoreactive T cell driven inflammation. However, recent imaging, histological and genetic studies have challenged this view, especially with respect to joint and nail disease, and provide a broader insight into the pathogenesis of PsA and associated nail involvement. Clinically unrecognized enthesitis (inflammation at tendon and ligament attachments) is commonly seen in early PsA at all sites of the disease. Specifically, enthesitis is associated with adjacent osteitis or bone and synovial inflammation. Even in normal joints, normal insertions are associated with microdamage and inflammatory change, strongly suggesting that local tissue specific, or what has been described as autoinflammatory factors, may dictate disease expression. Distal interphalangeal (DIP) joint disease in PsA is associated with diffuse inflammation that envelops the nail root and adjacent bone. In fact, the nail is intimately linked to entheses, with the extension tendon of the DIP joint sending fibres from bone that envelop the nail root in an interdigitating fashion. Furthermore, the joint collateral ligament enthesis has fibres that merge with the lateral borders of the nail. Other anchorage mechanisms include fibres that directly tether the nail plate to the underlying periosteum, which itself is closely anchored to the extension tendon. The frequent microdamage and tissue repair at normal enthesis attachment sites in healthy joints has resulted in a proposed new model of PsA pathogenesis embracing the concept of autoinflammation, whereby tissue specific factors, including microtrauma, lead to regional innate immune activation and persistent inflammation, as an alternative to primary immunopathology driven by T and B cell abnormalities. Unlike the classical autoimmune diseases, which may attack a completely normal organ, autoimmunity in psoriatic disease is likely to involve tissues where there is intrinsic dysregulation of the target tissues. These tissue specific factors related to the enthesis appear to be key to the phenotypic expression of diseases hitherto regarded as autoimmune. The pathogenesis of PsA, nail disease and to a lesser extent psoriasis therefore appear to have an autoinflammatory (innate immune driven) rather than autoimmune basis. Taken together, these findings are important for better understanding PsA, nail disease and psoriasis, and for conceptualizing the immunopathogenic basis of these diseases and further exploring the role of enthesitis in their pathophysiology.

The pathogenesis of psoriatic arthritis and associated nail disease: not autoimmune after all?

PURPOSE OF REVIEW: Both psoriasis and psoriatic arthritis (PsA), and by implication psoriatic nail disease, have been considered as autoimmune disorders. This was based on the assumption that T-cell-directed responses against common skin and synovial antigens led to shared immunopathological mechanisms at these different sites, which was indirectly supported by the human leucocyte antigen-Cw6 disease association. This study draws on recent microanatomical and genetic studies of PsA, psoriasis and psoriatic-associated nail disease to show how the prevailing autoimmunity concepts for psoriatic disease need to be redrawn, especially in the case of joint and nail disease. RECENT FINDINGS: Recent microanatomical studies confirm that normal tendon and ligament insertion points to bone (entheses), the key territory for the inflammatory reaction associated with PsA, being subject to microdamage that strongly points to a role for microtrauma in the joints, which is reminiscent of Koebner responses in the skin. Furthermore, the nail is functionally integrated with entheses associated with the distal phalanx that provides anchorage to the skin and joint. Although type 1 psoriasis is strongly linked to the human leucocyte antigen-Cw6, recent genetic studies have suggested that both joint and nail disease do not share this association. SUMMARY: These microanatomical and genetic insights have important implications for a better understanding of PsA and nail disease and for an improved understanding of the psoriatic disease spectrum.

Solitary sclerotic fibroma of skin: a possible link with pleomorphic fibroma with immunophenotypic expression for O13 (CD99) and CD34.

BACKGROUND: Solitary sclerotic fibroma (SF) presents as a well circumscribed dermal nodule, composed of sparse spindle cells with alternating wavy collagen fibers arranged in a storiform pattern. The histogenesis and nature of this histologically distinct lesion are uncertain. Whether this peculiar tumor represents a true hamartoma or a degenerating end of various fibrous lesions such as pleomorphic fibroma (PF), dermatofibroma, or angiofibroma is still controversial. High proliferating index of spindle cells in SF argues against the possibility of being a degenerating end product of another lesion. METHODS: We studied morphological features and immunoprofile of eight SFs, in comparison with four PFs, one collagenized dermatofibroma, two angiofibromas, and two periungual fibromas. Immunostains for CD34, CD31, O13 (CD99), Factor XIIIa, S-100, CD68 (KP-1), and MIB-1 were carried out using a labeled streptavidin-biotin method with DAKO-automated immunostainer. Paraffin blocks of two SFs were reprocessed for electron microscopic studies. Clinical data of all patients with SF were also reviewed. RESULTS: Spindle cells and pleomorphic cells in SF and PF showed diffuse immunoreactivity for CD34 and O13 but were negative for CD31, S-100, and CD68. Spindle cells in one dermatofibroma and one angiofibroma were positive for Factor XIIIa. Proliferating index (MIB-1) was very low in all cases of SF, contradicting some previous reports. CONCLUSIONS: SF is a fibrotic lesion with cells positive for CD34 and O13. It shares a common immunoprofile with PF but is distinct from dermatofibroma and other common spindle cell lesions of skin. O13 expression in SF has not been previously described.

A lesson for unraveling complex aspects of novel immunodeficiencies from the human equivalent of the nude/SCID phenotype.

The human equivalent form of the severe combined congenital immunodeficiency of the nude/SCID mouse has been recently described in 2 siblings originating from a small community in southern Italy. Similar to the mouse, the human phenotype is characterized by a profound T cell ontogenetic defect associated with congenital alopecia and nail dystrophy. The disease is related in either mice and humans to molecular alterations of the gene encoding a forkhead/winged helix transcription factor, which is selectively expressed in thymic epithelia. Remarkably, due to the selectivity of the tissue expressivity of the gene responsible for the syndrome, this is the first example of SCID not primarily related to an hematopoietic cell abnormality, but rather to thymic aplasia. The opportunity to study immunological reconstitution in the absence of a functioning thymus following a bone marrow transplantation from a related HLA-identical sibling gave us insight into the role of the thymus in in vivo T cell ontogeny and maintenance of T cell functionality. This model led us to address a few general issues that may have clinical implications.

Spontaneous inflammatory disease in HLA-B27 transgenic mice is independent of MHC class II molecules: a direct role for B27 heavy chains and not B27-derived peptides.

Although association of HLA-B27 with human spondyloarthropathies has been known for several years, its role in disease pathogenesis is not understood. Recently, a few investigators have proposed that presentation of B27-derived peptides by MHC class II molecules may be the underlying mechanism. HLA-B27 transgenic rat and mouse models have provided a new tool for understanding the exact role of B27 in disease pathogenesis. HLA-B27 mice lacking endogenous beta2-microglobulin (B27+ beta2m(o)) develop disease after they are transferred from the barrier facility to the conventional colony. This model was utilized to test the hypothesis that B27-derived peptide presented by MHC class II molecules is the cause of the disease. The MHC class II knockout gene, A beta(o), was bred into our B27+ beta2m(o) mice, and disease manifestation was monitored. These mice develop spontaneous disease, demonstrating that MHC class II molecules do not play a major role in B27-related disease. Thus, the disease is not manifested by presentation of B27-derived peptides by class II molecules, since these mice are devoid of H2-A and H2-E molecules. Furthermore, in vivo treatment with mAb against the heavy chain of B27 reduced the incidence of disease in B27+ beta2m(o) mice. Our results clearly demonstrate that B27 heavy chains are directly involved in the disease process.

Congenital Alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs.

We report on two sisters affected by congenital alopecia, nail dystrophy, and a severe T-cell immunodeficiency, presumably inherited as an autosomal-recessive disorder. The T-cell defect was characterized by severe functional impairment, as shown by the lack of proliferative response and upregulation of activation markers following mitogen stimulation. The functional abnormality occurred in spite of the presence of phenotypically mature of the defect. This is the first observation reported on an ectodermal disorder, characterized by alopecia and nail dystrophy, observed at birth, in association with a primary immunodeficiency. The hypothesis that these two events may be casually related is discussed.

Association of high molecular weight melanoma-associated antigen expression in primary acral lentiginous melanoma lesions with poor prognosis.

In a recent study we detected marked differences in the antigenic profile of acral lentiginous melanoma (ALM) and nodular melanoma lesions. Furthermore, we showed that the human high molecular weight melanoma-associated antigen (HMW-MAA) is expressed with a significantly higher frequency in metastatic than in primary ALM lesions. Because of the potential role of HMW-MAA in the metastatic process of melanoma cells, in the present investigation we tested whether HMW-MAA represents a useful prognostic marker in ALM. Primary ALM lesions removed from 32 patients were stained with anti-HMW-MAA monoclonal antibody (mAb) in an immunoperoxidase reaction. The results were correlated with the expression of other markers defined by mAb, with clinical parameters of the disease, and with histopathological characteristics of the lesions. Only 9 of the 32 primary ALM lesions tested were stained by anti-HMW-MAA mAb. Expression of HMW-MAA was the only variable associated with patients' survival and disease-free survival. Both were significantly shorter in patients with HMW-MAA expression in their primary lesions. These results suggest that HMW-MAA may represent a novel prognostic marker in ALM, since phenotyping of primary ALM lesions with anti-HMW-MAA mAb may provide information about the prognosis of the disease which cannot be obtained with known prognostic parameters.

Trachyonychia associated with alopecia areata: a clinical and pathologic study.

Forty of 1095 patients (3.65%) with alopecia areata had severe nail changes that fulfilled the clinical criteria for the diagnosis of trachyonychia. Twelve of these patients had a nail biopsy. A mild to moderately dense lymphocytic infiltrate associated with exocytosis and spongiosis was detected in the proximal nailfold, nail matrix, nail bed, and hyponychium of 11 patients. One patient showed the pathologic changes of lichen planus; lichen planus of the skin developed 6 months after the nail biopsy. Immunohistochemical characterization on paraffin-embedded sections showed that the inflammatory infiltrate consisted of peripheral T lymphocytes. Immunophenotyping on frozen sections was performed in four cases. The results revealed a T4/T8 ratio of 2:1 and the presence of Langerhans cells in the nail matrix. Our results show that trachyonychia is an uncommon nail manifestation of alopecia areata. Distinctive pathologic features of mild to moderately dense lymphocytic infiltrate associated with exocytosis and spongiosis characterize trachyonychia as well as the other nail abnormalities caused by alopecia areata. The clinical association of trachyonychia with alopecia areata does not exclude that the nail abnormality can be due to other diseases such as lichen planus.

Immunofluorescence of the nail bed in pemphigoid.

A case of pemphigoid is described which is complicated by ulcerative colitis and a cicatrizing nail dystrophy. A longitudinal nail biopsy revealed linear deposits of C3 and IgM at the basement membrane zone. The relevance of these findings is discussed.