Enhancing diagnostic precision in psoriasis skin lesions: The role of ki-67 and a three-tier grading approach

INTRODUCTION

Psoriasis is a chronic immune-mediated inflammatory skin disorder with a multifactorial etiology involving genetic, immunological, and environmental factors. Clinically, it manifests as scaly, erythematous plaques commonly affecting the elbows, knees, scalp, and lower back. The most prevalent form is plaque psoriasis, while guttate, pustular, and erythrodermic variants are less common.^[1]

Histopathologically, psoriasis is characterized by marked keratinocyte hyperproliferation, parakeratosis, acanthosis, and a dense dermal inflammatory infiltrate.^[2,3] However, these features may also be seen in other non-psoriatic psoriasiform dermatoses (NPPD) such as lichen simplex chronicus, seborrheic dermatitis, pityriasis rubra pilaris, and certain drug reactions, leading to diagnostic overlap.^[4-6]

Due to these overlapping clinical and histological features, particularly in cases presenting with erythroderma or longstanding lesions, reliable diagnostic markers are essential. Ki-67, a nuclear protein expressed during active phases of the cell cycle, serves as a robust immunohistochemical (IHC) marker for cellular proliferation. Its expression in psoriasis is typically elevated and extends beyond the basal layer into the suprabasal epidermis, contrasting with the limited basal staining seen in other NPPD.^[7-10]

Several studies have demonstrated the diagnostic utility of Ki-67 IHC in distinguishing psoriasis from its mimickers.^[7,11,12] High Ki-67 labeling indices in psoriasis may aid in narrowing differential diagnoses when histological features alone are inconclusive. Although definitive cutoff values for Ki-67 expression remain to be standardized, its adjunctive role in dermatopathology is increasingly recognized.^[13,14]

This study evaluates Ki-67 expression in psoriasis and NPPD, correlating findings with histopathological patterns and inflammatory grading. The ultimate goal is to enhance diagnostic accuracy and contribute to establishing Ki-67 as a reliable marker in routine dermatopathological evaluation.

MATERIALS AND METHODS

This study was conducted over 1 year, incorporating retrospective data from 6 months and prospective data collected between February 2024 and June 2024.

RESULTS

The present study analyzed 32 skin biopsy samples, comprising 20 cases of psoriasis and 12 cases of NPPD. The psoriasis cases were diagnosed based on concordant clinical and histopathological features, while the NPPD group included cases with clinical suspicion of psoriasis that were histopathologically confirmed to be other conditions. All samples underwent evaluation using a standardized three-tier histological grading for key histological features, and Ki-67 immunohistochemistry was performed to assess cellular proliferation.

In the psoriasis group (n = 20), the most common clinical and histopathological subtype was chronic plaque psoriasis (75%, n = 15), followed by guttate psoriasis (15%, n = 3) and pustular psoriasis (10%, n = 2). In the NPPD group (n = 12), the most frequently encountered diagnosis was chronic dermatitis and allergic contact dermatitis (50%, n = 6), followed by lichen simplex chronicus (25%, n = 3), pityriasis rubra pilaris (16.7%, n = 2), and pityriasis lichenoides chronica (8.3%, n = 1).

Demographic analysis showed no statistically significant difference in age (P = 0.9375) or sex distribution (P = 0.5011) between the psoriasis and NPPD groups, indicating a comparable baseline demographic profile.

Histopathological examination revealed significant differences between the two groups. Confluent parakeratosis of Grade 3 was significantly more common in psoriasis cases (P = 0.022), whereas in NPPD, it was either absent or present in lower grades (Grade 1 or 2) and was typically focal. Regular acanthosis of Grade 3, characterized by uniform elongation of rete ridges across all HPF, was also significantly more frequent in psoriasis (P = 0.0173). Likewise, hypogranulosis or agranulosis was a consistent feature in psoriasis, predominantly observed as Grade 3, with a few cases showing Grade 2, and was significantly more common compared to NPPD (P = 0.0095). Minimal dermal inflammation was more frequently seen in psoriasis cases (P = 0.0325), whereas NPPD cases exhibited variable or more prominent inflammation depending on the specific diagnosis. In contrast, hyperkeratosis was seen in both groups and did not show a statistically significant difference (P = 0.3372), indicating that this feature alone is not helpful in distinguishing between the two conditions.

Ki-67 immunohistochemistry demonstrated notable differences in proliferative activity between the two groups. All 20 psoriasis cases showed positive Ki-67 staining, exhibiting >50-75% positivity in this study, reflecting high epidermal turnover. Among the NPPD group, 33% (n = 4) of the cases were negative for Ki-67, 50% (n = 6) showed positivity ≤50%, and only 16% (n = 2) exhibited >50% positivity, a difference that was statistically significant (P = 0.0173). However, the intensity of Ki-67 staining was not significantly different between the groups (P = 0.5809), suggesting that the extent of positivity rather than staining strength is diagnostically relevant [Table 3] for a comprehensive summary of the results.

DISCUSSION

The differentiation between psoriasis and NPPD remains a diagnostic challenge due to overlapping clinical and histopathological features such as hyperkeratosis, parakeratosis, agranulosis, regular acanthosis, and dermal inflammation. Features such as Munro’s microabscess and suprapapillary thinning are hallmark features of psoriasis, however due to their inconsistent presence in all cases, they were excluded from our grading parameters to maintain objectivity and reproducibility. Our study employed a three-tier histological grading for overlapping histopathological features alongside Ki-67 immunohistochemistry to enhance diagnostic accuracy.

Histopathologically, psoriasis cases exhibited significant features such as confluent parakeratosis, regular acanthosis, and hypogranulosis/agranulosis, predominantly graded as 3. These findings align with previous studies that emphasize these features as histologic hallmarks of psoriasis.^[15,16] In contrast, NPPD cases demonstrated focal or absent parakeratosis and irregular acanthosis, with variable grades, underscoring the heterogeneity within this group. Cesinaro et al.^[12] and Tortola et al.^[17] have documented similar differences between psoriasis and other psoriasiform disorders.^[12,17]

The Ki-67 proliferation index further distinguished the two groups. All psoriasis cases showed Ki-67 positivity, with 60% of the cases exhibiting >60% positivity, indicating heightened epidermal proliferation. Conversely, 33% of NPPD cases were Ki-67 negative, and a few cases had ≤50% positivity, and only 16% of cases showed >50% positivity. This statistically significant difference (P = 0.0173) corroborates findings from several earlier studies that reported markedly elevated Ki-67 expression in psoriasis compared to other dermatoses.^{[15,16,18,19]}

In our study, for example, one case of psoriasis vulgaris exhibited parakeratosis (Grade 3), agranulosis (Grade 3), regular acanthosis (Grade 2), and moderate dermal inflammation (Grade 2). Ki-67 immunohistochemistry revealed 60% positivity [Figure 1a-c].

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Figure 1:

(a) Hematoxylin and Eosin (H&E) at 10x, Low Power Field (LPF) - A case of psoriasis vulgaris. (b) H&E at 40x high-power field (HPF) -in psoriasis vulgaris showing parakeratosis (Grade 3), agranulosis (Grade 3), regular acanthosis (Grade 2), and moderate dermal inflammation (Grade 2) (c) Immunohistochemical at 40x, HPF, in psoriasis vulgaris Ki-67 showing 60% nuclear positivity.

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These findings are consistent with the known pathophysiology of psoriasis, which is characterized by rapid epidermal turnover and increased mitotic activity of basal keratinocytes.^[15,20] In contrast, many forms of NPPD, such as chronic spongiotic dermatitis and lichen simplex chronicus, exhibit variable or lower proliferative indices.^[21]. Ki-67, a nuclear protein expressed in all active phases of the cell cycle except G0, is a widely accepted marker of cellular proliferation and has been used as a differentiator in many dermatopathological studies.^[15,20]

Interestingly, in our study, a few NPPD cases with >50% Ki-67 positivity corresponded to lower histological grades (1-2) [Figure 2a-b], and another case of NPPD in our study showing Ki-67 positivity of 20% [Figure 3], suggesting that Ki-67 alone may not suffice for definitive diagnosis. Similar findings were observed by Sezer et al.^[15] and Abdelsalam et al.,^[7] who noted overlapping Ki-67 indices in some nonpsoriatic dermatoses.^[7,15,16] This observation emphasizes the necessity of integrating both histopathological grading and Ki-67 indices for accurate differentiation. Mizrak et al.^[9] and Kim et al.^[5] also advocated for the combined use of multiple histological and IHC parameters to improve diagnostic reliability.

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Figure 2:

(a) Hematoxylin and eosin (H&E) at 10x, lpf- a case of NPPD showing Grade 1 parakeratosis, agranulosis, irregular acanthosis, hyperkeratosis, and Grade 2 perivascular inflammation. (b) IHC at 40x, HPF Ki-67 - a case of non-psoriatic psoriasiform dermatoses showing 50% nuclear positivity.

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Figure 3:

Immunohistochemical, high-power field Ki-67 - another case of non-psoriatic psoriasiform dermatoses showing 20% nuclear positivity at 40x, high-power field.

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In addition to Ki-67, previous research has also explored adjunctive markers such as Cyclin D1, p53, Bcl-2, GLUT-1, and CD34 to aid in distinguishing psoriasis from its mimics.^{[15,16,19,21]} While our study focused on Ki-67, incorporating such markers in future investigations may further improve specificity.

Our demographic analysis revealed no significant differences in age or gender distribution between the two groups, consistent with existing literature that suggests these demographic factors do not markedly affect histopathological patterns or Ki-67 expression.^[16,18]

A few NPPD cases with >50% Ki-67 positivity corresponded to lower histological grades (1-2), suggesting that Ki-67 alone may not be sufficient for definitive diagnosis. This overlap underscores the limitations of relying solely on proliferation indices and highlights the necessity of integrating morphological assessment. Our study shows that a Ki-67 positivity threshold of >60%, when interpreted alongside structured histopathological grading, provides greater diagnostic reliability in distinguishing psoriasis from NPPD.

In particular, the combination of specific histological features, such as confluent parakeratosis, regular acanthosis, hypogranulosis, and minimal dermal inflammation, with Ki-67 expression exceeding 60% forms a robust diagnostic framework. While overlaps may still occur, especially in early or mild NPPD cases, the application of a standardized three-tier histological grading in conjunction with Ki-67 immunolabeling significantly enhances diagnostic precision.

Our findings reinforce the diagnostic value of integrating detailed histopathological criteria with Ki-67 immunostaining. This dual approach proves especially valuable in differentiating psoriasis from psoriasiform mimickers, where clinical and microscopic features may converge. The use of a structured grading system in our study ensures objectivity and reproducibility, while Ki-67 with a cutoff range of more than >60% provides an added layer of diagnostic support. Future research involving larger sample sizes and additional biomarkers such as cyclin D1 and GLUT-1 may further refine diagnostic algorithms and aid in optimizing patient management.^[15,16,21]

CONCLUSIONS

This study suggests that combining a structured three-tier histological grading with Ki-67 IHC positivity 60% or above may aid in improving the differentiation of psoriasis from NPPD. While Ki-67 supports the diagnosis of psoriasis, it cannot serve as a standalone marker for psoriasis. Integrating it with our structured histopathological grading improves diagnostic accuracy and reliability.