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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 2  |  Page : 57-63

Leukemia cutis: A study from a tertiary care hospital in North India


1 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Hematopathology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission12-Mar-2020
Date of Decision06-May-2020
Date of Acceptance24-Oct-2020
Date of Web Publication22-Dec-2020

Correspondence Address:
Dr. Uma Nahar Saikia
Department of Histopathology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdpdd.ijdpdd_33_20

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  Abstract 


Background/Objectives: Only anecdotal case reports or small case series have attempted to study the histomorphology patterns of leukemic infiltration. This study explored the possible association of leukemia cutis with, temporal course of disease, subtypes of leukemia, blast count, total leukocyte count, lactate dehydrogenase (LDH) levels, and histopathological patterns. Materials and Methods: Clinical and laboratory data were retrieved from the hospital information system. Selected cases were reviewed by two pathologists. Data in terms of demographics, clinical presentation, bone marrow findings, immunophenotype, and temporal course were recorded where available. Results: Twenty-three diagnosed cases of leukemia cutis were reported during the study period. There was no gender predilection with a wide age range (8–82 years). No particular trend was noted in relation to total leukocyte or bone marrow blast count. Common skin manifestations included multiple erythematous papular eruptions, frequently involving the skin of the limbs. All cases showed a consistently high serum LDH level. 11/23 (48%) showed cutaneous manifestation of undiagnosed leukemia or indicated worsening in a diagnosed case. The histological patterns varied from perivascular to diffuse dermal interstitial infiltration. In addition, subtle changes were seen in the form of fibrosis, thrombosis, and epidermotropism in 12%–50% of cases. The judicious use of a panel of immunohistochemistry was vital to establish a diagnosis. Conclusions: Leukemia cutis is a diagnostic challenge on histopathology due to lack of any specific pattern in absence of a clinical suspicion. Its diagnosis may be an indicator of undiagnosed leukemia or worsening in an already known case of leukemia.

Keywords: Histology, immunophenotype, leukemia cutis, temporal profile


How to cite this article:
Madakshira MG, Bishnoi A, De D, Sachdeva MU, Saikia UN. Leukemia cutis: A study from a tertiary care hospital in North India. Indian J Dermatopathol Diagn Dermatol 2020;7:57-63

How to cite this URL:
Madakshira MG, Bishnoi A, De D, Sachdeva MU, Saikia UN. Leukemia cutis: A study from a tertiary care hospital in North India. Indian J Dermatopathol Diagn Dermatol [serial online] 2020 [cited 2021 Jan 16];7:57-63. Available from: https://www.ijdpdd.com/text.asp?2020/7/2/57/304335




  Introduction Top


Leukemia cutis is described as clinically visible skin lesions caused by skin infiltration of neoplastic leukocytes.[1] The neoplastic leukocytes can be myeloid or lymphoid in the lineage. Myeloid leukemia cutis is much more common and is also variously named as myeloid sarcoma, primary extramedullary leukemia, granulocytic sarcoma, or chloroma.[2] Being a rare condition, data on prevalence or incidence are lacking in the literature, with most studies giving the frequency with respect to a subgroup of leukemia.[1],[3],[4] The clinical presentation is varied from single to multiple lesions, which has been reported from all parts of the body including the face, chest, and limbs.[1],[5] The morphology of the skin lesions has been reported to be reddish to violaceous papules, nodules, or plaques.[3],[6],[7] The various types of leukemia known to present as leukemia cutis include acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia, and adult T-cell leukemia/lymphoma. Clonal hematopoietic disorders such as myelodysplastic syndromes have also been known to present as leukemia cutis. The prevalence of leukemia cutis has been reported to be 2%–3% in patients with underlying systemic leukemias.[8] Of the various types of leukemias, cutaneous involvement is most common in myeloid leukemias. The histopathology of these lesions has varied patterns from perivascular or periadnexal to diffuse dermal infiltration.[1],[9],[10] The cytomorphology of leukemic cells in conjunction with a judicious use of immunohistochemistry and a correlation with peripheral blood and/or bone marrow studies have been reported to be essential facets in arriving at the final diagnosis of leukemia cutis.[10] This study attempted to analyze a cross-section of histologically proven cases of leukemia cutis to draw any association between the temporal relationship of the disease, subtype of leukemia with the dermatological presentation, blast counts, lactate dehydrogenase (LDH) levels, and histopathological patterns.


  Materials and Methods Top


The retrospective cross-sectional study included all cases diagnosed as leukemia cutis on histology from 2015 to 2018. The records were retrieved from the hospital information system and the data in terms of demographics, clinical presentation, peripheral blood counts, bone marrow findings, immunophenotype, and LDH levels were tabulated where available. The respective skin biopsy was retrieved from the records and was reviewed by two dermatopathologists. The slides were reviewed to confirm the diagnosis and to record various patterns of cell infiltration, immunohistochemistry expression, and any additional significant histological features. A descriptive analysis of the collected data [Table 1] was carried out using Microsoft Excel Software.
Table 1: Frequency of cases as per diagnosis

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  Results Top


A total of 23 cases of leukemia cutis were diagnosed during the study period of 4 years. Among the subtypes, acute myeloid leukemia was the most common (14 cases), followed by chronic myeloid leukemia (6 cases) [Table 1]. The temporal profile of cases showed that 17 cases of cutaneous leukemia occurred during the course of systemic leukemia, 4 cases presented concurrently with systemic leukemia, whereas two cases – one of myeloid sarcoma and other of B-ALL presented as aleukemic leukemia without any bone marrow involvement at the time of cutaneous presentation [Table 2]. Among those cases having preceding systemic leukemia, the bone marrow was in remission in 12 cases. However, leukemia cutis was an indicator of underlying accelerated or blast crisis in a total of three cases and relapse in one case of acute promyelocytic leukemia and chronic myeloid leukemia each. The time period between the initial diagnosis of leukemia and skin lesions showed that the mean period of appearance of skin lesions was 2.75 months in cases where the bone marrow was in remission, whereas it was 6.8 months in cases where leukemia cutis was an indicator of relapse or crisis [Figure 1]. At the time of the skin biopsy, the total leukocyte count varied from 1100 to 66,900 per cubic millimeter [Table 3]. Similarly, the blast or promyelocyte percentage on bone marrow studies showed a wide variation from absent to as high as 90% [Table 3].
Table 2: Demographics, site and appearance of skin lesions, diagnosis, and temporal association

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Figure 1: Distribution of temporal profile of cases having a preceding diagnosis of systemic leukemia (Y axis-number of months)

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Table 3: Peripheral total leukocyte count, bone marrow blast count, and serum lactate dehydrogenase levels

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The cases were equally represented by males and females with 11 and 12 cases each [Table 1]. The age at diagnosis was spread from the first to eighth decade of life with a range of 9 to 82 years with a mean of 45 years [Table 2]. There was a good admixture of both single (10 cases, 43%) and multiple (13 cases, 57%) skin lesions in the study group [Table 2]. The most common morphology of skin lesions [Figure 2]a was erythematous papules (12 cases, 52%) [Figure 2]b, followed by nodules (8 cases, 38%) [Figure 2]c and ulcers (3 cases, 13%). The skin lesions had a predilection for the skin of limbs (9 cases), followed by trunk (5 cases) and abdomen (3 cases) [Table 2]. The serum LDH, in all cases, showed a consistent value of more than 200 units (normal range: 180 units per cubic milliliter) with the highest value being 1700 units [Figure 3] and [Table 3]. The histological patterns were tabulated following a review of the glass slides [Figure 4]. The most common pattern was subtle to diffuse perivascular and periadnexal infiltration, with rare instances of accompanying fibrosis, spongiosis, dermal vessel thrombus, epidermotropism, and ulceration [Figure 5]. Depending on the morphology and presence of an underlying history of leukemia, the immunohistochemistry panel varied from case to case [Figure 6]. However, they could be subtyped into four groups – myeloid (myeloperoxidase), monocytic (CD163 and CD68), blasts or primitive cell markers (CD117, CD34, and TdT), and specific lineage markers (CD3, CD20, and CD79a) [Table 4].
Figure 2: (a) Illustration of skin lesions in a case of leukemia cutis, (b) shows an erythematous papule and (c) shows a nodular lesion

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Figure 3: Distribution of serum lactate dehydrogenase levels in cases (blue line: mean value; black line: institutional cutoff value)

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Figure 4: Distribution of histopathological patterns

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Figure 5: Case 22, hematoxylin and eosin stained section shows diffuse dermal perivascular and periadnexal infiltrate (×4 magnification) (a); Case 13 hematoxylin and eosin stained sections show increased stromal fibrosis with insinuating neoplastic cells (×40 magnification) (b); and Case 15 hematoxylin and eosin stained section shows the involvement of panniculus by infiltrating cells with the presence of fibrin thrombi in the dermal artery (×20 magnification) (c)

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Figure 6: Case 22 hematoxylin and eosin stained section shows predominant blasts having open chromatin and prominent nucleoli and dense eosinophilic cytoplasm with accompanying eosinophils (×100 magnification) (a); immunohistochemistry with myeloperoxidase highlights the myeloid lineage of cells (b) and CD34 highlights the blasts among the myeloid cell population (c)

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Table 4: Immunohistochemical profile of skin lesions

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  Discussion Top


Leukemia cutis is defined as cuticular infiltration of the skin by neoplastic leukocytes, which results in clinically apparent skin lesions.[11] By this definition, all subtypes of leukemia have a probability of manifesting as leukemia cutis which include both myeloid and lymphoproliferative disorders.[1] We encountered a wide spectrum of cases which included various subtypes of acute myeloid leukemia (14 cases, 61%), chronic myeloid leukemia (6 cases, 26%), both B- and T-cell types of ALL (1 case, 4% each), and a single case of myeloid sarcoma (1 case, 4%). Among myeloid disorders manifesting as leukemia cutis, acute myeloid leukemia is more frequent as compared to chronic myeloid leukemia, occurring in about 10%–15% of patients.[5],[10],[12] According to the French–American–British subtype of acute myeloid leukemia, the myelomonocytic and monocytic subtype have a higher frequency of presenting as leukemia cutis with an incidence ranging from 3.7% to 15%.[1],[3],[13] Cutaneous infiltration by neoplastic cells in cases of ALL is rare having <1% incidence.[14],[15]

The temporal profile of skin lesions highlighted that the skin lesions were indicators of initial diagnosis in 26% of cases, whereas Kang et al. reported 17% of cases having been diagnosed with concurrent systemic leukemia.[5] However, deterioration of underlying systemic illness in the form of bone marrow relapse and acceleration or blast crisis was seen in 21% (5 cases). Similar cases in the literature have illustrated that leukemia cutis indeed may rarely be the initial manifestation of undiagnosed leukemia or portend a red herring in known cases of leukemia.[16],[17],[18],[19] Among the cases having a preceding diagnosis of systemic leukemia, Kang et al. reported a mean interval of 16.2 months before the development of leukemia cutis.[5] The index study further showed a delayed manifestation of leukemia cutis (mean 6.8 months) among those cases having an underlying relapse or crisis in the bone marrow, in comparison to cases where the bone marrow was in remission (mean 2.75 months). We had a case of myeloid sarcoma and one case of B-cell ALL with a lack of increase in blasts on a concurrent bone marrow examination and on follow-up for 16 and 18 months, respectively. Such cases of cutaneous involvement by acute leukemia in absence of an increase in blast count on bone marrow examination have been described as cases of aleukemic leukemia cutis.[20],[21]

The cases also showed a wide variation of peripheral blood leukocyte count and neoplastic cells in bone marrow at the time of presentation of leukemia cutis. This is in concurrence with previous studies which did not show any consistent association between the peripheral blood leukocyte count and blast counts in the bone marrow studies.[4],[5],[20] There was equal representation of both genders with a wide age range of 9 years to 82 years. There are no congruous clinical or demographic differences in patients with or without leukemia cutis with respect to gender or age in the literature.[5],[6],[12],[13],[22] A higher incidence of manifestation of leukemia cutis in children has been reported with 30% cases of congenital leukemia developing leukemia cutis.[1],[23] These infants have been described as cases of “Blueberry Muffins” who have a diffuse violaceous papulonodular rash.[24] However, no case of congenital leukemia was encountered in this series.

The clinical presentation included erythematous papular lesions (12 cases, 52%), followed by nodular lesions (7 cases, 30%). This is similar to published studies which have reported violaceous hemorrhagic papules or nodules as a common presentation of leukemia cutis.[5],[6],[12],[22] These lesions can, however, be variable during the course of disease.[16] The skin lesions were seen to affect all parts of the body, with the affliction for skin of extremities. Earlier case series have also shown a higher frequency of involvement of the legs and arms, followed by the chest.[1],[3],[5],[6],[22] Anecdotal reports have indicated a predilection of skin lesions at the site of previous inflammation, though it was not seen in our series.[25],[26] The serum LDH was consistently high which is indicative of high tumor cell burden, and similar observations have been reported previously as well.[1],[13] High serum LDH may be a subtle clue for leukemia cutis when differentiating these lesions from histomorphological mimics.[27]

We observed a wide variety of histopathological patterns in the present series with perivascular and periadnexal dermal infiltrate being most common, similar to previous literature.[1],[9],[10] There have been instances of increased stromal fibrosis as seen in 11 cases (48%) in our series, which has been reported with relative frequency previously.[1],[9],[28] Occasionally, epidermotropism, ulceration, dermal vessel thrombus, and subcutaneous involvement by clonal leukocytes were observed in the present series. Our study highlights the lack of a specific histopathological pattern for leukemia cutis making the diagnosis dependent on a high index of suspicion similar to previous studies.[9],[12],[13],[22],[28]

Immunohistochemistry remains an important adjunct in establishing the diagnosis and characterizing the lineage of neoplastic leukocytes. The most useful antibodies to identify the myeloid lineage were MPO (Myeloperoxidase), followed by CD117 in our series. This is similar to the results shown by Cronin et al., who in addition have described the use of the aberrant expression of T-cell marker CD43.[8] Primitive markers such as CD34 and TdT were useful to delineate the blasts and immature cells. In comparison to the reduced to absent expression of blasts in the series by Cronin et al., our series showed moderate to bright expression of the blasts in the skin biopsies.[8] Aberrant expression of CD34 in a subset of cells in cases of acute promyelocytic leukemia has been reported earlier.[29] The case of B-cell lymphoblastic leukemia demonstrated the utility of CD79a over CD20 as the favored B-cell marker because CD20 is not expressed in primitive B-cells.[30] CD68 and in particular CD163 are excellent markers of monocytic lineage, as shown in our series as well.[31] Although the panel of antibodies for immunohistochemistry on paraffin sections remains limited in contrast to those used for immunophenotyping by flow cytometry, it nevertheless helps in distinguishing it from the nonneoplastic inflammatory mimics.[10],[32]

The reason for homing of neoplastic cells to skin remains elusive, though the interaction of certain combined expressions of chemokine receptors in the skin microenvironment and their corresponding specific adhesion molecules on neoplastic leukocytes is suggested. The presence of activated lymphocyte function-associated antigen on T-cells, which helps to home onto and bind to Intercellular Adhesion Molecule-1 on endothelial cells of dermal capillaries is one of the mechanisms.[1] In cases of acute myeloid leukemia with leukemia cutis, there appears to be a role played by chemokine receptors of CXCR4, CCR5, CX3CR1, and CXCR7, which are seen to be preferentially expressed on the blasts homing onto the skin when compared to the blasts within the marrow.[33] Increased expression of matrix metalloproteinases (MMP) such as MMP-2 has been attributed to facilitate the migration in some myeloid leukemia.[34]

In summary, leukemia cutis remains a rare skin manifestation and myeloid disorders tend to present more frequently as leukemia cutis. It presents commonly as an erythematous papular rash over the skin of extremities and is associated with high serum LDH levels. Importantly, skin manifestation may herald the presence of an underlying undiagnosed leukemia or indicate a relapse or aggressive turn in a known case of leukemia. There is no specific histopathological pattern seen in leukemia cutis cases which may vary from subtle perivascular infiltration to dense pan-dermal and subcutaneous involvement. Hence, a high index of clinical suspicion and judicious use of immunohistochemistry markers is of paramount importance in establishing the diagnosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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