Mucocutaneous Manifestations of Leukemias and Lymphomas: A Clinical Study from a Tertiary Care Center in North India

Abstract

Background:

Mucocutaneous manifestations are common in hematological malignancies, but are generally misinterpreted. About two-thirds of the patients with hematological malignancies have mucocutaneous manifestations. Specific manifestations include leukemia cutis, leukemic vasculitis, and mucosal hyperplasia. Non-specific manifestations include reactive dermatoses, infective dermatoses, and miscellaneous manifestations. Mucocutaneous manifestations help in depicting the course and prognosis of hematological malignancies.

Aim and Objectives:

To determine the frequency and pattern of mucocutaneous manifestations in patients with leukemia and lymphoma, and to determine the degree of correlation between various mucocutaneous manifestations and the types of leukemias and lymphomas.

Patients and Methods:

This cross-sectional study was conducted in hematology and dermatology outpatient and inpatient departments in a tertiary care center in North India for 18 months. The study included 177 newly diagnosed leukemia and lymphoma patients who had not undergone chemotherapy.

Results:

Mucocutaneous manifestations were noted in 87.57% of patients, with specific manifestations in 5.08% (gingival hyperplasia = 3.39%, leukemic vasculitis = 1.13%, leukemia cutis = 0.56%) and non-specific manifestations in 87.01% (reactive dermatoses = 4.52%, infective dermatoses = 30.5%, miscellaneous = 76.27%). Acute myeloid leukemia (AML) showed the highest frequency (96.88%) of mucocutaneous involvement. AML was significantly associated with pallor (P value <0.001), thrombocytopenic purpura (P value <0.001), xerosis (P value = 0.023), and bacterial infections (P value = 0.028).

Limitations:

A small sample size and a cross-sectional design, that precluded the correlation between course of muco- cutaneous manifestations and disease progression.

Conclusion:

Mucocutaneous manifestations are common in acute leukemias, particularly myeloid lineage, due to bone-marrow suppression, immune dysregulation, and cutaneous spread. B-cell neoplasms show a higher propensity for skin involvement and paraneoplastic phenomena due to their aggressive nature compared to T-cell neoplasms.

Introduction

Skin is a crucial diagnostic tool for systemic diseases due to the accessibility for non-invasive clinical evaluation. Mucocutaneous manifestations can provide the first clue for diagnosing systemic malignancies, including leukemias and lymphomas, in some cases. Mucocutaneous manifestations have been observed in up to 40.3–75% of hematological malignancies like leukemias and lymphomas. Mucocutaneous manifestations of leukemias and lymphomas are broadly categorized as ‘specific manifestations’ and ‘non-specific manifestations’.[1,2]

Specific manifestations are the direct result of skin metastasis by the neoplastic cells. They present clinically as multiple infiltrated papules, plaques, nodules, and gum infiltration, with the incidence varying from 1.3%–20% in various studies. They are more commonly noted in acute myeloid leukemia (AML) patients. Specific manifestations are the markers of poor prognosis with a mortality rate of 41.17–88%.[2,3]

Non-specific manifestations (25–40%) are observed more frequently than specific eruptions. They may arise due to paraneoplastic phenomenon, indirect effects of bone marrow failure such as thrombocytopenic hemorrhage and opportunistic infections in neutropenic patients, chemotherapy- and radiotherapy-related adverse effects, graft-versus-host disease, etc. Other miscellaneous skin associations include acquired ichthyosis, reactions to insect bites, generalized pruritus, and drug rash. Cutaneous infections of various etiologies, including bacterial, viral, fungal, and parasitic, tend to assume an atypical clinical picture due to the individual’s immunosuppressed status resulting from bone marrow failure and ongoing chemotherapy administration.[2]

The dermatological findings are an important clue for hematological diagnosis if present early in the disease course and reliable prognostic markers if present late in the disease course. Thus, they should not be overlooked. Clinical and histopathological features of mucocutaneous lesions may correlate well with the systemic parameters apart from being an indicator of the invasive potential of the malignancy, thus enabling the correct staging process.

The current study aims to determine the pattern of mucocutaneous manifestations in the specified group so the knowledge gained can be applied to diagnose the early stages of leukemias and lymphomas. An attempt to establish the association between various mucocutaneous manifestations and the types of leukemias and lymphomas has also been made, which may aid in typification of the hematological malignancy. However, the latter requires more research and evidence for better substantiation.

Patients and Methods

This cross-sectional study was conducted in the departments of Dermatology and Haemato-Oncology for one and a half years, from November 2019 to May 2021 at Christian Medical College & Hospital, Ludhiana, after approval from the institutional research board and ethics committee (IEC, CMCL) vide letter no. IECCMCL/106692019 dated October 24, 2019. Based on sample size calculation, 177 patients presenting to the outpatient and inpatient departments with clinical diagnoses of leukemia and lymphoma who fulfilled the study eligibility criteria were enrolled after obtaining a signed informed consent. Parental consent was obtained for children less than 18 years, along with assent consent for children more than 7 years.

Inclusion Criteria:

• All newly diagnosed patients with leukemia or lymphoma.

Exclusion criteria:

• Leukemia and lymphoma patients who had received bone marrow transplants.

• Patients who were on chemotherapy.

• Solid organ malignancy.

• Patients who did not give an informed consent.

Baseline characteristics, demographic details, and specific details related to mucocutaneous complaints were documented. A detailed dermatological examination was conducted. Relevant investigations like potassium hydroxide (KOH) skin scraping, KOH nail clipping, skin biopsy, direct immunofluorescence, and immunohistochemistry, etc., were done, wherever indicated, to establish the diagnosis.

Statistical analysis

The data was entered in a Microsoft Excel sheet and analyzed using Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, ver. 21.0. Categorical variables were presented as numbers and percentages (%). Quantitative continuous data was presented as mean ± SD and median with 25^th and 75^th percentiles (interquartile range). The association between qualitative variables was calculated using Chi-square and Fisher’s exact tests, whichever was applicable. A ‘P’ value of <0.05 was considered significant.

Results

A total of 177 participants were observed during this study. The median age of the study participants was 44 years with a range of 0.75–88 years. The mean age was 44.17 ± 21.5 years. There was a male preponderance overall with a male-to-female ratio of 1.56:1.

Among the 177 participants, 134 (75.7%) patients had leukemia while 43 (24.3%) patients had lymphoma. AML was the most common neoplasm (36.16%) followed by acute lymphoid leukemia (ALL) (21.47%), non-Hodgkin’s lymphoma (NHL) (20.34%), chronic myeloid leukemia (CML) (8.48%), chronic lymphoid leukemia (CLL) (8.48%), and Hodgkin’s lymphoma (3.95%). There was one case each of aleukemic leukemia (AL) and juvenile myelomonocytic leukemia (JMML).

At the time of examination, 155 (87.57%) patients had at least one or more mucocutaneous manifestation/s. A total of 68 mucocutaneous manifestations were noted, with a mean of 1.53 dermatoses per patient. Specific mucocutaneous manifestations were noted in 9 (5.08%) and non-specific mucocutaneous manifestations were noted in 154 (87.01%) subjects [Table 1].

Table 1.

Mucocutaneous manifestations in the study subjects

Specific mucocutaneous manifestations
Mucocutaneous manifestation	Frequency*	Percentage
Gingival hyperplasia	6	3.39%
Leukemic vasculitis	2	1.13%
Leukemia cutis	1	0.56%
Non-specific mucocutaneous manifestations
Mucocutaneous manifestation	Frequency*	Percentage
1. Reactive dermatoses	8	4.52%
Sweet syndrome	3	1.69%
Erythema nodosum	2	1.13%
Erythema multiforme	1	0.56%
Pyoderma gangrenosum	1	0.56%
Paraneoplastic pemphigus	1	0.56%
2. Infective dermatoses	54	30.51%
A. Fungal infections	47	26.55%
Oral candidiasis	29	16.38%
Onychomycosis	21	11.86%
Dermatophyte infections	6	3.39%
Paronychia	4	2.26%
B. Bacterial infections	10	5.65%
Furunculosis	5	2.82%
Folliculitis	3	1.69%
Echthyma	2	1.13%
Abscess	1	0.56%
C. Viral infections	6	3.39%
Herpes simplex infection	5	2.82%
Herpes zoster	1	0.56%
D. Infestations	2	1.13%
Classical scabies	2	1.13%
3. Miscellaneous	135	76.27%
Pallor	82	46.33%
Nail findings	59	33.33%
Thrombocytopenic purpura	46	25.99%
Xerosis	29	16.38%
Seborrheic keratosis	6	3.39%
Cherry angioma	6	3.39%
Others**	-	-

*One patient can have one or more than one manifestation. **Other miscellaneous mucocutaneous manifestations observed were: papular urticaria (2.82%), cheilitis (2.82%), acne vulgaris (2.82%), dermatosis papulosa nigra (2.82%), post inflammatory hyperpigmentation (2.82%), seborrheic dermatitis (2.26%), hirsutism (2.26%), non-specific eruptions (2.26%), ichthyosis (2.26%), asteatotic dermatitis (2.26%), keratosis pilaris (2.26%), glossitis (1.69%), acneiform eruption (1.69%), lentigines (1.69%), prurigo nodularis (1.13%), pruritus (1.13%), stomatitis (1.13%), therapeutic scar (1.13%), venous eczema (1.13%), urticaria (1.13%), acanthosis nigricans (1.135), chronic eczema (1.13%), striae atrophicans (1.13%), lymphedema (1.13%), geographic tongue (0.56%), female pattern hair loss (0.56%), black hairy tongue (0.56%), purpura fulminans (0.56%), psoriasis (0.56%), atopic dermatitis (0.56%), vasculopathic ulcer (0.56%), palmar callosities (0.56%)

Specific mucocutaneous manifestations

Specific mucocutaneous manifestations including three dermatoses viz. leukemia cutis (0.56%), leukemic vasculitis (1.13%) [Figure 1 (a)], and gingival hyperplasia (3.39%) [Figure 1 (b)] were noted in 9 (5.08%) patients [Table 2]. The lesional morphology of specific cutaneous infiltrates varied from gingival hyperplasia to papules, plaques, and nodules. Histopathological examination of leukemia cutis (1 case) demonstrated lymphoid neoplastic cells encroaching upon the dermis and subcutaneous tissue. The focal areas showed foreign body macrophages against the blue background of neoplastic cells giving a ‘starry sky appearance’ [Figure 2]. Immunohistochemistry of the lymphoid neoplastic cells showed a positive staining pattern with markers such as CD-20, Bcl-2, c-Myc, and MUM-1 with 95% Ki67 proliferative index [Figure 3].

Figure 1.

Clinical presentation of specific leukemic infiltrates: (a) Leukemic vasculitis presenting as palpable purpura on bilateral lower limbs in acute myeloid leukemia (AML) patient, (b) Gingival hyperplasia in a patient with AML

Table 2.

Distribution of specific manifestations in the study subjects

Specific Manifestation	AML (n=64)	CLL (n=15)	NHL (n=36)	Total (n=177)
Gingival hyperplasia	5 (7.81%)	1 (6.67%)	0	6 (3.39%)
Leukemic vasculitis	2 (3.13%)	0	0	2 (1.13%)
Leukemia cutis	0	0	1 (2.78%)	1 (0.56%)
Total	7 (10.94%)	1 (6.67%)	1 (2.78%)	9 (5.08%)

AML – Acute myeloid leukemia, CLL – Chronic lymphocytic leukemia, NHL – Non-Hodgkin’s lymphoma

Figure 2.

A 88-year-old male with non-Hodgkin’s lymphoma developed indurated cutaneous nodules on chest area. Histopathology of the involved skin on: (a) 40× magnification (Hematoxylin and Eosin stain) shows sheets of lymphoid neoplastic cells with few scattered foreign body macrophages infiltrating into dermis and adipose tissue giving a typical ‘starry sky appearance’, suggestive of ‘leukemia cutis’, (b) 400× magnification (Hematoxylin and Eosin stain) shows neoplastic lymphoid cells with centroblastic morphology, vesicular 2-3 nucleoli, and scanty cytoplasm

Figure 3.

Immunohistochemistry of the lymphoid neoplastic cells in a diffuse large B-cell lymphoma patient with leukemia cutis (400× magnification) demonstrates positivity for markers such as MUM-1, CD-20, BCL-2, c-Myc with 95% Ki67 proliferative index

Non-specific mucocutaneous manifestations

Non-specific manifestations were noted in 154 (87.01%) subjects. They were further subdivided into reactive dermatoses (4.52%), infective dermatoses (30.5%), and miscellaneous manifestations (76.27%). A total of 65 dermatoses were observed under this category with five reactive, eleven infective, and forty-nine miscellaneous dermatoses. Sweet syndrome [Figures 4 and 5] and oral candidiasis were the most common reactive and infective manifestations, respectively. Both of them were more commonly observed in AML patients. Other miscellaneous non-specific manifestations have been listed in Table 1. Pallor and thrombocytopenic purpura were significantly associated with AML (P values were < 0.001).

Figure 4.

(a) A 73-year-old male with acute myeloid leukemia had multiple erythematous papules, plaques, and nodules on posterior neck and upper back, (b) Histopathology (Hematoxylin and Eosin stain) of the involved skin on low power (40× magnification) shows dense perivascular and interstitial inflammatory infiltrate in dermis, (c) High power (400×) magnification (Hematoxylin and Eosin stain) shows inflammatory infiltrate composed of neutrophils (blue arrow), lymphocytes (orange arrow), histiocytes (green arrow) and plasma cells (red arrow) in perivascular and interstitial dermis suggestive of ‘Sweet syndrome’

Figure 5.

(a) A 57 years old female with acute myeloid leukemia had erythematous plaques on upper limb, (b) Histopathology (Hematoxylin and Eosin stain) of the skin under low power (40× magnification) shows moderately dense perivascular infiltrate composed of lymphocytes and histiocytes, (c) High power (Hematoxylin and Eosin stain) (400×) shows perivascular neutrophilic infiltrate (red arrow) along with leucocytoclasia, suggestive of ‘Sweet syndrome’

Discussion

The mean age of our study participants was 44.17 ± 21.5 years. Aggarwal et al.[2] observed the mean age of leukemia patients to be 37.35 ± 14.6 years, which was comparable to our study. There was an overall male preponderance in our study with a male-to-female ratio of 1.56:1, similar to the results obtained by Merlo et al.,[4] (1.61:1) Aggarwal et al.,[2] (2.26:1) and Novak et al.[5] Asthana et al.[6] hypothesized a multifactorial etiology behind male predilection including gender bias in healthcare accessibility and hormonal, genetic, and environmental factors.

The most common neoplasm in our study was AML(36.16%). Other studies on mucocutaneous manifestations in hematological malignancies also observed AML to be the most common hematological neoplasm in their study groups. Dong et al.[7] conducted a statistical analysis to determine incidence trends in hematological malignancies, and concluded that leukemia cases continue to rise due to the increased availability of diagnostic facilities.

We observed mucocutaneous manifestations in 87.57% of patients. Various other studies on hematological malignancy patients showed dermatological manifestations ranging from 8.39% to 75%.[2,8,9,10,11] The incidence rose from 75% pre-chemotherapy to 92% post-chemotherapy in a study by Kumar et al.[8] Table 3 provides a comparative analysis of various mucocutaneous manifestations in patients with hematological malignancies.

Table 3.

Comparative analysis of various mucocutaneous manifestations in patients with hematological malignancies

Mucocutaneous Manifestations	The present study	Agggarwal et al.[2]	Haque et al.[10]	Pulido-Diaz et al.[11]
No. of patients with mucocutaneous manifestations	87.57%	40.3%	66.75%	42%
Specific manifestations	5.08%	3.06%	6.29%	5%
Non-specific manifestations	87.01%	37.2%	-	60%
Reactive dermatoses	4.52%	7.6%	-	-
Infective dermatoses	30.5%	26.5%	25.19%	33.33%
Miscellaneous	76.27%	-		-
Thrombocytopenic purpura	25.99%	-	13.38%	-
Ichthyosis	2.26%	-	14.96%	-
Pruritus	1.13%	-	18.11%	-
Prurigo	1.13%	-	6.29%	-

Specific infiltrates were noted to range from 0.29% to 8.6% in various other studies, similar to our study where 5.08% of patients had specific leukemic infiltrates. The morphological spectrum of specific mucocutaneous manifestations comprised of nodules, plaques, ulcers, purpura, papules, tumors, erythroderma, maculopapular rash, periorbital chloromas, macules, and gum infiltration in various other published studies.[2,9,10,11,12,13,14] We report a higher incidence of specific dermatological manifestations in the AML subgroup. Madakshira et al.[15] also noted a higher frequency of leukemia cutis in myeloid malignancies, especially AML, (61% of leukemia cutis cases had AML) due to preferential expression of certain chemokine receptors (CCR5, CXCR4, CXCR7, and CX3CR1) on myeloid blast cells along with increased matrix metalloproteinase-2 expression, which play a significant role in their skin homing process. In a study by Yaqoob et al.,[16] cutaneous infiltrates were noted in 8.26% of NHL subjects as against 2.78% in our study. It was hypothesized that the B-cell phenotype shows cutaneous invasion more commonly than the T-cell phenotype. Our findings correlate well with the given hypothesis, as we observed a diffuse large B-cell lymphoma patient with biopsy-proven leukemia cutis. The above observation could be due to the more aggressive nature of B-cell neoplasms with a higher tendency for cutaneous spread.

Non-specific manifestations (87.01%) were much more frequent than specific manifestations (5.08%) in our study. Yalcin et al.[17] and Haque et al.[10] reported non-specific dermatological manifestations in two-thirds of the patients, which correlates with our findings.

The reactive group of manifestations was more common in AML. This indicates the increased role of immunological dysfunction behind the reactive phenomenon seen in AML patients, as suggested by the findings of Aggarwal et al.[2] We observed a case of paraneoplastic pemphigus [Figures 6 and 7] in CLL. Silva et al.[18] and Didona et al.[19] observed that 38–42% and 18–29% of paraneoplastic pemphigus cases occur in patients with NHL and B-CLL, respectively. Cao et al.[20] reported an incidence of 0.71% for the same in CLL patients, which is lower than what has been observed by us (6.67%).

Figure 6.

A 67 years old male with chronic lymphoid leukemia had ‘polymorphous skin lesions’ including tense as well as flaccid purulent vesicles and bullae, erosions, crusting and few lichenoid plaques, clinically suggestive of paraneoplastic pemphigus. Severe haemorrhagic stomatitis with peculiar crusting involving vermillion border of lips was noted

Figure 7.

A chronic lymphoid leukemia patient with paraneoplastic pemphigus on histopathological examination of the involved skin: (a) Low power (40× magnification, Hematoxylin and Eosin stain) microscopy shows suprabasal split with ‘row of tombstone appearance’ of the basal layer, (b) High power (400×) microscopy shows blister cavity filled with acantholytic cells, lymphocytes, and histiocytes, (c) Direct immunofluorescence (400× magnification, fluorescein isothiocyanate anti-C3) shows C3 positivity (2+) at basal and intercellular level

Among infective manifestations, Zaman et al.[21] and Kumar et al.[8] reported oral candidiasis to be the most common infection in their studies, which is comparable to our findings. Aggarwal et al.[2] observed a higher frequency of bacterial infections. We observed a higher frequency of bacterial and fungal infections in the AML subgroup, whereas viral infections and parasitic infestations were mostly present in ALL patients. Aggarwal et al.[2] found a significant association between viral infections and ALL. A higher incidence of bacterial infections in myeloid neoplasms may occur due to defective phagocytic immune mechanisms. A higher incidence of viral infections in the lymphoid group suggests defective cell-mediated immunity in the latter. Zaman et al.[21] quoted that acute leukemias were more often associated with infective conditions considering the immunocompromised state following the cytopenic effects on immune cells in acute hematological malignancies. We observed 3 cases of atypical infections in the setting of hematological malignancy including one case of atypical oral herpes zoster with bilateral distribution, one case with cutaneous abscess, and one case with multiple furuncles. One of the above cases had concomitant specific cutaneous infiltrates invading the dermal vessels. The co-existence of specific cutaneous infiltrates and atypical manifestations of the infection is attributed to localized defective skin milieu due to leukemic infiltrates and generalised immunocompromised state collectively fostering the process of superinfection. There are a few case reports in the literature highlighting atypical infestations or infections in patients with concurrent leukemic infiltration of the skin.[21,22,23]

Miscellaneous manifestations were the most commonly noted manifestations in our study (76.27%) representing a broad spectrum of heterogeneous findings. This is in congruence with the findings of Kumar et al.[8] and Pulido-Díaz et al.[11] Pande et al.,[24] in their study, concluded that disorders of hemostasis constitute the majority of hematology-related skin findings, akin to our observations. Yalcin et al.[17] and Gebri et al.[13] concluded that non-specific mucocutaneous manifestations related to bone marrow failure are much more common in acute leukemias, particularly AML. We observed a higher frequency of generalized pruritus in Hodgkin’s lymphoma (14.29%). As described by Rubenstein et al.,[9] pruritus, prurigo, and eczema were common cutaneous symptoms in patients with Hodgkin’s lymphoma. Seshadri et al.[25] regarded the above cutaneous manifestations as paraneoplastic with the role of histamine, tumor metabolites, and other immune pathways in the pathogenesis of prurigo.

Limitations

A larger sample size would have allowed for better generalization of the study findings. Also, since it was a cross-sectional study, it neither recorded the course of mucocutaneous manifestations with respect to disease progression, nor did it correlate mucocutaneous findings with systemic parameters. Thus, further research on the nature and course of mucocutaneous manifestations with respect to the hematological malignancies would greatly aid in patient management.

Conclusion

Mucocutaneous manifestations, often non-specific, frequently occur in AML due to bone marrow suppression and immune dysregulation. Bacterial and fungal infections are more common in AML, while viral and parasitic infections are prevalent in ALL due to their distinct impacts on phagocytic and immune responses. Specific cutaneous manifestations, though less frequent, are notable in subgroups of AML and B-cell neoplasms, reflecting a higher tendency for skin involvement, and indicating poorer prognosis when present.

Ethics statement

The patients in this manuscript have given written informed consent to the publication of their case details.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)

We confirm that there was no use of AI-assisted technology in writing or editing of the manuscript. No images were manipulated using AI.

Funding Statement

Nil.