A Rare Case of Erythroderma in a Primary Cutaneous Anaplastic

Large Cell Lymphoma: A Diagnostic Challenge

Agung Mohamad Rheza

, Irene Dorthy Santoso

, Ika Anggraini

, Venessa Fikri

, Riesye Arisanty

Selviyanti Padma

, Sondang P. Sirait

Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia / dr. Cipto Mangunkusumo

National General Hospital, Jakarta

Department of Anatomic Pathology, Faculty of Medicine Universitas Indonesia / dr. Cipto Mangunkusumo National

General Hospital, Jakarta

Keywords: erythroderma, anaplastic large cell lymphoma, Hodgkin lymphoma, non-Hodgkin.

Abstract: Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin's lymphoma. It usually originates in

lymph nodes, although its origin in other tissues, including skin, has been reported. Identification of the

lymphoid activation antigen (CD30) has now clearly established the lymphoid origin of ALCL. Recent reports

suggest that in some cases cutaneous ALCL pre-existing skin disease may be a feature. This is usually mycosis

fungoides (MF), although psoriasis has also been reported. A diagnosis of ALCL is usually made by a

dermatologist following a series of diagnostic tests and procedures, including physical examination and

history, blood tests, skin biopsy and/or lymph node biopsy, immunophenotyping may also be done to identify

specific types of lymphoma. In selected cases, molecular tests may be helpful in establishing the diagnosis. A

fifty one years old man came with chief complaint of reddish, pruritic patch all over his body and nodules on

his right axilla and buttock. Two skin biopsies were collected, resulted a spongiotic psoriasiform hyperplasia

found in drug eruption and mixed cellularity Hodgkin lymphoma. Immunohistochemistry (IHC) shows

positive CD30 and CD43, Ki-67 on 80% of the cells and negative CD3, CD20, ALK, CD1a, CD15, PAX-5,

AE1/AE3 with conclusion of non-Hodgkin lymphoma - ALCL.

1 INTRODUCTION

Erythroderma is defined as a generalized redness and

scaling of the skin. However, it does not represent a

defined entity, as it is the clinical presentation of a

variety of diseases. Most commonly, erythroderma is

due to generalization of pre-existing dermatoses (such

as psoriasis or atopic dermatitis), drug reactions or

cutaneous T-cell lymphoma (CTCL). Attention

should also be focused on the potential systemic

complications of erythroderma including death. In

addition, long-lasting erythrodermas may be

accompanied by cachexia, diffuse alopecia,

palmoplantar keratoderma, nail dystrophy and

ectropion (Bolognia et al., 2012; Dento et al., 1992).

Primary cutaneous CD30

lymphoproliferative

disorders (PCLPD) are the second most common

group of CTCL, accounting for approximately 30% of

CTCLs after MF/Sézary syndrome (SS). This group

includes primary cutaneous anaplastic large cell

lymphoma (C-ALCL), lymphomatoid papulosis

(LyP), and borderline cases (Stein et al., 2000).CD30

ALCL itself is a rare form of non-Hodgkin lymphoma

(NHL), accounts for 2-3% of all NHLs and 10.2% of

all T/NK-cell lymphomas (Willemze et al., 2005;

Foss, 2013). ALCL may be classified according to the

location of the original tumor: primary nodal, primary

cutaneous, and secondary cutaneous. Primary nodal

ALCL describes disease arising in lymph nodes. It

typically occurs in children, runs an aggresive course,

and may spread to extranodal sites, including the skin,

lung, bone, and gastrointestinal tract. Primary C-

ALCL originates in the skin. In contrast to primary

nodal disease, it is most common in adults and is

indolent. It comprises one or more tumor nodules

exceeding 2 cm in diameter. Tumor nodules are often

purplish red and frequently become ulcerated. Most

common sites are trunk and extremities. Secondary

cutaneous ALCL arises in patients with underlying

CTCL, and like primary nodal disease is aggresive and

carries a poor prognosis. The cutaneous lesions of all

types of ALCL typically present as solitary or multiple

500

Rheza, A., Santoso, I., Anggraini, I., Fikri, V., Arisanty, R., Padma, S. and Sirait, S.

A Rare Case of Erythroderma in a Primary Cutaneous Anaplastic Large Cell Lymphoma: A Diagnostic Challenge.

DOI: 10.5220/0008160705000504

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 500-504

ISBN: 978-989-758-494-7

ulcerated nodules, and sometimes progressed to

erythoderma. Primary C-ALCL is classified as

malignant tumor, normally affects adults. The

majority of primary C-ALCL cases published in the

literature do not show spontaneous regression (Stein

et al., 2000; Willemze et al., 2005; Foss, 2013). There

are two types of ALCL, ALK (anaplastic lymphoma

kinase)-positive ALCL and ALK-negative ALCL.

ALK-negative ALCL is a mature T-cell lymphoma

with CD30 expression, morphologically identical to

ALK-positive ALCL but lacks the expression of ALK.

It represents 40-50% of all ALCLs, but occurs in older

population (male predominance, median age 58 years)

(Foss et al., 2013). In ALK-negative cases, one study

showed the frequencies of the T-cell antigen

expression were CD2 (100%), CD3 (50%), CD4

(40%), CD7 (40%), CD5 (25%), and CD8 (20%)

(Muzzafar et al., 2009). Other study noted the

expression of CD15 is aberrant, and a negative CD20

and PAX-5 (both are rarely positive in ALCL)

indicated a NHL (Pletneva & Smith, 2014).

The affected individuals present with

lymphadenopathy, and extranodal involvement is very

rare. Because C-ALCL and systemic forms are

morphologically and immunophenotypically identical

(and C-ALCL cen extend locoregionally to lymph

nodes), the clinical information is imperative to

distinguish between the two (Stein et al,. 2000). When

skin lesions are presenting manifestation of systemic

ALCL (S-ALCL), the distinction of skin lesions in S-

ALCL from CD30

PCLPD is imperative. The

distinctions between these two can be difficult on

purely clinical grounds and may be difficult as well to

achieve by routine histopathology. ALK protein is

expressed in skin lesions of most patients with S-

ALCL but not in the large majority of patients with

CD30

PCLPD (Foss et al., 2013).

The cytology of the tumor cells is identical to

ALK-positive ALCL but, in general, the tumor cells

tend to be larger and pleomorphic than its ALK-

positive counterpart. Histologic variants are not

strictly defined, but some cases resemble the

lymphohistiocytic variant and others the Hodgkin-like

forms. The background cells can include histiocytes,

plasma cells, eosinophils, and small lymphocytes

(Stein et al., 2000). Tumor cells in both LyP and C-

ALCL are derived from activated T-cells which

express CD30 antigen. The CD30

cells are larger than

normal lymphocytes and have basophilic cytoplasm

and large nuclei with a prominent nucleolus

resembling immunoblasts. These cells often are bi- or

multinucleated giving the appearance of Reed-

Sternberg cells. Mitoses are frequent and often

atypical. In C-ALCL, tumor cells form large clusters

or sheets that generally extend from the dermal-

epidermal junction down into the subcutaneous fatty

tissue (Foss, 2013).

Although there is accumulating evidence that

ALCL and Hodgkin disease (HD) are biologically

distinct, the morphologic and immunophenotypic

border between these disease categories is not sharp in

all instances. These ambiguous cases contain

relatively dense nodules or sheets of tumor cells with

features of classic Hodgkin and Reed-Sternberg cells.

One of the most difficult differential diagnoses of

primary cutaneous ALCL is large cell transformation

of MF which carries a worse prognosis. The large MF

cells occur in sheets and are usually CD30

, both

features shared with C-ALCL. The diagnosis of large

cell transformation of MF is generally made clinically

when there are accompanying patches and plaques

typical of MF. MF tumors with large cell

transformation often contain a spectrum of

lymphocytes with convoluted nuclei generally lacking

in primary cutaneous ALCL (Foss, 2013; Muzzafar et

al., 2009). ALK-positive ALCL usually has a better

prognosis (5-year survival of 70%) compared with

ALK-negative ALCL (5-year survival of 49%) (Foss,

2013; Pletneva et al., 2014).

2 CASE

A 51-year-old man admitted to our outpatient clinic

with chief complaint of reddish and pruritic, scaly

patch throughout his body which he started to

recognize initially on both thighs three years ago

without hospital admission. Having no improvement

with herbal medicine (mangosteen extract) for about

two years, and widespread of the patch, he went to the

local hospital later on. He was diagnosed as psoriasis,

and the dermatologist gave him moisturizer and

cetirizine but still no improvement. He was then

referred to Cipto Mangunkusumo National Hospital

because two nodules appeared on right buttock and

armpit, with the latter accompanied with purulent

wound. From physical examination (Figure 1), a scaly

erythematous patch spread all over his body along

with alopecia of the scalp, eyebrows, and eyelashes.

Fissures of the palms and soles, ectropion from both

eyes, were also found. On his right axilla, a single

tumor-presenting nodule covered with granulated,

purulent, and necrotic tissue. The tumor was tender,

ouval with 5 cm in diameter. The other one on his

right buttock was 4 cm in diameter and no pain on

palpation.

A Rare Case of Erythroderma in a Primary Cutaneous Anaplastic Large Cell Lymphoma: A Diagnostic Challenge

501

Figure 1. Patient clinically presenting with generalized erythroderma (A, B, C). Hair, eyebrows, eyelashes, mustache loss and

ectropion are also seen (D). Fissures on both palms (E). A tumor-presenting ulcerated nodule on right axilla (F)

Figure 2. (A) Skin biopsy showing infiltrate with large Hodgkin-like cells in a background of small lymphocytes. (B) Lymph

node from the same patient, showing thick bands of fibrosis mimicking classical Hodgkin lymphoma. (C) Section of the right

axilla lymph node showed mixed cellularity Hodgkin's disease. There was effacement of the normal architecture by a mixed

infiltrate comprising mononuclear Hodgkin's and bi-nuclear Reed-Sternberg cells, lymphocytes, plasma cells, eosinophils and

histiocytes. In some uninvolved lymphoid tissue, a marked histiocytic response was noted. Immunohistochemistry assay

shows: (D) diffuse CD3 in dermis, (E) CD30 highlights the tumor cells forming nodular aggregates divided by dense fibrosis

and variability in cell size of the tumor cells, (F) a more scattered image of CD20

The patient was diagnosed as erythroderma et

causa CTCL and tumor stage mycosis fungoides with

secondary infection, while waiting for the

confirmation from histologic findings and

immunohistochemistry assay. Ultrasonography test

was perfomed, with multiple lymphadenopathy were

found on both inguinal and axilla, confirming

systemic involvement, no intraabdominal

involvement, and a cystic mass at right gluteus. The

skin biopsies from two areas showed a spectrum of

drug eruption from erythrodermic area of upper right

arm, while the one from right axilla tumor showed

mixed cellularity Hodgkin's lymphoma. The

immunohistochemistry assay from right axilla tumor

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resulted the following: positive CD30, CD43, Ki-67

on 80% of the atypical cells, and negative CD20,

CD3, ALK, CD1a, CD15, PAX-5, and AE1/AE3

(Figure 2). These findings came to a conclusion of

non-Hodgkin lymphoma, ALK-negative ALCL.

3 DISCUSSION

Anaplastic large cell lymphoma is an uncommon

disease which comprises a number of heteregenous

conditions. The disease usually arises in lymph nodes

where these tumors morphologically resemble

histiocytic lymphoma. Lymphonodal ALCL is an

aggresive lymphoma with rapid extranodal spread

and poor prognosis and skin involvement estimated

occurs in 15% of cases. The clinical spectrum of

primary C-ALCL includes plaques, nodules, and

ulcerated tumours and inflammatory lesions.

The patient reported here had an unusual clinical

course with a 1-year prodrome of non-specific

erythroderma preceded by reddish, pruritic scaly

patch on both thighs two years before. Most cases of

primary C-ALCL arise in normal skin, though pre-

existing mycosis fungoides is well recognized. At

first we diagnosed the patient with MF because florid

erythroderma with marked ectropion clinically

suggestive of MF/SS, however, we still underwent

further investigations for confirmation of diagnosis

since a painful, ulcerated nodule appeared on his right

axilla.

Two biopsies were performed during the course

of the erythrodermic phase of the illness. The one

from the right arm showed a hyperkeratotic

epidermis, half parakeratotic, spongiotic psoriasiform

hyperplasia, exocytosis of lymphocytes, and basal

cells vacuolisation. Lymphoid inflammatory cells

were accumulated at dermal papila. At superficial

part of the dermis there were sparse infiltrate of

lymphocytes. These features concluded as a drug

eruption. Histological examination from the right

axilla nodule showed infiltration of the dermis by

atypical cells which were arranged in strands and

sheets, rough chromatin, noted pleomorphic, and

eosinophilic cytoplasm. Epidermis part were

hyperkeratotic, parakeratotic, achantotic with

granulated tissue. Reed-Sternberg cells were also

found. Mitotic cells easily found. These concluded as

a mixed cellularity Hodgkin lymphoma. We cannot

concluded drug eruption as the diagnosis since it did

not match with the patient's history and clinical

features. A result of Hodgkin lymphoma was

sometimes deceiving as it could also mimicking non-

Hodgkin lymphoma. Thus an immunohistochemistry

assay is needed to confirm the diagnosis.

Immunohistochemistry assay of this patient

showed positive findings of CD30, CD43, and Ki-67

at about 80% of the anaplastic cells. CD20, CD3,

ALK, CD1a, CD15, PAX-5, AE1/AE3 were negative.

A positive CD30 and negative ALK strongly suggest

that this patient suffer from ALCL, ALK-negative

type. Based on one study, the frequency of CD3 in

ALK-negative ALCL was 50%. Another study

showed expression of CD15 is aberrant, and a

negative CD20 and PAX-5 indicated a NHL. Thus we

concluded this patient is still well-accepted in an

ALCL ALK-negative spectrum, regarding negative

results of CD3, CD20, and PAX-5.

4 CONCLUSIONS

We report a very rare case of erythroderma originated

from C-ALCL. It is very challenging for us to

establish a diagnosis regarding confusing relation of

history, clinical, histopathologic, and

immunohistochemistry findings of the disease,

including a Hodgkin disease-mimicking feature of

NHL and various immunohistochemistry assay

results. ALCL itself is already a rare case in a

population and an erythroderma with a painful,

ulcerated nodule make it more laborious for

dermatologists and pathologists to establish a

diagnosis. This unusual case both expands the

spectrum of cutaneous disease associated with

erythrodermic ALCL and highlight the importance of

early biopsy and immunochemistry in patients with

erythroderma presentation.

REFERENCES

Bolognia, JL., Jorizzo, JL., Schaffer, JV., 2012.

Dermatology. 3rd ed. China: Elsevier. Chapter 10,

Erythroderma; p. 171-82

Denton, K., Wilson, C. L., & Venning, V. A., 1992.

Primary cutaneous anaplastic large‐cell

lymphoma with a prolonged erythrodermic

prodrome. British Journal of Dermatology, 126(3),

pp. 297-300.

Foss, F., 2013. T-cell lymphomas. New York: Humana

Press. Chapter 2. Epidemiology and prognosis of T-cell

lymphoma; p. 25-40.

Foss, F., 2013. T-cell lymphomas. New York: Humana

Press. Chapter 5. Primary cutaneous and systemic

CD30

T-cell lymphoproliferative disorders; p. 71-86.

Muzzafar, T., Wei, E. X., Lin, P., Medeiros, L. J., &

Jorgensen, J. L., 2009. Flow cytometric

immunophenotyping of anaplastic large cell

lymphoma. Archives of pathology & laboratory

medicine, 133(1), pp. 49-56.

Pletneva, M. A., & Smith, L. B., 2014. Anaplastic large cell

lymphoma: features presenting diagnostic

A Rare Case of Erythroderma in a Primary Cutaneous Anaplastic Large Cell Lymphoma: A Diagnostic Challenge

503

challenges. Archives of Pathology and Laboratory

Medicine, 138(10),pp. 1290-1294.

Stein, H., Foss, H. D., Dürkop, H., Marafioti, T., Delsol, G.,

Pulford, K., ... & Falini, B., 2000. CD30+ anaplastic

large cell lymphoma: a review of its histopathologic,

genetic, and clinical features. Blood, 96(12), pp. 3681-

3695.

Willemze, R., Jaffe, E. S., Burg, G., Cerroni, L., Berti, E.,

Swerdlow, S. H., ... & Grange, F., 2005. WHO-EORTC

classification for cutaneous

lymphomas. Blood, 105(10), pp. 3768-3785.

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