ARTICLE
Auteur(s) : Hiroko Sugiyama1, Kenji Asagoe1,
Shin Morizane1, Takashi Oono1, Fusako
Okazaki2, Keiji Iwatsuki1
1Department of Dermatology, Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences:
2-5-1 Shikata-cho, Okayama 700-8558, Japan
2Department of Dermatology, Fukuyama City Hospital:
5-23-1 Zaou-cho, Fukuyama 721-8511, Japan
accepté le 6 Août 2007
Anaplastic large cell lymphoma (ALCL) is the second most common
group of cutaneous T-cell lymphomas (CTCLs), which is characterized
pathologically by the cohesive proliferation of large CD30-positive
cells, which tend to invade the peripheral sinus of regional lymph
nodes. ALCL is divided into two categories: primary systemic and
primary cutaneous ALCL. Based on previous criteria, primary
cutaneous lymphomas were defined as non-Hodgkin lymphomas
presenting in the skin, with no evidence of extracutaneous disease
at the time of diagnosis and within the first 6 months after
diagnosis, as assessed by appropriate staging procedures [1]. In
the current criteria, however, the term “primary cutaneous
lymphoma” has been used without the observation period [2].
Most patients with ALCL present with solitary or localized
nodules or tumors, and have a favorable prognosis [2]. In primary
cutaneous ALCL, the overlying epidermis of the tumor is often
ulcerated with epidermal hyperplasia or pseudocarcinomatous
hyperplasia (PCH) [3-6]. Patients with ALCL may present with
acquired ichthyosis, which is often associated with Hodgkin’s
lymphoma, characterized by the presence of CD30-positive neoplastic
cells [7, 8]. An unusual case of cutaneous ALCL associated with
marked epithelial hyperplasia mimicking keratoacanthoma, both
clinically and pathologically, has been described [9]. These
observations indicate that epithelial proliferation or epithelial
tumors are closely related to the occurrence of ALCL.
In addition to these epithelial changes, marked tissue and
peripheral neutrophilia have occasionally been reported in ALCL
[10, 11]. Under such conditions, the large atypical lymphoid cells
may be obscured by the massive infiltrate of eosinophils and
neutrophils. Because of the interference with epithelial
proliferation and neutrophilic infiltration, the diagnosis of ALCL
in these cases is challenging both clinically and
histologically.
Lymphocyte markers determined by immunostaining usually provide
beneficial diagnostic findings for lymphomas, but null cell-type
ALCL may lack almost all lymphocyte markers [12, 13]. In such
cases, only CD30 expression provides a clue to the diagnosis of
ALCL. We recently encountered a patient with cutaneous ALCL who had
been misdiagnosed with undifferentiated squamous cell carcinoma
because of the prominent PCH, the absence of LCA expression, and
the aggressive clinical behavior.
Case report
A 58-year-old man who underwent surgical removal of a rapidly
growing tumor on the nose was referred to our clinic for further
examination. In January 2006, a rice-sized papule appeared on the
left root of the nose and became enlarged. At the beginning of
February, he visited a nearby hospital and underwent a skin biopsy.
Within a month, the papule became a protruded, ulcerative tumor
with a broad pedicle (figure 1A). The tumor was
totally removed surgically, followed by skin grafting under a
tentative diagnosis of undifferentiated squamous cell carcinoma on
22 February, 2006. Since a subcutaneous tumor suggestive of
metastasis was detected in the left preauricular area in a
follow-up examination (figure 1B), the patient
was referred to us in May, 2006.
Laboratory test results revealed a white blood cell count of
7 600/μL, a red blood cell count of 4.65 ×
10 6/μL, and hemoglobin levels of 15.8 mg/dl. Blood
chemistry tests showed no abnormalities, including lactate
dehydrogenase and soluble interleukin 2 receptor levels. Computed
tomography (CT) revealed enlarged lymph nodes in the left
preauricular and cervical regions. The regional lymph nodes were
resected and processed for routine histopathological and
immunohistochemical examinations, together with the primary lesion
on the nose which had previously been removed.
In the primary skin lesion, epithelial cells proliferated to
form irregularly elongated, mesh-like structures adjacent to the
overlying epidermis (figure 2A). Many nests
composed of anaplastic large cells were present in the mesh-like
structures. Small neutrophilic abscesses were also present (figure 2B). A
screening immunostaining revealed that the proliferating epithelial
cells were positive for keratin, while anaplastic cells in the
nests were negative (figure 2C). Neither the
epithelial cells nor the anaplastic cells expressed LCA (CD45)
(figure 2D),
whereas small reactive lymphocytes were positive for LCA. In the
lymph nodes, large atypical cells, some of which had mirror-imaged
nuclei, were present in the peripheral sinus and T-zones in a
single cell or a grouping fashion (figure 3). These
histopathological findings suggested the possibility of ALCL, and
prompted us to examine the expression of lymphocyte markers,
including CD30 and epithelial membrane antigen (EMA), in primary
and metastatic lesions. The anaplastic large cells were positive
for CD30 (figure
4) and vimentin, and weakly positive for EMA. The following
markers were negative: CD3, CD4, CD8, CD15, CD20, CD25, granzyme B,
TIA-1, anaplastic lymphoma kinase (ALK), and Epstein-Barr
virus-encoded small nuclear RNA. Southern blot analysis
demonstrated a clonally rearranged band of T-cell receptor, gamma
chain gene. Based on these findings, we diagnosed the present case
as null cell-type ALCL with a T-cell lineage. A whole body CT scan
revealed no visceral or other nodal involvement. And a bone marrow
biopsy showed normocellular marrow without infiltration of lymphoma
cells.
Due to the rapid progression of the tumor growth and regional
lymph node metastasis, the patient was treated with a combined
chemotherapy, followed by autologous peripheral blood stem cell
transplantation. Although the patient had been in complete
remission for 4 months, new skin lesions recurred on the face. The
second line of polychemotherapy was performed successfully.
Discussion
Because of marked PCH, the lack of LCA expression, and rapid
progression, the accurate diagnosis of ALCL was delayed in the
present case. Monoclonal antibodies directed against LCA have been
proposed as a useful tool for differential diagnosis between
malignant lymphomas and poorly differentiated non hematopoietic
tumors. Some cases of ALCL, however, have been reported to lack LCA
expression [12, 13]. In the present case, anaplastic cells in the
primary skin tumor and metastatic lymph node lesions expressed CD30
antigens without any lymphocyte markers, and carried the clonal
rearrangement of T-cell receptor genes. These findings made it
possible to make a diagnosis of null cell-type ALCL with a T-cell
lineage. Our case indicates that a diagnosis of ALCL cannot be
excluded even when LCA expression is negative.
Previous reports have indicated that epithelial hyperplasia,
including its mild forms, can be observed in approximately 28-55%
of cases of ALCL [6]. As compared with previous cases showing
epithelial hyperplasia [3-6], the present case showed a more
prominent PCH which enclosed the islands of anaplastic cells. As a
result, a papillomatous, protruded skin tumor was present on the
face. Because of the clinical and histopathological findings,
together with a lack of LCA expression, the present case was
misdiagnosed as undifferentiated squamous cell carcinoma. Although
no clear explanations were made, previous reports have suggested
the involvement of epidermal growth factor (EGF) and transforming
growth factor-alpha (TGF-α) produced by ALCL cells and epidermal
expression of EGF, TGF-α and EGF receptor in the development of
epithelial hyperplasia [4]. But this hypothesis remains
controversial [6]. In addition to epithelial hyperplasia, acquired
ichthyosis is often associated with ALCL and Hodgkin’s lymphoma,
both of which are characterized by the presence of CD30-positive
neoplastic cells [7, 8]. These observations, therefore, suggest
that ALCL cells are capable of producing functional cytokines that
may alter epithelial hyperplasia and keratinization.
According to the WHO-EORTC classification proposed in 2005 [2],
our case can be classified as “primary cutaneous” ALCL, although
the clinical behavior was too aggressive for usual primary
cutaneous ALCL cases. When we adopt the former EORTC criteria [1],
the present case should be excluded from the “primary cutaneous”
category because lymph node metastasis occurred within 6 months of
diagnosis. We should, therefore, recognize that aggressive cases of
ALCL must be included in the new classification system, and that
the prognosis of primary cutaneous ALCL may not be as favorable as
previously evaluated.
Acknowledgments
Funding/Support: None. Financial Disclosures: The authors have no
relevant financial interest in this article. We would like to thank
medical students (H. Miyahara, M. Yoshida, T. Yabuuchi, A Yamamoto,
N. Morizane) in Okayama University for acquisition of clinical
data.
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