Primary rare anaplastic large cell lymphoma, ALK positive in small intestine: case report and review of the literature
Cao et al. Diagnostic Pathology
Primary rare anaplastic large cell lymphoma, ALK positive in small intestine: case report and review of the literature
Qinghua Cao 1 2
Fang Liu 2 4
Shurong Li 2 3
Ni Liu 1 2
Lihui Li 1 2
Changzhao Li 1 2
Tingsheng Peng 1 2
0 58 , Zhongshan Road II, Guangzhou 510080 , China
1 Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University
2 Abbreviations: ALCL , Anaplastic large cell lymphoma; CT, Computed tomography; DLBCL, Diffuse large B cell lymphoma; EATL, Enteropathy-associated T-cell lymphoma; EBER, Epstein-Barr virus (EBV)-encoded small RNA; GI, Gastrointestinal; HL, Hodgkin's lymphoma; IHC, Immunohistochemistry; ISH, In situ hybridization; MALT , Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue; NK/TL, NK/T-cell lymphoma; PBL , Plasmablastic Lymphoma; PTCL, NOS, peripheral T-cell lymphoma, not other specified
3 Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University , Guangzhou 510080 , China
4 Department of Oncology, Nanfang Hospital, Southern Medical University
5 1838 Guangzhou Dadao Bei Avenue , Guangzhou 510515 , China
Background: Primary anaplastic large cell lymphoma, ALK positive in small intestine is clinically rare and the clinical, radiological and pathological information are generally not available. Here, we report a case of 32-year-old male with ALK positive anaplastic large cell lymphoma at the junction of jejunum and ileum, and highlight the clinicopathological features and the differential diagnosis of this type lymphoma. Case presentation: The patient presented with right middle abdominal mass for 1 month with sporadic pain. Computed tomography (CT) showed a mass measured 8.5 × 7.4 × 4 cm at the junction of jejunum and ileum. The diagnosis was made after pathological examination of the excised tissue by enterectomy. Grossly, the mass was located predominately in intestinal wall with grayish appearance and blurry boundary. Microscopically, almost all layers of the intestinal wall were infiltrated by pleomorphic tumor cells with diffuse and cohesive growth pattern. The neoplastic cells were mainly medium to large size with moderate basophilic cytoplasm. Most of them had hyperchromatic nuclei and prominent nucleoli. “Hallmark” cells were easily detected. Immunohistochemically, tumor cells are characterized by CD30, ALK, CD5, TIA-1, Granzyme B, EMA positive staining, and CD2, CD3, CD7, CD4, CD8, CD20, CD79a negative staining. The Epstein-Barr virus encoded RNAs (EBERs) genome was also negative. A diagnosis as primary small intestinal ALK positive anaplastic large cell lymphoma was finally made. The patient received CHOP chemotherapy and is alive till now without recurrence 5 months after enterectomy. Conclusions: Primary small intestinal ALK positive anaplastic large cell lymphoma is rare. The accurate diagnosis should be based on combined consideration of clinical characteristics, CT image and pathological features, and should be distinguished from other lymphomas or solid tumors in small intestine.
Anaplastic large cell lymphoma; ALK positive; Small intestine
Anaplastic large cell lymphoma (ALCL) was first
identified by Stein et al. in 1985 . It belongs to peripheral
T-cell lymphoma characterized by large neoplastic cells
with abundant cytoplasm and eccentric horseshoe- or
kidney-shaped nuclei. According to the WHO
classification (4th Edition), primary systemic ALCL includes two
distinct entities: anaplastic lymphoma kinase (ALK)
positive and ALK negative . ALCL mostly affects
lymph nodes, with uncommon involvement of
extranodal sites including soft tissue, bone, lung and liver .
Cases of ALCL involving small intestine are therefore
very rare. So far, there are only a few case reports in the
literature [4–7]. Nevertheless, detailed clinical,
radiological and/or pathological information of these cases
are generally not available. Herein, we report a rare case
of primary ALK positive ALCL involving small intestine
accompanied with comprehensive clinicopathological
features and discussion of differential diagnosis.
A 32-year-old man presented with right middle
abdominal mass for 1 month and sporadic pain without fever,
nausea, vomit or diarrhea. The patient was admitted to
our hospital due to sudden severe pain in the abdomen.
Physical examinations showed no abnormality and there
was absence of palpable superficial lymphadenopathy. A
computed tomography (CT) scan showed a mass
measured 8.5 × 7.4 × 4 cm at the junction of jejunum and
ileum involving the adjacent intestinal wall and adipose
tissue (Fig. 1). The colon and rectum were not affected,
and there was no obvious involvement of the mesenteric
lymph nodes in the immediate vicinity. The liver and
spleen were also normal in CT image. There was no
obvious enlargement of the mediastinal lymph nodes by CT
scanning of thorax. Laboratory examinations revealed
negative results for tumor markers of digestive tract
including AFP, CEA, CA125, SCC and CA199. Blood
routine examination showed white blood cell count at 5.42 ×
109/L, the lymphocyte count at 1.5 × 109/L, the red cell
count at 5.33 × 1012/L, hemoglobin count at 142 g/L, and
the platelet count at 350 × 109/L respectively. All the
parameters of the peripheral blood cells were found in
normal range. After the final diagnosis as primary ALK
positive anaplastic large cell lymphoma, the patient
received CHOP chemotherapy and is alive till now without
recurrence 5 months after jejunectomy and ileectomy.
Material and methods‚ The specimen was fixed in a 10 %
neutral formalin solution and embedded in paraffin. A
4μm-thick section was stained with hematoxylin-eosin
(H&E) for routine microscopy. Immunohistochemical
(IHC) staining was performed using the EnVision
Detection System (DAKO, Denmark). Commercially available
Fig. 1 Computed tomography (CT) scan of an abdominal mass. CT
showed a mass involved small intestines measured 8.5 × 7.4 × 4 cm in
coronal view (a) sagittal view (b) and transverse section (c)
monoclonal antibodies were employed CD20 (Mouse
mAb(L26);1:200), CD79a (Mouse mAb;1:200), CD2 (Mouse
mAb(AB75);1:200), CD3ε (Mouse mAb (F7.2.38);1:200),
CD5 (Mouse mAb(CD5/54/F6);1:300), CD7 (Mouse mAb
(CBC. 37);1:200), CD4 (Mouse mAb(4B12);1:200), CD8
(Mouse mAb (C8/ 144B);1:200),CD30 (Mouse
mAb(BerH2);1:200), ALK (Mouse mAb (ALK1);1:200), Granzyme B
(Mouse mAb(GrB-7);1:400), EMA (Mouse
mAb(MC7);1:200), CD10 (Mouse mAb(SS2/36);1:200), Bcl-2 (Mouse
mAb(8C8); 1:500), Bcl-6 (Mouse mAb (PG-B6p);1:200),
MUM-1(Mouse mAb(Mumlp);1:200), CD38(Mouse
mAb (HIT2);1:200), CD138(Mouse mAb(MI15);1:200),
CD56(Mouse mAb(123C3);1:300), CyclinD1 (Mouse
mAb(DCS-6);1:200), CD21 (Mouse mAb(1 F8);1:200),
Kappa (Mouse mAb(R10-21-F3);1:400), Lambda (Mouse
mAb(N10/2);1:200) and Ki67 (Mouse mAb(MIB-1);1:200).
The primary antibodies of TIA-1(Mouse mAb
(2G9A10F5);1:200) were from Zhongshan company.
In situ hybridization (ISH) with Epstein-Barr virus
(EBV)-encoded small RNA (EBER) oligonucleotides was
used to test the specimens for the presence of EBV small
RNA in formalin-fixed, paraffin-embedded sections using
a hybridization kit (DAKO, Denmark).
Grossly, the mass is measured as 9 × 7.5 × 4 cm with
local invasion of small intestine. On the cut surface,
normal structures of intestinal wall were totally destroyed.
The mass was located predominately in intestinal wall
with grayish appearance and unclear boundary (Fig. 2).
Hemorrhage and necrosis were absent.
Microscopically, almost all layers of the intestinal wall
were infiltrated by pleomorphic tumor cells with diffuse
and cohesive proliferation pattern (Fig. 3a). The
neoplastic cells were mainly medium to large size with moderate
slightly basophilic cytoplasm. Most of them had
hyperchromatic nuclei and prominent nucleoli showing
immunoblastic and plasmablastic cell features. Hallmark
large cells with eccentric horseshoe- or kidney-shaped
nuclei often with an eosinophilic region near the
nucleus, were detected easily. Additionally, neoplastic cells
with mirror-image nuclei resembling Reed-Sternberg
cells were also identified (Fig. 3b, c). Mitotic cells were
Immunohistochemically, the neoplastic cells were ALK
positive with both nuclear and cytoplasm staining
(Fig. 3d). In addition, these cells are positive for CD30
(Fig. 3e), CD5 (Fig. 3f ), TIA-1 (Fig. 3i), Granzyme B and
EMA, whereas negative for all of others biomarkers
including CK, CD2, CD3, CD7, CD4 (Fig. 3g), CD8
(Fig. 3h), CD56, CD10, Bcl-6, Mum-1, Bcl-2, CD38,
CD138, Kappa, Lambda, CD21, and CyclinD1. The
proliferation index was approximately 80 % as assessed by
Ki-67 staining (Fig. 3j). In situ hybridization (ISH) for
EBERs study showed no positive signals.
Based on the above findings, this tumor was diagnosed
as anaplastic large cell lymphoma (ALCL), ALK positive.
Bone marrow biopsy revealed no tumor cells infiltration.
Primary gastrointestinal (GI) tract lymphoma is
uncommon and only accounts for 1–4 % of all GI malignances
. According to Dawson et al. , the diagnosis of GI
lymphoma should meet the following 5 criteria: (1)
absence of palpable superficial lymphadenopathy; (2) no
evidence of enlarged mediastinal lymph nodes; (3)
normal total and differential white blood cell counts; (4) a
predominance of bowel lesions at laparotomy with only
the lymph nodes obviously affected in the immediate
vicinity; (5) absence of tumor involvement of the liver
and spleen. Small intestine is the second most common
site affected by primary GI lymphoma which ranks after
stomach . Intestinal B-cell lymphomas occur more
frequently than T-cell lymphomas at the ratio of 6:1
. As reported, the most common subtype of primary
intestinal lymphoma is diffuse large B-cell lymphoma
and extra-nodal marginal zone lymphoma of
mucosaassociated lymphoid tissue (MALT lymphoma) [10–12].
Among the T-cell lymphomas of GI tract, peripheral
Tcell lymphomas (PTCL), enteropathy-associated T-cell
lymphoma (EATL) and NK/T-cell lymphoma (NK/TL)
are the common subtypes [12, 13]. In a retrospective
Korean study, 42 primary GI T-cell lymphomas were
assessed out of which 17 cases are located in small
intestine. Among the 17 small intestinal T-cell lymphomas,
Fig. 2 Macroscopic appearance of the intestinal mass (arrows). Cut surface showed normal structures of intestinal wall were totally destroyed. The
mass was located predominately in intestinal wall with grayish appearance and breezing boundary
Fig. 3 Microscopic features of the intestinal tumor. a The intestinal wall were infiltrated by pleomorphic tumor cells with sheet-like pattern
(HE × 40); b c The neoplastic cells were mainly medium to large size with moderate pale cytoplasm, hyperchromatic nuclei and prominent nucleoli.
“Hallmark” cells were easily found. Reed-Sternberg cell-like cell can be detected (HE × 400); d Tumor cell showed nuclear and cytoplasmic
staining for ALK; Tumor cells were positive for CD30 e CD5 f TIA-1 i negative for CD4 g CD8 h (Envision × 100); j Ki67 staining showed almost
80 % proliferation index (Envision × 100)
10 lesions (58.8 %) could be classified as EATL type II, 4
cases (23.5 %) as NK/TL, 2 cases (11.8 %) as PTCL, and
only 1 case (9.5 %) as ALCL . Another study from Japan
reported only 1 case of ALCL (6.7 %) among 15 intestinal
T-cell lymphomas in small intestine . Hence, ALCL
primarily occurred from small intestine is very rare.
According to WHO classification of tumors of
hematopoietic and lymphoid tissues (4th Edition), ALCL
was divided into ALK-positive and ALK-negative
subtypes based on expression of ALK or ALK gene
rearrangement . ALK/Nucleophosmin (NPM1) gene
fusion was the most common genetic alteration. In
addition, variant ALK rearrangement partners have been
recognized subsequently including TPM3, ATIC, and
TFG. Mechanistically, rearrangements of these genes
result in the up-regulation of ALK protein. Moreover, the
pattern of ALK immunostaining depends on different
types of genetic alterations [14, 15]. In this regard, ALK/
NPM1 fusion is characterized by both nucleus and
cytoplasm staining, whereas fusions of ALK with other
partners lead to diffuse cytoplasmic staining only .
Compared with ALK-negative ALCL, ALK positive
ALCL occurs more frequently in younger patients with
favorable outcomes [17, 18]. Most of the patients
diagnosed with ALK negative ALCL are reported to have
cutaneous, hepatic, or gastrointestinal lesions . In this
regard, Kim identified 4 ALK negative ALCL in GI tract
including 2 in duodenum, 1 in large intestine, and 1 in
small intestine . In another report by Carey MJ, only
3 ALK negative cases were found out of 4 small intes
tinal ALCL . Based on our observations and other
reports, it seems that ALK negative ALCL tends to invade
intestine. However, since the number of cases is very
small, a larger patient cohort is needed to make a solid
Moreover, diagnosis of intestinal ALCL should be
made after exclusion of other lymphomas which show
similar cell morphology and/or ALK positive staining.
The most important differential diagnosis was ALK
positive diffuse large B cell lymphoma (ALK positive
DLBCL), which was now considered as a distinct entity
[2, 19]. It was characterized by monomorphic large
plasmablast- or immunoblast-like cells with large central
nucleoli. It is histologically very close to ALCL and
metastatic carcinoma in lymph node at low
magnification because of its sinusoidal growth pattern. The
neoplastic cells often lack the expression of
lineageassociated leukocyte antigens as CD3, CD5, CD20, or
CD79a, but express ALK [2, 19, 20]. Therefore it could
lead to the diagnosis of ALCL “null cell” phenotype.
However, ALK positive DLBCL constantly lack the
expression of CD30 in immunohistochemistry, and
strongly express plasma cell markers such as CD138 and
CD38, which demonstrates the features of terminally
differentiated B-lineage origin of the tumor cells. Moreover,
unlike both the nucleus and cytoplasm staining in
ALCL, the staining of ALK in DLBCL exhibits granular
cytoplasmic staining indicating the CLTC/ALK fusion
protein [19, 20]. In the present case, besides ALK and
CD30 expression, the neoplastic cells were also positive
for T lymphocyte lineage markers as CD5, TIA-1, and
Granzyme B, while negative for CD20, CD79a, CD38,
CD138, suggesting the T-cell origin of these cells and
the diagnosis of ALK positive ALCL.
Plasmablastic Lymphoma (PBL) should also be
considered as one of the differential diagnosis because of the
morphology of the neoplastic cells mimicking
centroblastic and immunoblastic cells. The neoplastic cells of
plasmablastic lymphoma expressed markers
characterizing plasma cell phenotype including CD 138, CD38,
Vs38c either kappa or lambda light chain, and IRF4/
MUM1, whereas without the expression of T cell
phenotype. Although the neoplastic cells frequently expressed
EMA or CD30, they did not express ALK [2, 21].
Moreover, EBV EBER in situ hybridization is positive
in 60–75 % of the cases of PBL [2, 21]. Based on the
immunophenotype in this case, the diagnosis as PBL
was not correct.
Peripheral T-cell lymphoma, not other specified
(PTCL, NOS) deserves additional attention in terms of
differential diagnosis. It encompassed all mature T-cell
neoplasms lacking specific features that would allow its
categorization in any of the better-defined subtypes of
post-thymic T-cell lymphoma. In some cases, tumor
cells infiltrate lymphatic sinuses and consist of CD30
positive large cells predominantly, which result in
difficulty of distinguishing it from ALK negative ALCL. In
fact, diagnostic criteria for ALK negative ALCL are still
evolving, particularly in distinguishing it from other
CD30 positive PTCL, NOS [15, 22]. In ALK negative
ALCL, all tumor cells are positive for CD30, mainly on
the cell membrane and in the Golgi region. Particularly,
the staining of CD30 are strong and of equal intensity in
all the tumor cells [16, 23]. By contrast, CD30 staining
in PTCL, NOS is usually heterogeneous and
comparatively weaker than that in ALK negative ALCL .
Additionally, the diagnosis of ALK negative ALCL should be
reserved for cases with the morphology of ALCL
accompanied with a cytotoxic T-cell phenotype including TIA-1,
perforin and Granzyme B . Nevertheless, other
pathologists consider ALK negative ALCL as an anaplastic
variant of PTCL, NOS, in light of its poor prognosis and
partially overlapping phenotype [18, 25, 26].
In addition, ALCL occured in the GI tract must be
distinguished from enteropathy associated T-cell lymphoma
(EATL), type I, which is considered as a complication of
celiac disease (gluten-sensitive). In Type I EATL, the
cytological composition of tumor cells is varied, and
more polymorphous than Type II lymphomas [25, 27].
In this regard, ALK negative ALCL may closely resemble
CD30 positive EATL. However, unlike ALCL, usually
EATL is not positive for both EMA and ALK. In
addition, EATL is mainly CD8 positive rather than CD4
positive. Its association with celiac disease or villous
atrophy further distinguishes itself with ALK positive
ALCL [2, 28].
Since some of the tumor cells in ALCL resemble
classic Reed-Sternberg cells which are “hallmark” cells in
Hodgkin’s lymphoma (HL), differential diagnosis should
also include HL. Fortunately, it is not difficult to
differentiate HL from ALCL if it is ALK positive, but at times
it may be a challenge when it comes to ALK negative
ALCL. In this case, expression of EMA, clusterin, or
CD56 in tumor cells may help to support a diagnosis of
ALK negative ALCL, as the staining of these markers are
known to be absent in HL . Jaffe have suggested that
HL-like ALK negative ALCL should be diagnosed only
when tumor cell morphology closely resemble Hodgkin’s
lymphoma but immunohistochemical study show
characteristics of ALCL (positive staining for CD30, EMA,
CD3 but negative for EBV and B-cell markers) .
In addition to lymphatic tissue tumor, ALK
rearrangements can also be detected in other malignancies, including
inflammatory myofibroblastic tumors [30, 31], non-small
cell lung cancers , neuroblastomas  and embryonal
rhabdomyosarcomas . However, these malignancies
are readily distinguishable from ALCL is based on their
distinct morphology. Moreover, some specific
immunohistochemistry markers which were not known to be
expressed in ALCL but in the other malignancies can
support the diagnosis, including rhabdomyosarcoma markers
MyoD1 and Myogenine and non-small cell lung cancers
In general, we reported a rare case of primary intestinal
ALK positive large cell lymphoma and highlighted the
clinicopathological features and differential diagnosis.
The case reported a rare primary anaplastic large cell
lymphoma in small intestine. As intestine can be involved
by other types of lymphomas, the final diagnosis should
be made with the combination of clinical feature, PET-CT
image, pathological morphology, immunophenotype, and
genetic features. For this patient, the final diagnosis was
made as primary ALCL, ALK positive, stage IIIA.
Although the prognosis depends on the response to
chemotherapy, ALK positive may predicts a favorable prognosis
in this case.
Availability of data and materials
The data and materials are available to be shared.
TP and QC made the final diagnosis, QC and FL drafted the manuscript and
performed the literature review; TP contributed to concept, approved the
final version of the manuscript. SL contributed to radiological information.
NL carried out the immunohistochemical examination. LL collected the
clinical data. CL participated the revision of the manuscript. All authors read
and approved the final manuscript.
Consent for publication
Written informed consent was obtained from the patient’s for publication of
this case report and any accompanying images. A copy of the written
consent is available for review by the Editor-in-Chief of this journal.
Ethics approval and consent to participate
The authors declare that the data supporting the findings of this study are
available within the article. The manuscript was approved by the Ethics
Committee of The First Affiliated Hospital of Sun Yat-sen University.
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