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2020, Volume 36, Number 2, Page(s) 173-177
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DOI: 10.5146/tjpath.2018.01446 |
Core Biopsy Diagnosis of ALK Positive Inflammatory Myofibroblastic Tumor of Lung: An Interesting Case |
Ritesh SACHDEV1, Ishani MOHAPATRA1, Shalini GOEL1, Kulbir AHLAWAT2, Neelam SHARMA3 |
1Department of Pathology, Lab Medicine and Transfusion Medicine, Medanta - The Medicity Hospital, SECTOR 38, GURGAON, INDIA
2Department of Radiology, Medanta - The Medicity Hospital, SECTOR 38, GURGAON, INDIA
3Department of Medical Oncology, Medanta - The Medicity Hospital, SECTOR 38, GURGAON, INDIA |
Keywords: Anaplastic lymphoma kinase, Inflammatory myofibroblastic tumor, Lung, Immunohistochemistry, Core needle biopsy |
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Inflammatory myofibroblastic tumor (IMT) of lung is a rare tumor, accounting for ~0.7% of all lung tumors with varied clinical and radiological
presentations. The origin of this tumor is unknown but some studies suggest that it might be a true neoplasm as some mutations on chromosome
2p23 of anaplastic lymphoma kinase (ALK) have been found to be related to this tumor. The morphology of IMT is quite vague and the
histopathological diagnosis is predominantly given on excision specimens; in fact, only 6.3% of cases are diagnosed based on analysis of biopsy
specimens alone. We illustrate a case of IMT diagnosed in a young male on core biopsy, where the case presented with a large tumor in the lung
with metastases to multiple sites that was hence unresectable. Post 3 months of treatment with Crizotinib, there was significant reduction in the
tumor size. Another interesting finding was that the ALK immunostain, which helped immensely in the diagnosis, was appreciated better on the
Ventana platform rather than on the Dako platform. |
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Inflammatory myofibroblastic tumor (IMT) of lung is a
rare tumor accounting for ~0.7% of all lung tumors. It has a
varied clinical and radiological presentation. Clinically, the
patients usually present with respiratory symptoms such as
cough, dyspnoea, fever, fatigue and haemoptysis. Rarely,
features of airway obstruction are seen. Radiologically,
this tumor can be cystic or homogeneous, endobronchial
or parenchymal, and with or without clear margins. The
origin of this tumor is unknown but some studies call it a
reactive process while a few of them suggest that it might be
a true neoplasm as some mutations on chromosome 2p23
of anaplastic lymphoma kinase (ALK) have been found to
be related to this tumor. The morphology of IMT is quite
vague and the histopathological diagnosis is predominantly
given on excision specimens; in fact, only 6.3% of cases are
diagnosed based on analysis of biopsy specimen alone 1-4. We hereby present a case of IMT in a young male with
features of airway obstruction, where the case had multiple
tumors involving the lung, mediastinum, liver and bone,
and was diagnosed on core biopsy from the lung at our
hospital. |
Top
Abstract
Introduction
Case Presentation
Disscussion
References
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A 31-year-old male came with complaints of dry cough,
breathlessness, weight loss and loss of appetite for the last 3
months. CECT (Contrast enhanced computed tomography)
chest was done at an outside facility and the differentials
considered were adenosquamous carcinoma, mesothelioma
or solitary fibrous tumor. Core biopsy was also done, and
a possibility of adenosquamous carcinoma was favored in
view of the clinical and radiological findings. Due to paucity
of tissue, immunohistochemistry (IHC) was not attempted.
The patient came to our institute for a second opinion and
treatment. On examination, the patient had pallor and a
performance status of 2. CECT chest and abdomen were
repeated and revealed a large heterogeneously enhancing
lesion which involved the right middle and lower lobe
and measuring approximately 12.9 (AP) x 11.9 (TR) x
9.6 (CC) cm with presence of coarse calcification (Figure
1). The lesion was closely abutting the right upper lobe
bronchus with involvement of the mediastinal pleura and
pericardium, and extending into the mediastinum. The fat
plane between the lesion and the liver were also effaced at
places with likely diaphragmatic and liver involvement.
The mass was impinging on the supero-posterior surface
of the liver (Figure 1). The lesion was seen closely abutting
the descending aorta, right atrium, inferior vena-cava,
right main pulmonary artery, right sided pulmonary veins,
left inferior pulmonary vein and left atrium (Figure 1).
There were multiple heterogeneously enhancing soft tissue
pleural and parenchymal lesions seen in both lung fields,
with the largest measuring approximately 4.2x2.3x1.9 cm.
There were multiple heterogeneously enhancing lymph
nodes seen in the pre-tracheal, para-tracheal and right
hilar regions, with the largest measuring 1.8x1.5 cm. The
liver measured 21.7 cm in its cranio-caudal extent with
ill-defined hypodense areas and peripheral enhancement
in segment VI. The CECT findings were suspicious for
malignant etiology with lung, liver, bony and mediastinal
nodal metastasis. Other investigations showed normal
renal and liver function tests, normal thyroid function
tests, non-reactive viral markers and normal coagulation
studies. On the basis of the clinical and radiological inputs,
a diagnosis of metastatic carcinoma involving the liver and
lymph nodes with primary from the lung was considered.
Complete blood count revealed anemia (Hemoglobin:
5.2g/dL), mild leukocytosis (14.02x103/cumm) and mild
thrombocytosis (717x103/cumm). Peripheral smear
showed no abnormal cells. Bone marrow examination
was also performed and showed a fair number of plasma cells with a polyclonal pattern of distribution. In view of
the above findings, serum protein electrophoresis was also
done and no “M” band was seen. Under CT guidance, a
core biopsy of right upper lobe lung nodule was done
under local anaesthesia using an 18G biopsy needle
(multiple cores measuring 1.0-1.7 cm). These core biopsies
showed proliferation of bland spindle cells (Figure 2A),
at places arranged in long fascicles, in an inflammatory
background consisting of many plasma cells with scattered
lymphocytes (Figure 2B-D). Native lung parenchyma was
seen within the lesion. The closest differential considered
was IgG4 related disease due to the bland nature of the
spindle cells in the background of plasma cells. Other
differentials such as leiomyosarcoma and mesothelioma
were also considered but were ruled out due to the bland
morphology and presence of inflammatory background.
On IHC, these spindle cells expressed ALK (Figure 2E, F)
and SMA (Figure 2K), whilst they were negative for desmin,
cytokeratin, CD117, S-100 (Figure 2G-J), CD21 and IgG4
immunostain. ALK immunostaining was done on the Dako
platform using monoclonal mouse anti-human CD246
antibody (clone ALK1) which showed focal positivity with
weak intensity (Figure 2F). ALK immunostain was then
also performed on the Ventana platform using monoclonal
rabbit anti-human CD246 antibody (clone D5F3), which
showed a higher proportion of cellular staining with higher intensity in the spindle cells (Figure 2E). A diagnosis of an
inflammatory myofibroblastic tumor (IMT) of the lung
was given. ALK gene re-arrangement by FISH (Florescent
in-situ hybridization) was attempted but yielded a noncontributory
result due to the exhaustion of the tissue block
after performing the immunohistochemistry.
Click Here to Zoom |
Figure 1: CECT chest and abdomen pre-treatment (A and C) and 3 months post treatment (B and D). A) Coronal view of the large
heterogeneously enhancing lesion which involved the right middle and lower lobe of the lung, impinging on the supero-posterior surface
of the liver. C) Axial view of the large mass involving the right middle and lower lobe of the lung with coarse calcification, involving the
mediastinal pleura and pericardium and extending into the mediastinum. B&D) Coronal and axial view showing reduction in the size
of the tumor. |
Click Here to Zoom |
Figure 2: A) Low magnification shows core biopsy with proliferation of bland spindle cells (H&E; x20). B-D) High magnification shows
different areas observed in the biopsy such as areas with predominance of lymphoplasmacytic infiltrate and spindle cells arranged in
long fascicles. (H&E; x40). E-F) IHC shows comparison of ALK immunostains, on both the Dako platform using monoclonal mouse
anti-human CD246 antibody (clone ALK1) which showed focal positivity with weak intensity (F; x40) and the Ventana platform using
monoclonal rabbit anti-human CD246 antibody (clone D5F3) reported as strong positive (E; x40). Spindle cells are negative for the
following: G)Desmin H) CK I) CD117 and J) S-100 (IHC; x40). K) SMA positivity in neoplastic cells (IHC; x40). |
Following diagnosis, the patient was started on Crizotinib
and has till date completed 3 months of therapy. CECT
findings on comparison with the previous scan reveal
interval reduction in the previously noted right lung mass
and multiple lung nodules, now measuring approximately
10.9 (AP) x 9.5 (TR) x 8.6 (CC) cm (previously measured
12.9 (AP) x 11.9 (TR) x 9.6 (CC) cm) (Figure 1). |
Top
Abstract
Introduction
Case Presentation
Disscussion
References
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Inflammatory Myofibroblastic Tumor (IMT), previously
called inflammatory pseudotumor, plasma cell granuloma,
histiocytoma or fibroxanthoma, was first described in
the lung in 1939. The lung being the primary site, it has
also been described in other extra pulmonary sites such
as the spleen, lymph nodes, esophagus, stomach, salivary
glands, breast, epididymis, central nervous system, and soft
tissues 1. Matsubara et al. used the term inflammatory
pseudotumor and described three subgroups depending on
the cell type encountered in a mass: organizing pneumonia,
fibrous histiocytoma, and lymphoplasmocytic type. In all
three types, an intra-alveolar organizing inflammation was observed and they hypothesized that an inflammatory
pseudotumor probably originates from an organizing
pneumonia. 2. In 1990, the term IMT was used based on
the morphology and the immunohistochemical features
of the spindle cells in these lesions resembling those of
myofibroblasts. Most reports suggested an inflammatory or
infective pathogenesis (~30% of cases are associated with
respiratory infections) with an exaggerated response to
tissue damage and subsequently pseudotumor formation.
There were reports that suggested a true neoplastic nature
with clonal chromosomal changes in chromosome 2. These
changes are found in region 2p23 with activation of the
ALK gene proving that at least a few IMT’s were indeed
true neoplasms rather than reactive processes 1,3,4.
IMT shows a slight predominance in children and young
adults, as seen in our case 1. Usually the patients present
with nonspecific symptoms such as cough, dyspnea,
hemoptysis, chest pain, fever and fatigue. Weight loss and
anorexia are rare 1. However, the present case had both
weight loss and loss of appetite along with respiratory
symptoms and airway obstruction, suggesting the spread
of the disease. Radiologically, the tumor has varied
presentations ranging from a single nodule to multiple
nodules (rare) either limited to the lung or rarely involving
the pleura, diaphragm, mediastinum or liver. On CT scan,
the tumor had a heterogeneous appearance with solid and
cystic areas, small calcifications and irregular borders,
and thus a wide range of differentials including metastatic
tumors were considered 1,4. Lymphadenopathy is an
uncommon finding but extensive lymphadenopathy was
noted in our case 4. Radiology, fine needle aspiration, or
tru-cut biopsies are often not able to distinguish between
an IMT, a sarcoma, or other low-grade malignancies 4.
According to various studies, the diagnosis has proven to
be very difficult and almost only possible after complete
resection of the tumor, with only ~6.3% cases reported
being diagnosed on biopsy alone 3,4. The morphology
of the biopsy was largely non-specific with presence of
spindle shaped myofibroblasts along with inflammatory
cells including plasma cells. The closest differential
considered was IgG4 related disease in view of the presence
of plasma cells. However, the IgG4 immunostain was
negative, thus excluding this lesion in the present case. The
myofibroblasts were positive for SMA and ALK (both on
the Dako and Ventana platform). Coffin et al. studied 59
cases of IMT and noted that cytoplasmic ALK reactivity
was seen in cases with clonal changes in chromosome 2,
as observed in 56% of cases 5. ALK immunostaining was
performed on both platforms, Dako and Ventana, with
different antibody clones. The rabbit monoclonal antihuman
CD246 antibody (clone D5F3) used on the Ventana
platform was found to be staining a higher proportion of
cells (>50%) with higher intensity (Grade 3) than the mouse
monoclonal anti-human CD246 antibody (clone ALK1) on
the Dako platform. Taheri et al. in their study showed that
D5F3 antibody stained 76% and ALK1 antibody stained
72% of IMTs. Compared to staining with ALK1, D5F3
stained a higher proportion of cases extensively (>50%
cells) (76% vs. 28%) and with high intensity (grade 3; 76%
vs 0%) 6. This was noted in the present case. The Ventana
platform was new in our institute and this was the first case
where the ALK immunostain was repeated on the Ventana
as well, thereby confirming the diagnosis on the limited
quantity of the tissue sample received.
ALK-negative IMTs occurred in older patients and had
greater nuclear pleomorphism, atypia, and atypical mitoses,
and also metastasized widely. ALK reactivity was associated
with local recurrence, but not distant metastasis, which
was confined to ALK-negative lesions 5. However, in our
case all the features were seen along with involvement of
the adjacent sites (liver, bone and lymph nodes). Complete
resection of the tumor is considered the treatment of choice
with the prognosis depending on the tumor size (less than
or equal to 3 cm) and ALK reactivity 3,5. In our case, the
mass was large and hence chemotherapy was started as
the treatment modality. Coffin et al. have concluded that
ALK reactivity may be a favorable prognostic indicator in
IMT 5. Reduction in the size of the tumor (~2 cm) has
been noted post 3 months of therapy, which points towards
the positive ALK reactivity seen in this tumor. The overall
3-year survival rate is about 82% and the overall 5-year
survival rate is about 74% 3,4.
This case posed a diagnostic challenge as the radiology
and clinical picture was suggestive of malignancy and on
histopathology only core biopsy was received on which
the architecture of the lesion could not be appreciated.
IMT is predominantly a morphological diagnosis based on
the architecture of the spindle cells and is usually difficult
to diagnose on core biopsies; a strong vigilance and indepth
knowledge of this entity along with a wide variety
of immunohistochemical markers therefore helps in
reaching a conclusive diagnosis. The novel anti-ALK rabbit
monoclonal antibody (D5F3 clone) demonstrates a much
higher proportion of cell staining with a higher intensity,
thus giving a superior overall performance of ALK protein
in IMT.
CONFLICT of INTEREST
The authors declare no conflict of interest |
Top
Abstract
Introduction
Case Presentation
Discussion
References
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1) Hammas N, Chbani L, Rami M, Boubbou M, Benmiloud S,
Bouabdellah Y, Tizniti S, Hida M, Amarti A. A rare tumor of
the lung: inflammatory myofibroblastic tumor. Diagn Pathol.
2012;7:83.
2) Matsubara O, Tanliu NS, Kenney RM, Mark EJ: Inflammatory
pseudotumors of the lung - progression from organizing
pneumonia to fibrous histiocytoma or to plasma-cell granuloma
in 32 cases. Human Pathology 1988;19:807-14.
3) Chen CK, Jan CI, Tsai JS, Huang HC, Chen PR, Lin YS, Chen
CY, Fang HY. Inflammatory myofibroblastic tumor of the lung-
-a case report. J Cardiothorac Surg. 2010;5:55.
4) Van den Heuvel DA, Keijsers RG, van Es HW, Bootsma GP, de
Bruin PC, Schramel FM, van Heesewijk JP. Invasive inflammatory
myofibroblastic tumor of the lung. J Thorac Oncol. 2009;4:923-6.
5) Coffin CM, Hornick JL, Fletcher CD. Inflammatory
myofibroblastic tumor: comparison of clinicopathologic,
histologic, and immunohistochemical features including ALK
expression in atypical and aggressive cases. Am J Surg Pathol.
2007;31:509-20.
6) Taheri D, Zahavi DJ, Del Carmen Rodriguez M, Meliti A, Rezaee
N, Yonescu R, Ricardo BF, Dolatkhah S, Ning Y, Bishop JA,
Netto GJ, Sharma R. For staining of ALK protein, the novel D5F3
antibody demonstrates superior overall performance in terms of
intensity and extent of staining in comparison to the currently
used ALK1 antibody. Virchows Arch. 2016;469:345-50. |
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Abstract
Introduction
Case Presentation
Discussion
References
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