| Abstract|| |
Background: Peripheral neuroblastic tumors arise from the sympathoadrenal lineage of the neural crest. They have been classified according to the International Neuroblastoma Pathology Committee (INPC) into Four categories according to International Neuroblastoma Pathology Committee (INPC): a) Neuroblastoma (NB) b) Ganglioneuroblastoma (GNB), nodular c) Ganglioneuroblastoma, intermixed, and d) Ganglioneuroma (GN). Because of the rarity of extra-adrenal peripheral neuroblastic tumors, limited information is available regarding the chemotherapy of NB and GNB. A few case reports or case series with a small number of patients have been documented in the literature. Aim: To describe the clinicopathological characteristics of extra-adrenal peripheral neuroblastic tumors. Materials and Methods: Clinical, histopathological, and immunohistochemistry (IHC) findings of 18 cases were retrieved. Immunohistochemistry at the time of diagnosis was performed using Ventana Benchmark XT. The mean value was calculated using the Microsoft Office Excel 2019 software. Results: The posterior mediastinum was the most commonly affected extra-adrenal site in our study. Neuroblastoma consisted of eight cases (six in children, two in adults), of which four cases were poorly differentiated and the other four cases were differentiating. Two cases had favorable histology. The bone marrow and cervical lymph node metastasis were documented. Of the four GNB cases, one patient developed bone metastasis. All patients of NB and GNB received combination chemotherapy. One out of six GN patients presented with a large retroperitoneal mass encasing the aorta and renal vessels, mimicking a sarcoma. Conclusion: Extra-adrenal peripheral neuroblastic tumors do not pose any diagnostic issue in adequate tissue sampling. In limited material, immunohistochemistry is needed. The chemotherapy regimen has not been standardized due to rarity. Further molecular testing and targeted therapy may be of help in the future.
Keywords: Chemotherapy, extra-adrenal, ganglioneuroblastoma, ganglioneuroma, MKI, neuroblastoma
|How to cite this article:|
Shankaralingappa S, Patra S, Gami A, Trivedi P, Chalaliya AK. Extra-adrenal peripheral neuroblastic tumors: A clinicopathological study of 18 cases. Indian J Pathol Microbiol 2023;66:278-85
|How to cite this URL:|
Shankaralingappa S, Patra S, Gami A, Trivedi P, Chalaliya AK. Extra-adrenal peripheral neuroblastic tumors: A clinicopathological study of 18 cases. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Jun 3];66:278-85. Available from: https://www.ijpmonline.org/text.asp?2023/66/2/278/346697
| Introduction|| |
Peripheral neuroblastic tumors represent a spectrum of benign to malignant neoplasms arising from the sympathoadrenal lineage of the neural crest and include neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). They represent the third most common childhood neoplasm and are the most common malignancy occurring in the first year of life. A subset of tumors shows spontaneous regression or maturation while others behave aggressively. The most common primary site of neuroblastoma is the adrenal gland (40%). The extra-adrenal sites are retroperitoneum (25%), posterior mediastinum (15%), pelvis (5%), and paravertebral region (3–5%). Ganglioneuromas, the most mature spectrum within the group, are diagnosed more commonly in older children, adolescents, and adults. The International Neuroblastoma Pathology Committee (INPC) has defined four categories of peripheral neuroblastic tumors: NB; GNB, nodular; GNB, intermixed; and GN. The amount of neuroblastic component with its differentiation and Schwannian stroma determine the morphologic criteria.
Extra-adrenal NB is very rare in children as well as in adults and a few case reports or case series with a small number of patients have been documented in the literature.,, Here, we present a clinicopathological study of 18 cases of extra-adrenal peripheral neuroblastic tumors, of which NB, GNB, and GN comprised of eight, four, and six cases, respectively.
| Materials and Methods|| |
The study was conducted at the Department of Oncopathology at a tertiary care cancer hospital in India, retrospectively within a period of 5 years (January 2016 to January 2021) with 18 cases of extra-adrenal peripheral neuroblastic tumors. Of them, eight cases (Case nos. 1–8) were NB, four cases (Case nos. 9–12) were GNB, and six cases (Case nos. 13–18) were of GN and were diagnosed in this period. The olfactory neuroblastoma cases were not included in the study. Clinical, histopathological, immunohistochemistry (IHC), and therapeutic data of the 18 cases were retrieved from the pathology archives and analyzed. The mean value was calculated using the Microsoft Office Excel 2019 software.
Immunohistochemical analysis was performed at the time of diagnosis in all the cases either in biopsy or in excision specimen on formalin-fixed paraffin-embedded tissue by fully automated machine (Ventana Benchmark XT) using monoclonal antibodies CD117 (Cell marque-1:100, YR145), CD34 (DAKO-1:50, QBEnd10), CD45 (Thermo-1:100, RA/RO), CD99 (Thermo-1:50, H036-1.1), Terminal deoxynucleotidyl transferase (TdT) (BioGenex-1:50, EP266), Desmin (BioGenex-1:30, D33), Friend Leukemia Integration-1 (FLI-1) (Cell marque-1:75, MRQ-1), Synaptophysin (Thermo-1:50, SP11), Chromogranin A (Cell marque-1:100, LKH110), S100 (Thermo Scientific-1:100, clone 4C4.9), SOX10 (SRY-related HMG-box 10) (Ventana-RTU, clone SP267), SMA (Smooth muscle actin) (Thermo Scientific-1:50, clone 1A4), NSE (Neuron specific enolase) (Leica-1:30, NCL-NSE-435).
| Results|| |
NB (n = 8): In the present study, there was a wide age ranging from 6 months to 45 years. Predominantly, males were affected (male-female ratio, 7:1). The posterior mediastinum (n = 6) was the most commonly affected site followed by retropharyngeal space and retroperitoneum, one case each. The mean tumor size was 8.5 cm (range, 4.7–11 cm). Two patients (Case nos. 1 and 8), developed cervical lymph nodal metastasis and Case no. 8 also had bone marrow involvement [Figure 1]. In the rest of the cases, the bone marrow involvement in distant metastasis was not documented [Table 1].
|Figure 1: Neuroblastoma, poorly differentiated; (a) Contrast-enhanced CT—a posterior mediastinal mass encroaching paravertebral region (yellow arrow); (b) Neuroblasts with rosettes and neuropil (H and E, 40X); (c) Bone marrow biopsy—diffuse infiltration by malignant small round cells (H and E, 4X); (d) Lymph node metastasis (H and E, 20X); (e) CD45 expression in lymphocytes while the metastatic focus is negative (IHC, 20X); (f) Metastatic focus in node shows synaptophysin expression (IHC, 20X); CT—Computed tomography; H and E—Hematoxylin and eosin; IHC—Immunohistochemistry; CD—Cluster of differentiation|
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|Table 1: Demographic and clinicoradiological parameters of patients of extra-adrenal peripheral neuroblastic tumors|
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Materials submitted for histopathological examination (HPE) mostly consisted of linear tissue cores from Trucut biopsy for primary diagnosis before chemotherapy (n = 6); post neoadjuvant chemotherapy (NACT) excision (n = 1), and solid tissue pieces (n = 1). Details of histopathological findings have been provided in [Table 2]. Two histological types of NB were found, poorly differentiated (n = 4) [Figure 1] and differentiating (n = 4) [Figure 2]. Of the eight cases, two patients had favorable and the rest six patients had unfavorable histology based on their age and the mitotic karyorrhectic index (MKI) [Table 2]. All the cases of NB showed positivity for synaptophysin, chromogranin, NSE, and CD56. Other markers such as CD99, FLI 1, CD45, desmin, and TdT were negative.
|Figure 2: Neuroblastoma, differentiating; (a) Gross: a multinodular, solid-cystic mass received in pieces, cut surface (white arrow) of the solid area shows pale yellow gelatinous appearance; (b) Fibrous septa separates the neuroblastic nodules (H and E, 10×); (c, d) Neuroblasts and differentiating neuroblasts on the neuropil-rich background (H and E, 40×); (e) Differentiating neuroblasts with ganglion cells (H and E, 40×); (f) Strong expression of synaptophysin by neuroblastic cells (IHC, 40X); CT—Computed tomography; H and E—Hematoxylin and eosin; IHC—Immunohistochemistry|
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|Table 2: Gross, Histopathologic, and Immunohistochemistry findings in extra-adrenal peripheral neuroblastic tumors|
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The primary mode of therapy was chemotherapy (CT) (six cycles of vincristine, doxorubicin, cyclophosphamide, and cisplatin) in all eight cases followed by excision in two cases (Case nos. 1 and 4). These two cases were diagnosed and treated outside and came to our institution after the completion of six cycles of NACT. One of them also received radiotherapy (RT).
Two patients were lost to follow-up (Case nos. 1 and 6 after 7 and 4 months, respectively). The mean follow-up for the rest was 14.5 months. Four patients died of the disease, two patients (Case nos. 2 and 3) showed residual lesions of 5 and 4.5 cm, respectively after the completion of six cycles of CT.
GNB (n = 4): In this group, the age range was from 1 to 16 years. The males outnumbered the females (male-female ratio, 3:1). The most common site affected was the posterior mediastinum (n = 3) and one case was in the parapharyngeal space. The mean tumor size was 5.4 cm (range 2.8–7 cm). The bone marrow was free of tumor involvement in all cases. Case no. 10 had bone metastases [Table 1].
En-block excision (post-NACT) was performed in two cases (Case nos. 10 and 11). The primary diagnosis for these two cases was done outside and the slides were reviewed in our department. Linear tissue cores were obtained from Trucut biopsy in the rest of the two cases before NACT. On microscopy, the neuroblastic component varied from 1 to 10% and 5 to 10% in post- and pre-NACT cases, respectively. Both maturing and mature ganglion cells along with abundant Schwannian stroma were evident in all four cases [Figure 3]. Two cases were categorized as GNB, intermixed type (Case nos. 10 and 11). The other two cases could not be typified based only on the linear tissue cores. The neuroblastic cells and ganglion cells expressed synaptophysin, chromogranin, and NSE, whereas Schwann cells showed diffuse S100 expression.
|Figure 3: Ganglioneuroblastoma; (a) CT scan—a right parapharyngeal mass (arrow) with foci of calcification (arrowhead); (b) Section from core biopsy-differentiating neuroblasts with neuropil and Schwannian stroma (H and E, 40X); (c) Neuroblastic component with occasional differentiating neuroblasts (H and E, 40X); (d–f) Neuroblastic component shows a strong and diffuse expression of synaptophysin (d), S100 (e) and NSE (f) (IHC, 40X). CT—Computed tomography; H and E—Hematoxylin and eosin; IHC—Immunohistochemistry; NSE—Neuron-specific enolase|
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Four cycles of NACT were given to all, followed by excision in Case nos. 10 and 11 and RT in Case nos. 10 and 12. The mean follow-up period was 15.5 months. One patient (Case no. 10), who had bone metastasis, died of the disease after a follow-up period of 24 months. Another patient (Case no. 11) became disease-free after complete surgical resection post-NACT. Case nos. 9 and 12 had residual lesions at 12 and 8 months of follow-up, respectively.
GN (n = 6): All the patients in this group were adults with an age range from 24 to 73 years (mean age 36.5 years). The females were predominantly affected (male-female ratio, 2:1). The most common site was posterior mediastinum (n = 3), followed by retroperitoneum (n = 2), and retropharyngeal space (n = 1). The mean tumor size was 9.8 cm. Bone marrow examination was done in only one case (Case no. 16) but it was free of tumor. None of them had distant metastasis.
In five cases, tumor excision was performed. Two of them were diagnosed for the first time in our institute and the other three patients were diagnosed outside and slides were reviewed in our department. One patient (Case no. 16) was lost to follow-up and no further treatment was done in our institute.
In Case no. 13, resection of tumor along with segmental resection of the colon and right nephrectomy were performed with suspicion for retroperitoneal sarcoma. Radiology showed a large mass, abutting the duodenum and encasing the aorta and renal vessels with a wide area of necrosis [Figure 4]. In the Trucut biopsy, histopathology showed only a few spindle cells in the background of predominantly infarct-type necrosis. Hence, no definite opinion could be given and the patient underwent laparotomy. In the other four cases (excluding Case no. 16, whose surgery was not done in our institution), the primary biopsy diagnosis corroborated with the excision specimen.
|Figure 4: Ganglioneuroma; (a) CT scan—a retroperitoneal mass abutting the intestine (yellow arrow), encasing the aorta (blue arrow); (b) Gross: Predominantly hemorrhagic and necrotic with peripheral viable tumor nodules. (c) Admixture of mature ganglion cells and Schwann cells on a collagenized stroma (H and E, 40X) (d) Large area of infarct-type necrosis and hemorrhage (H and E, 20X); (e) Synaptophysin expression by ganglion cells (IHC, 40X); (f) S100 expression by Schwann cells and ganglion cells (IHC, 40X). CT—Computed tomography; H and E—Hematoxylin and eosin; IHC— Immunohistochemistry|
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Histopathological examination revealed a variable number of mature ganglion cells intricately admixed with the Schwann cells. A wide area of infarct-type necrosis was evident in Case no. 13 [Figure 4]. The ganglion cells expressed synaptophysin, chromogranin, and NSE. S100 immunoreactivity was seen in the Schwann cells and ganglion cells. The tumor cells were negative for CD117, DOG 1, SMA, desmin, and CD34. The mean follow-up period was 6.7 months. No patient had any local recurrence or distant metastasis.
| Discussion|| |
The diagnosis of peripheral neuroblastic tumors can be made on a core-needle biopsy or excision biopsy. Adequate sampling is of utmost importance to classify the tumor. Core-needle biopsies are usually sufficient, but accurate classification may not be possible in a limited tissue sample. This is particularly true in the case of nodular subtype of GNB where a core biopsy may fail to sample a Schwannian stroma-poor neuroblastic component.
NB is the most common malignant extracranial solid tumor in childhood. It is extremely rare in adults and usually occurs in the adrenal medulla or in paraspinal sympathetic ganglia, as its childhood counterpart. In the present study, two cases occurred in the adults (Case nos. 2 and 7) out of eight cases, similar to a published case in the literature.
The clinical findings of extra-adrenal NB depend upon the site of origin in the sympathetic nervous system—cervical, thoracic, lumbar, or sacral. Our finding of posterior mediastinum as the commonest involved site is supported by a series of cases (n = 18) published in the literature. Determination of MKI is crucial to evaluate neuroblastoma. The MKI is defined as the number of cells with mitoses or karyorrhexis per 5,000 cells and is classified as low (<100), intermediate (100–200), or high (>200). MKI is prognostically important and is dependent on a patient's age. The INPC classification system further classifies tumors as favorable histology (FH) or unfavorable histology (UH) based on the age at diagnosis, degree of neuroblastic differentiation, amount of Schwannian stroma, and MKI. Neuroblastoma with undifferentiated phenotype and/or with a high MKI is considered UH. Poorly differentiated and differentiating NB are designated as FH or UH depending on the age of the patient and the MKI. Assigning the tumor as FH or UH correlates with the behavior and clinical outcome. In our series, all the cases of UH had worse clinical outcomes.
Microscopically, neuroblastoma is composed of nests or groups of neuroblasts separated by thin fibrovascular septae with scant to nil Schwannian stroma. The neuroblasts have round to oval nuclei, stippled (“salt-and-pepper“) chromatin, scanty cytoplasm, and inconspicuous nucleoli. Undifferentiated NB is characterized by a uniform population of primitive small round cells without any identifiable neuropil. Poorly differentiated NB, the most common subtype, is characterized by nests of neuroblasts in a neuropil background with or without Homer–Wright rosettes and less than 5% of differentiating neuroblasts. Differentiating NB shows abundant neuropil with more than 5% of the differentiating neuroblasts. The differentiating neuroblasts show evidence of differentiation toward ganglion cells with large, eccentric nuclei, vesicular chromatin, and prominent nucleoli.
The differential diagnosis of NB includes other pediatric small round blue cell tumors including rhabdomyosarcoma, Wilms tumor, lymphoblastic lymphoma, Ewing sarcoma, and desmoplastic small round cell tumor. The diagnosis of undifferentiated NB needs IHC. Small biopsies also require IHC since the sampling issue may limit the amount of identifiable neuropil. The neuroblasts express neural crest markers, tyrosine hydroxylase and PHOX2B, and neuroblastoma marker NB84. PHOX2B is highly sensitive and specific for NB, including the undifferentiated subtype, which often fails to express tyrosine hydroxylase. Neuroblastoma is also variably positive for synaptophysin, chromogranin, NSE, PGP9.5, CD56, CD57, NFP, and lack expression of CD99, desmin, TdT, FLI-1, and CD45. Differentiating NB also expresses S100 and SOX10 in variable proportion. In the present study, all eight cases expressed synaptophysin, chromogranin, and NSE in poorly differentiated variety and S100 and SOX10 in the differentiating type. PHOX2B, tyrosine hydroxylase, and NB84 study were not done. Thev-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification study was also not done in the present study.
The most common location of GNB is in the adrenal gland (35%) followed by the retroperitoneal ganglia (30%), the posterior mediastinum (20%), pelvis (2–3%), and rarely in the cervical region and pleura.,, In the present study, one 2-year-old patient presented with parapharyngeal mass and the most common location we found was posterior mediastinum. This finding contradicts the above-published data and may be due to the small sample size. A vast majority of GNB cases are diagnosed before 10 years of age., Although cases of adolescent or adult-onset GNB have been reported in the literature, they are extremely rare.,,,,,, Less than 50 cases of adolescents or adult mediastinal GNB have been reported to date.,,,, In the literature, although it has been equally reported for both genders, we found a male predominance in the present study. The most common sites for metastasis are bone (Hutchinson's syndrome), bone marrow, liver (Pepper syndrome), and skin ('blueberry muffin' syndrome) in patients less than 1 year., Rarely lung and brain metastasis are also documented. In our series, one patient (Case no. 10) developed metastasis to the bone and skull, similar to a case recently reported in the literature. He also had radiologically suspicious enlarged lymph nodes in the parapharyngeal area, but the patient died before histological or Positron Emission Tomography and Computed Tomography (PET-CT) confirmation.
Imaging modalities, most commonly used for the assessment of GNBs, are computed tomography and MRI., The features of GNBs are variable on contrast-enhanced CT, ranging from well-marginated, oblong paravertebral masses with homogeneous enhancement to irregular, cystic, hemorrhagic appearance., Calcifications in the form of a coarse or finely-stippled or curvilinear is found in approximately 50% of GNBs, similar to our finding [Figure 3]a.
The nodular subtype of GNB is composed of a discrete neuroblastic nodular (Schwannian stroma-poor) component coexisting with an intermixed GNB (Schwannian stroma-rich) or GN (Schwannian stroma-dominant). Grossly, the cut surface shows one or more nodules frequently associated with hemorrhage and necrosis. The tumor surrounding the nodule is tan to pale white and firm. Microscopically, the nodules represent the neuroblastic component and are often well-demarcated from the surrounding GNB or GN areas. On the other hand, GNB, the intermixed subtype is well-circumscribed, solid with a firm, tan, homogenous cut surface. Although fibrous bands are discernible, a distinct nodule is not evident. Microscopically, it is characterized by an intermixed population of well-defined islands of naked neuropil with neuroblastic cells having variable differentiation toward differentiating neuroblasts and maturing ganglion cells.
The best treatment modality available for mediastinal GNBs is radical surgery early in the course of the disease.,,,,,,, It has a favorable prognosis with 2- and 5-year survival rates of 92 and 88%, respectively, reported in a large series. In general, older children with NB/GNB carried a poorer outcome than the younger ones., In addition, the tumor size at diagnosis may be related to the prognosis in adult GNB. In adults, GNB of more than 8 cm diameter tends to metastasize to other distant organs. The size of the lesion in Case no. 10 (8cm) was almost comparable to the cut-off and those in the other reports of mediastinal GNB.,,,, This patient was older (16 years), developed bone metastasis, and died of the disease after 24 months of diagnosis. Hence, adolescent/adult GNB cases should be carefully followed up even after complete resection.
There is limited information about the role of chemotherapy and other optional therapeutic agents in GNB. In the pediatric population, the drugs used are 2–4 cycles of cyclophosphamide, vincristine, doxorubicin, and combinations with cisplatin and etoposide. Raina et al. reported a case of GNB which showed an excellent response to the combined chemotherapeutic agents. However, very little information is available to date regarding the efficacy of chemotherapy for advanced or metastatic GNB. Several case series have documented the usefulness of NACT in patients with NB/GNB,,, but the effects on the prognosis remain unclear because of the rarity of the disease. In the present series, one patient (Case no. 11) responded very well to the combination NACT followed by surgical resection and has been disease-free after 18 months of follow-up. A younger age (1 year) and small tumor size (2.8 cm) may play a crucial factor in this case. Palliative RT is usually helpful for local disease control and in metastatic advanced cases.
GNs are slow-growing benign tumors occurring more frequently in children over the age of 10. The most common locations are the posterior mediastinum and retroperitoneum. Other rare sites, reported in the literature, include the heart, spermatic cord, bone, pelvis, gastrointestinal tract, cervical region, parapharyngeal, and supraclavicular areas., They can present even as incidentalomas in children. Ganglioneuromas are typically detected during routine imaging. On CT scan, they appear well-circumscribed and they tend to grow around major blood vessels without luminal narrowing. On MRI, ganglioneuromas appear homogeneous and have a relatively low signal intensity on T1-weighted images. On T2-weighted images, the signal intensity is proportional to the ratio of myxoid stroma to cellularity as well as to the amount of collagen present at the tumor site. In our case, in Case no. 13, the tumor encased the aorta and renal vessels. The ureter was compressed resulting in mild hydronephrotic changes in the kidney [Figure 4]a.
Grossly, GN is similar to the intermixed subtype of GNB. On microscopy, it is characterized by mature and/or maturing ganglion cells distributed within abundant Schwannian stroma (Schwannian stroma-dominant) without neuroblasts or neuropil. GN is divided into two subtypes: mature and maturing GN. The mature subtype shows only mature ganglion cells on a Schwannian stroma. The maturing subtype is composed mainly of Schwannian stroma with scattered maturing ganglion cells as well as mature ganglion cells.
The differential diagnosis of GN is wide-ranging from benign and malignant lesions including neurofibroma, schwannoma, NB, GNB, pheochromocytoma, gastrointestinal stromal tumor (GIST), and retroperitoneal sarcoma. Neuroblastoma and GNB can be differentiated readily by the presence of the neuroblastic component and distinctive neuropil. Neurofibroma usually lacks capsule and consists of Schwann cells with wire-like collagen fibrils (shredded carrot appearance), mast cells, myxoid areas, Wagner–Meissner corpuscles, and paucity of mature ganglion cells. Immunohistochemically, they express strong CD34, S100, and focal calretinin. Schwannoma is characterized by Antoni A, Antoni B areas along with Verocay bodies and characteristic hyalinized thrombosed blood vessels. GIST usually shows myxoid background with fascicles of spindle and epithelioid cells with strong expression of CD117 and DOG1. Retroperitoneal spindle cell sarcomas show fascicles of malignant spindle cells with mitotic activity and coagulative tumor necrosis.
The management of GN involves a total surgical excision when feasible, but, in some instances, it can be challenging because of its tendency to encase the nearby vessels or vital anatomical structures as in one of our case (Case no. 13). After surgical resection, the prognosis is excellent.,, The slow-growing character of the tumor requires a long-term follow-up in operated patients, including repeated imaging along with careful physical examination for local recurrence. After complete removal, usually, they do not recur but a malignant transformation of a pre-existing GN into malignant peripheral nerve sheath tumor has been described.
| Conclusion|| |
Extra-adrenal peripheral neuroblastic tumors are rare. They must be included in the differential diagnosis at an unusual site or age. Histomorphological diagnosis is usually straightforward except in undifferentiated cases of NB or in limited biopsy material. Immunohistochemistry helps in such diagnostic dilemmas. The treatment protocol has not been standardized due to the rarity of the disease and followed in a manner the same as adrenal gland tumors. Targeted therapy may come in the future with advances in our understanding of the pathogenesis of the disease.
We acknowledge our limitations of having a small sample size in each category, non-availability of NB84 and PHOX 2B immunohistochemistry, and absence of ancillary techniques to detect MYCN amplification or ALK amplification/mutation.
We are thankful to all the staffs of histopathology and immunohistochemistry department for their material support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Oncopathology, The Gujarat Cancer, and Research Institute, New Civil Hospital Campus, Asarwa, Ahmedabad - 380 016, Gujarat
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]