Ossifying Fibromas of the Head and Neck Region: A Clinicopathological Study of 45 Cases

Abstract

Ossifying fibromas of the head and neck region are classified as cemento-ossifying fibroma (COF) (odontogenic origin), and two types of juvenile ossifying fibromas: juvenile trabecular ossifying fibroma (JTOF), and juvenile psammomatous ossifying fibroma (JPOF). The potential for recurrence in JTOF and JPOF and the discovery of newer molecular signatures necessitates accurate histological classification. Over 12 years (2005–2017), a total of 45 patients with 51 tumours were retrieved and reviewed for clinic-pathological features from the archives of a tertiary care oncology centre. Of 45 cases, COF, JTOF and JPOF comprised 13 (28.9%), 11 (24.4%) and 18 (40%) cases respectively. Three cases were unclassifiable. M: F ratio was 1:3.3, 1.1:1, 2:1 for COF, JTOF and JPOF respectively with an age range of 6–66 years (mean: 24.6, median; 18.1 years). The most common site for COF was mandible, for JTOF was maxilla, and for JPOF was ethmoid sinus. One case of mixed JTOF and JPOF histology was seen. Aneurysmal bone cyst-like areas were seen in 26.6% of cases, most commonly in JPOF. Follow up was available in 23 cases, and ranged from 4 to 207 months. Three cases of JPOF had a recurrence and one patient with JTOF had residual disease after surgery. One case of COF demonstrated increased parathyroid hormone levels. COF, JTOF, and JPOF are clinically, radiologically and histologically distinct entities. Surgical resection is the mainstay of treatment. JPOF has a higher incidence of recurrence as compared to JTOF and COF and hence needs a more aggressive follow-up.

Introduction

The journey and nomenclature of the different types of ossifying fibromas (OFs) have finally culminated in the form of the changes in the recent WHO classification of Head and Neck tumours under the rubric of “fibro-osseous tumours”. Till the 2017 WHO classification of Head and Neck Tumours, “cemento-ossifying fibroma” could be used synonymously with the term “ossifying fibroma”. However, in the 4th edition, Head and neck ossifying fibromas, for the first time, were classified into cemento-ossifying fibroma (COF), juvenile trabecular ossifying fibroma (JTOF), and juvenile psammomatous ossifying fibroma (JPOF), which are rare, benign, yet locally aggressive tumours [1]. Notably, the odontogenic origin of COF from the periodontal ligament was recognised, and it was classified as a separate entity in “benign mesenchymal odontogenic tumours”, as well as the “odontogenic variant of ossifying fibromas” under the “fibro-osseous category” [1]. Due to ever-changing nomenclature and classification, and rarity, there is a lack of valid clinic-pathological comparison among the three subtypes, especially COF. None of the published studies till date have classified and evaluated the clinic-pathological features of all three subtypes of OFs as per the recent nomenclature. The need for accurate sub-classification is not mere semantics due to the potential for recurrence in JTOF and JPOF, the discovery of newer molecular signatures and differences in the management among the three variants. However, the same is precluded by the significant overlap among each other, and with other fibro-osseous and odontogenic lesions. Further, histological typing is dependent on the morphological features in the Hematoxylin and Eosin (H&E) stained slide alone, as there are paucity and the limited role of immunohistochemistry or molecular tests in fibro-osseous lesions of the head and neck.

Our study aims to evaluate, compare and contrast the clinical parameters, imaging findings and detailed histomorphological features of the three recently-classified subtypes of ossifying fibromas of the head and neck region, namely COF, JTOF, and JPOF.

Materials and Methods

This is a retrospective and observational study. A total of 45 patients with 51 tumours were retrieved from the archives of a single tertiary care oncology centre, from 2005 to 2017 (12 years), and reviewed. Inclusion of lesions such as fibrous dysplasia, focal and florid cemento-osseous dysplasias (COD), syndrome-associated lesions in the series was avoided during the review. All the cases of COF included in this study presented as mass lesions demarcated from the adjacent bone, as opposed to COD which is usually an incidental finding, and inseparable from the surrounding bone. Thus COD, taking into account the clinical and imaging findings, was ruled out with reasonable certainty in the present study, as histology is unable to differentiate the two entities. All the cases were reviewed by two head and neck pathologists and reclassified into COF, JTOF, and JPOF according to the recent 2017 WHO classification. Three cases (6.7%) were non-classifiable into any of these categories and were labelled as OF, not specified further. All these three cases were small biopsies, two from mandibular lesions, and one from a maxillary bony lesion which showed proliferation of benign fibroblastic stroma with scattered interspersed mature lamellar bony trabeculae. No cementum, immature bony trabeculae or any psammomatous calcification was seen in the material available to potentiate an accurate subclassification. The relevant clinical findings (age, sex, site of occurrence) were recorded from the electronic medical record system. The salient radiographic characteristics including circumscription, matrix if any, contrast enhancement (CE) pattern which refers to the enhancement of the lesion on contrast-enhanced magnetic resonance imaging (MRI)/ computed tomography (CT) scan imaging which was further classified as absent or present/significant enhancement, calcification and composition were obtained from the images stored in Picture Archiving and Communication System(PACS) and reviewed by the radiologist who was blinded to the final histopathological diagnosis of these cases.

Results

Of a total of 42 cases, COF comprised 13 cases (28.9%); there were 11 cases (24.4%) of JTOF and 18 cases of JPOF (40%). Histological examination revealed a benign fibro-osseous proliferation in all three variants with deposition of a different kind of matrix material, which is essentially the differentiating factor among the three entities (Table 1).

Table 1.

Clinicopathological findings of COF, JTOF and JPOF

Parameters	COF (mean age in years) (N = 13)	JTOF (mean age in years) (N = 11)	JPOF (mean age in years) (N = 18)
Age range (years)	10–65 (31 years)	6–57 (14 years)	12–66 (21.9 years)
M:F	1:3.3	1.1:1	2:1
T size	3–10 cm	4–12 cm	3–10 cm
Site	Mandible (13 cases)	Maxilla (11 cases)	Paranasal sinuses (ethmoid sinus) (18 cases)
Type of calcification	Cementum and osteoid	Immature Trabeculae	Psammomatous calcification/Ossicles
Bony trabeculae	Mature (periphery of the lesion)	Immature (direct ossification of cells)	Mature, rounded with psammomatous calcification
ABC like areas	1 Case (with JTOF like areas)	2 Cases	9 Cases
Mitosis	Occasional	Occasional	0–2/10 hpf
Necrosis	Not seen	Not seen	Not seen
Recurrence	None	1 Case (9%)	3 Cases (20%)

COF Cemento-ossifying fibroma, JTOF Juvenile trabecular ossifying fibroma; JPOF Juvenile psammomatous ossifying fibroma; T tumor; M male; F female; T tumour; hpf high power field; ABC aneurysmal bone cyst

COF

It occurred between 10 and 65 years of age with a mean age of 31 years and showed distinct female predilection with M: F ratio of 1:3.3. All cases of COF were seen in the mandible (13/13 cases, 100%) (Fig. 1a, b). None of the COF cases extended beyond the gnathic bones. One patient with COF had high serum PTH levels of 108.5(normal range: 11–69) pg/ml with an unremarkable parathyroid scan (Table 1). Radiographically, COF showed a well-defined lesion with variable appearance ranging from completely radiolucent, mixed to completely radiopaque appearance with size varying from 3 to 10 cm (Fig. 1b) (Table 2). All the cases of COF underwent surgical resection. On gross examination, COF cases were well-circumscribed lesions separated from the surrounding normal bone by a thin layer of fibrous tissue, which enables them to be shelled out as an intact lesion at surgical removal. On histology, all lesions showed circumscription with peripheral bony trabeculae of native bone. The pattern was uniformly seen as an occurrence of small osteoid trabeculae surrounded by osteoblasts. Ovoid calcified structures resembling “cementicles” were seen in all cases, albeit in varying amounts (Fig. 1c, d). Intervening areas showed a moderately cellular proliferation of bland appearing spindle cells with fine chromatin and moderate cytoplasm. Mitotic activity and necrosis were absent. One case of COF had areas of immature bony trabeculae in the central perivascular region reminiscent of JTOF. Aneurysmal bone cyst-like changes (ABC-like) were seen in one case, a hitherto unreported finding.

Fig. 1.

a A lady with a swelling in the right mandibular region; b On imaging, a COF lesion shows a radiolucent solid appearing, well-demarcated lesion on CT scan; c Histology, on low power, shows numerous hyper-eosinophilic deposits of matrix material with interspersed spindle cells. (H&E*, X100); d Histology, on high power, shows the matrix to be cementum-like material with central purple material and peripheral osteoid seams (H&E*, X400). The intervening spindle cells are bland and monotonous appearing with no appreciable mitotic activity. *Hematoxylin and eosin stain

Table 2.

Radiological findings of COF, JTOF and JPOF

Radiological findings	COF (4 cases)	JTOF (4 cases)	JPOF(10 cases)
Margins	Well-defined	Well-defined	Well-defined
Matrix	Absent	Curvilinear	Ground glass
aContrast enhancement	Absent	Significant enhancement	Significant enhancement
Calcification	Present	Present	Present (focal)
Composition	Solid	Solid and cystic	Predominantly cystic

COF Cemento-ossifying fibroma, JTOF Juvenile trabecular ossifying fibroma; JPOF Juvenile psammomatous ossifying fibroma

^aContrast Ehancement pattern refers to increased radiopacity on computed tomography or increased signal intensity on magnetic resonance imaging after administration of intravenous contrast

JTOF

The age range seen was 6–57 years with a mean age of 14 years. An almost equal M: F distribution with a ratio of 1.1:1 was seen. All cases (11/11 cases) involved the maxilla and upper alveolus (Fig. 2a, b). Radiographically, a solid-cystic pattern with heterogeneous areas, spiculated calcifications and subtle bone expansion was seen with size varying from 4 to 12 cm (Fig. 2b) (Table 2). The borders were well-demarcated except for 3 (3/11, 27.3%) cases which showed aggressive imaging findings in the form of infiltrative rather than expansile borders, and were labelled as “locally aggressive fibro-osseous neoplasms, malignancy needs exclusion”. Also, a cystic component was seen in 9 cases of JTOF, which had been mislabeled as necrosis in 5 cases with pre-operative imaging from outside centres rendering a diagnosis of malignant tumour/ aggressive histology on outside imaging report. All cases of JTOF were treated by complete resection. Gross examination revealed well-demarcated but unencapsulated tumours involving the upper-alveolar and maxillary apparatus. A characteristic pattern of curvilinear thin brown strands (Fig. 2c) on a cut surface in specimens excised en-bloc was seen. Histologically, the lesions were well-demarcated from the surrounding native bone by either remnant lamellar bony trabeculae in the form of a ring/shell around the lesion by a fibrous pseudocapsule. The curvilinear thin brown strands are seen on gross examination (Fig. 2c) corresponded to organized foci of haemorrhage, immature bony trabeculae and pseudocystic stromal degeneration as described by Slootweg et al. [2]. The zones of ossification were composed of predominant areas of cellular fibroblastic proliferation with abrupt immature bony trabeculae, which had prominent osteoblastic rimming and foci of lacy osteoid (Fig. 2d). The osteoid in these cases was intimately admixed within the stromal tissue and was difficult to identify. In other cases, there were more mature elongated woven bony trabeculae which were lined by osteoblasts and were surrounded by pseudocystic stromal degeneration and focal osteoclastic activity, giving it the typical “paint-brush strokes like” appearance (Fig. 2e). An admixture of both these areas was seen as well. Peri-trabecular clefting and chondroid differentiation were absent. An aneurysmal bone cyst (ABC) like changes were seen in 18% of cases; mitoses were infrequent with a range of 0–2/10 hpf (high power fields), no atypical mitoses or necrosis were seen. The three cases on imaging that had infiltrative margins showed mucosal ulceration due to the mass effect of the tumour with underlying fibrosis and inflamed granulation tissue however, the main tumour was circumscribed and non-infiltrative.

Fig. 2.

a A 14-year-old boy with a large swelling almost involving the right hemi-face; b CT scan shows characteristic spiculated calcifications, which are also seen on gross examination; c Gross shows a characteristic pattern of curvilinear thin brown strands on the cut surface which correspond to tiny haemorrhages (arrow); d Low power microphotograph to show the histology corresponding to the curvilinear strands seen on imaging as well as in the gross specimen; e These strands represent organising foci of ossification with transitioning of fibroblasts into the woven bone with intervening haemorrhage, osteoclastic and osteoblastic activity (H&E*, X100 and X400 respectively). *Hematoxylin and eosin stain

JPOF

It occurred between 12 and 66 years with a mean age of 21.9 years. A distinct male predilection with an M: F ratio of 2:1 was seen. All the cases occurred in paranasal sinuses (18/18 cases) (Fig. 3a–d), especially the ethmoid sinus. Radiographically, a multiloculated expansile mass with both solid and cystic pattern varying from 3 to 10 cm in size and enhancing thick septations (Fig. 3b–d) (Table 2) was noted. In 15/18 (83.3%), the tumour demonstrated a sharp border with the native bone with no demonstrable changes in the native bone except for expansion at the site of the tumour. However, in 3 cases (3/18, 16.7%), the native bone was expanded with ground glass appearance, simulating fibrous dysplasia. Some of the JPOF cases showed mucocele of the paranasal sinuses, especially the sphenoid sinus. In 2 cases, the imaging showed predominantly cystic areas suggesting a possibility of an aneurysmal bone cyst. Grossly, JPOF was removed both in-toto and as multiple fragments due to its site of occurrence. In tumours that were excised, a clear demarcating border was visible to the naked eye. On histology, it was characterized by rounded bony ossicles with multiple spherical calcifications, spatially oriented, irregularly and sparsely distributed, resembling psammoma bodies embedded within a cellular stroma (Fig. 3e). Larger irregular calcifications described as “ginger-root” were also noted. Mitoses were 2–3/10 hpfs; no atypical mitoses or necrosis was seen. Two cases had areas resembling fibrous dysplasia (Fig. 3f) on histology. ABC- like- changes (Fig. 3g), corresponding to cystic change on imaging, were seen in 50% of cases. In 2 cases with imaging diagnosis of ABC, the ABC like areas were the dominant finding on histology and only a small focus in one of the multiple sections sampled showed foci of JPOF. In one of the cases with “fibrous dysplasia-like” ground glassing of the native bone, extensive remodelling of the native bone was seen in the form of new bone formation at the interface of the tumour and the native bone.

Fig. 3.

a A young male with naso-orbital region swelling and disorganized facial symmetry with increased inter-canthal distance, more on the left side; b Coronal T1 c T2-weighted and d Postgadolinium T1-weighted MR images showing multiloculated expansile mass centered in the Ethmoid and Frontal sinus. The mass is predominantly cystic with enhancing thick septations; e Characteristic histology of JPOF with a cellular proliferation of fibroblasts with foci of osteoid with superimposed rounded psammomatous calcification. The degree of calcification may vary from case to case and even in different areas within the same case (H&E*, X200); f JPOF with areas of maturation resembling foci of fibrous dysplasia (H&E*, X400); g Aneurysmal bone cyst-like areas in JPOF with an area of haemorrhage lined by giant cells. *Hematoxylin and eosin stain

Follow up was available in 23 cases, and ranged from 4 to 207 months. Three cases of JPOF and one patient with JTOF had residual disease after surgery. None of the cases showed malignant transformation.

Discussion

A variety of benign fibro-osseous lesions can develop in the head and neck; OFs are the most common among them. In 2005 WHO classification, ossifying fibroma was not included in the chapter on odontogenic tumours; it was however discussed under "bone-related lesions” [3]. In 2017, the consensus group felt that the term cemento-ossifying fibroma is suitably descriptive and indicates that these lesions are specific to the tooth-bearing areas of the jaws and can be distinguished from the two juvenile variants of ossifying fibroma. The new 4th edition (WHO 2017) therefore classifies COF as a benign mesenchymal odontogenic tumour which distinguishes it from JTOF and JPOF that are non-odontogenic and are classified under benign fibro-osseous lesions [1].

Comparison of All Three Entities of OFs with Each Other and the Existing Literature

OFs are not restricted to a particular age group with a wide range of age distribution. The cases in the present study had an age distribution of 6–66 years (mean: 24.6; median: 18.1 years) which is in accordance with the age range of 6–85 years in the published literature [4–8]. The age group, however, varies among the three entities with COF, JPOF and JTOF representing the descending order of age at presentation [5, 9–12] as substantiated in the present study as well.

Variable sex predilection has been reported for OFs in different studies. Jones et al. (2006) and Chang et al. (2008) have reported a higher female predilection of OFs; the three types not classified separately [6, 7]. The rest of the literature, including the present study, agrees for COF showing female predominance whereas JTOF and JPOF exhibiting male predilection [2, 9, 11]. The various subtypes of OFs are consistently site-specific, and that is an important point that helps in the sub-classification of these tumours. The present study showed all cases of COF occurred in the mandible, and was restricted to gnathic bones, and of JTOF in the maxilla-upper alveolus region which concludes that COF and JTOF favour gnathic bones [2, 4, 7–9]. All cases of JPOF in our study developed within the sinonasal bones (ethmoid sinus), which corroborates well with frequently reported sites of occurrence in other case series [8, 13, 14].

Radiologically, OFs may present as a unilocular radiolucency, a mixed radiolucent-radiopaque lesion, or a radiopaque mass. COFs with time shows an increase in calcification and it is visualized as a radio-opaque mass, a finding more common in our series due to the late presentation of our patients and a prevalent gender bias. Mixed radiolucent-radiopaque lesions can generally be distinguished from JTOF by the site as COFs are usually located at the tooth-bearing region of the jaws and age of the patient as JTOF usually occurs at a younger age. JTOF and JPOF can be distinguished radiologically as the former primarily shows radiolucent appearance with irregular and scattered calcifications in contrast later exhibit well-defined, discrete borders with ground-glass opacity which was also found in the present study [9, 10]. The enhancement pattern on CECT/CEMRI varied between the odontogenic (COF) and non-odontogenic subtypes of OF(JTOF and JPOF); the latter showing a bright enhancement after contrast administration while the former being largely non-enhancing. The difference in enhancement pattern may due to the solid-cystic composition of JOFs compared to the predominantly solid COFs.

Histologically, OFs showed fibrous stroma with patterns of calcification that varied with COF, JTOF and JPOF. COF showed both cementicles and osteoid with moderately cellular stroma, JTOF showed osteoid trabeculae within variably cellular stroma and JPOF showed multiple characteristic ‘psammomatoid’ ossicles within a cellular stroma. Most of the previous reports suggest an overlap between cementum of COF, and psammomatous ossicles of JPOF, hence it is unclear whether the cases of JPOF reported in extra-sinonasal sites [11, 14] are truly JPOF with round ossicles and psammoma bodies or they are cases of long-standing COF with ossification/calcification of cementum. Slootweg et al., in their case series of 15 cases of JTOF showed characteristic gross and histological findings which distinguish it from COF and JPOF [2]. Similarly in the present study, it was noted that JTOF cases showed multinucleated giant cells, pseudocystic stromal degeneration and haemorrhage cluster which form elongated curvilinear strands that are even visible with the naked eye as thin brown lines on gross examination. The present study has shown 12 cases of ABC formation: one in COF, two in JTOF and nine in JPOF. Development of aneurysmal bone cyst is commonly reported in JPOF followed by JTOF but none has been reported in COF to date [9, 14]. As seen in our study, these cysts tended to occur more commonly in younger patients in the first and second decades of life [9]. In 2 cases of JPOF, the ABC-like areas were the dominant histological findings with scanty tumour islands in the wall of these cysts, thus emphasizing the need for thorough sampling.

One patient with JTOF, in our series, had residual disease after being operated at another institution; the reported rates of recurrence in the literature for JTOF being 15–20% [2]. JPOFs are associated with the maximum recurrence rate among the three subtypes, as seen in the current study as well. However, whether the high recurrence rate of JPOF is due to its biological aggressiveness or a result of incomplete resection due to the involvement of the sinonasal region, an area requiring a highly specialized surgical skill, is unclear.

None of the cases in this study showed any areas, upfront or on recurrence, suggestive of a higher grade lesion/transformation.

COF

The differential diagnosis of COFs with fibrous dysplasia is complicated and rests upon considering the clinical (female predilection for COF vis-à-vis male for FD) and radiological findings (interface with adjoining bone; well demarcated in COF vis-à-vis ill-defined and blending type in FD) [15]. However, histology is the final “gold-standard” [15] to make this distinction between COF and FD. Variation in the mineralization can help to distinguish COF from FD, which shows a more constant pattern throughout the lesion.

COF can be distinguished from most other benign and malignant lesions of mucosal and odontogenic origin. Cemento-osseous dysplasia (COD) is an incidentally detected, usually multifocal lesion in Asian women [16]. The unifocality, and characteristic round shape due to centrifugal growth pattern of COF, on imaging, differentiates it from the irregular, and ill-demarcated appearance of COD. However, the two are indistinguishable on histomorphology [16, 17]. All the cases in the present study were unifocal mass lesions, clearly demarcated from the adjoining bone and hence resected accordingly.

JTOF

The distinguishing feature of JTOF from FD, a common differential diagnoses, on histology is the organised structure of haemorrhage, osteoclastic activity, woven bone and osteoblastic rimming which is sharply demarcated (brush border appearance in JTOF) from the adjacent native bone which can distinguish the random, "Chinese-letter" like a pattern of bone formation merging with the surrounding native bone (in FD). Peri‐trabecular clefting was reported in 86.5% of FD cases, and none of the OF cases [18]. JTOF requires surgical management and the treatment of fibrous dysplasia is determined by age of the patients and their clinical presentation [19–21], thus mandating their accurate distinction.

Both the clinical and histological features of JTOF may mimic osteosarcoma (OGS), especially in small biopsies with significant treatment-related implications. Chondroid differentiation, significant atypia, atypical mitoses and necrosis favour OGS and rule out the possibility of JTOF. A word of caution regarding the use of immunohistochemical markers for distinguishing the above possibilities. The “new-age” markers MDM2, CDK4 and SATB2, initially thought to be suggestive of OGS, may be found in JPOF and JTOF [22, 23].

JPOF

JPOF on imaging as well as on histology (due to inadequate sampling) may be mistaken for an aneurysmal bone cyst (ABC) more so, as half or more of the JPOFs may have areas of ABC within them. The difference in management necessitates the distinction between these entities, and thus adequate sampling, preferably submitting the entire specimen is advisable as the JPOF areas may not be observed in every portion of the tumour, thus leading to possible diagnostic error. Histologically, JPOF may superficially resemble primary extracranial psammomatoid meningioma (PEPM) which is a rare subtype of psammomatoid meningiomas occurring in the paranasal sinuses [24]. Careful examination of histological features and the use of relevant immunohistochemical markers help distinguish the two [24].

HRPT2 gene plays a vital role in the autosomal dominant hyperparathyroidism-jaw-tumour (HPJT) familial cancer syndrome; the associated jaw tumours being ossifying fibromas, are not further specified/subclassified [25, 26]. All the OFs reported in this syndrome were gnathic in origin [25, 26] and based on the microphotographs in reported cases, it can be deduced that HPJT syndrome is associated specifically with COF rather than other subtypes of OF, a finding which requires further investigation. The present study also showed increased serum PTH in one case of COF in which it was tested, possibly due to the haploinsufficiency of the HRPT2 gene [25, 26]. Recently, it was also discovered that JOFs demonstrate the rearrangement in the long arm of Chromosome 12 spanning the MDM2 and RASAL1 gene [27]. The patients in this series were not tested for HRPT2 gene mutations or GNAS mutations.

Conclusion

Ours is the first study to classify and compare the clinical, imaging and histomorphological features of the three recently classified subtypes of OFs, namely COF, JTOF, and JPOF. Comparing these three entities together, we can conclude that all three entities show distinct clinic-pathological presentation. COF is a long-standing lesion characterized by the involvement of only gnathic bones, most commonly the lower jaw, in young to middle-aged women, a round shape on gross examination, and a moderately cellular stroma with a variable amount of violaceous “cementicles”. JTOF, prototypically, is a tumour of the upper jaw of teenage boys with a history of relatively rapid growth, which on imaging, gross and histology is a well-demarcated tumour with identifiable zones of ossification in the form of “garland-like arrangement of oedema, pseudo-cystic stromal degeneration, bony trabeculae, osteoclasts and osteoblasts. A young male with sinonasal mass characterizes JPOF, which on histology, shows a cellular stroma with ossicles showing “magenta pink” psammomatous calcification, along with ABC-like areas. A higher incidence of recurrence in JPOF as compared to JTOF and COF underscores the need for a planned excision in specialised centres with trained surgeons coupled with a more aggressive follow-up.

Author Contributions

SRN, NM, SUR: Study Concepts; SRN, NM: Study Design; SRN, NM, SUR, MB, AP, SKA, ST: Data Acquisition.

Funding

None of the authors have any relevant financial disclosures.

Data Availability

On request.

Declarations

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethcial Approval

This is a retrospective observational study done in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No additional procedures were performed on the participants as a part of this study. All received the standard of care for their condition and was as per the ethical standards.

Informed Consent

An informed consent has been obtained from all the study participants or their guardians (only in case of minors) for the treatment received by them, and for photographing and/or televising appropriate portions of their body and the use of this information and their histopathological material for medical, educational or scientific research (including publication) purposes after sufficient anonymization of patient particulars.