Functioning and Disability in Alzheimer’s Disease

Opinion

Alzheimer’s disease (AD) corresponds to a complex neurodegenerative disorder that leads to a progressive decrease in brain metabolism functionally and morphologically (Deture, et al. [1-3]). Their presentation is progressive and chronic, with a subsequent loss of cognitive function (Justin M Long [3]). AD is the most common form of dementia and may contribute to 60- 70% of cases (WHO [4]). The majority of cases occur after age 65, comprising late-onset AD (LOAD), while cases occurring earlier than age 65 are considerably rarer, constituting less than 5% of all cases and are termed early-onset AD (EOAD) (Alzheimer’s, Long [3,5]). In addition, the risk of AD is 60% to 80% dependent on hereditary factors, with more than 40 genetic risk loci associated with AD already identified (Tanzi [6]). Also, the APOE alleles have the strongest association with the disease (Scheltens, et al. [7,8]). Moreover, in recent years, it is fast becoming one of the most costly, deadly, and burdensome diseases of this century (Scheltens, et al. [5,7]). The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is three times higher when based on a biological definition of the disease (Scheltens, et al. [7]). Functionality is conceptualized as the ability of a person to carry out the activities necessary to achieve wellbeing through the interrelation of their fields: biological, psychological (cognitive and affective) and social (Hopper [9]).

Under this definition, the International Classification of Functioning, Disability and Health (ICF) proposes a conceptual framework that establishes a standard language to describe health and its different dimensions (WHO [10]). It was approved by the (WHO [10]), and since then, it has had high applicability in the field of health rehabilitation (Hopper [9]). (Figure 1) lists the three components of this model: body functions and structures, activity and participation. The first component is related to physiological and psychological functions and anatomical elements; the second component refers to the individual execution of tasks and activities; the third component is related to the development of social situations (WHO [10]). Functional impairment is a core symptom of AD (Arrighi, et al. [11,12]). The most precise indicator of functional deterioration is the decrease in the performance of activities of daily living (ADL) (Arrighi, et al. [11,13,14]). A report using ICF has pointed out that activity and participation are restricted to domestic life, self-care and mobility, communication, interaction, and social relations (Muò, et al. [13]). In addition, subjects who appeared more compromised on the Mini-Mental State Examination (MMSE) and Global Deterioration Scale (GDS) showed more significant function impairment, activity limitation, and participation restriction (Muò, et al. [13]).

Figure 1: International Classification of Functioning, Disability, and Health (ICF) (WHO 2001).

Executive dysfunction and decreased general measures of cognitive functioning have also been reported to be associated with decreased ability to perform instrumental ADLs (Pereira, et al. [15]). ADLs are affected progressively and hierarchically associated with cognitive decline, but substantial variability persists between individuals and the relative order of affected items (Arrighi, et al. [11]). It has also been pointed out that there are disability profiles with restricted patterns of time use in a variety of domains encompassing both compulsory and discretionary activity, accompanied by a significant increase in a passive activity, such as sleeping during the day or sitting in front of the television (Lomax, et al. [16]). Also, restrictions in the social and environmental contexts of the patient’s life and diminished levels of subjective enjoyment have been associated with their pattern of daily use of time (Hopper, et al. [9,16]). Currently, the ICF consists of 1,424 mutually exclusive categories that, taken together, cover a complete and comprehensive spectrum of human experience and are organized as a hierarchical structure of 4 levels differentiated from least to greatest precision (WHO [17]). The ICF categories are indicated using alphanumeric codes with which it is possible to classify functioning and disability, both at the individual and population levels.

According to this hierarchical structure, the highest-level category (4th) shares the attributes of the lowest level category (1st) to which it belongs. In addition, ICF qualifiers are used to quantify the magnitude of a problem in the different ICF categories, which are mathematically weighted quality descriptors that record the presence or severity of a problem at the bodily, personal, or social level (WHO [10]). Thus, a problem can suppose a deterioration, a limitation or a restriction that can be qualified from 0 (no problem: 0-4%), 1 (slight problem: 5-24%), 2 (moderate problem: 25-49%) , 3 (severe problem: 50-95%) to 4 (total problem: 96- 100%). For their part, environmental factors are quantified with a negative or positive scale that indicates the extent to which an environmental factor acts as a barrier or facilitator (WHO [17]). The ICF is a helpful tool for describing health status in patients with AD since it highlights important aspects of daily life that are not usually considered in activities of daily living scales, such as communication, social relationships, and recreation and leisure (Badarunisa, et al. [9,12,18]).

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Gastric Barotrauma ERCP-Related

Mini Review

A 73-year-old woman was referred to us for endoscopic biliary drainage of obstructive jaundice due to a pancreatic mass diagnosed by abdominal computed tomography (CT) scan (Figure 1A). Endoscopic Retrograde CholangioPancreatography (ERCP) was performed with CO2 insufflation under general anesthesia. Wire-guided cannulation of the papilla was gently attempted with the long route because of the distorted anatomy of the descending duodenum (Figure 1B) and was suddenly stopped by the anesthesiologist when blood came from the aspiration tube. Withdrawing the duodenoscope, petechial lesions and deep longitudinal actively oozing mucosal tears were seen in the lesser curvature of the stomach from the angulus (Figure 1C) to the gastroesophageal junction, consistent with gastric barotrauma. This gastric “cat scratch” is a rare phenomenon that, following LaPlace’s law, arises when sudden high gaseous pressure leads to increased wall tensions. It occurs in the lesser gastric curvature probably because this part of the stomach has a lower capacity for distension, owing to the lack of mucosal folds and the presence of the gastrohepatic ligament [1]. At the end of the procedure the patient immediately experienced epigastric pain and abdominal distention without any sign of perforation. This is the first case report showing gastric barotrauma during ERCP.

Figure 1:

A. Abdominal computed tomography showing double-duct sign: the combined dilatation of the common bile duct and pancreatic duct, caused by pancreatic mass.

B. Wire-guided cannulation of the papilla with the long route at x-rays.

C. Petechial lesions and deep longitudinal actively oozing mucosal tears in the lesser curvature of the stomach at the angulus and the gastroesophageal junction (Figure D).

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Assessment of Target Volume Definition for Contemporary Radiotherapeutic Management of Retroperitoneal Sarcoma: An Original Article

Introduction

Soft tissue sarcomas are relatively rare and comprise a heterogeneous group of malignancies. While the most common localization for soft tissue sarcomas includes the limbs, a considerable proportion occur in the retroperitoneum. Soft tissue sarcomas include a variety of histologic subtypes such as liposarcomas, undifferentiated-unclassified tumors, and leiomyosarcomas. Among the group of soft tissue sarcomas, retroperitoneal sarcomas deserve utmost attention since they represent a heterogeneous and relatively rare group of tumors originating from mesenchymal cells with considerably high rates of local recurrence and mortality. Surgery has been the principal mode of management for retroperitoneal sarcomas, however, complete surgical removal may not be achievable particularly in the setting of large tumor sizes and involvement of nearby critical structures. In an attempt to improve therapeutic outcomes, the use of radiation therapy (RT) has been addressed [1-7]. Surgical resection with negative margins may be challenging to achieve in some circumstances and neoadjuvant or adjuvant therapeutic strategies may be considered. RT may be utilized as a local treatment option, however, adverse radiation effects should be considered [1-7]. Critical advances in the millennium era for improved RT outcomes include sophisticated technologies along with state of the art irradiation techniques [8-46]. Accuracy and precision in target volume definition may be considered as a more important aspect of state of the art radiotherapeutic strategies to comply with these contemporary improvements. An overwhelming majority of RT centers currently make use of Computed Tomography (CT) simulation for radiotherapeutic management of retroperitoneal sarcomas. Clearly, CT remains to be a viable imaging modality for this purpose, however, incorporation of other imaging modalities such as Magnetic Resonance Imaging (MRI) may lead to improved target definition. Herein, we evaluate multimodality imaging based RT target definition for radiotherapeutic management of retroperitoneal sarcomas.

Materials and Methods

Herein, we had the purpose of investigating whether any improvement may be achieved through the incorporation of multimodality imaging in the target volume definition process for radiotherapeutic management of retroperitoneal sarcoma. To achieve this goal, a thorough appraisal has been utilized to shed light on this important aspect. We have carried out thorough comparative investigation of RT target volume definition. To be utilized for actual treatment and comparison purposes, a ground truth target volume was outlined individually by board certified radiation oncologists. Patients who have been allocated to RT for retroperitoneal sarcoma were included, and decision making for RT has been performed on a multidisciplinary basis. At the outset, alternative treatment strategies and protocols have been thoroughly discussed. Synergy (Elekta, UK) linear accelerator (LINAC) has been utilized for treatment delivery. Selected patients underwent CT-simulation at the CT-simulator. After the CT-simulation process has been completed, acquired images have been transferred to the contouring workstation. Outlining of structure sets including treatment volumes and critical structures comprised an important aspect of RT planning. Treatment volume determination has been performed by either the CT-simulation images only or by fused CT and MR images. A comparative analysis has been performed for evaluation of treatment volume determination by CT only and with incorporation of CT-MR fusion based imaging.

Results

Patients with retroperitoneal sarcoma referred to Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences were assessed for treatment volume definition by either CT-only imaging or by CT-MR fusion based imaging in this original research article. Lesion size, localization and association with critical structures, and disease extent were among the considered tumor associated characteristics. Also, we individually took into account the patient ages, symptoms, and performance status before radiotherapeutic management of retroperitoneal sarcoma. The reports by American Association of Physicists in Medicine (AAPM) and International Commission on Radiation Units and Measurements (ICRU) have also been considered for improved treatment planning. Radiation physicists played a significant role in generation of optimal RT plans by taking into account the recent informatory guidelines and clinical experience. Considered parameters in RT planning included the critical organ dose limitations, tissue heterogeneity, electron density, CT number and HU values in CT images. Primary aim of treatment planning was to achieve optimal treatment volume coverage while respecting the preset critical organ dose limitations. Modern treatment equipment has been used for irradiation, and we made use of contemporary image guidance strategies such as kilovoltage cone beam CT and electronic digital portal imaging for optimal setup verification. As the primary outcome of this study, the ground truth target volume was observed to be identical with CT-MR fusion based imaging for precise RT of retroperitoneal sarcoma.

Discussion

Although relatively rare, retroperitoneal sarcomas comprise a heterogeneous group of tumors originating from the mesenchymal cells. They may be typically associated with high rates of local recurrence and resultant mortality. While the main therapeutic option includes surgical resection to achieve optimal treatment results, complete removal of the tumor may not be achieved in some patients particularly when the tumor is large and in intimate association with surrounding critical structures. Within this context, RT may be considered in selected patients as another local therapeutic approach [1-7]. The primary objective of irradiation is eradication of as many tumor cells as possible without damage to normal tissues. However, achieving an optimal therapeutic ratio by RT may be hampered by critical organ dose constraints and the desired ablative doses of irradiation may sometimes not be administered due to the risk of excessive radiation induced toxicity. Several contemporary RT techniques and strategies have been developed recently to improve the toxicity profile of radiation delivery. Nevertheless, target definition has gained more importance and relevance with the availability of contemporary RT strategies. In this context, target definition for optimal RT planning is an indispensable component of sophisticated RT approaches. Meanwhile, CT-simulation is the most frequently used procedure for RT planning in a plethora of cancer centers. Cross sectional imaging with thin CT slices has clearly improved target and critical organ definition for radiotherapeutic management, however, incorporation of additional imaging with MRI may further refine this critical procedure. Fusion of CT-simulation and MR images may allow for exploiting the advantage of multimodality imaging. Indeed, the addition of MRI to CT images has been demonstrated to improve RT planning for a variety of cancers [47-80]. At this standpoint, we cordially believe that this study may add to the accumulating data on this subject and may have pertinent clinical implications for utilization of multimodality imaging for optimal RT of retroperitoneal sarcoma. We conclude that our study indicates improvement in treatment volume determination for precise RT of retroperitoneal sarcoma by integration of MRI in RT target definition process albeit with the requirement for further supporting evidence.

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Mental Depression©

Pharmaceutical Drugs Can Cause Permanent Harm

A person depressed is immersed in gloom. For them, everything is bad, they see no hope. They are constantly exhausted. Their glass is always half empty and all the traffic lights are at red. They may well blame someone. They drag down all those close to them and can cause mental depression in others. This is a common plight that is not cured by modern pharmaceutical medicine or drug wielding psychiatrists. A doctor will prescribe an anti-depressant drug to help the patient cope. All that does is switch off part of the brain and prolonged consumption causes permanent brain damage. If they stop taking the drug, stress increases and in fear they become more drug dependant. Good business for the pharmaceuticals. There is no known drug that repairs thoughts. The brain is the hardware, in computer terms, and thoughts are the software. Depression is a software problem. Emotions can be chemically stimulated but there is no control. For example, alcohol shifts the mood towards extraversion and caffeine can shift the other way with an inability to relax and that causes harm. Thoughts out of control are dangerous. At one extreme a person can think they are invincible and at the other commit suicide. No doctor should ever consider mood shifting for medical healing.

The only way to manage thoughts is conversation. We used to follow the explanations of Sigmund Freud and snigger at the technique of a patient on the psychiatrist’s couch until the drug makers took over and repaired the brain chemically. If a patient was not helped by one drug, they were given an alternative with the explanation that they were not responding properly, the patient’s fault. This suited the doctors who are called general practitioners with ten minutes to process each patient. A conversation about a person’s troubles could take an hour. The patient, who was helpless, hence their depression, never complained other than to often demand a stronger dose. Long term follow-ups confirmed that the person was now coping. To cope with life was regarded as a cure. Drug dependency had been caused (Figure 1).

Figure 1.

The Spectrum of Emotions

Below is a diagram of the spectrum of emotions. I used this first in an article about The Life Switch. When the mood is below normal, there is no healing. A depressed person is not just unhappy, they are ill. Aches and pains get worse. The immune system does not work. Add drugs to the helpless body and the immune system completely packs in (Figure 2). I observe, watch and listen to patients treated by Calsonic. A few weeks ago, a hunch that Cell Sonic is anti-depressant was confirmed. I visited St James Clinic in Birmingham to meet two lady professors from Poland when were interested in our technology. https://stjamesxh-clinic.com/. Here we are outside. I am the old man in a bow tie (standard garb for a professor) (Figure 3). The directors of St James are Hieu Tran standing between the ladies and Syed Ahmed on my left. The visiting professors are from Rzeszów University. Agnieszka Banas-Ząbczyk is on the left in the picture and Marta Kopańska is in the middle of the group. Both ladies were treated twice by the machine which at St James is called CS1. I explained what the machine does and how we understand it works on the body. The discussion then centred on the CS1 (Cell Sonic) making the patient feel happy. Hieu told of a miserable man who never smiled being seen after a treatment to be smiling. He told his friends it was the machine that did it.

Agnieszka said the same. She felt lifted, relaxed and welcomed more treatments. Marta agreed. Agnieszka said that neurons were being sent into the brain. Here is the machine (Figure 4). St James [1] have developed a standard procedure to treat the spine regardless of what the patient came to the clinic for. In the photo below, Hieu is showing the lady what to do. She is in the process of buying a machine for her own clinic (Figure 5). The protocol is 1,000 pulses at energy level 4.The treatment takes about five minutes with the machine banging at four a second. It can be felt but is not painful. Indeed, the patient enjoys the treatment. Three forces are emitted by the shock head (called a wand in America): pressure, electrical field and light. The spine is connected to the brain and all the organs (Figure 6). By treating the spine with Cell Sonic all the organs receive an electrical boost from the electrical field. There is no direct contact with an electrical charge from the machine (Figure 7). Credit and thanks are given to Dr Jerry Tennant for these illustrations [2]. His book and lectures on “Healing is Voltage” are first class (Figure 8-12). The frequencies needed to stimulate the cells and the related emotions are fully served by Cell Sonic because every pulse is a bang covering a full range of frequencies from high to low.

Figure 2.

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Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

Figure 11.

Figure 12.

The very high frequencies are attained by the short rise time of a Cell Sonic pulse lasting a billionth of a second, the time taken for electricity to travel 1 mm as it shorts across the gap in the electrode of the shock head. The resulting sound and flash of lightning is the same as a thunderstorm but smaller. Here below is an explanation of shockwaves taken from HMT, a Swiss company I represented in Britain before they went out of business twenty years ago. Their problem was that doctors demanded endless clinical trials costing the company more than they could afford until they ran out of money. I then formed Cell Sonic and have avoided the pitfalls that beset HMT. The electrohydraulic system is far superior to other methods. Also important is the means of switching the high voltage passing through the electrode. Cell Sonic uses the fastest possible. Slower methods such as a cascade of thyristors cannot achieve the high frequencies needed to restore body cells. Breaking kidney stones is one thing. Generating cell restoration is another and only Cell Sonic has the frequency range needed [3,4].

Conclusion

The discovery that Cell Sonic reduces and helps remove mental depression is a valuable addition to the medical tool kit. Drugs are not used so there are no side effects. The effects have been observed for ten years and reported to me from different continents. In some cases, patients with brain disease are being treated with pulses aimed directly into the brain. Whether this is better than sending the neurons to the brain through the spinal cord remains to be seen. The brain is surrounded by bone as is the spinal cord, so the pressure and light parts of the pulse have little effect. That leaves the electrical field and in bursts of a billionth of a second at low energy levels, no side effects are detected. The mental improvements are accumulative. When the person grows new brain tissue or other parts of the brain take over from the parts damaged by drugs, the person is lifted into the upper half of the emotional spectrum where the immune system becomes active and thus starts the upward spiral of feeling better because the body is healing. When pain is stopped, proper sleep allows the immune system to work and the person is lifted out of gloom into a bright, smiling day.

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The Trailing Fecundation Epithelioid Trophoblastic Tumour

Preface

The World Health Organization (WHO) classifies Epithelioid Trophoblastic Tumour (ETT) as a category of Gestational Trophoblastic Neoplasia (GTN). Initially scripted by Shih and Kurman in 1998, the exceptional epithelioid trophoblastic tumour emerges as a derivative of neoplastic, chorionic- type, intermediate trophoblastic tissue and is associated with a variable clinical representation [1]. Epithelioid trophoblastic tumour may frequently coexist with placental-site trophoblastic tumour and the entities necessitate appropriate segregation. Nevertheless, a comprehensive, universally accepted protocol of tumour discernment, appropriate therapeutic regimen and duration of therapy for epithelioid trophoblastic tumour remains obscure.

Disease Characteristics

Epithelioid trophoblastic tumour commonly occurs within the reproductive age group and is usually discerned following a gestational event such as a full-term delivery, molar pregnancy or spontaneous abortion. Tumefaction is exceptionally delineated within postmenopausal women [2,3]. Epithelioid trophoblastic tumour appears to be associated with a preceding gestational trophoblastic neoplasm, preceding normal pregnancy or preceding spontaneous abortion [2,3]. Epithelioid trophoblastic tumour follows antecedent pregnancy by several months or years Generally, the neoplasm may follow a previous gestational event beyond > 6 years [2,3]. Serum beta Human Chorionic Gonadotropin (β-HCG) levels appear elevated [2,3]. Epithelioid trophoblastic tumour configures up to 2% of gestational trophoblastic neoplasia (GTN) and is associated with proportionate mortality of nearly 24%. Incidence of epithelioid trophoblastic tumour following a term pregnancy is nearly 1 in 150,000 pregnancies. The neoplasm exhibits pertinent ethnic variation [2,3]. Commonly, tumefaction may be situated within the uterine fundus, lower uterine segment or endo-cervix. Infrequently, pulmonary parenchyma or abdominal wall exhibit the lesion in the absence of a uterine neoplasm. Non metastatic neoplasms confined to the uterus are associated with comprehensive (~100%) disease- associated survival although metastatic tumours demonstrate around 60% proportionate survival [2,3].

Clinical Elucidation

The neoplasm is commonly discerned upon locations such as uterus or lower uterine segment, cervix or pulmonary parenchyma. Sites such as vagina, broad ligament, fallopian tubes or associated pelvic organs are infrequently implicated [4,5]. The gradually progressive neoplasm remains confined within the uterus for an extended duration. Thus, vaginal bleeding or amenorrhea is a commonly discerned clinical symptom [4,5]. Incriminated subjects depict irregular, variable vaginal bleeding, Abnormal Uterine Bleeding (AUB) or mild vaginal discharge. Preceding gestational event followed by abnormal uterine bleeding may indicate the occurrence of gestational trophoblastic neoplasia as epithelioid trophoblastic tumour [4,5]. The neoplasm may manifest as a nodule confined to a Caesarean scar or follow a spontaneous abortion with retained Products of Conception (POCs) [4,5]. Generally, the lower uterine segment exhibits a painful tumefaction of variable magnitude and vaginal bleeding along with mildly elevated serum beta Human Chorionic Gonadotropin (β-HCG) levels [4,5]. Majority of neoplasms are devoid of a Y chromosome complement [4,5].

Histological Elucidation

Macroscopically, discrete tumour nodules or a cystic or haemorrhagic tumour mass exhibits deep-seated infiltration within circumscribing soft tissue. Cut surface is whitish, tan or brown and depicts focal haemorrhage and tumour- induced necrosis. Focal ulceration and configuration of a fistula is frequently observed [6,7]. Grossly, a well-defined, pearly white, friable tumefaction with a fascicular external surface and magnitude of up to 5 centimeters appears to invade the uterine serosa and incriminates in excess of > 50% of myometrium. Usually, the neoplasm emerges as a solid, well circumscribed lesion confined to the cervix or as an extrauterine, localized tumefaction. Besides, the neoplasm may manifest as a discrete, solitary, nodule with a well circumscribed perimeter [6,7]. Cut surface is solid, tan or brown with focal haemorrhage and necrosis. Frequently, the neoplasm configures nodules or tumour masses and depicts an expansive growth pattern [6,7]. Upon microscopy, tumefaction is composed of solid cellular zones, elongated articulations and tumour cell nests. The well-defined, nested growth pattern is configured of miniature tumour cells with minimal nuclear pleomorphism and lack of intercellular bridges. A “ pushing” tumour perimeter is exemplified by the neoplasm [6,7]. The nodular, well circumscribed neoplasm exhibits focal, peripheral tumour infiltration. Mononuclear, uniform tumour cells are configured in nests and cords. Tumour cell nests are admixed with an eosinophilic, fibrillary, hyaline-like substance composed of type IV collagen along with onco-foetal and adult subtypes of fibronectin [6,7]. Cells of chorionic- type, intermediate trophoblastic tissue exhibit moderate, eosinophilic to clear cytoplasm imbued with glycogen, spherical nuclei, miniature, distinctive nucleoli and distinct cellular membranes. Tumour calcification is frequent [6,7]. Circumscribing stromal cells appear decidua-like. Exceptionally, focal regions resembling placental- site nodule, placental-site trophoblastic tumour or choriocarcinoma can be discerned [6,7]. The neoplasm can simulate mature stratified squamous epithelium and appears to re-epithelialize endometrial surface or endocervix. Fragments of endocervical tissue may be admixed with clusters of intermediate trophoblastic cells [6,7]. Mean tumour mitotic count appears at an estimated 2 per 10 high power fields although up to 20 mitosis per 10 high power fields may be discerned. Atypical mitotic figures can be delineated. Tumefaction enunciates extensive or “geographic” necrosis [6,7]. Tumour is composed of intermediate trophoblastic cells imbued with abundant eosinophilic cytoplasm and vesicular nuclei. Tumour cell aggregates are surrounded by a fibrous tissue stroma whereas tumour cells may circumscribe and replace walls of medium-sized vascular articulations and spaces [6,7]. Uterine serosa abutting the neoplasm may depict zonal rupture with tumour cell infiltration and focal necrosis. Soft tissue perimeter may be devoid of discernible tumour cell infiltration. Adjacent pelvic lymph nodes are preserved and lack tumour metastases [6,7].

Immunohistochemistry

Tumour cells are intensely, diffusely immune reactive to Cytokeratin Cocktail (CK) AE1/AE3, cytokeratin 18, Cyclin E, Cyclin D1, CD10, Epithelial Membrane Antigen (EMA), inhibin-α, E-cadherin, prolyl 4-hydroxylase, Human Leucocyte Antigen G(HLA-G), hydroxy-delta-5-steroid dehydrogenase 3 beta and steroid delta- isomerase 1 (HSD3B1), GATA3 and p63. Focal immune reactivity to Human Placental Lactogen (HPL), Human Chorionic Gonadotrophin (HCG) and CD146 (Mel-CAM) is observed [8,9]. Ki-67 nuclear labelling index exceeds > 10%. The neoplasm may display immune staining with PD-L1, thus corroborating beneficial therapeutic outcomes with employment of immune checkpoint inhibitors [8,9]. Tumour cells are immune non-reactive to smooth muscle actin (SMA), desmin and CD117 [8,9] (Figures 1-8) [10-16].

Figure 1: Epithelioid trophoblastic tumour exemplifying nests and cords of intermediate trophoblastic cells with abundant, eosinophilic cytoplasm and vesicular nuclei [10].

Figure 2: Epithelioid trophoblastic tumour exhibiting nests and cords of intermediate trophoblastic cells with eosinophilic cytoplasm and vesicular nuclei and a circumscribing stroma with tumour cells replacing vascular articulations [10].

Figure 3: Epithelioid trophoblastic tumour enunciating cords and aggregates of intermediate trophoblastic cells admixed with foci of necrosis [11].

Figure 4: Epithelioid trophoblastic tumour depicting aggregates of intermediate trophoblastic cells surrounding zones of geographic necrosis [12].

Figure 5: Epithelioid trophoblastic tumour delineating a layering of intermediate trophoblastic cells with eosinophilic cytoplasm and focal necrosis [13].

Figure 6: Epithelioid trophoblastic tumour demonstrating intermediate trophoblastic cells invading vascular elastic tissue and circumscribing vascular lumen [14].

Figure 7: Epithelioid trophoblastic tumour displaying strands of intermediate trophoblastic cells admixed with enlarged foci of geographic necrosis [15].

Figure 8: Epithelioid trophoblastic tumour with intermediate trophoblastic cells immune reactive to p63 [16].

Differential Diagnosis

Epithelioid trophoblastic tumour requires a segregation from conditions such as

a) A typical placental site nodule which is discovered incidentally and characteristically displays moderate to severe cytological atypia of the trophoblastic tissue. A borderline Ki-67 nuclear labelling index of up to 10% is observed [17,18].

b) Keratinizing squamous cell carcinoma of the cervix is composed of tumour cells which configure and infiltrate surrounding stroma as irregular, anastomosing tumour cell nests or singular cells. Enveloping stroma can be desmoplastic or invaded by inflammatory cells. Foci of stromal dehiscence or desmoplastic reaction can be observed [17,18]. Superficial stromal invasion or lymphoid and vascular invasion may be delineated. Tumour grading is contingent to features such as nuclear pleomorphism, nucleolar magnitude, mitotic activity and tumour cell necrosis. Keratin pearls, abundant keratohyaline granules and intercellular bridges may be exemplified. Tumour cells depict enlarged, hyperchromatic nuclei, coarse chromatin and inconspicuous nucleoli. The neoplasm is immune reactive to cytokeratin 5, cytokeratin 6 and p16. Tumefaction is immune non reactive to cytokeratin 18 [17,18].

c) Placental site nodule is a lesion discovered incidentally upon microscopy. The minimally cellular lesion exhibits trophoblastic cells imbued with bland nuclei. Extensive hyalinization and an absence of calcification or necrosis is observed. Mitotic activity is minimal and a decimated K-i67 nuclear labelling index of below < 8% is delineated [17,18].

d) Placental- site trophoblastic tumour exhibits an infiltrative pattern of tumour expansion. Disseminated, multinucleated, intermediate trophoblastic cells accumulated upon the implantation site are common. Frequently, tumour cells appear aggregated into confluent sheets [17,18]. Peripheral neoplastic fragments exhibit singularly disseminated cells, cords or nests of trophoblastic cells. Characteristically, tumour cells segregate individual fibres or group of muscle fibres and infiltrate the myometrium. Vascular invasion is common wherein tumour cells infiltrate and replace walls of myometrial vascular articulations. Tumour cells are incorporated with an abundant amphophilic, eosinophilic or clear cytoplasm, pleomorphic, enlarged, convoluted or hyperchromatic nuclei associated with significant nuclear atypia. Majority of neoplasms depict a minimal mitotic count. Focal calcification or necrosis is absent. The neoplasm is diffusely immune reactive to Mel-CAM and Human Placental Lactogen (HPL). Ki-67 nuclear labelling index is elevated to up to 30% [17,18].

Investigative Assay

Upon ultrasonography, a tumefaction of variable magnitude may be discerned within the lower uterine segment or region of Caesarean scar. Sonography depicts a sharply defined tumefaction along with a hypoechoic halo situated upon the site of a preceding surgical procedure [19,20]. Upon ultrasonography, epithelioid trophoblastic tumour may manifest as a neoplasm with a well circumscribed perimeter and a hypo-echogenic halo [19,20]. Intraoperative inspection may depict a scar associated dehiscence situated upon the site of preceding surgery. Adjoining viscera may be uninvolved [19,20]. Computerized tomography of the thoracic, abdominal and pelvic cavity may exhibit tumour metastasis [19,20]. Colour Doppler may exemplify a specific “peripheral” pattern of vascular outflow. Colour Doppler of tumefaction associated with dehiscence of surgical scar appears devoid of central or peripheral vascular perfusion. Serum beta Human Chorionic Gonadotropin (Β-HCG) levels are elevated whereas Human Placental Lactogen (HPL) values appear normal and are non indicative of disease activity or prognostic outcomes [19,20].

Therapeutic Options

Comprehensive surgical excision of the neoplasm is recommended and an optimal therapeutic strategy. Total abdominal hysterectomy along with or the absence of bilateral salpingo-oophorectomy or adnexal eradication is contemplated as a cogent treatment modality for epithelioid trophoblastic tumour. Alternatively, an exploratory laparotomy may be performed [19,20]. A haematoma may accompany the neoplasm confined to isthmus or diverse uterine segments. Morphologically, circumscribing pelvic viscera appear intact and uninvolved. Reconstruction of the uterus may be required [19,20]. Adjuvant chemotherapy is usually unnecessary and the neoplasm appears resistant to chemotherapy. Stage I disease can be appropriately managed with total abdominal hysterectomy [19,20]. Prognostic factors indicating unfavourable outcomes are designated as

a) Duration from antecedent pregnancy exceeding > 48 months

b) Elevated mitotic count exceeding > 6 mitosis per 10 high power fields

c) Cellular and nuclear atypia

d) Vascular invasion

e) Myometrial invasion beyond inner one third of uterine myometrium

f) Diffuse, multifocal uterine disease

g) Stage III or stage IV disease as per International Federation of Obstetrics and Gynaecology (FIGO) anatomical staging. Pertinent staging is a significant prognostic factor [19,20]. Tumefaction following antecedent pregnancy beyond > 48 months in the absence of adverse factors can be subjected to surgical procedures as total abdominal hysterectomy with bilateral salpingectomy wherein adjuvant chemotherapy remains unnecessary, especially in individuals wishing to preserve fertility. Oophorectomy may be circumvented in macroscopically unremarkable ovaries [19,20]. Neoplasms associated with metastasis are suitably managed with surgical resection and adjuvant chemotherapy [19,20]. A combination of complex surgical manoeuvers along with adjuvant chemotherapy is recommended in females with elevated serum beta human chorionic gonadotropin (β-HCG) levels and metastatic disease. Commonly, an antecedent gestational event exceeding > 48 months and advanced disease stage are cogent indicators of an inferior prognostic outcome [19,20].

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