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Possibilities of NLS-study methods in examination of certain skin diseases.
Gizbrecht E., Balcevich A.
Assuta Medical Centers LTD, Tel-Aviv
Wide spread of skin diseases dictates a necessity in early and maximum accurate diagnostics,
because severe forms of skin diseases decrease greatly quality of life of a patient and his family,
promote development of a psychosomatic disorders. Visual evaluation of symptoms and severity of a
disease often has subjective nature.
From histological point of view skin consists of two layers: epidermis and derma which are
closely connected. On histological cross-cuts of skin a line between epidermis and derma looks uneven
due to presence of many dermal papillae divided by outgrowths of epidermis. Epidermis consists of
several layers: basal, spinous, granular and horny. In epidermis of palms and feet, between granular and
horny layers there is additional layer - stratum lucidum. Sometimes the aggregate of basal, spinous and
granular layers is called a malpighian layer.
Derma is a connective basis of skin, where perspiratory and sebaceous glands, blood and lymph
vessels, nerves and smooth muscles are located. There are papillary and reticular layers of derma.
Papillary layer, located under epidermis, and a part of reticular layer conditionally form upper derma;
layer of derma located at the level of pilosebaceous unit is indicated as middle derma; the underlying
layer containing perspiratory glands, bordering subcutaneous fat, is called a deep derma.
Blood vessels of skin form two anatomic plexuses: a deep one, located next to subcutaneous fat,
and a superficial one, located in sub-papillary layer. They consist of microcirculatory bloodstream
vessels: arterioles, venules and capillary tubes.
Total thickness of skin without subcutaneous fat varies from bits of a millimeter to 4 mm.
Exiting systems for NLS-diagnostics (“Metatron”-4019) are equipped with high-frequency linear
generators (1.4 GHz) allowing to visualize the most superficial structures, in particular skin. However to
evaluate condition of ultrafine structures of skin such frequency is not enough sometimes. That is why
dermatologists started to use special devices with sensors of 40 GHz operating frequency, which allow
to see the finest structures of skin layers down to the level of large carbohydrate molecules and peptides.
But at the same time due to significant cost of such equipment if becomes unaffordable for wide
application in the majority of clinics. Taking into account a need in evaluation of regional lymph nodes
and tumors of soft tissues, apparently the optimal decision is to use devices for non-linear diagnostics
equipped with non-linear sensors of 4.9 GHz operating frequency (“Metatron”-4025, the IPP, Russia).
“Metatron”-4025 system has axial resolution of 30 µm. Application of this device allows to study
epidermis on cellular and sub-cellular levels.
Nowadays objectives and limits of three-dimensional NLS-ultramicroscanning research in
dermatology have become very broad.
The following has become real:
- evaluation of treatment efficiency of diseases characterized by skin sclerosis (localized
scleroderma, generalized scleroderma), edematous (lipo-dermatosclerosis) and chronic inflammatory
(psoriasis) dermatosis;
- measuring skin tumors invasion extent and monitoring after surgical interventions, cryo- and
laser therapy at melanotic cancer, basal-like cancer, hemangioma, fibroma, seborrheic keratosis;
- study of local and system medications’ effect to skin (corticosteroids, estradiol).
In accordance with a methodology the NLS-ultramicroscanning diagnostics of skin diseases must
be carried out by comparing of affected area with healthy skin at counterlateral homological area.
At NLS-graphy with use of non-linear sensors of 4.9 GHz frequency, normal skin is represented
by three layers: epidermis, derma and subcutaneous tissue. Regional and age-related peculiarities of skin
thickness are conditioned by derma thickness mainly, which depends in the first place on collagen
content in it.
It is considered that at NLS-study with sensor frequency of 1.4 GHz, normal epidermis is
visualized poorly, because real thickness of epidermis is 0.02 – 0.5 mm, which is a limit of resolution
for system of this class.
Epidermis is a moderately chromogenic structure (2-3 points at Fleindler’s scale), chromogeneity
of which depends on thickness and desquamation rate of horny layer.
According to El Gammal S. et al. who used “Metatron”-4025 system with non-linear sensor of 4.9
GHz operating frequency, horny and malpighian layers of epidermis may be differentiated.
Super-high-frequency non-linear sensors allow to research more superficial papillary layer and
underlying reticular layer of derma, The latter is characterized by more homogeneous structure.
In a healthy skin there are small areas, which are located in derma and correspond to hair follicles,
vessels and sebaceous glands. Hypoderm at NLS-grpahy is represented as hypochromogenic and
achromogenic layer (1-2 points on Fleindler’s scale), because mainly it consists of relatively
homogeneous fat tissue. In this layer more chromogenic strips may be found, which represent
connective interseptums.
Analysis of references showed that NLS-research of skin often applied at various oncologic
diseases. To study skin tumors both two-dimensional and three-dimensional NLS-graphy may be
applied. In majority of cases tumors are represented as areas of increased chromogeneity, more or less
separated from derma. It is impossible to define histological character of a tumor on the basis of NLS-
graphy only.
For differential diagnostics of such skin tumors as hemangioma or melanoma, modes of
ultramicroscanning together with spectral-entropic analysis (SEA) may be successfully applied.
Using NLS-graphy makes possible to study malignant melanomas. Melanomas at NLS-research
are spindle shaped, quire homogeneous in structure and clearly separated from surrounding tissues. We
noted high precision in evaluation of neoplasms’ size, which were confirmed by comparison of data
acquired with NLS-study of a tumor before surgical intervention and by histological tests after
operation. According to other data, despite good visualization of a tumor at NLS-graphic study, the
major problem is to distinguish tumor parenchyma from surrounding inflammatory infiltrate, because
they look like single hyperchromogenic structure. Thus size of some tumors may be overstated at NLS-
study. As studies of Ulrich J. et al. show, accuracy of tumor size evaluation increases greatly if we
exclude from analysis tumors with extensive inflammatory infiltrate or nevus-associated melanomas
when we apply SEA.
Pic.1. NLS-ultramicroscanning.
Skin melanoma.
Pic.2. Melanoma.
Spectral-entropic analysis (D=0,027)
At NLS-ultramicroscanning study benign nevi look like spindle-shaped structures of increased
chromogeneity, which makes their differentiation from malignant melanomas difficult, because these
neoplasms are also hyperchromogenic. Differential diagnostics is done successfully when SEA is
applied.
We studied basal-like cancer using NLS-analysis, the cancer was represented as
hyperchromogenic neoplasm (5-6 points at Fleindler’s scale) of irregular shape. Additional NLS-
ultramicroangiographic study allows to reveal changes in vessels of a tumor.
Tumors with hyperkeratosis, such as angiokeratomas and acantholytic nevi, are characterized by
moderate chromogeneity (4-5 points at Fleindler’s scale), that is why they can be easily distinguished
from other tumors, for example, from malignant melanomas.
NLS-ultramicroscanning may provide accurate visualization of morphological damages of skin at
psoriasis. Epidermis at psoriasis is thickened and moderately chromogenic (3-4 points at Fleindler’s
scale). At the level of derma’s papillary layer a hyperchromogenic stripe of various thickness, more
intense at the acute stage, is present. Thus, according to NLS-graphy data we may judge about acuity of
a disease. When we use SEA – high spectral similarity with “Psoriasis” etalon (D<0,425).
Pic.3. NLS-ultramicroscanning of skin of right
hand index finger at generalized scleroderma.
Pic.4. NLS- ultramicroscanning. Epidermis at
psoriasis.
NLS-study of skin of patients suffering from generalized scleroderma we found that acquired data
varies depending on activity of the disease. When we study the acute stage of the disease we note sub-
epidermal hyperchromogenic stripe wider than in case of healthy skin, which is a result inflammatory
infiltration. A structure of a thickened derma becomes heterogeneous due to presence of achromogenic
areas against a hyperchromogenic background. With connective tissue thickness and chromogeneity
increasing, the difference between derma and hypoderm disappears.
Pic.5. NLS-ultramicroscanning. Scalp skin at
psoriasis.
Pic.6. Spectral-entropic analysis. Psoriasis
(D=0,214).
Subacute stage of generalized scleroderma is characterized by disappearance of sub-epidermal
hyperchromogenic stripe, at the same time derma’s structure becomes homogeneous and its thickness
decreases.
Moreover, to diagnose generalized scleroderma a researcher should apply evaluation of spectral
similarity to the etalon of this process by using of SEA, which is the basic diagnostic sign. To evaluate
changes of skin at localized scleroderma Cosnes A. et al. used non-linear sensor of 4.9 GHz frequency.
Thus, thanks to modern NLS-technologies, more accurate evaluation of changes at various skin
diseases becomes possible; it allows not only to improve diagnostics and start treatment in proper time,
but to ensure control of the treatment efficiency.
References:
1. Paltsev М.А., Potekayev N.N., Kazantseva I.А. and others. Clinical and morphological diagnostics of
skin diseases. М.: Medicina, 2004. p.12–17.
2. Jemec G.B., Gniadecka M., Ulrich J. Ultrasound in dermatology. Part I. High frequency ultrasound
//Eur. J. Dermatol. 2000. V. 10. № 6. P. 492–497.
3. Ulrich J., Voit C. Ultrasound in dermatology. PartII. Ultrasound of regional lymph node basins and
subcutaneous tumours // Eur. J. Dermatol. 2001. V. 11. № 1. P. 73–79.
4. Cammarota T., Pinto F., Magliaro A., Sarno A. Current uses of diagnostic high frequency US in
dermatology // Eur. J. Radiol. 1998. V. 27. Suppl.2. P. S215–S223.
5. Vogt M., Kaspar K., Altmeyer P. et al. High frequency ultrasound for high resolution skin imaging//
Frequenz. 2000. V. 54. № 1–2. P. 12–20.
6. Schmid Wendtner M.H., Burgdorf W. Ultrasound scanning in dermatology // Arch. Dermatol. 2005. V.
141. № 2. P. 217–224.
7. Vogt M., Ermert H. Development and evaluation of a high frequency ultrasound based system for in
vivo strain imaging of the skin // IEEE Trans. Ultrason. Ferroelectr. Freq. Control. 2005. V. 52. № 3. P. 375–385.
8. Turnbull D.H., Starkoski B.G., Harasiewicz K.A. et al. A 40–100 MHz B scan ultrasound backscatter
microscope for skin imaging // Ultrasound Med. Biol. 1995. V. 21. № 1. P. 79–88.
9. Marghoob A.A., Swindle L.D., Moricz C.Z. et al. Instruments and new technologies for the in vivo
diagnosis of melanoma // J. Am. Acad. Dermatol. 2003. V. 49. № 5. P. 777–779.
10.El Gammal S., El Gammal C., Kaspar K. et al. Sonography of the skin at 100 MHz enables in vivo
visualization of stratum corneum and viable epidermis in palmar skin and psoriatic plaques // J.Invest. Dermatol.
1999. V. 113. № 5. P.821–829.
11.Hoffmann K., Gerbaulet U., El Gammal S., Altmeyer P. 20 MHz B mode ultrasound in monitoring the
course of localized scleroderma (morphea) // Acta Derm. Venereol. Suppl. 1991. V. 164. P.3–16.
12. V.I. Nesterov. Computer nonlinear diagnostics. Collection of scientific papers of the Institute of
Practical Psychophysics “Current problems of NLS-diagnostics”. Tome 1. Moscow. Katalog, 2006, p. 5-6.
13. V. Artukh, U. Shovkoplyas, A. Gavrilov. Computer non-linear analysis and its role in diagnostics.
Collection of scientific papers of the Institute of Practical Psychophysics “Current problems of NLS-diagnostics”.
Tome 1. Moscow. Katalog, 2006, p. 9-12.
14. V.I. Nesterov. 3D NLS diagnostics. Prospect of development. Collection of scientific papers of the
Institute of Practical Psychophysics “NLS-diagnostics in medicine. Prospect of development”. Tome 3. Moscow.
Katalog, 2010, p. 5-8.
3D NLS-graphy in full-scale study of urinary bladder tumors.
A.M.Shmerkovich, K.S.Kogan
Moscow scientific-research oncological institute named after Gertsen P.A.
This article explains the possibilities of 3D NLS-graphy in full-scale study of urinary bladder tumors.
365 patients suffering from malignant tumoral affection of urinary bladder were examined. 317 patients
(86.8%) suffered from bladder cancer, 4 patients (1.1%) suffered from sarcoma, 6 patients (1.6%) suffered
from tumor deposits of another primary site, 2 patients (0.5%) suffered from malignant non-Hodgkins
lymphoma with bladder affection, 36 patients (9.9%) had tumor ingrowths into bladder wall from adjacent
organs. Possibilities of the method in primary and differential diagnostics and also in detection of local
prevalence of urinary bladder tumors depending on their localization are demonstrated in the given article.
There is also a description of the difficulties when performing NLS-diagnostics of urinary bladder tumors.
INTRODUCTION
Malignant urinary bladder tumors fill 8th
position in male and 18th
position in female patients within
the structure of oncological diseases. Urinary bladder tumor is in the 4th
position among oncourological
diseases according to the absolute rate of growth (the first three positions are: prostate cancer, renal cancer
and testicular cancer). The multiplicity of rudiments and frequent recuring is characteristic for the tumors of
urinary bladder.
In all the countries in majority of cases (90-95%) the tumors of urinary bladder are morphologically
transient cell carcinomas; the rest of cases relate to squamous cell cancer and adenocarcinoma. Non-
epithelial tumors consist less than 1%.
The main and the most reliable method of urinary bladder cancer diagnostics in clinical practice is still
cystoscopic examination with gathering of cytological or histological material. But this method does not
allow estimation of tumor invasion depth into bladder wall. The depth of invasion is one of the essential
factors when choosing surgical treatment: transurethral resection is not possible in case of affection of wall’s
muscular layer (category T2). In case of invasion of perivesical cellular tissue and tumor spread to the
adjacent organs (T3-T4) the risk of regional lymphatic glands affection increases: it consists 30% at T2 stage
and it reaches 65% at stage T4.
Computer tomography, magnetic resonance tomography and transurethral ultrasonic examination are
mainly used over the last years as corrective diagnostics methods to determine the depth of urinary bladder
tumor invasion. According to the information provided by Nesterova V. and others the recent method of 3D
NLS-research may become crucial both when specifying the prevalence rate of bladder cancer and when
performing case monitoring. Such advantages of the method as availability, painlessness and absence of
radiation exposure allow performing multiple researches when carrying out case monitoring.
Goal of the given article is to study 3D NLS-research possibilities in primary and corrective
diagnostics of malignant urinary bladder tumors, examination of complications which develop during NLS-
research of urinary bladder and also systematization, correction and supplementation of NLS-
semiotics of urinary bladder tumors.
MATERIAL AND METHODS OF THE STUDY
Full-scale 3D NLS-research of 365 patients (aged 26 - 83) with malignant tumoral affection of urinary
bladder was performed in the Institute named after Gertsen P.A. 317 patients (86.8%) suffered from bladder
cancer, 4 patients (1.1%) had sarcoma, 6 patients (1.6%) suffered from tumor deposits of another primary
site, 2 patients (0.5%) had malignant non-Hodgkins lymphoma with bladder affection, 36 patients (9.9%)
had tumor ingrowths into bladder wall from the adjacent organs. Male patients consisted the majority – 273
patients (74.8%) and 92 female patients (25.2%).
All patients were examined using 3D NLS-research of urinary bladder. In all cases the microscanning
of urinary bladder wall with spectral-entropy analysis of tissue structures was performed to provide
differential diagnostics of various cancer types. 3D NLS-research was performed using «Metatron»-4025
system (IPP, Russia) with 4.9 GHz frequency sensor.
All patients were operated on not later than 2 weeks after performance of NLS-research, the data of
morphological research were compared with the results of NLS-ultramicroscanning with spectral-entropy
analysis.
We have carried out NLS-ultramicroscopic research of 28 patients with no urinary bladder pathologies
to examine NLS-ultramicroscopic features of healthy urinary bladder wall.
RESULTS AND DISCUSSION
1. Ultramicro-NLS-semiotics of urinary bladder tumors. Difficulties of NLS-diagnostics of
urinary bladder tumors
We have developed ultramicro-NLS-semiotics of healthy urinary bladder wall and urinary bladder
wall with tumoral affection. Healthy urinary bladder wall has 2.5-8.0 mm. in thickness (depending on its
filling). In majority of cases it is possible to visualize 3 layers of bladder wall:
1) inner layer corresponds to mucous membrane with submucous layer; in its normal state – moderate
hypochromogenic (2-3 points according to Fleindler’s scale)
2) middle layer corresponds to muscular layer; in its normal state – hypochromogenic (2 points
according to Fleindler’s scale);
3) outer layer corresponds to adventitious membrane; in its normal state – a-hypochromogenic (1-2
points according to Fleindler’s scale);
Most commonly urinary bladder cancer in 3D NLS-microscopic image has an appearance of exophytic
formation of high hyperchromogenecy (5-6 points according to Fleindler’s scale) of round or irregular-shape
with uneven surface. In case of absence of infiltrating growth the line between tumor bottom and urinary
bladder wall is sharply defined, even and hypochromogenic (1-2 points). In case of infiltration the line
between tumor bottom and urinary bladder wall firstly becomes uneven, obscure then there appear tumor
structures in the wall’s depth. In this case wall layers stop differentiating. If the tumor grows into the whole
wall’s depth then the outer contour of the wall becomes uneven, sometimes obscure.
Pic. 1. 3D NLS-graphy. Bladder cancer in Pic. 2. NLS-ultramicroscanning of urinary bladder wall.
urinary triangle area. Urinary bladder cancer.
Tumor grows into prostate gland Onset of invasion of muscular layer.
Tumor with an endophytic component in invasion area is most frequently achromogenic, sometimes it
is isochromogenic. If the tumor grows endophytically it is most frequently isochromogenic in all parts. In
our opinion the detection of low chromogenic (1 point according to Fleindler’s scale) areas in the tumor of
urinary bladder is always indicative of infiltrating growth presence.
Tumor may be singular but tumors of urinary bladder most frequently have multifocal growth type up
to total affection of the whole bladder. Detailed examination of all bladder walls is necessary because of
this. Sizes, shape, chromogenecy and intensity of nodules invasion into the wall may be different in case of
multifocal growth.
Major problems when performing NLS-research are faced when diagnosing the invasion into the
submucous layer or when diagnosing the onset of invasion into the muscular layer. Spectral-entropy analysis
often allows solving of such problems.
Tumors (especially endophytic ones) which affect major part of bladder wall may cause its sharp size
reduction (microcystis). Small bladder capacity in such patients and also in patients who were surgically
treated (often repeated due to repeated relapses) may complicate the detection of tumor’s invasion depth.
Urinary bladder tumors (more often multifocal) in combination with intravesical clots may be
complicated for interpretation. Intravesical clots accompanied by macrohaematuria sometimes fill the whole
bladder cavity. In these cases it is always possible to differentiate the tissue of the tumor nodule from clots
using spectral-entropy analysis.
Diagnostic difficulties appear when detecting the depth of tumor invasion if the nodule is located in
urinary triangle (Lieutaud body) especially when it overlaps on the contour of prostate gland. Image
unsharpness of wall layers may be caused by multiple surgical interferences in case of bladder tumor
relapses and also intravesical immune- or chemotherapeutical treatment and layering of urinary salts.
The sensitivity of NLS-method in detection of tumor invasion depth in such patients may be
decreased.
Tumors coming from urachus must be described individually. When performing cystoscopic
examination the tumors of urachus do not differ from a common bladder tumor. But certain difficulties may
arise during NLS-research if one does not know the semiotics typical for urachus tumors. Urachus tumor is
characterized by the location on the frontal wall in upper part of the bladder and also there is a presence of
hyperchromogenic fibrotic fold (5-6 points according to Fleindler’s scale) of particular thickness that goes
upwards, gradually narrows and binds the tumor with omphalus. It may seem as if tumor invasion spreads to
adjacent tissues (however such tissues may not exist). Doppler sonography often detects intense blood flow
both in tumor bottom and along fibrotic fold. During diagnostics of such tumor it is necessary to perform
thorough examination to exclude premature metastasis in abdominal membrane, lymph glands and lungs.
Not only epithelial but also non-epithelial tumors may be found in urinary bladder. Despite the
infrequency of such diseases the diagnosis may be presupposed during NLS-research based on typical
ultramicroscopic picture. Preservation of complete or partial integrity of wall’s mucous layer is the
particular feature of non-epithelial tumors. In this case the major part of the node is located in wall’s depth
and beyond its borders.
Early relapse detection during case monitoring is one of the goals of NLS-research of patients who
suffer from bladder tumors. Semiotics of relapsing bladder tumors in patients after organ preservation
treatment does not have any fundamental differences from semiotics of primary tumors. Relapse of the
tumor after cystectomy looks like nodus of increased chromogenecy of regular or irregular shape with even
or uneven contour in bladder bed.
Metastatic affection of urinary bladder is possible (though quite rarely) besides presence of its primary
tumors. There are 2 typical variants of NLS-graphic picture for metastases that go into bladder wall. The
first one is round-shape tumor located in the wall’s depth with sharp smooth contour. Such variant resembles
non-epithelial tumor judging by NLS-picture. The second variant (rarer type of metastasis) is the tumor that
spreads on the wall; it resembles common picture of invasive cancer of urinary bladder. Information on
anamnesis and also the results of spectral-entropy analysis allow correct diagnosing.
Рис 3. Spectral-entropy analysis.
Leiomyosarcoma of urinary bladder (D=0.091)
More occasional variant of secondary affection of the bladder that sometimes cause diagnostic
difficulties is the intergrowth of tumors into wall of the bladder from the adjacent organs (most frequently it
is cancer of large bowel, neck of womb or prostate gland). When tumor ingrows into the wall of the bladder
this wall interrupts on the area that adjoins to the tumor and it is replaced by the tumor. Mucous layer may
be preserved or the tumor that ingrows in it may press into the lumen of the bladder. If the tumor comes
from large bowel then extraorgan tumor component that ingrows into urinary bladder changes to a typical
symptom of the affected hollow organ. If the formation comes from the neck of womb then the tumor which
is located in urinary bladder directly goes into changed neck. Nonorganic extraperitoneal tumors may
seldom ingrow into the wall of urinary bladder.
Pic. 4. NLS-scanning. Pic. 5. 3D NLS-graphy. Cervical cancer;
Cancer of the upper-and middle ampullar parts ingrowth into urinary bladder.
of straight intestine; ingrowth into urinary bladder.
The ingrowth into prostate gland is typical for tumors of urinary bladder located in the area of urinary
triangle; and ingrowth into urinary bladder wall is typical for prostate gland tumors. Differential diagnostics of
organ affiliation of prostate gland and urinary bladder tumors in case of ultramicroscanning has no real
difficulties in 95% of patients. Although there may appear some diagnostic difficulties if the process is
locally advanced and when urinary bladder in the area of urinary triangle and prostate gland (in rare cases
when multifocal tumoral affection of both organs is present) are involved into this process.
In majority of cases the clinical picture in such patients does not allow performing differential
diagnostics. Regardless of primary tumor localization there is distinct ankylurethria, often chronic urine
retention (especially if the tumor developed in patient with benign prostatic hyperplasia), pain syndrome and
macrohaematuria. Clinical picture does not exclude the possibility of prostate cancer and normal level of
prostate-specific antigen. The increase of prostate-specific antigen is not an absolute diagnostic indicator of
prostate cancer; although prostate-specific antigen is an organo-specific glycoproteid it is not OncoMarker
itself.
We have performed a full-scale study (including 3D NLS-ultramicroscanning with spectral-entropy
analysis and cystoscopy with targeted biopsy) of 28 patients with advanced cancer of urinary bladder who
were treated by cystprostatevesiculectomy and 17 patients with advanced cancer of prostate gland detected
by biopsy.
The analysis of NLS-picture in these patients was supplemented by spectral-entropy criteria of
morphologic affiliation of the primary tumor. The following signs are the most significant ones in
specification of primary process localization of large-scale urinary bladder tumors that ingrow into prostate
gland:
1) localization of the maximum tumor component in urinary bladder;
2) multicentric affections of urinary bladder;
3) presence of the sharp edges between tumor and prostate gland contours.
The absence of abovementioned signs and localization of general tumor mass in gland itself are the
most typical factors of prostate gland tumor.
Taking abovementioned signs into account allows accurate detection of which organ the locally
advanced tumor comes out from – whether it is urinary bladder or prostate gland. The accuracy of the
diagnostics of primary tumor site with consideration of these signs is 89.3%.
After performing of histological examination the multifocal synchronous tumoral process is found in 9
(32.1%) out of 28 patients with locally advanced cancer who had underwent surgery. These patients also
suffered from localized prostate cancer besides urinary bladder cancer. The secondary tumor was diagnosed
with the use of spectral-entropy analysis only in 1 of these patients.
As can be seen from the above the incidence of prostate gland cancer in these patients was the same as
in elder men of full set population. Doctor was not searching secondary tumor in prostate gland because he
was concentrated on solution of urinary bladder cancer prevalence problem. Obtained data demonstrates that
prostate cancer must be excluded as much carefully than in elderly patients in general in case of advanced
urinary bladder cancer.
2. The possibilities of various methods of NLS-research in case of urinary bladder tumors
The most statistically reliable method of NLS-research in case of urinary bladder tumors is an
ultramicroscopic research with the usу of spectral-entropy analysis. Such method provides the detection of
the tumor less than 3 mm., specifies its localization and in case of its invasive form it allows specifying its
proportion in relation to adjacent organs and tissues. It is possible to examine the layers of bladder wall in all
patients when using 3D NLS-ultramicroscopic research. We use spectral-entropy analysis in case of any
process localization in urinary bladder after performance of ultramicroscopic research. Only endocavitary
ultramicroscopic research is the most effective method for examination of all tumor aniages in case of
multicentric growth.
The visualization of small sized formations (less than 4 mm.) is complicated in case of common non-
scaling NLS-research; in more rarely cases the visualization of larger tumors located on the frontal urinary
bladder wall is complicated. Performance of spectral-entropy analysis with ultramicroscanning always helps
to make correct diagnosis in cases like these. The frontal urinary bladder wall which is put close to an
abdominal wall is visualized with considerable zooming in, which allows examining both wall layers and
their correlation with tumor nodule.
Common 2D NLS-research (which was put high hopes on) did not obtain widespread use in our
country. Such method allows good visualization of superficial formations though relatively large ones (from
6-8 mm).
In case of deep invasion it is not always possible to estimate the exterior contour of the tumor. These
peculiarities lower the effectiveness of 2D NLS-graphy method in detection of invasion depth into the
bladder wall.
At the present time we are able to use extensively NLS-research of urinary bladder tumors with 3D
reconstruction. The method allows visually presentation of the tumor and its correlation with surrounding
tissues when making decision on choosing of surgical procedures type, and it allows storing the information
in digital format. Information storing provides the possibility for attending doctors to subsequently review
the whole 3D information block which gives more objectiveness to 3D NLS-research.
CONCLUSIONS
1. Urinary bladder wall in 3D ultramicroscopic imaging has three-layer structure.
2. In case of urinary bladder cancer the common 2D NLS-research allows visualization of the tumor if
its size is more than 5 mm. When performing 3D-ultramicroscopic research the tumors less than 2 mm. can
be detected, it is also possible to define tumor’s growth form (exophytic, endophytic or combined one) and
its invasion depth into the wall (prevalence of invasion influence both on disease prognosis and therapy
method).
3. Major problems appear when diagnosing of initial tumor invasion into muscular layer.
Ultramicroscanning with spectral-entropy analysis helps defining the depth of invasion when this occurs.
4. Familiarity with typical semiotics allows making the correct diagnosis when performing NLS-
research in cases of non-epithelial tumors of urinary bladder and urachus tumors.
5. Information recording of anamnesis and performance of spectral-entropy analysis allow
presupposing the correct diagnosis in case of metastases into urinary bladder wall of tumors of another
primary localization.
6. Ultramicroscopic research with the use of spectral-entropy analysis allows specifying if the tumor
which had been detected in urinary bladder emanates from the bladder wall or it is just a part of the tumor
that emanates from other organs (large bowel, neck of womb, prostate gland and etc.) and ingrows into
bladder wall.
7. To perform an appropriate diagnostics it is necessary to use all available NLS-research means
considering the predisposition of urinary bladder tumor to multifocal growth.
8. Ultramicroscopic NLS-researches are the most effective ones when performing diagnostics of
urinary bladder tumors. 3D reconstruction of the image increases both the effectiveness of diagnostics and it
also provides more informative presentation of detected changes and it gives the possibility for reviewing of
stored information.
9. In case of urinary bladder cancer it is necessary keep in mind the possibility of synchronous prostate
cancer.
1
DIAGNOSTIC POTENTIALITIES OF THREE-
DIMENSIONAL NLS-GRAPHY
V.I.Nesterov, V.I.Nesterova
This publication contains modern principles of three-dimensional images rendering in
accordance with NLS-graphy data. Also it gives overall evaluation of three-dimensional NLS
graphy diagnostic value for revealing of various diseases in comparison with other methods of
hardware diagnostics, such as roentgenography, computerized tomography and magnetic
resonance imaging. Special attention is paid to advantages and disadvantages of various
techniques of three-dimensional images rendering.
Three-dimensional pictures of human’s internal organs became a part of general practice
in early 90’s after computer tomographic scanners were equipped with powerful computing
systems capable of controlled processing of two-dimensional crosscuts. Nowadays three-
dimensional representation of elements of diagnostically interesting zone is an everyday reality
in leading clinics of the world.
Method of three-dimensional representation of diagnostic data is generally related to
powerful hardware resources, i.e. acquiring of parallel (or placed at previously specified angles)
magnetic-resonance, roentgen or NLS-graphic images with their following integration into single
visual array where an operator can separately visualize bones, muscles, soft tissues, vessels,
nerves etc. highlighting them with color while other tissues are shown in gray semitransparent
tone.
Rendering of three-dimensional NLS-graphic images of abdominal cavity organs is
considered nowadays to be an experimental task mainly. Rarely used due to its low information
value method of creating of separate two-dimensional images of abdominal cavity organs by
means of NLS-visualization is much more interesting for rendering three-dimensional diagnostic
images.
In addition to solving of usual objectives on the basis of two-dimensional NLS-graphy of
abdominal cavity organs data many parallel diagnostic tasks are solved by means of non-linear
algorithms and massive calculations application.
Maybe that is how should be explained so accurate results described in one of the first
reports about three-dimensional reconstruction on the basis of transabdominal NLS-data (T.G.
Kuznetsova, R.A. Sorokina).
We place our great hopes on three-dimensional NLS-graphy, first of all related to its
application in endoscopy. In 2010 V.I. Melushko theoretically justified an opinion that
application of three-dimensional NLS-research in laparoendoscopic surgery will allow to “look
beyond the horizon” and see anatomic structures which cannot be visualized when using
laparoscope. He believed that NLS-graphy is diagnostically efficient, safe and affordable
procedure.
2
A.Y. Shvack and L.P. Goltsova (Pic.1) found out that at size changing of hepatic focal
formations two- and three-dimensional NLS-graphy are equally precise when shape of
neoplasms is relatively simple - close to roundish or oval. However, the authors state that if
shape of neoplasms is complex, results of two-dimensional NLS-graphy matched in 65% of
cases only, when at three-dimensional visualization – in 92% of cases.
Pic.1. 3D-image of hepatic neoplasms foci
In 2010 S.A. Volkova and A.V. Zaitsev reported about results of three-dimensional
transabdominal NLS-graphy application in diagnostics of hepatobiliary system, in particular for
specifying diagnostics of previously revealed neoplasms. The objective of their research was
accuracy evaluation of three-dimensional NLS-graphy method with application of spectral-
entropic analysis (SEA). Acquired results were compared with information gathered by
computed tomographic portal venography carried out on spiral tomograph. Altogether 62 cases
were analyzed including those with hepatic neoplasms sized from 1.5 cm to 12.3 cm. The
researches showed that three-dimensional model built on the basis of NLS-data (Pic.2) contains
more precise and valuable diagnostic information in comparison with usual two-dimensional
NLS-graphy or data acquired with CT. The authors believe that three-dimensional NLS-graphy
is financially affordable procedure for diagnostic of tumor affections.
3
Pic.2. Ultramicroscanning of hepatic tubules at liver cancer
Above mentioned studies (except single publications about diagnostics of stomach and gall
bladder pathologies) are almost everything we have in sphere of systematized studies about
three-dimensional reconstruction of organs and neoplasms in abdominal cavity based on date
acquired with transabdominal NLS-studies which were ever mentioned in periodic scientific
literature.
Mentioned difficulties of methodological and computing character are leveled in a great
measure by endoscopic and intraoperational NLS-research of abdominal cavity and small pelvis
organs, when the most difficult stage of three-dimensional visualization becomes textural
segmentation of acquired two-dimensional picture.
Hishimura T. et аl. (Pic.3) compared results of endoscopic ultrasonography of
gastrointestinal neoplasms with date acquired with NLS-scanning.
4
Pic.3. 3D NLS-image of large intestine cancer
In two cases of esophagus cancer, in two cases of rectum cancer and in 7 of 10 cases
(Pic.4) of stomach cancer results of three-dimensional reconstruction made on the basis of NLS-
graphy were accurate in relation to depth of tumorous invasion.
Pic.4. 3D-image of stomach cancer
5
Japanese scientists Katamaki S. et аl. (Pic.5) reported in 2011 about preliminary results
of three-dimensional NLS-graphy application in 26 patients. Three-dimensional reconstruction
made on the basis of three-dimensional pictures allowed to define presence of metastatic
affection of surrounding organs and in 4 of 6 cases of bile duct cancer – to define volume of
tumorous tissue.
Pic.5. 3D NLS-picture of common bile duct cancer
with affection of regional lymph nodes
Fox P. et аl. (Pic.6) used NLS-study for three-dimensional reconstruction of esophagus picture in
5 patients suffering form esophagus cancer. The research was carried out with sensor’s
frequency of 4.9 GHz. Three-dimensional pictures were reconstructed on the basis of series of
cross-cut pictures. Precise three-dimensional visualization of tumor’s structure and surrounding
tissues were acquired in all cases. In this study proper determining of tumorous process stage
was achieved in three of four cases. The authors note special diagnostic value of pictures
showing longitudinal sections of tumor which allow to define precisely its length and connection
with mediastinal structures.
6
Pic.6. Longitudinal 3D NLS-image of esophagus cancer
Among of the most standardized methods of research are three-dimensional NLS-graphy
of rectum and NLS-scanning of prostate.
German oncoproctologists Operbein K. et аl. (Pic.7) have studied more than 100 patients
suffering from rectum tumors with three-dimensional NLS-graphy.
Pic.7. 3D NLS-image of rectum cancer
7
Diagnostic accuracy of three-dimensional ultrasound research in this group was 89%, at the same
time accuracy of two-dimensional NLS-graphy in the same group of patients was 76%. Accuracy
of these methods in defining of pararectal lymph nodes affection was 85% at three-dimensional
visualization and 71% in accordance with two-dimensional data. The authors believe that three-
dimensional NLS-graphy allows to overcome well known limitations of two-dimensional NLS-
study which are usually faced at obstructing tumor and in revealing of recurrent cancer of
rectum.
Operbein K. et аl. also used three-dimensional NLS-graphy to detect recurrent
malignization of rectum in patients after surgical treatment of rectum cancer. Possibilities of
two-dimensional NLS-study in these cases are strictly limited due to massive growth of fibrous
tissue. Data for three-dimensional reconstruction was acquired by Operbein K. and Schmidt A.
who used non-linear scanner co-manufactured by IPP (Omsk, Russia) and the firm's Clinic Tech
Inc. (USA) with operating frequency of 9.6 GHz. Three-dimensional NLS-graphy have helped to
find pararectal neoplasms in 28 of 163 patients. Spectral-entropic analysis confirmed recurrent
cancer in 7 patients and metastatic affection of lymph nodes in 2 patients correspondingly.
Therapists of pediatric surgery department Stubdreier H. et аl. (Pic.8) of Tübingen
University (Germany) used three-dimensional NLS-graphy of pelvic floor as an auxiliary
diagnostic instrument for determining of surgical tactics for treatment of children suffering from
stool incontinence. The study included visualization of sphincter muscles and rectum walls;
results of the study were confirmed by data acquired with spiral computed tomography. A
distinctive feature of this study was using of interactive tissue segmentation of organs and tissues
by means of 4D TISSUE mode application during their three-dimensional visualization.
Pic.8. 3D-ultramicroscanning of rectum cancer
8
Chun L.G. et аl. (Pic.9) carried out three-dimensional NLS-graphy of malignant prostate
gland in 46 patients. In accordance with gathered diagnostic data cryoablation of prostate gland
was fulfilled.
Pic.9. 3D NLS-graphy of malignant prostate gland
Possible diagnostic value of three-dimensional NLS-graphy is most clearly seen during
examination of small pelvis organs in women, where conventional diagnostic methods allow to
see advantages and disadvantages of each of them.
Akuda T. et аl. have not got any additional information using three-dimensional NLS-
graphy in comparison with usual two-dimensional NLS-study which revealed uterine cavity
septa in one woman, fibroid foci in three women and endometrial polyp in one woman of five
examined patients.
Spanish gynecologists Brisoles H. et аl. have studied possibilities of three-dimensional
NLS-graphy, transvaginal sonography, transvaginal Doppler sonography, hysteroscopy and usual
hysterosonography in diagnostics of endometrial tumors and defining of endometrium thickness
during hormonal treatment in 16 patients. Three-dimensional NLS-study was found the most
accurate diagnostic method of all methods studied.
Chun L.G. et аl., a group of gynecologists of Temple University (Philadelphia) in 2011
reported about results of comparative study of diagnostic efficiency of three-dimensional and
two-dimensional NLS-graphy. Altogether 8 women (Pic.10) suffering from surgical diseases of
ovaries were examined. Later on all patients were subjected to explorative laparotomy or
diagnostic laparoscopy. NLS-graphy data was compared with intraoperational findings and
results of macroscopic and histological studies. In all eight cases three-dimensional NLS-graphy
managed to define correct diagnosis before surgical intervention. It is especially important that in
absence of difference in diagnostic accuracy of three-dimensional and two-dimensional study of
9
cysts and benign neoplasms, two-dimensional NLS-graphy turned out to bell less accurate in
detecting of malignant tissues, giving both false-positive and false-negative results.
Pic.10. 3D-ultramicroscanning of ovarian cancer
Spoun N. et аl. (Pic.11) have carried out comparative evaluation of two-dimensional and
three-dimensional NLS-graphy accuracy in specifying diagnostics of uterine neck cancer. The
study was carried out in 61 women one day before surgical intervention; accuracy of three-
dimensional examination was in range of +6.68 to -6.1 ml, two-dimensional – from +12.46 to -
10.98 ml.
Pic.11. 3D-ultramicroscanning of uterus cervix cancer
10
French gynecologists Sarida M. et аl. used three-dimensional NLS-graphy for diagnostics
of atropic pregnancy in 12 women with amenorrhea period above 6 weeks. Laparoscopy detected
atropic pregnancy in 9 cases, only in 2 of them it was found on NLS-pictures. Hence the authors
believe that this diagnostic method is ineffective, especially for early non-invasive detection of
gestational sac development in fallopian tube.
Other methodologically valuable results for evaluation of advantages of three-
dimensional representation of NLS-graphic data were results acquired at NLS-study of
mammary glands.
Bluhmberg S.O. et аl. (Pic.12) have used three-dimensional NLS-graphy of mammary
gland in study of 48 women, 18 of which had malignant neoplasms of mammary gland. The
therapists reported about 4 false-positive mammary gland cancer diagnoses against two cases of
false-positive diagnoses when two-dimensional NLS-graphy was used. At the same time the
authors note that three-dimensional NLS-graphy has advantages in evaluation of edge zones and
shape of pathological nidus and also at multifocal affection of mammary gland.
Pic.12. 3D-image of mammary gland cancer
English breast physicians Havies L. et аl. (Pic.13) of Bristol University used three-dimensional
NLS-graphy of mammary gland and in some cases managed to reveal and detect internal
structure of intraductal carcinoma by means of spectral-entropic analysis, and neoplasms
simulating microinvasive carcinoma. Such outstanding diagnostic results authors achieved using
non-linear sensor of 9.6 GHz frequency that allowed to get resolution of 30 microns.
11
Pic.13. 3D-ultramicroscanning of mammary gland cancer
A peculiar etalon test of diagnostic efficiency of three-dimensional reconstruction at complex
configuration of source two-dimensional data is considered NLS-scanning of bloodstream,
results of which are compared with similar data acquired by traditional and well known
radiographic contrast study.
In 2011 Bljger K. et аl. (Pic.14) reported about results of a study than have been carried out in
University hospital of Antwerp and were devoted for “reconstruction of bloodstream’s
geometry” in accordance with data of radiographic contrast angiography and intracoronary NLS-
study. After evaluation of reconstruction precision of studies performed on special phantoms, the
authors agreed to consider acquired results “very realistic” and offered a number of criteria for
comparative evaluation of three-dimensional bloodstream reconstruction precision. Clinical part
of the study contained comparison of reconstructed three-dimensional images of coronary
arteries with data acquired with usual angiograms. The difference was less than 5%.
12
Pic.14. 3D-image of coronary artery
Prust G.J. et аl. note the following advantages of reconstructed images of arteries,
acquired with intravascular NLS-study: 1) a vessel may be seen from different sides and angles,
2) its direction may be seen, 3) changes of vessel’s diameter are clearly visible, 4) a possibility to
get a cross-section of a vessel in any plane of scanning, 5) condition and location of intravascular
stent may be found with high precision.
Kogan S. et аl. (Pic.15) have determined high diagnostic efficiency of three-dimensional
intravascular NLS-graphy in visualization of arterial wall structure and its pathological changing.
The authors believe that intravascular NLS-graphy with following three-dimensional
reconstruction significantly excels coronary angiography, because it have better resolution and
allow to reveal many hidden neoplasms; that is why it is irreplaceable at study of coronary
arteries condition after heart transplantation.
13
Pic.15. 3D-ultramicroscanning of vascular wall
The most impressive was using of three-dimensional NLS-study data for intraoperative
navigation and computed modeling of surgical manipulations.
Serbia S. – a head of obstetrics and gynecology department of Washington University
reasonably stated that three-dimensional NLS-study is a potential diagnostic instrument which in
near future will become the main source of data for preoperative surgical training which uses
individual diagnostic data.
Three-dimensional NLS-graphy may be widely used in cardiosurgery as a method of
intraoperational navigation. Quite character in this relation is a study of cardiothoracic surgeons
from North Carolina Abrams O.H. et аl. (Pic.16) who presented in 2011 a detailed report about
wide clinical application of intraoperational three-dimensional NLS-graphy during replacement
of cardiac valves. The authors say that this diagnostic method helped them to get important
intraoperational data when they used spectral-entropic analysis about morphological peculiarities
of valves, which weren’t revealed by echocardiography and Doppler sonography.
14
Pic.16. 3D NLS-picture of cardiac valves
The authors say that this diagnostic method helped them to get important intraoperational
data when they used spectral-entropic analysis about morphological peculiarities of valves,
which weren’t revealed by echocardiography and Doppler sonography.
Going beyond the most optimistic ways of possible application of three-dimensional
NLS-graphy, Parris D. et аl. (Pic.17) use data about prostate gland structure acquired by this
method for computerized control of robot (!) movement during fulfillment of transrectal
resection.
Pic.17. 3D-ultramicroscanning of prostate gland
15
An unique and apparently having no equals in efficiency navigation algorithm was
offered by Hatayama T. et аl. – scientists of Tokio University in 2012. They reported about
possibility of precise matching of three-dimensional pictures acquired by CT and MRI in
preoperational period with data of three-dimensional NLS-research acquired during
neurosurgical intervention. NLS scanner of 4.9 GHz frequency was an integral part of a system
and had built-in positioning device. The authors report about successful clinical application of a
system in three cases and note good complementarity of NLS-graphic pictures and MRI and CT
data. On the one hand, not visualized on NLS-picture parts of surgical intervention zone were
filled by pictures got during preoperational period; on the other hand precise intraoperational
positioning of various anatomic objects on NLS-sonogram allowed to identify them without any
doubts. According to the authors, even preliminary results of this study allow to think about
beginning of a new stage in intraoperational navigation based on NLS-graphic three-dimensional
pictures of human body, which was not possible at separate application of above mentioned
methods or inaccurate matching of pictures acquired with this method.
On the whole in comparing of diagnostic efficiency of indirect visualization various
methods, NLS-graphy, significantly pressed in surgical room by such hardware titans as CT and
MRI, in 2 recent years started to get new significance because of improving of both visualization
method itself and results of three-dimensional reconstruction on the basis of NLS-graphy data.
Improving of diagnostic equipment
Thanks to a number of qualitative changes of NLS-diagnostic devices, NLS-graphy
potentials were widened to extent unthinkable even few years ago, when CT and MRI had
obviously growing advantage in surgical gastroenterology.
Application of high-frequency sensors during NLS-studies in gastroenterology allowed to
move early diagnostics of pathology to a qualitatively new and higher level. By means of
spectral-entropic analysis and ultramicroscanning it is possible to diagnose superficial carcinoma
of esophagus or stomach, when cancerous cells infiltrate mucous and sub-mucous levels only
and initial manifestations of metastases in perioesophageal and periogastric lymph nodes. It is
considered that application of high-frequency sensors at three-dimensional visualization ensures
determining of depth and length of tumorous infiltration into stomach walls in 93.6% of cases.
Besides using of high-frequency sensors allows to excel all known methods of polyps and bile
papilla cancer diagnostic, at the same time specificity of the method at preoperational diagnostic
of choledocholithiasis reaches 94%. And finally, there is information that application of high-
frequency sensors allows to visualize concrements not visible even at intraoperational
cholengiography.
Conclusion
Even now when methods of three-dimensional NLS-diagnostics are in stage of formation
and standardization, it is possible to conjecture direction of their further development in relation
to mutual competence and complementarity.
16
In 2011 Dupta D. and Supuy X.E. while noting that for the last 5 years significant
difference in visualization methods at acute abdominal pathology was related to CT mainly,
stated that at the present time, thanks to technological improvement of NLS-scanners, NLS-
graphy must become the first diagnostic instrument for patients suffering from acute stomach
pain and women suffering from acute pain in right lower quadrant of stomach and small pelvis.
The authors believe that computed tomography is necessary only when NLS-graphy turned out
to be diagnostically inefficient. According to the authors place of MRI in diagnostic sequence at
acute surgical diseases of abdominal cavity organs is uncertain due to absence of its wide
application.
Sun K., Bergman P. and Flager W. of Cambridge University hav e developed an
algorithm of “wire” model of organs building on the basis of their frequency characteristics,
acquired by various methods of medical registration. The most demonstrative result of this
algorithm application is its application of liver model reconstruction on the basis of three-
dimensional NLS-study, the authors say.
Thus role of three-dimensional NLS-research in combined diagnostics is constantly
growing and becoming quite unique. At the same time in modern high-quality representation of
diagnostic data, in particular in surgical gastroenterology, two-dimensional models in many
cases are insufficient for acquiring of comprehensive diagnostic information.
Other important aspect is improving of applied methods of three-dimensional diagnostic
data presentation, which will help to implement numerous possibilities of efficient visualization
of researched objects and use their graphic images for computer training simulators and real
intraoperational navigation.
Solving of these problems is the most efficient way to improve quality of preoperational
diagnostics and boosting of surgical accuracy.
Achieved hardware-software level of ultramicroscanning and spectral-entropic analysis,
gathered positive experience of topological and tissue segmentation of organ’s virtual pictures,
rapid development of three-dimensional animation software available for average personal
computer allow to put a reasonable question about need in development and clinical approval of
practically acceptable and unified methods of three-dimensional parametric animation on the
basis of NLS-data.
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