The Impact of skin cancer. The role and importance of Dermatopathology today
C. Solovan
University Clinic of Dermatology and Venereology, Timisoara
This October (2009) in Timisoara - Romania will be held the first conference of dermatopathology under the aegis of Romanian Society of Dermatopathology (SRDP). Dermatopathology is the most important aid to clinical diagnosis in dermatology. Its value in establishing a specific diagnosis of all kinds of diseases, inflammatory and neoplastic chief among them, is unquestioned. Today the field of dermatopathology has expanded beyond traditional morphologic evaluation by gross and light microscopy to include electron microscopy, immunohistochemistry and molecular biology.
Nearly all the major congresses and scientific meetings in dermatopathology have been organized by dermatologists. Thus, dermatopathology can be considered, historically and scientifically, to have derived primarily from dermatology.
Dermatopathology combines two separate, although related disciplines, to wit, clinical dermatology and general pathology. Both fields are rooted in morphology and both have much in common. We view dermatopathology as the combination of macroscopic pathology (i.e., clinical diagnosis of skin diseases) and microscopic pathology (i.e., diagnosis of skin diseases with the aid of a lens of various magnifications).This definition leads to the logical conclusion that for a dermatologist to practice dermatopathology, he or she must have solid grounding in general pathology, just as a general pathologist who practices dermatopathology must have training in clinical dermatology.
Dermatopathology not only is important in routine diagnosis of skin lesions but it is also an effective vehicle for teaching dermatology and pathology to medical students and residents in those specialities precisely because insights into the cause, mechanisms and treatment of various cutaneous disorders become possible by virtue of being able to correlate the clinical features in living color with the histopathologic findings.
This scientific meeting represents the very beginning of dermatopathology in Romania and we hope that will be very attractive for dermatologists as well as for other doctors!
Changes in the TNM Classification of Skin Tumors (7th edition)
Prof. Dr. med. Christian Wittekind and Dr. Med. Tanja Gradistanac
Institut fur Pathologie, Universitatsklinikum Leipzig, Liebigstrasse 26, D-04103 Leipzig,
E-Mail: wittc@medizin.uni-leipzig.de
Abstract
In the seventh edition of the TNM Classification many of the tumor sites have remained unchanged from the sixth edition. However, in some tumor entities major alterations are to be expected, among which are tumors of the skin. These changes will be shown and discussed in this presentation the classifications apply to carcinomas of the skin (including eyelid, excluding vulva and penis), to malignant melanomas of skin (including eyelid) and to Merkel cell carcinoma.
There are no changes in describing the headings for each tumor type or in the definition of the regional lymph nodes. The summary of skin carcinoma is as follows:
| T1 | < 2 cm |
| T2 | > 2 cm |
| T3 | Deep structures |
| T4 | Skull base, axial skeleton |
| N1 | Single, < 3cm |
| N2 | Single, > 3 to 6 cm Multiple, < 6 cm |
| N3 | > 6 cm |
Newly introduced have been some high risk features which are:
| Depth/Invasion | > 4 mm thickness Clark level IV Perineural invasion Lymphovascular invasion |
| Anatomic location | Primary site ear Primary site non-glabrous lip |
| Differentiation | Poorly differentiated or undifferentiated |
Note: AJCC considers Stage I tumors with more than one High Risk feature as Stage II.
Carcinomas of the Skin of Eyelid (ICD-O C44.1) should be histologically confirmed and cases should be divided by histological type. The regional lymph nodes are the preauricular, submandibular and cervical lymph nodes.
TNM Clinical Classification - T - Primary Tumor, N - Regional Lymph Nodes
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ |
| T1 | Tumor 5mm or less in greatest dimension not invading the tarsal plate or eyelid margin |
| T2a | Tumor more than 5 mm, but not more than 10 mm in greatest dimension or any tumor that invades the tarsal plate or eyelid margin |
| T2b | Tumor more than 10mm, but not more than 20 mm in greatest dimension or, involves full thickness eyelid |
| T3a | Tumor more than 20 mm in greatest dimension or any tumor that invades adjacent ocular or orbital structures or any tumor with perineural invasion |
| T3b | Tumor whose complete resection requires enucleation, exenteration or bone resection |
| T4 | Tumor is not resectable due to extensive invasion of ocular, orbital, craniofacial structures or brain |
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
Stage Grouping
| Stage 0 | Tis | N0 | M0 |
| Stage IA | T1 | N0 | M0 |
| Stage IB | T2a | N0 | M0 |
| Stage IC | T2b | N0 | M0 |
| Stage II | T3a | N0 | M0 |
| Stage IIIA | T3b | N0 | M0 |
| Stage IIIB | Any T | N1 | M0 |
| Stage IIIC | T4 | Any N | M0 |
| Stage IV | Any T | Any N | M1 |
There are no changes in malignant melanomas of the skin.
A TNM classification for Merkel cell carcinoma of the skin has been introduced:
| TNM | Clinical Classification |
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ |
| T1 | Tumor 2 cm or less in greatest dimension |
| T2 | Tumor more than 2 cm but not more than 5 cm in greatest dimension |
| T3 | Tumor more than 5 cm in greatest dimension |
| T4 | Tumor invades deep extradermal structures, i.e., cartilage, skeletal muscle, fascia or bone |
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
| N1a | Microscopic metastasis (clinically occult: cN0 + pN1) |
| N1b | Macroscopic metastasis (clinically apparent: cN1 + pN1) |
| N2 | In-transit metastasis |
Note: In-transit metastasis: a tumor distinct from the primary lesion and located between the primary lesion and the draining regional lymph nodes or distal to the primary lesion.
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| M1a | Skin, subcutaneous tissues or non-regional lymph node(s) |
| M1b | Lung |
| M1c | Other site(s) |
Stage Grouping
| Stage 0 | Tis | N0 | M0 |
| Stage I | T1 | N0 | M0 |
| Stage IA | T1 | pN0 | M0 |
| Stage IB | T1 | cN0 | M0 |
| Stage IIA | T2, T3 | pN0 | M0 |
| Stage IIB | T2, T3 | cN0 | M0 |
| Stage IIC | T4 | N0 | M0 |
| Stage IIIA | Any T | N1a | M0 |
| Stage IIIB | Any T | N1b, N2 | M0 |
| Stage IV | Any T | Any N | M1 |
The background for the introduction of new classification and the changes in the existing classifications will be discussed. In addition, explanatory notes will be presented as well as site-specific recommendations for pT and pN.
Skin cancer as a public health problem
Ursoniu S.
Department of Public Health, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
Skin cancer remains a major public health problem. Cancer of the skin (including melanoma and basal and squamous cell skin cancers) is the most common of all types of cancer. The number of people who develop basal and squamous cell skin cancers each year is not known for certain. Statistics of most other cancers are known because they are reported to cancer registries, but basal and squamous cell skin cancers are not reported. According to the Romanian West Region Cancer Registry 12.36 new cases of melanoma per 100,000 population were detected during 2008. This type of cancer comes in fourth place after bronchopulmonary, colorectal, and gastric carcinoma. The American Cancer Society estimates that about 68,720 new melanomas will be diagnosed in the United States during 2009. Melanoma accounts for less than 5% of skin cancer cases but causes a large majority of skin cancer deaths. More than 1 million basal and squamous cell skin cancers are found each year in United States. Most of these (about 800,000 to 900,000) are basal cell cancers. Squamous cell cancer is less common - there are about 200,000 to 300,000 cases per year. Efforts to decrease the morbidity and mortality associated with skin cancer are gradually shifting toward primary prevention. Primary prevention efforts should not only be limited to using sunscreen, but should also focus on reductions in ultraviolet light exposure. Secondary prevention efforts include professional skin examinations and skin self-examination. Tertiary efforts focus on the prevention and detection of additional primary skin cancers.
The impact of tumor neoangio and - lymphangiogenesis capacity on patient's prognosis
Ch. Rosenberger*, C. Solovan**
* Medical University Berlin
** University Clinic of Dermatology and Venereology, Timisoara
Angiogenesis and lymphangiogenesis reflects an equilibrium between angiogenesis growth factors (pro-angiogenic) and angiogenesis inhibitors (antiangiogenic). Angiogenesis involves a series of defined steps. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway plays an important role in angiogenesis. Akt1 is involved in angiogenesis and tumor development, as well as hypoxia inducible factor. Matrix Metalloproteinases are involved in both physiologic and pathologic angiogenesis by degrade extracellular membrane components to permit new blood vessel formation. Angiogenic effects of the VEGF family are thought to; VEGF and its receptors promote cell growth and survival through a mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway. Up to 60% of cancers express VEGF.
In a healthy adult blood vessels are stable. Growth of new blood vessels from preexisting ones occur during growth and development, wound healing but also involved in tumor developement, invasion and metastasis but other disease processes too (psoriasis). Melanoma cells secrete basic Fibroblast Growth Factor (bFGF) and express VEGF, PDGF, TGFβ ;the TNF-family is involved in angiogenesis, invasion and metastasis too and being able to induce Il-8, VEGF, MMPs.
Anti-angiogenic agents appear to be most effective for cutaneous cancers when used in combination with cytotoxic treatments. EGFR is over-expressed in metastatic cutaneous SCC. Cetuximab has been used for treatment of aggressive or metastatic disease, and complete clinical clearance of a cutaneous SCC with Bortezomib. Activated Akt was increased in Spitz nevi and melanomas as compared to benign nevi. Microarray analysis demonstrated that patients with strong phosphorylated Akt expression in melanoma tissue has a lower 5-year survival. Sorafenib for metastatic MM had partial response and produced stable disease in a low number of patients.
Sirolimus for Kaposi Sarcoma resolved 16/17 lesions in one patient with Mediterranean KS. Combination therapy of cytotoxic agents and anti-angiogenic agent may be more effective.
Beyond the H&E Stain in Melanocytic Neoplasia: Emerging Molecular Tests for the Diagnosis of Melanoma
Aleodor A Andea, M.D.
University of Alabama at Birmingham
Melanoma is the leading cause of death among primary cutaneous neoplasms. Despite significant efforts directed towards finding new therapies, after the disease spreads to distant sites, there is little that can be offered to the patients in term of treatment options. The best chance for cure is obtainable by early detection followed by surgical excision. Currently, the gold standard for the diagnosis of melanoma, and especially for differentiation from benign melanocytic neoplasms (melanocytic nevi), is histopathologic examination. However, despite constant refinement of morphological criteria, in a significant number of cases a definitive diagnosis of melanoma remains elusive.Recent molecular studies have revealed genomic differences between melanomas and melanocytic nevi. Although both melanomas and nevi share initial genetic alterations such as mutations in BRAF and NRAS oncogenes, there are significant differences in the presence or absence of clonal chromosomal aberrations. While the majority of melanomas demonstrate numerous chromosomal gains and losses, benign nevi have no detectable chromosomal abnormalities. In addition, melanomas appear to have deficient cell cycle control mechanisms. These findings have prompted new, albeit yet to be proven, hypotheses regarding mechanisms of progression in melanoma and the relationship between melanomas and benign nevi. On a more practical note, the significant differences in the pattern of chromosomal alterations have proven to have diagnostic implications. Assays evaluating these abnormalities are starting to be implemented into clinical practice and could become important tools in the diagnosis of this deadly disease. The course will discuss the new theories regarding oncogenetic pathways in melanocytic neoplasia. Various techniques that can be used to detect chromosomal alterations in melanocytic lesions and assist in diagnosis such as comparative genomic hybridization using metaphase chromosomes and microarrays as well as fluorescent in situ-hybridization assays will be explained and illustrated.
Preoccupations of the Morphopathology discipline of the 'Victor Babes' Medicine and Pharmacy University of Timisoara, concerning the various clinical specialties
Elena Lazar, Anca Muresan, Codruta Lazureanu
Morphopathology discipline, 'Victor Babes' Medicine and Pharmacy University of Timisoara
The first full professor of the Morphopathology discipline was professor Benedict Menkes, Ph.D. At the leadership of the discipline were: Lecturer Augustin Muresan, Ph.D., between 1956 and 1959, professor Leonida Georgescu, Ph.D., between 1960 and 1991, professor Nicolae Tudose, Ph.D., between 1991 and 2004, and starting with 2004 and until the present day, professor Elena Lazar, Ph.D.
The Morphopathology discipline activates in a completely restored facility, and includes its own course hall, 3 halls for practical activities, a museum, 2 laboratories and offices for its teaching staff. The discipline's staff consists of 10 teaching staff members and 2 laboratory technicians. The technical and material endowments allow the performance of an optimal didactic process with our students, of the post-graduate education and of the scientific research activity.
The Morphopathology is taught in the 3rd year of General Medicine (in Romanian and in English languages), in the 2nd year of Dentistry and 2nd year of the Clinical Laboratory College. Between 1995 and 2002, under the leadership of professor Nicolae Tudose, Ph.D., have been drawn up and issued, at the disposal of the students, the Morphopathology course and the Practical Activities Guide, issued in 3 successive editions, the Morphopathology course in English language and the course for the students belonging to the Physiokinetotherapy section. Professor Elena Potencz, Ph.D. guided the elaboration of two courses for the students in the Dentistry section.
Under the leadership of Mrs. professor Elena Lazar, Ph.D., were drawn up: a new course for the students of the General Medicine Faculty (General Morphopathology and Special Morphopathology (Eurobit Publishing House, Timisoara, 2008, respectively 2009), two guides regarding practical activities in successive issues (Eurobit Publishing House, Timisoara, 2008 and Eurostampa Publishing House, Timisoara, 2008); Lecturer Marioara Cornianu, Ph.D., was preoccupied with the drawing up of the General Morphopathology course for the Dentistry section (Eurobit Publishing House, Timisoara, 2008); Head of works, Codruta Lazureanu, M.D., has elaborated the course 'General Pathology - textbook and practical sessions' second issue, for the English section of the General Medicine Faculty (Eurobit Publishing House, Timisoara, 2008); Lecturer Anca Muresan, Ph.D., has drawn up the course of Morphopathology for the Clinical Laboratory College (Eurobit Publishing House, Timisoara, 2007).
For all the academic years, the teaching of the courses and the practical demonstrations beneficiate of an iconography rich in colors - lantern slides, CDs, video recordings. The discipline's museum, with its rich collection of macroscopic preparations, as well as the hospitals' morgues, ensures the Morphopathology teaching the possibility to illustrate the macroscopic lesional sublayer of various afflictions.
Within the discipline is performed a scientific research activity to which take part, besides the teaching staff, candidates for a doctor's degree, residents, students. This activity is proven by finalized doctoral thesis, as well as by a large number of works published or presented at various scientific manifestations. In the last two years, there were organized post-graduate courses: 'Cervix's Pre-cancer and Cancer' during the period between 24th and 27th January 2007; 'Intraepithelial and Borderline Lesions in Pathology', January 2008.
Within the discipline functions the department for services providing, offering high-degree specialty assistance, by histopathological and immunohistochemical techniques. Thus, a special attention is granted to the biopsies received from the Dermatology discipline, but also from other petitioners in Timisoara or from the surrounding area. Within the specialty preparation, the dermatology resident physicians perform a Pathologic Anatomy probation period within the Pathologic Anatomy Service of the Emergency Clinical Municipal Hospital of Timisoara. They take part in the orientation of the macroscopic pieces, the histopathological processing and in the elaboration of the diagnosis. Also, the resident physicians of the dermatology section present essays regarding some recent literature data or of some special clinical cases, during the anatomoclinical meetings, which are held within the Morphopathology discipline.
Romanian Dermatopathology at the moment
Aurel Doru Chirita MD, DipI CDP-UEMS
Dermatologist / Dermatopathologist, 'Carol Davila' Central Clinical Emergency Military Hospital Bucharest, 'Domina-Sana' Medical Center Bucharest.
As far as Dermatopathology is concerned, compared to what is happening in the rest of the world (USA, Canada, Australia, U.K., Germany, etc.), it can be said that in Romania Dermatopathology is practically inexistent. At present there are no internationally accredited Training Centers in Dermatopathology and consequently no fully trained and board-certified dermatopathologists engaged in the full-time practice of Dermatopathology. There are also no centers for Dermatopathology research and not even a Dermatopathology laboratory full equipped to perform all the required tests for an accurate and complete diagnosis. Moreover, a consistent communication between dermatologists and pathologists is lacking sometimes and this impends on reaching the final diagnosis. Most of the time, pathologists are not actively engaged in the management of the patient. This is one of the reasons why dermatologists are not determined to perform skin biopsies. Consequently, there is no interest on the part of residents in dermatology or pathology to learn dermatopathology by integrating clinical findings with the histological ones. However, there is a group of enthusiastic people who are constantly working and fighting for Dermatopathology to become a well recognized subspecialty in our country, a subspecialty that would certainly serve both the physicians and their patients.
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Dermatologic management of cutaneous lymphomas
M. Costache
Uroderm Medical Center, Arad, Romania
Cutaneous lymphomas include various types of clonal lymphoproliferative disorders. They are rare diseases and, although some are a manifestation of systemic lymphoma, the majority arises primarily from the skin.
These primary cutaneous lymphomas comprise both T- and B-cell subtypes and represent a wide spectrum of disorders, which at times can be difficult to diagnose and classify.
Accurate evaluation of patients with suspected or known cutaneous lymphoma requires the integration of many sources and types of information, including clinical evaluation, microscopic analysis of tissue, immunophenotyping, gene rearrangement studies, clinical staging.
Diagnosis should be based on knowledge of specific lymphoma types as described in modern classification systems.
Management of patients with cutaneous lymphoma requires collaboration among dermatologists, dermatopathologists, hematopathologists, and medical, surgical and radiation oncologists.
The adequate treatment approach depends on the exact diagnosis.
Overview of WHO and WHO/EORTC classifications of cutaneous lymphomas
Aleodor A Andea, M.D.
University of Alabama at Birmingham
Cutaneous lymphomas represent some of the most elusive neoplastic entities in dermatopathology. The frequent changes in classification schemes and diagnostic criteria present significant challenges for dermatopathologists and dermatologists alike. The last decade has witnessed considerable debate regarding the classification and terminology of primary cutaneous lymphomas. The controversy emerging from the use two competing classification schemes, one developed by the European Organization of Research and Treatment of Cancer (EORTC) in 1997 and the other by WHO in 2001, came to an end with the introduction of a consensus EORTC/WHO classification in 2005. The new WHO classification of lymphomas, released in 2008 introduced however, additional changes in some diagnostic categories.
The course will present an overview of the 2005 WHO/EORTC and 2008 WHO classification schemes of cutaneous lymphomas outlining the similarities and differences between them. Histopathologic diagnostic criteria and the utility of immunohistochemical markers will be discussed and demonstrated for the entities presented. The course will also elaborate on the importance of ancillary molecular studies including T-cell receptor and immunoglobulin gene rearrangement studies in the diagnosis of lymphomas.
KIRs as new diagnostic markers for cutaneous T cell lymphomas
Martine Bagot
Department of Dermatology, Skin Research Center and Inserm U976, Hôpital Saint-Louis, Paris
The distinction between Sezary syndrome (SS) and benign erythrodermic inflammatory diseases (EID) is sometimes difficult to make both clinically and on skin biopsies, since histomorphology can provide non specific results. New markers of circulating malignant Sezary cells have been recently described, especially CD158k/KIR3DL2 and T-plastin, that could help for the diagnosis of erythroderma in skin samples. We analyzed thirteen frozen skin specimens from SS patients and 26 from EID for CD158k/KIR3DL2 expression using immunohistochemistry with AZ158 monoclonal antibody, which also recognizes the monomeric CD158e/KIR3DL1 receptor. Although positive in all SS samples, immunohistochemistry appeared not to be enough discriminant between SS and EID. Therefore in all samples disclosing a significant staining with AZ158 mAb, CD158k/KIR3DL2, CD158e/KIR3DL1 and T-plastin mRNA expression were analyzed on the same skin specimen using conventional and/or quantitative real time RT-PCR. Interestingly, only CD158k/KIR3DL2 transcripts were found to be significantly overexpressed in skin biopsies from patients with SS (P<.0001), including when normalization to CD3 expression was achieved (P=.0003). In light of these findings, CD158k/KIR3DL2 transcripts appear to be a unique molecular marker of SS in skin samples, allowing differential diagnosis with benign EID in routine practice.
CD158k/KIR3DL2 is also a sensitive and specific marker for Sezary cells which can be used to evaluate tumor burden in the blood. We evaluated the interest of CD158k/KIR3DL2 in detecting and evaluating blood tumor load during the follow up of SS patients. The absolute CD3+CD158k+ lymphocyte count was compared to the absolute count of cytomorphologic Sezary cells and was correlated to clinical flares in a cohort of SS patients. Twenty-five patients were included in the study and 48 blood samples were analysed. The absolute count of CD3+CD158k+ cells strongly correlated the absolute count of atypical circulating cells (r=0.97, p<10-15). The tumor burden evaluated by CD3+CD158k+ immunostaining was significantly associated to clinical flare up (p<10-4). Thus, CD3+CD158k+ phenotyping is a reliable and objective test to monitor the blood tumor burden in SS patients under systemic therapy.
Emerging concepts in the diagnosis & treatment of cutaneous lymphoma: a clinician's perspective
Lauren C. Hughey, M.D.
University of Alabama at Birmingham
Objectives:
Cutaneous T-cell lymphomas present in a variety of ways. They often mimic inflammatory skin conditions delaying diagnosis for years. Furthermore, once these cases are diagnosed as lymphomas, it is often difficult to classify them when they don't follow the textbook pattern and exhibit differing clinical, histologic, and immunohistochemical markers. This talk will discuss a diagnostic algorithm to use for patients with suspected mycosis fungoides as well as a treatment algorithm. The session will briefly mention revised staging of these MF and Sezary patients. A few cases will be presented to highlight the variable presentation and behavior of these lymphomas.
Outline:
- Algorithm to approach dx.
- Algorithm to approach treatment
- Brief mention of new drugs
- Quick review of new staging
- Case Unknowns
Take home points:
- - Not every case fits the textbook
- - Diagnosis and treatment must be individualized
Cutaneous Pseudolymphomas
Rajalakshmi Tirumelea
St. John's Medical College, Bangalore, India
Cutaneous Pseudolymphomas encompass a wide spectrum of diseases with varied aetiology and morphology. The term lacks specificity and is often used as a "waste basket", conveying little meaning to the treating Dermatologist. It is essentially a reactive, polyclonal, lymphoproliferative process that heals spontaneously after the inciting factor is removed. It can be either B-cell or T-cell dominant. It is useful to recognize their predominant histologic pattern, i.e. band-like, nodular, diffuse or perivascular, that helps us in categorizing them correctly. Immunohistochemistry and clonality studies are sometimes used to make a diagnosis with specificity. This lecture will focus on a pattern-based approach to these lesions and critically look at the role of clonality in solving such cases.
Particular cutaneous lymphomas: Mycosis fungoides and the multiple faces of it.
Irina Margaritescu MD, DipRCPath
Dermatologist/Dermatopathologist, "Domina-Sana" Medical Center Bucharest.
Mycosis fungoides is the prototype of cutaneous T-cell lymphomas and can be defined as a peripheral, epidermotropic T-cell lymphoma initially presenting in the skin and showing stepwise clinical progression from patches to plaques and tumours, and distinctive histological, phenotypic and genotypic features. The histologic diagnosis of MF in the initial phases is based on numerous subtle changes like: superficial perivascular infiltrates of lymphocytes, lymphocytes aligned as solitary units in the basal layer of the epidermis, lymphocytes in the spinous zone in conjunction with scant spongiosis, and sometimes in the upper reaches of the epidermis, such as the granular zone, lymphocytes within the epidermis larger than those within the dermis, wiry bundles of collagen in haphazard array in the upper part of the dermis in association with patchy lichenoid infiltrates of lymphocytes. Apart from the classical form of MF, there are several variants of this disease with unusual or atypical clinical and/or histopathological features. These comprise epitheliotropic MF (folliculotropic, syringotropic and alopecia mucinosa), hypopigmented MF, poikilodermic MF, hyperpigmented MF, pagetoid reticulosis and granulomatous MF. Sometimes, is quite difficult to distinguish it histopathologically from other lymphomas (lymphomatoid papulosis, adult T cell leukemia/lymphoma, CD8-positive cytotoxic T-cell lymphoma, etc.) or some inflammatory diseases (spongiotic dermatitis, psoriasis, pitiriasis alba, lichen striatus, lymphomatoid drug eruption, etc). A careful clinico-pathological correlation is essential in these cases and a complete work-up, including immunoprofile and genetic studies are mandatory to reach the correct diagnosis.
Patch-stage Mycosis Fungoides - Diagnosis on Histology
Rajalakshmi Tirumelea
St. John's Medical College, Bangalore, India
The histologic diagnosis of early Mycosis Fungoides (MF) and its' distinction from inflammatory dermatoses is challenging, owing to the overlap of several features. However, there are effective histologic criteria described recently to diagnose early MF. Some of these include: pattern of epidermal reaction, disproportionate epidermotropism, tagging of lymphocytes along the basal layer, haloed lymphocytes, convoluted lymphocytes, larger epidermal lymphocytes, wiry dermal collagen, absence of oedema, eccrine infiltration, folliculotropism, follicular mucin, involvement of papillary and reticular dermis, monomorphous infiltrates, atypia of dermal lymphocytes and stuffed dermis. Some of these criteria show a good sensitivity and specificity. A combination of histologic patterns and cytology of lymphocytes is reliable in distinguishing MF from inflammatory dermatoses. No single criterion is discriminatory. This lecture will define and demonstrate these features and also focus on the pitfalls.
Primary Cutaneous B-Cell Lymphomas - Clinical, Morphological and Immunophenotypical Characterisation
Rosemarie Herbeck¹,², D. Teodorescu Brinzeu³, Sylvia Hartmann¹, Alis Dema, ²,&sup4; Elena Lazar&sup4;, C. Solovan³, V. Feier³, M. L. Hansmann¹
¹Senckenberg Institute for Pathology, "Johann Wolfgang Goethe" University of Frankfurt/Main, Germany
²Deparment of Pathology, County Emergency Clinical Hospital of Timisoara, Romania
³Deparment of Dermatology, "Victor Babes" University of Medicine Timisoara, Romania
&sup4;Deparment of Pathology, "Victor Babes" University of Medicine Timisoara, Romania
Introduction: Cutaneous lymphomas (CL) represent a unique group of extranodal lymphomas, ranging between 25% and 35% among extranodal non-Hodgkin lymphomas. Approximately 65% of CL are T-cell types, 25% B-cell types, and 10% are uncommon forms.
The WHO-EORTC classification for cutaneous lymphomas, published in 2005, includes three main entities of primary cutaneous B-cell lymphomas (CBCL): primary cutaneous marginal zone B-cell lymphoma (pcMZL), primary cutaneous follicle centre lymphoma (pcFCL) and primary cutaneous diffuse large B-cell lymphoma, leg type (pcDLBCL).
Aim: To review the clinical, histological and phenotypical features of the main entities of CBCL.
Materials and methods: Histological review was performed on HE and immunohistochemical stained sections from CBCL cases retrieved from the files of the Pathology Department of the University of Frankfurt/Main, Germany, between 2007 and 2009.
Results: Clinically, pcMZL is usually manifested as solitary or multiple nodules with predilection sites on the upper arms and upper back. Histologically, pcMZL is characterised by a nodular or diffuse infiltrate composed of small to medium-size lymphoid cells with indented nuclei and an abundant, pale cytoplasma. They are immunohistochemical CD19+, CD20+, CD79a+, CD5-, CD10-, bcl-6- and bcl-2+. In contrast to cpMZL, pcFCL shows a predilection for the scalp, forehead and trunk and appears as erythematous nodules and surrounding plaques. PcFCL is histologically characterised by a nodular or diffuse infiltrate represented by a relatively monomorphic cellular admixture of centrocytes and centroblasts. The tumour cells express CD19, CD20, CD79a, bcl-6 and variably CD10 by negativity for bcl-2. PcDLBCL occurs usually on the leg and less frequently on other sites as solitary or grouped violaceous nodules, frequently ulcerated. The microscopic aspect is a dense diffuse infiltrate, composed of centroblasts and/or immunoblasts with large nuclei, prominent nucleoli and a high mitotic activity. Immunophenotypically, the infiltrate is CD20+, CD79a+, bcl-6+, bcl-2+, MUM1+, CD5- and CD10-. In all three entities, clonally rearranged immunoglobulin genes can be regularly detected by PCR molecular studies.
Conclusion: PcBCL are a heterogeneous group of B-cell lymphomas that originate in the skin, with the absence of extracutaneous disease at diagnosis. Precise classification of CBCL can be achieved only after a complete synthesis of clinical, histopathological, immunophenotypical and molecular features.
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Old and new concepts on melanocytic neoplasia!
H. Kittler
Dermatology, Medical University, Viena
Melanocytic neoplasms: Confusing concepts, now and then!
With regard to the decision whether a given melanocytic skin lesion is benign or malignant histopathology is the diagnostic gold standard. However, it has to be kept in mind that it is an imperfect gold standard in part because it depends on subjective interpretations of morphologic findings. In historical perspective different concepts and guidelines have been used for the histopathologic diagnosis of melanocytic proliferations. Over time some concepts became accepted universally by dermatologists and dermatopathologists, others disappeared completely, and others have been rehashed repeatedly under different names. It is very illuminative to challenge historical concepts in the light of new observations. Examples of concepts that are still a matter of debate are (1) the of model stepwise of "tumor progression" whereby a "common acquired nevus" transforms into a "dysplastic nevus" which then converts into melanoma in situ, (2) the concept of the "dysplastic nevus" as a marker of melanoma risk, (3) the concept of Spitz nevi, (4) the nomenclature of melanocytic nevi, and (5) the concept of melanoma in situ. The weakness of all historical concepts is the fact that they have been developed from an isolated point of view whereas future concepts will have to integrate clinical, dermatoscopic, dermatopathologic and molecular findings.
The role of dermatopathology in the management of melanocytic neoplasms
Aurel Doru Chirita MD, DipICDP-UEMS
Dermatologist/Dermatopathologist, "Carol Davila" Central Clinical Emergency Military Hospital Bucharest, "Domina-Sana" Medical Center Bucharest.
Melanocytic neoplasms include a large variety of benign and malignant neoplasms with distinct clinical, morphological and genetic profiles. For diagnosis of melanocytic lesions, dermatopathologists use architectural and cytological features which, together with a careful clinico-pathological correlation, enable them to clearly distinguish a nevus from a melanoma in most of the cases. However, in a percentage of cases this distinction is extremely difficult if not impossible. Moreover, different dermatopathologists/pathologists use different criteria for diagnosis of melanoma, which implies certain variability in classification of pigmentary lesions. Even though same criteria are used for diagnosis of a melanocytic lesion by different dermatopathologists, there is always a certain degree of subjectivity in applying these criteria. Consequently, there is a limitation in reaching a consensus for the histologic diagnosis of melanocytic lesions. Other limitations are biopsy type and size of the biopsy. One solution for these problems is application of an algorithm which evaluates whether a particular melanocytic lesion is a melanoma or not and use the following major criteria: size, symmetry, circumscription and maturation. Also, for identification of "exceptions to the rule" the following criteria are used: major criteria not already addressed, "too Many Melanocytes", stroma/elastosis, anatomic site, type of nevus, evidence of prior trauma, melanocytes above the DE junction, variation in sizes, shapes and confluence of nests, atypia, mitoses, necrosis. In addition, when reporting a melanoma, it is essential to record the tumor thickness, level of invasion (especially for thin melanomas <1 mm in thickness), presence or absence of ulceration, perineural infiltration, regression and microsatellitosis.
Difficult melanocytic neoplasms
Irina Margaritescu MD, Dip RCPath
Dermatologist/Dermatopathologists, "Domina-Sana" Medical Center Bucharest.
Distinction between a melanocytic nevus and a melanoma is usually straightforward. However, in a percentage of cases this distinction is extremely difficult if not impossible. An algorithm based on certain histologic criteria and careful clinico-pathological correlation can help a dermatopathologist/pathologist reach an accurate diagnosis. Combined congenital nevus vs. melanoma arising in association with a congenital melanocytic nevus, Spitz's nevus vs. "spitzoid" melanoma, blue nevus vs. melanoma arising in a blue nevus, congenital nevus vs. "nevoid" melanoma, desmoplastic melanoma, melanoma with regression/ regressed melanoma, melanocytic nevi on special sites, spindle cell melanoma vs. other spindle cell neoplasms, metastatic melanoma, recurrent nevus vs. recurrent melanoma are but some of the problematic cases a dermatopathologists/pathologist is confronted with in their daily practice. I will present some of the most difficult cases of melanocytic lesions, pointing out the particular histological criteria used for their diagnosis.
Junctional melanocytic proliferations on sun-damaged skin: benign or malignant?
Almut Boer*, M.D., Volker Steinkraus*, M.D.
*Dermatologikum, Hamburg
The diagnosis of melanoma in situ can be challenging especially when a lesion occurs in sun damaged skin. In this context, melanoma often shows proliferations of single melanocytes with few nests and little scatter of melanocytes above the basal layer; atypia of melanocytes may be scant. Moreover, actinic hyperplasia of melanocytes makes it difficult and sometimes impossible to assess accurately circumscription and symmetry of a melanocytic proliferation. A variety of other conditions may mimic melanoma in situ on sun damaged skin, especially junctional proliferations of melanocytes in solar lentigo, above fibrous papules of the face, or above dermal melancytic nevi. Immunohistochemical stainings with HMB 45, S100, and Melan A may facilitate the differential diagnosis because they highlight the architecture of melanocytic proliferations but each of the stainings also has its own disadvantages. For example, HMB 45 stains also pigmented atypical keratinocytes in pigmented actinic keratosis, Melan A may stain dyskeratotic pigmented keratinocytes in lichen planus-like keratosis, and S100 may occasionally fail to stain melanocytes of a melanoma while staining accurately Langerhans cells giving the wrong impression of a keratinocytic lesion.
In this presentation both, benign and malignant junctional proliferations of melanocytes will be presented in comparison and together with immunohistochemical characteristics in order to demonstrate the most reliable criteria for differentiation.
Spizoid melanocytic neoplasm. A discussion
Anca Croitoru MD
University of Alabama at Birmingham
Spitzoid nevi are a distinct subset of melanocytic proliferations, characterized by large epithelioid or spindle shaped melanocytes. Because of the overlap of their features with some of the features of melanoma, they were initially considered "melanoma of childhood", as in the seminal paper published by Sophie Spitz, MD, in 1948. While the majority of Spitz nevi present in childhood are benign, atypical variants and lesions present in older patients raise substantial difficulties in diagnosis and fundamental questions about their biologic behavior, critical in understanding their relationship with melanoma.
Giant basal cell carcinoma - Histopathological considerations when Mohs micrographic surgery is applied
Mihaela Leventer, Konstantinos Koutsioukis, Sanda Achim, Tudor Stanescu, Ana-Maria Dumitrescu, Claudia Ciobanu, Diana Placintescu, Nectara Mitroi
Dermastyle Clinic - Bucharest, Romania
Giant basal cell carcinoma is usually an epithelial tumor of the trunk that gets considerable size, with an aggressive histopathological pattern and a high risk of local recurrence and metastasis. Sometimes the clinical appearance and its location make it hard to distinguish from a multicentric superficial basal cell carcinoma and may lead to incorrect therapeutic modalities. Histological recognition of this clinical variant is necessary for a proper curative approach and avoidance of potential recurrence or metastasis.
We present a similar case excised by Mohs microsurgery in which resulted an impressed primary defect because of the subclinical tumor extension.
Idiopathic cutaneous angiosarcoma on the malar region excised by Mohs micrographic surgery - Histopathological diagnostic problems and therapeutic modalities
Konstantinos Koutsioukis, Mihaela Leventer, Sanda Achim, Claudia Ciobanu, Diana Placintescu, Ana-Maria Dumitrescu, Nectara Mitroi
Dermastyle Clinic - Bucharest, Romania
Cutaneous angiosarcoma is a rare malignant tumor, derived from endothelial cells. It is characterized by a polymorphous clinical appearance, rapidly evolving and aggressive with frequent local recurrences, distant metastasis and poor clinical outcome.
We present a case of idiopathic cutaneous angiosarcoma in the malar region excised by Mohs micrographic surgery. The rarity and aggressiveness of these tumors is discussed in terms of histological appearance and differential diagnosis, as well as treatment options.
Morphological Stages of Pilomatricoma
Romanita Glaja¹, C. Solovan², Bogdana Pascaru³
¹Departament of Pathology - City Hospital, Timisoara, Romania
²Departament of Dermatology - U.M.F."V.Babes",Timisoara, Romania
³City Hospital, Timisoara, Romania
Pilomatricoma is a benign epidermal appendage tumor with differentiation toward hair cortex cells. It is composed of varying percentages of basophilic cells (hair matrix-like basaloid cells) and keratinized remnant cells (known as "shadow cells"). The transition of basophilic cells to shadow cells is gradual and there is another form of tumor cells, with pycnotic nucleus, known as "transitional cells", which are considered apoptotic cells. The natural course of pilomatricoma is a chronological process in which the lesion begins as infundibular matrix cyst and ends up as a calcified and ossified nodule with no viable epithelial component.
Based on the morphologic findings in individual lesions, four distinctive histopathologic types of pilomatricomas could be identified, and these were interpreted to represent stages in the evolution of this neoplasm: early, fully developed, early regressive and late regressive. Early lesions ( two cases ) were small cystic structures lined by squamoid and basaloid epithelium containing keratin filaments and faulty hair matrix material composed of shadow cells. Fully developed lesions (eight cases) were large neoplasms lined by basaloid epithelium at their periphery, and within, composed of irregularly shaped, densly packed zones of cornified masses containing shadow cells. Early regressive lesions ( seven cases) had no apparent epithelial lining but did have basaloid cell foci at the periphery, as well as granulation tisue with inflammatory infiltrate and multinucleated histiocitic gigant cells. Late regressive lesions ( four cases ) had no epithelial component and were composed of irregularly shaped, partially confluent masses of faulty hair material and calcified ( one case metaplastically ossified) shadow cells embaded in a desmoplastic stroma.
Controversies and certainties in the histological diagnosis of dysplastic nevi and melanoma in situ
*M. Rotaru, **R. Glaja , ***A. Nati
*Faculty of Medicine, Dematology Department, Sibiu
** Bioclinica Timisoara, Pathology Department
Academic Emergency Hospital, Sibiu, Dermatology Department
From the definition of dysplastic nevi by Clark in 1978, revisions specialists on clinical and histopathological features of dysplastic nevi evolves continue and early diagnosis of melanoma in situ remains a major desideratum of specialist.
At present there are relatively well delineated clinical and histological criteria for diagnosis of dysplastic nevi, acquired melanocytic nevi, atypical lentiginous nevi, lentiginous nevi, lentiginous melanoma or lentigo maligna.
There are limit situations in clinical practice that can create disputes between the pathologist and dermatologist to confirm the diagnosis of dysplasia or melanoma in situ.
This paper aims to point out the most significant issues for histological diagnosis of each form mentioned above to illustrate and discuss the 5 cases studied which are representative of the group.
We performed a retrospective study of 14 dysplastic nevi from a total of 67 lesions which were examined clinical and histological. Patients aged between 26 and 75 years, average age 42, 3 with lesions located in the anterior chest, back, limbs, neck and genitals. The clinical diagnosis was dysplastic nevi (9 cases) and clinical suspicion of melanoma in situ (5 cases).
In our opinion it is required a more precise definition of histological criteria for both dysplastic nevus and in situ melanoma.
Pigmented lesion with strange dermoscopy and pathology
Paul I. Ionescu, Simona Enache
Vitan Clinic, Bucuresti
It is a pigmented lesion located on the medial aspect of the left breast in a 54 years old female, lesion which dermoscopically shows a lot of comedo-like openings and horny cysts on a large area and a small area with a very discrete blue veil over some remnants of an atypical pigment network.
Pathology shows inconclusive features, but immunohistochemistry establishes the diagnosis.
Special Stains and Immunohistochemistry in Melanocytic Lesions
C. Solovan, Loredana Boghian, I. Argyris
University Clinic of Dermatology and Venereology, Timisoara
Immunohistochemistry is based on use of antibody-based reagents for localization of specific antigens in tissue. The enzyme-antibody-antigen complex is visualized as a red product in the aminoethyl carbozole (AEC) method. The diaminobenzidine method (DAB) can alternatively be used giving a brown reaction; however, this may be difficult to distinguish from melanin pigment. Principles of Immunohistochemistry:1) Select a panel based on the histological differential diagnosis;2) Evaluate the immunohistochemical reaction;3) Interpretation must be made in the context of the histomorphology, clinical scenario, and a comprehensive understanding of the various nuances of the panel of markers used. Melanocytic Markers: S100, MART1 (Melanoma Antigen Recognized by T-cells), HMB45, MITF (Microphthalmia Transcription Factor), Tyrosinase, NKI-C3, PNL2, SM5-1, MUM-1 (Multiple Myeloma-1), SOX-10. Proliferation Markers: MIB-1, PCNA (Proliferating Cell Nuclear Antigen), MCM protein 2 (Minichromosome Maintenance), MPM-2 (Mitosis Specific Phosphoprotein), pHH3 (phosphor-Histone H3). In most cases, IHC is not required, but in some situations it can augment routine histology. IHC markers are virtually never completely specific and sensitive. The published literature on IHC markers is generally limited to small numbers of cases. Some lesions still defy classification, even with extensive IHC. While trends have been identified, IHC alone cannot completely predict the biologic behavior of a neoplasm. Immunohistochemistry continues to evolve with identification of increasing antibodies. Some markers can serve as surrogate protein markers of underlying genetic events and in some cases result in identification of therapeutic options and predict response.
Sambata
Adnexal neoplasms: Diagnosis step by step
Almut Boer, M.D., Volker Steinkraus, M.D.
Dermatologikum, Hamburg
Adnexal neoplasms of the skin represent an often neglected subject of dermatopathology. The manifold expressions of more than 70 different epithelial neoplasms seem difficult to classify. Even though most of the lesions are bengin, an accurate diagnosis is necessary because several adnexal neoplasms are indicators of inherited syndromes with implications for follow up and treatment of the patients. Moreover, malignant analogues of the tumors may occur in their benign counterparts and need to be identified with precision.
This lecture emphasizes a stepwise procedure to identify adnexal neoplasms with surety starting from terminology and embryology. Rudiments of embryology explain the various types of adnexal differentiation and their tendency to occur together in a single neoplasm because of their embryologic relationship. Clarification of terminology is required for a proper classification of diseases based on principlas of Virchowian pathology. In a next step, various types of adnexal differentiation are presented based on their resemblence of structures in the normal tissue. Identification of differentiation is crucial for categorisation of adnexal neoplasms of the skin and assists also in the assessment of benign versus malignant neoplasms apart from other criteria such as silhouette and cytopathology. Finally, examples of common and less common adnexal neoplasms are given, highlighting criteria for accurate diagnosis of them.
Skin Adnexal Tumours - Diagnosis by silhouette
Rajalakshmi Tirumelea
St. John's Medical College, Bangalore,India
Skin adnexal tumors are daunting diagnostic problems. Cytologic atypia does not always imply malignancy and "typia" does not underscore a benign course. The bewildering array of differentiation they display and the ever-expanding list of entities add further to the confusion. Subtyping lesions with accuracy becomes important in some cases to recognize clinical association, as in Sebaceous tumours and this requires a good understanding of the embryologic origins and structure of cutaneous adnexae. Even experienced pathologists falter sometimes. In such a situation, it is important to answer two questions: 1) Is the lesion benign or malignant and 2) Has it been completely excised? In this context, what come to our aid are architectural features or silhouettes of these lesions. There are several useful criteria such as symmetry, V-shape, geometry, borders, nature of stroma, type of clefting, to list a few. These are best appreciated on scanning magnification. It is possible to accurately distinguish benign from malignant proliferations and this lecture will describe the differences in detail. Pathologists should heed the impression formulated on scanner view, before evaluating cytologic features.
The molecular profile of the soft tissue tumors of the skin: its diagnostic impact and the potential application in targeted therapy
Marius Raica
"Victor Babes" University of Medicine and Pharmacy
Department of Histology and Molecular Pathology
Timisoara, Romania
Abstract
Soft tissue tumors (STT) of the skin still represent a major problem in terms of the pathological diagnosis and prognosis. Based on routine examination, less than 30% of these tumors are correctly classified and frequently, STT are designated as sarcoma with spindle, round, pleomorphic or myxoid cells. The rate of proliferation of STT, as detected by Ki67 expression is quite different even in the same group and cannot be used for diagnostic purpose.
An extensive panel of antibodies is generally used in the last decade in order to classify STT according to WHO requirements. In the first step it should be excluded a spindle cell carcinoma, a malignant melanoma and a lymphoid proliferation. This is not always very easy, because the partial overlapping with markers expressed by STT is a common finding. On the other hand, a panel that consists of cytokeratin AE1/3, Melan A and CD45 is helpful in most of the cases.
The second question is related to the histogenesis of these tumors. Previously it was thought that a definite mature cell of the soft tissue gives rise to a specific tumor. Now it is known that remnant mesenchymal cells of the adult proliferate to form STT and during their natural evolution they differentiate to one or many cell lines. This explains on one hand the complexity of the molecular profile and the existence of polyphenotypic tumors. Immunohistochemistry is largely available in last 20 years and seems to be a good surrogate of gene molecular analysis. Based on the immunohistochemical expression of specific markers, it is now possible to perform the correct pathological diagnosis with accuracy that exceeds 90% in terms of sensitivity and specificity. A new classification of the STT was recently introduced, according to results obtained with methods of molecular pathology.
The third question is how useful is the molecular diagnosis of STT for treatment and if there is a good correlation between costs and benefits? There are some very good examples that support the beneficial role of these methods, like CD117-positive or podoplanin-positive tumors. A new field in therapy was opened after the detection of growth factors by tumor cells of STT, like PDGF and VEGF, and specific inhibitory drugs for clinical use are already available on the market.
An Update on Primary Cutaneous Neuroendocrine Carcinoma (Merkel Cell Carcinoma)
Aleodor A Andea, M.D.
University of Alabama at Birmingham
Primary cutaneous neuroendocrine (Merkel cell) carcinoma (MCC) was initially reported in 1972 by Toker et al. under the heading of trabecular carcinoma. Subsequent ultrastructural studies revealed the presence of dense core neuroendocrine granules in the cytoplasm of tumor cells similar to those seen in Merkel cells, which is why MCC has gradually replaced the original name. MCC is an uncommon skin tumor however, its incidence is on the rise. MCC affects predominantly the Caucasian population and is more frequent in males and elderly. It usually occurs in sun-damaged skin of the head and neck region or extremities, but may also involve sun-protected sites.
Among skin tumors, MCC is regarded as one of the most aggressive cancers surpassing melanoma in its dismal prognosis with survival rates at 5 years ranging from 29% to 74%. The mainstay of therapy for this tumor is currently surgical excision with negative margins. Unfortunately after the disease spreads to distant sites there is little that can be offered to the patients in term of treatment options.
The course will present the most recent data regarding the clinical, histological and immunophenotypical characteristics of MCC. Certain problems and pitfalls in the morphologic diagnosis of MCC will be discussed such as the potential for confusion with basal cell carcinoma, metastatic small cell carcinoma, lymphoma or even small cell variant of melanoma. While tumor stage is an important prognostic factor, recent data will be presented demonstrating that histologic factors such as tumor pattern, tumor depth and lymphovascular invasion have prognostic implications independent of tumor stage. Finally the course will elaborate on recent insights in the pathobiology of MCC including the discovery of a novel member of the polyoma virus family, named Merkel cell polyomavirus integrated in the genome of MCC.
Autoimmune blistering diseases associated with neoplasia
Cassian Sitaru
Department of Dermatology, University of Freiburg, Germany
In a group of organ-specific autoimmune diseases, blistering of the skin and mucous membranes is caused by autoantibodies against structural proteins of the skin. While occasional associations with tumours have been reported in patients with different autoimmune blistering diseases, several of these conditions are considered true paraneoplastic syndromes. Paraneoplastic pemphigus is mainly associated with B cell lymphoma and other haematological disorders, but it may also occur in patients with benign tumours, like thymoma or Castleman's tumour. Direct immunofluorescence microscopy shows deposition of IgG both in the intercellular space and at the dermal-epidermal junction. Unlike the classic types of pemphigus, in which indirect immunofluorescence is positive only on stratified squamous epithelial substrates, paraneoplastic pemphigus sera also often show staining of other types of desmosome-containing tissues, including bladder, heart and liver. Autoantibodies from patients with paraneoplastic pemphigus immunoprecipitate a characteristic set of at least 7 epithelial antigens. Patients with a particular form of mucous membrane pemphigoid caused by autoantibodies against laminin 332 have an increased relative risk for malignant solid tumors. The mechanisms underlying the association of malignancy with autoimmune blistering diseases are unknown. Understanding the mechanisms of the production of pathogenic autoantibodies and their relation with the development of the associated neoplasy should greatly facilitate the development of more specific diagnostic tests and therapeutic strategies.
Kaposi's sarcoma located on the irradiated breast for cancer - case presentation
V. Patrascu, A. M. Vilcea, C. Georgescu, L. E. Stoica
Kaposi's sarcoma (KS) is usually a multicentric disease, characterized by cutaneous and/or visceral lesions; there were described four clinical types: Mediterranean variant, endemic African KS, AIDS-associated KS, and KS in iatrogenically immune-compromised patients.
We present the case of a female patient, 75 years old, admitted in clinic for multiple angiomatous, infiltrative plaques and three tumors, one centimeter diameter and same color each, located on the right breast. Medical history revealed that 7 years ago the patient suffered a lymphectomy with axillary dissection for an invasive ductal carcinoma of the right breast. Surgical treatment of cancer was completed with 25 sessions of breast radiation therapy, and 5 years treatment with Tamoxifenum, patient's post-therapeutic evolution being considered very well.
The present lesions occurred three month ago, a tumor being excised for histopathologic exam which established the KS diagnosis. There were no clinical or paraclinical signs of visceral involvement.
We consider that this case may be included in the last variant of KS aforementioned. The occurrence of KS on irradiated surface may be the consequence of HHV8 zonal activation through a radio-induced immunodepression, but other factors may be involved as well: the direct action of the ionizing radiation on polyclonal cells involved in the occurrence of the KS's lesions; local alteration of iron metabolism; oxidative-stress induction.
We discuss the differential diagnosis problems and therapeutically modalities. Considering the fact that lesions are strictly localized, without extra-cutaneous involvement, we consider that this patient has a good prognosis after treatment.
Atypical forms of cutaneous melanomas - reviews data applying on a case report
Vasile Liliana*, Condor Alina**, Lazar Elena*, Buzete George*, Cucui Vasile***, Cojocaru Silvia*, Pascaru Bogdana*
*Department of Histology, University of Medicine and Pharmacy Victor Babes, Timisoara, Romania;
**Department of Dermatology, Emergency Military Hospital Timisoara, Romania;
***Department of Surgery, Emergency Military Hospital Timisoara, Romania.
Objectives. Melanomas usual classification is based on macular growth stage evaluation. These malignant melanocytic lesions show a great phenotypic variability in growth nodular stage.
Material and methods. A patient PC, male, 74 years old came to the doctor with a right calcaneo-plantar ulcero-proliferative-nodular lesion, with a few months course, with local discomfort and functional impairment. Presumptive diagnosis was Kaposi sarcoma. The lesion was excised and sent for histopathological, macroscopic, microscopic examination in usual histological and immunohistochemical technique.
Results. A malignant tumoral proliferation was identified with fusiform cells, uniform nuclei, some of them hyperchrom, with nucleoli, tumoral cells with brown pigment(possible melanic), a rich mitotic activity; associated lymphocytic inflammatory infiltrate in spots. Tumoral proliferation includes adnexal structures of the tegument and is ulcerated.
Discutions. Histopathological aspects lead to a malignant tumoral proliferation with fusiform cells(S100+ protein, CD34, Desmine, panCK) suggesting a malign desmoplastic melanoma.
Conclusions. Immunohistochemistry helps in solving the difficulty of clinical and histological lesional classification.
Immunohistochemistry in cutaneous neoplasms
C. Solovan
University Clinic of Dermatology and Venereology, Timisoara
Immunohistochemistry is a method for localizing specific antigens in tissues/cells based on antigen-antibody reactions. The antibodies (monoclonal/polyclonal) are tagged with enzymes, fluorochromes, metals or radiolabels to enable their detection.
Commonly used methods:
- 1) Immunoperoxidase methods
- 2) Avidin-Biotin method
- 3) Labelled Streptavidin-Biotin method
- 4) Polymer techniques
Immunohistology of skin
Keratinocytes: Keratins
Melanocytes: S100, HMB 45, Melan A, MITF
Langerhans cells: S100, Langerin, CD1a
Sweat/Sebaceous glands: CEA, EMA
Lymphocytes: CD45, CD3 (T cell), CD20, 79a (B cell), CD4,8, CD 56 (NK cell) CD 30
Mesenchymal components: Vimentin, smooth muscle actin, Desmin, Myogenin
Blood vessels: CD31, 34
Lymphatics: D2-40
Epithelial proliferations
These markers are most useful in determining the line of differentiation of a cell in poorly differentiated neoplasms. The most commonly used reagents are cytokeratins, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). CK 20 is used to diagnose Merkel cell carcinoma. CK 7 marks cells of Paget's disease. Non-epithelial neoplasms, such as epitheloid sarcoma and epitheloid angiosarcoma, occasionally show positive staining.
EMA is a glycoprotein located in secretory mammary cells. EMA has been of most utility aiding in the diagnosis of extramammary Paget's disease, eccrine neoplasms, and sebaceous carcinoma. CEA is a normal protein product of the goblet cells found in the small and large intestines. It is sometimes useful in the diagnosis of metastatic adenocarcinoma, extramammary Paget's disease, and eccrine neoplasms. BER-EP4 is positive in Basal cell carcinoma.
Metastatic carcinoma of unknown origin
| CK 20- | CK 20+ | |
| CK 7+ | Breast, lung, mesothelioma, ovary, endometrium | Bladder, pancreas |
| CK 7- | Hepatocellular, prostate, renal, neuroendocrine, SCC of lung | Colon |
Melanocytic proliferations
S-100, HMB 45 and Melan A are markers of melanocytic lineage. Normal unstimulated melanocytes and the intradermal component of nevi do not usually stain. Melan A is a very sensitive marker. Desmoplastic melanomas are often negative for HMB 45 and Melan A. S-100 is the only positive marker.
Mesenchymal proliferations
Vimentin is a broad-spectrum, non-specific marker of mesenchymal differentiation. Tissues that do not express Vimentin are not suitable for performing other immunostains, as it indicates suboptimal fixation/processing.
Desmin, smooth-muscle actin, Myogenin: Muscle differentiation
CD31, CD 34 highlight vascular endothelial cells. CD 31 is more sensitive, except in Kaposi sarcoma, where CD 34 is preferred. DFSPs express CD 34. Dermatofibromas are positive for Factor XIIIa.
Spindle cell neoplasms
| CK | Vimentin | S100 | SMA | |
|---|---|---|---|---|
| Squamous Cell Carcinoma | + | - | - | - |
| Atypical Fibroxanthoma | - | + | - | - |
| Malignant Malenoma | - | + | + | - |
| Leiomyosarcoma | - | + | - | + |
Lymphoid proliferations
Diagnosis of infiltrates with a follicular growth pattern (B cell)
| Reactive | Folicular Lymphoma | Marginal Zone Lymphoma | |
| Germinal centers: | |||
| CD 20 | + | + | + |
| CD 3 | + | - | + |
| bc1-6 | + | + | + |
| CD 10 | + | + | + |
| bc1-2 | - | + (may be neg in primary cutaneous FL) | - |
| Interfolicular areas: | |||
| Neg for bc1-6 & CD 10 | bc1-6 & CD 10 + cells | bc1-2 pos cells | |
| Plasma Cells | Occasional | May be + | Sheets, monotypic light chain |
Always remember...
- Never rely on a single antibody
- Markers should always be used in panels
- Beware of false positives and technical errors
- Pattern of staining is important
- Check internal/other controls
- Interpretation should always be based on morphology
Limits in the histopathological diagnosis of early melanoma
Rodica Cosgarea, Simona Senila, Loredana Ungureanu, Elisabeta Candrea, Razvan Bucur, Liliana Rogojan, Magda Petrescu
Clinica Dermatologie, UMF"Iuliu Hatieganu", Laborator Anatomie Patologica, Spitalul Clinic Judetean de Urgenta Cluj-Napoca
The histopathological diagnosis is sometimes difficult to be done, especialy when it develops from preexisting melanocytic nevi which change to melanoma. Very often, by dermatoscopy we can do the diagnosis of early melanomas because there are some subtle dermatoscopic structures which allow to have a suspicion for melanoma.
By the histopathological exam, the melanoma diagnosis is sometimes difficult to be done, especialy if the changed structures of the nevi are limited and the sections can not be "catched".
We present some cases of patients with pigmented lesions who had in dermatoscopic examination few structures which indicated a possible melanoma, based on an ununiform distribution of black dots and globules, black dots and globules in the perifery, blue-grey fine dots, blue-white veil, negative pigment network, alteration of the vassels.
Because of the small dimensions of the transformed parts of a melanocytic lesion it is better to be indicated the area of the nevi where the suspect strucutres are found by dermatoscopy. In this manner, the incipient and limited melanoma can be identified by dermatoscopy and confirmed by pathology.
Clinico-pathological correlations:
Erythema elevatum et diutinum in an HIV positive patient
Irina Margaritescu MD, DipRCPath, Aurel Doru Chirita MD, DipICDP-UEMS
Erythema nodosum in association with Sweet's syndrome: different patterns of the same pathological process
Irina Margaritescu MD, DipRCPath, Aurel Doru Chirita MD, DipICDP-UEMS
Netherton's syndrome and psoriasis: related disorders?
Irina Margaritescu MD, DipRCPath, Aurel Doru Chirita MD, DipICDP-UEMS