Slides for residents

1. Slides for residents Dr F.Iraji

17. Case 1 • An 84 year old white male with newly diagnosed basaloid squamous cell carcinoma of the right mandibular gingiva was referred to our clinic by otolaryngology for 6-12 month history of right sided facial induration and erythema. The patient denied any pain or pruritus, but endorsed a sensation of tightness of the right face. He had no prior history of radiation therapy.

18. Clinical History • On physical exam, the right side of his face was faintly erythematous, with firm woody induration extending from temple to jaw line and just medial to the nasolabial fold. A sclerotic focus was noted centrally on the right cheek. Asymmetry was observed between the right and left face, most prominent infraorbitally and at the nasolabial fold.  Assessment of cranial nerve VII was unremarkable. A tissue biopsy was performed.

19. Histopathology • revealed an abundance of vascular channels in the dermis that stained positive for CD31 (endothelial cell marker), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE 1), and D2-40 (lymphatic endothelial cell marker); and negative for human herpes virus 8 (HHV 8).  Ten percent of the endothelial cells stained positive for Ki67. No squamous cell carcinoma was identified.

20. Cutaneous angiosarcoma • Clinical presentation and histopathology:Angiosarcoma is a rare high-grade malignant tumor derived from vascular and lymphoid endothelium. Cutaneous angiosarcoma is most often reported on the face and scalp in elderly patients, or in association with chronic lymphedema or prior radiation. Over 50% of cutaneous angiosarcomas are located on the head and neck, • Early disease is usually benign-appearing, often described as bruise-like and poorly defined. As lesions progress, induration, nodularity, edema, bleeding, and ulceration may occur. The variable and subtle clinical findings contribute to later patient presentation and diagnosis, by which time patients may develop advanced disease. 

21. Histology • reveals atypical endothelial cells lining anastomosing and infiltrative vascular spaces in the dermis. Cellular pleomorphism and mitoses are variable, and less well-differentiated patterns with poorly-formed vascular channels or sheets of endothelial cells are commonly encountered. Cells express positivity with CD31, CD34, von Willebrand factor, Ulex europaeus 1 agglutinin, and vascular endothelial growth factor (VEGF) immunohistochemical stains, but not HHV 8.

22. Prognosis • Cutaneous angiosarcoma is an aggressive tumor with several factors contributing to an overall poor prognosis. There is a high rate of disease recurrence, related in part to delays in initial diagnosis, prevalence of multifocal disease, and difficulty defining clinical and surgical margins. Metastatic rate is also high, with early metastases to the lung and pleural cavity, lymph nodes, liver, bone, and other soft-tissues. Despite aggressive treatment with surgical excision plus adjuvant radiation, local recurrence and/or metastases are found in most patients. • .

23. Prognosis • Specific factors impacting survival have been debated in the literature. Many studies agree that large tumor size (greater than 5 cm) is the most consistent indicator of poorer prognosis. Other studies argue that histologic grade, including epithelioid morphology, mitoses, necrosis, and depth of invasion, is a more significant predictor of survival. Anatomic site, older age of patient, medical co-morbidities, and presence of metastases at presentation may also impact survival, though the significance of these factors is unclear. Most patients succumb to the disease within 2 years of diagnosis. The 5 year survival rate for cutaneousangiosarcoma is 10-35%, compared with 50-60% for other soft-tissue sarcomas

24. Treatment • Treatment of cutaneous angiosarcoma is difficult, with most recommendations evolving from case series. Tumors may be multifocal, extend well beyond clinical margins, and have satellite lesions that complicate therapy.  For local disease, wide surgical resection of the primary cutaneous lesion, as well as utilization of frozen tissue sections to define clear margins is employed. Unfortunately, due to the nature of the tumor, margins are often positive despite extensive surgical resection, and patients may need repeated surgeries for remaining disease

25. Treatment • . Regardless, studies have demonstrated a high percentage of patients with residual sarcoma following numerous resections. Wide surgical excision is especially complicated on the head and neck, and post-operatively, patients risk significant mutilation, with functional and cosmetic sequelae.  Cure is rare with surgery alone; for this reason, radiation with wide treatment field is utilized as adjuvant therapy following excision for local disease control.  Radiation as monotherapy is not curative, but may be used as palliation for extensive non-resectable disease.

26. Treatment • Adjuvant chemotherapy following surgery and radiation has been described with mixed results. Neoadjuvant chemotherapy may be employed to reduce the size of the primary tumor in an attempt to improve cosmetic and functional outcomes following surgery, however studies have demonstrated recurrence rates of over 50%, and suggest that neoadjuvant therapy does not significantly affect survival or recurrence rates.  It is not clear if chemotherapy for metastatic disease improves overall survival; its use is limited by patient co-morbidities and toxicity.  VEGF monoclonal antibodies (bevacizumab) and tyrosine kinase inhibitors (sorafenib) have been studied in trials for the treatment of cutaneous angiosarcoma with promising results.

27. Case 2 • A 67-year-old caucasian man with no medical problems presented with multiple sores on his bilateral lower extremities and few on trunk, arms and genitalia  Patient denies fever, chills, night sweats fatigue weight loss, hemoptysis, hematuria, hematochezia, abdominal pain.  Patient denies history of inflammatory bowel disease or malignancy.  Patient denies any recent travel or new medications.

28. Physical Exam • The patient's lower extremities had multiple ulcers with erythematous raised borders, few with satellite pustules and multiple erythematous, indurated plaques with central ulcerations, + odor.The glans penis had ulcerative, erythematous plaques resembling a balanitis.The upper extremities had violaceous, indurated plaques with central crusting.

29. Case 2 • Laboratory Data • CBC, LFTs, BUN/Cr, SPEP, ANA, RF, ANCA, ESR, CRP-normal • Imaging • CT of chest/abdomen/pelvis with and without contrast-normal • Microbiology • No fungus or mycobacterium isolated. • Histopathology • Punch biopsy specimen revealed ulcer with a heavy underlying neutrophilic and granulomatousinfiltrate.  Deep dermis with fibrosis, lobular proliferation of capillaries.  Special stains (PAS, GMS, Fite, Afb, Gram) negative.

30. Pyoderma gangrenosum (PG) • has been described in association with a wide variety of disorders, including Crohn’s disease, arthritis, rheumatologic and hematologic conditions, HIV infection, sarcoidosis, hereditary hypogammaglobulinemia, iatrogenic immune suppression, malignancy.  Pathogenesis is unknown, but autoimmune mechanisms including immune complex-mediated neutrophilic vascular reactions have been suggested.  The differential diagnosis includes Wegener’s granulomatosis, polyarteritisnodosa, lymphoma, sporotrichosis and antiphospholipidsyndrome. •   PG is a global disease.  It most commonly affects women between 20 and 50 years of age. Fifty percent of patients have an underlying systemic disease.  Approximately 4% of cases of PG occur in infants and children.

31. Pyoderma gangrenosum (PG) • Major clinical forms of PG include bullous, pustular, superficial, granulomatous and ulcerative and, in our case, disseminated.  The initial lesion is frequently a pustule on an erythematous to violaceous base, an erythematous nodule or a bulla.  The characteristic lesion is an ulcer with a necrotic undermined border.  The base can be purulent or vegetative. • Skin biopsy specimens typically reveal necrosis, ulceration, and abscess formation with a dense neutrophilic infiltrate. The differential diagnosis depends on the form and stage of the disease.  Broad categories includeinfection, lymphoma, panniculitis, vasculitis, Sweet’s syndrome, Behcet’s disease, malignancy.

32. Treatment • First line therapy for disseminated disease is systemic corticosteroids or cyclosporine or a combination of the two.  Experimental therapies include thalidomide, mycophenolate mofetil, tacrolimus, dapsone, azathioprine, infliximab, intravenous immunoglobulins, granulocyte and monocyte adsorption apheresis, plasmapheresis, cyclophosphamide

33. Case 3 • 32 year old white female at 25 weeks of gestation presents with itchy rash on abdomen and lower extremities for 1 month. She complains of intense pruritus. She has similar but milder rash in two previous pregnancies. At that time, she was diagnosed as eczema and rash was controlled with triamcinolone cream.  The patient has no other known medical issues. • Physical exam • Erythematous edematous patches and plaques on the abdomen and erythematous patch with irregular border in left lower extremity were found. Erythematous round papules with hemorrhagic crusts were scattered in lower extremities.

34. Histopathology • Histology (H&E) showed interface dermatitis with numerous eosinophils (see figure 3-5). DIF shows linear deposits of C3 at the dermoepidermal junction.

35. Pemphigoidgestationis • Pemphigoidgestationis is a rare vesiculobullous disease of pregnancy and the most important to exclude.1 Pemphigoidgestationis is also called gestational pemphigoid or herpes gestationis. It is intensely pruritic and develops in late pregnancy or immediate postpartum period. The incidence of the disease is estimated 1 in 50,000 in North America, 1 in 40,000 in the UK. The disease is distributed worldwide. • PemphigoidÂgestationis usually presents during the second (34% of patients) or third trimester (34% of patients) of pregnancy although the onset could occur during the first trimester (18% of patients) and during the postpartum period (14%).2 The abrupt onset of intensely pruriticurticarial lesions are typically located on the abdomen, in 50% of cases almost always involve the umbilicus. 3This could rapidly progresses to a generalized pemphigoid-like eruption. But the face, mucous membranes, palms and soles are usually spared. Although the clinical presentation and course may be variable, it generally improves in the third trimester and flare at the time of delivery (in 50-75% of patients).

36. Pemphigoidgestationis • Most disease spontaneously remits over weeks to months after delivery without treatment. The disease could recur with oral contraceptives usage and menstruation. Patients with a history of pemphigoidgestationis seems to be at increased risk for the subsequent development of Graves disease.4 Newborns can develop urticarial-like or vesicular skin lesions due to the passive transfer of IgG1 antibodies from the mother to the fetus. These skin lesions resolve within days to weeks as the antibodies are slowly catabolized. Additionally, there is an increased risk of prematurity and small-for-gestational-age neonates. No increased fetal morbidity or mortality has been reported.5

37. Pathophysiology • The pathogenically relevant auto-antigen has been identified as a 180 kDatransmembranehemidesmosomal protein (BPAG2). This protein has N-terminal end which is embedded within the intracellular component of the hemidesmosome and C-terminal end extracellularly. The extracellular section contains a series of collagenous components interspersed by non-collagenous (NC) domains. The reactivity of the autoantibodies is directed against the N-terminal 45 amino acids of the 16th non-collagenous domain (NC16A), which is located next to the cell membrane. The autoantibodies (The anti-BPAG2) antibodies are IgG1 subclass and fix complement via the classical complement pathway in the skin. Consecutively chemoattraction of eosinophils and degranulation follows, resulting in tissue damage and blister formation.1 

38. Diagnosis and Treatments • The most important and useful tools to confirm a clinical diagnosis of pemphigoid gestationis are histopathologic tests: subepidermal vesicle and a perivascular infiltrate of lymphocytes and eosinophils along the dermal-epidermal junction. The gold standard of a diagnosis of the disease is the finding of C3 with or without IgG in a linear band along the dermal-epidermal junction. In salt-split skin specimens, antibody deposition is located along the bottom of the epidermal fragment.

39. Diagnosis and Treatments • Due to rarity of the disease, there are no therapeutic trials. In mild disease, potent topical corticosteroids, emollients with antihistamines could be used although there is general consensus of ineffectiveness of topical steroid and antihistamines. Systemic corticosteroids could be used for blistering disease (0.5-1mg/kg/day prednisone) until a good clinical response is achieved. Then prednisone can be tapered and maintained at the lowest effective dose.

40. Case 4 • A full term 1 day old white male from an uncomplicated pregnancy in a healthy mother was transferred to the neonatal intensive care unit for vesicles, blisters and desquamation of the hands and feet present at birth. The mother denied a history of herpes simplex virus and there was no family history of any blistering disorders. • The infant was otherwise healthy appearing and showed no signs of extramucocutaneous disease. Over the next several days, the patient began to develop additional blisters in areas of friction and minimal trauma including oral mucosa.

41. Case 4 • An attempt was made to induce microvesicles on an area of normal appearing skin on the chest. This area was immediately biopsied for H&E as well as by electron microscopy. Unfortunately, the H&E did not contain microvesicles and was notable only for occasional vesicles within cells of the basal layer. Electron microscopy also did not contain microvesicles, but did show hemidesmosomes, anchoring filaments, and tonofilaments. • Repeat biopsy was sent for immunofluorescent mapping studies, which again revealed vesicles within the basal layer. It was notable for the presence of type IV collagen, type VII collagen, keratin 14, laminin 332, alpha 6 integrin, beta 4 integrin, type XVII collagen, and plectin.

42. Diagnosis: • Epidermolysisbullosa (EB) is a group of genetic diseases characterized by blistering following friction or minor trauma (1,2). These are broadly classified into 3 subtypes based on the location of the split during blister formation:EB simplex (EBS)-separation within the basal keratinocytesjunctional EB (JEB)- separation of the basal layer of the epidermis from the basement membranedystrophic EB (DEB)- separation of the basement membrane from the dermis

43. Diagnosis: • The electron microscopic images demonstrate a relatively normal appearance of anchoring fibrils, formed by type VII collagen, which are usually absent in severe forms of DEB (1). On the other hand, changes in the basal layer are somewhat suggestive of EBS, however, EBS rarely has mucosal involvement (2). Overall, due to his clinical appearance, the presence of mucosal involvement, and the presence of anchoring fibrils, JEB, the subtype with the worst prognosis, is favored as the diagnosis

44. Diagnosis: • In addition to the many described mutations known to cause EB, it can be due to sporadic mutations, as well as novel mutations. EB can be the result of deficiencies in the number or function of proteins or a complete absence. Additional genetic workup is pending on this patient, but currently his genetic defect remains unknown. The gold standard for diagnosis of EB remains to be electron microscopy, as was done for this patient, but due to the expense, inconvenience, lengthy tissue preparation, and lack of availability, immunofluorescent microscopy is becoming an increasingly popular alternative .

45. Diagnosis: • At this time the primary treatment for all forms of EB is supportive, but research into improved therapies is ongoing. A recent small study demonstrated improvement in ulcer healing through the use of gentian violet . Encouraging results have been found in several patients with the recessive form of DEB who received stem cell transplants, but at this time it remains a very risky and experimental therapy . In the future, induced pluripotent stem cells may serve as a method to allow gradual replacement of abnormal skin with fully competent dermal fibroblasts and keratinocytes .

46. Diagnosis: • Many patients with genetic disorders such as EB have small islands of normal cells due to mosaicism, with mutationed clones that have recovered function of the disease-causing gene in very localized patches. Current research has shown promising results in conversion of keratinocytes and fibroblasts into stem cells which can then be expanded and differentiated back into skin.  • Differential Diagnosis includes other types of EB, other genodermatoses, autoimmune bullous diseases, and infections such as HSV, staph scalded skin, and bullous impetigo

47. Case 5 • A 57 year old Haitian American female presents with a 6-month history of asymptomatic bluish-grey patches on her anterior neck and inferior to her eyes. She has no similar lesions elsewhere and is otherwise healthy.Apart from Vaseline, she does not apply any other products to her face or neck. She takes no prescribed or alternative medications apart from a standard multivitamin. • On exam, bluish-grey hyperpigmented patches are apparent on her anterior neck and inferior to her eyes.  The patches parallel her skin folds, with sparing of the central fold. •  A skin biopsy is performed. Histopathology reveals a vacuolar interface dermatitis with prominent pigment incontinence and pigment-laden melanophages in the upper dermis.

48. Erythemadyschromicumperstans • Erythemadyschromicumperstans (EDP) was first described by Ramirez in El Salvador in 1957. It is an asymptomatic, chronic, slowly progressive cutaneous eruption that most common affects dark skinned Latin Americans. The disorder has no systemic manifestations.  The etiology of EDP, although unclear, is likely related to a cell mediated immune reaction. No triggering factor has been consistently identified, although various pesticides, fungicide, and medications have been reported to cause the disorder. Clinically, EDP is characterized by slate-grey to blue-brown macules, arranged symmetrically on the trunk, neck, and proximal extremities.  • As observed in this case, EDP affects the neck in approximately two thirds of patients; a number of cases have also documented periorbital involvement. 

49. Erythemadyschromicumperstans • Histologic features include vacuolar degeneration of the basal layer, colloid bodies, pigment incontinence, prominent dermal melanophages, and a perivascular mononuclear cell infiltrate in the upper dermis.The differential diagnosis in the case includes lichen planuspigmentosus, pigmented contact dermatitis (Riehl’s melanosis), and idiopathic guttate macular hyperpigmentation.   Differentiation from lichen planuspigmentosus (LPP) should be based primarily on clinical findings, as EDP and LPP are often indistinguishable histologically.   Clinical features of LPP that can help in differentiating it from EDP include: presence of associated pruritus, associated dark-brown papules, asymmetric and sun-exposed distribution of lesions, and mucosal involvement.

50. Erythemadyschromicumperstans • The clinical appearance of idiopathic eruptive macular hyperpigmentation can be very similar to EDP.  However, the vast majority of patients described with this disorder are children or teenagers.  Lesions of idiopathic eruptive macular hyperpigmentation often spontaneously remit over months to years.7 The histologic features of idiopathic eruptive macular hyperpigmentation include basilar keratinocytehyperpigmentation and prominent dermal melanophages.7  Importantly, no visible basal layer damage or lichenoid infiltrate is observed.7 This key feature is often helpful in distinguishing idiopathic eruptive macular hyperpigmentation from EDP.