- Email: [email protected]
Histopathology of inflammatory skin disease in oncological patients
MINI-Symposium: inflammatory skin pathology
Histopathology of inflammatory skin disease in oncological patients
such as steroids or chemotherapy) and general cutaneous manifestations of malignancy. In addition to these lesions, cutaneous metastases or direct cutaneous extension of internal tumours can be also seen in oncological patients, but they will not represent the subject of our overview.
Doina Ivan
Paraneoplastic syndromes By definition, paraneoplastic dermatoses represent a heterogeneous group of non-inherited skin conditions that arise in association with a distant malignancy.1 They reflect the remote effects of cancer rather than being caused by tumour growth or invasion. Generally, the clinical onset and course of cutaneous disorders precede or have a parallel evolution with internal neoplasm.2,6–8 The skin disorder may also herald a new or a recurrent neoplasm; therefore, recognition of these conditions may facilitate early detection of cancer, while the failure to recognize them may have significant adverse consequences. Pathogenesis of paraneoplastic syndromes is not completely understood, but considering the diverse nature of paraneoplastic mucocutaneous lesions, it is unlikely to have a uniform aetiological basis.9 It has been postulated that there is an association between these disorders and a variety of immune and cytokinemediated aberrations, as well as the possibility of a tumourinduced host immunological response.2,3,9 The list of paraneoplastic syndromes is extensive (Table 1). For this review we have selected to discuss in more detail the dermatoses that have a stronger casual relationship with the underlying malignancies and are specific enough on clinical and histological grounds for practical dermatological and dermatopathological recognition.10–14
Victor G Prieto
Abstract The spectrum of cutaneous lesions in oncological patients includes entities encountered in the general population, lesions associated with underlying malignant processes (such as paraneoplastic syndromes) and conditions related to the immunosuppressed status of these patients or their antineoplastic treatment. The paraneoplastic syndromes represent a group of skin conditions that may precede or coexist with the diagnosis of malignancy and may also signal tumour recurrences. In general, there is a high prevalence of immunosuppression in oncological patients, related to the alteration of humoral and cellular immunity or their immunosuppressive therapy. Thus, these patients are especially susceptible to certain infections associated with high morbidity and mortality. Correct and early recognition of the cutaneous manifestations in oncological patients provides an important insight into underlying malignant process, possible complications (iatrogenic or not) and prognosis. In this review we offer a practical overview of inflammatory or neoplastic conditions associated with internal malignancies and cutaneous infectious in oncological patients.
Keywords inflammatory skin diseases; infections; oncological patients Acanthosis nigricans Acanthosis nigricans, a common marker for benign conditions such obesity and hyperinsulinism/insulin resistance, is characterized by hyperpigmented, velvety or verrucous patches on intertriginous areas.15 Histologically the lesions are characterized by hyperkeratosis, papillomatosis and acanthosis. The characteristic hyperpigmentation of these lesions is mainly due to hyperkeratosis rather than to increase of melanocytes or melanin production. Sudden onset during adulthood with rapid progression and extensive involvement (including hands, feet, mucosal membranes) may signal an underlying malignancy.16 Malignant acanthosis nigricans is most commonly associated with adenocarcinomas, 70–90% of which have gastrointestinal origin, predominantly gastric. Other primary tumour sites include uterus, lung, ovary and liver. Approximately 20% of acanthosis nigricans with sudden onset precede the diagnosis of internal malignancy and its course correlates closely with that of the tumour.15,16
Introduction The association of evident or occult internal malignancies with various cutaneous lesions has been known for a long time.1–4 Early recognition of these cutaneous manifestations is of a paramount importance, especially considering that they may precede the diagnosis of malignancy, signal a severe immunosuppressed status and purport a great impact in overall morbidity, prognosis and mortality of these patients. Banal-appearing skin lesions in immunosuppressed patients, such as oncological patients, may represent an unusual infection, a marker of tumour progression or recurrence or a drug-related reactive process.5 For practical purposes, the cutaneous lesions in oncological patients can be categorized into paraneoplastic dermatoses, skin lesions related to the immunosuppressed status of these patients (disease-related or secondary to immunosuppressive therapy
Acquired ichthyosis It occurs in adulthood and resembles clinically the autosomal dominant ichthyosis, being characterized by diffuse rhomboidal scales on lower legs (with pretibial accentuation), trunk (especially back) and arms. Histologically there is hyperkeratosis with orthokeratosis and acanthosis, with reduction or loss of granular layer.17 A number of lymphoproliferative disorders are associated with acquired ichthyosis, especially Hodgkin lymphoma (in 70–80% of cases) but also in other lymphomas, leukaemias,
Doina Ivan MD is Dermatopathologist, Assistant Professor of Pathology and Dermatology at the Departments of Pathology and Dermatology, UT-MD Anderson Cancer Center, Houston, Texas, USA. Victor G Prieto MD PhD is Chief of Dermatopathology at the Departments of Pathology and Dermatology, UT-MD Anderson Cancer Center, Houston, Texas, USA.
DIAGNOSTIC HISTOPATHOLOGY 15:4
203
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Paraneoplastic syndromes
Most common associated malignancies
Most common associated malignancies Acanthosis nigricans Acquired ichthyosis Erythroderma
Hypertrichosis lanuginosa acquisita Erythromelalgia Pityriasis rotunda Melanosis Pruritus
Flushing Acquired tylosis (nonepidermolytic palmoplantar keratoderma) Acrokeratosis paraneoplastica (Bazex syndrome) Tripe palms
Scleromyxedema Scleroedema Subacute cutaneous lupus erythematosus Paraneoplastic pemphigus
Adenocarcinomas with gastrointestinal origin Hodgkin lymphoma Cutaneous T-cell lymphoma (Sézary), Hodgkin and nonHodgkin lymphoma Colorectal, lung and breast carcinoma Myeloproliferative disorders Hepatocellular and gastric carcinoma Melanoma, post-busulfan therapy Hodgkin disease, lymphomas, carcinoid, gastrointestinal tumours, insulinoma Carcinoid, medullary carcinoma of thyroid, leukaemia Oesophageal squamous cell carcinoma
Non-Hodgkin lymphoma, chronic lymphocytic leukaemia, Castleman disease Porphyria cutanea tarda Hepatocellular carcinoma (most frequent), lung and colon cancers, lymphoma Necrobiotic xanthogranuloma Haematological and lymphoproliferative malignancies Multicentric reticulohistiocytosis Haematological malignancies, breast, ovarian, carcinomas (no predominant malignancy) Chronic erythema nodosum Non-Hodgkin lymphoma, ovarian carcinoma Subacute pancreatic necrosis Pancreatic cancer Palmar fasciitis Ovarian cancer, lung carcinomas Table 1
Squamous cell carcinoma of aerodigestive tract Lung carcinoma, gastric carcinoma Florid cutaneous papillomatosis Gastric cancer Leser-Trélat sign
Amyloidosis Xanthomas Digital clubbing Hypertrophic osteoarthropathy Erythema gyratum repens
Necrolytic migratory erythema Vasculitis Pyoderma gangrenosum Sweet syndrome
Raynaud phenomenon Trousseau syndrome Dermatomyositis
DIAGNOSTIC HISTOPATHOLOGY 15:4
Plasma cell dyscrasia Lymphoma, multiple myeloma Lung, breast cancers
multiple myeloma and a few visceral tumours. Interestingly, this condition usually occurs after the diagnosis of underlying malignancy and parallels its course.18
Adenocarcinomas with gastrointestinal origin, lymphoproliferative disorders Multiple myeloma, thyroid or multiple endocrine neoplasia Multiple myeloma Lung carcinoma, mesothelioma Lung cancer Lung (most frequent), oesophageal and breast carcinomas Pancreatic alpha-cell tumour (glucagonoma) Haematological malignancies Acute myelogenous leukaemia, multiple myeloma Acute myelogenous leukaemia, other haematological malignancies Testicular cancer, genitourinary or gastrointestinal carcinomas Pancreatic cancer, lung or gastric carcinomas Ovarian cancer (most frequent), lung, gastrointestinal, breast carcinomas
Hypertrichosis lanuginosa acquisita It represents the sudden and progressive development of fine lanugo hair in an adult. It has a strong female predominance and the soft, non-pigmented hair initially covers the face and ears, and extends caudally covering almost the entire body, sparing the palms, soles and genitalia.19 Histologically, the lanugo hairs are often found implanted in a parallel position to epidermis and are surrounded by clusters of mantle epithelium containing immature sebocytes.20 Although rare, the presence of hypertrichosis lanuginosa correlates strongly with malignancies. In men, the most common associated tumour is lung carcinoma followed by colonic tumours, while in women colorectal cancer is the most frequent association, followed by lung and breast cancers. It usually appears late in the course of the malignancy, when the tumour has already become metastatic. Tripe palms These are rugose, velvety palms with exaggeration of dermatoglyphics that can be associated with acanthosis nigricans in the majority of cases.21 The histopathological features include hyperkeratosis, papillomatosis, acanthosis and sometimes mucin deposition. Its occurrence has a very strong correlation with underlying malignancies such as lung or gastric carcinomas. When both tripe palms and acanthosis nigricans are seen, the most common associated cancer is gastric carcinoma. In 60% of cases, tripe palms are present before or at the same time as cancer diagnosis. 204
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Acrokeratosis paraneoplastica (Bazex syndrome) This is characterized by psoriasiform lesions on acral areas, ears or nose that can be hyperpigmented and associated with nail dystrophy.22 Histologically there are hyperkeratosis, parakeratosis and acanthosis with focal spongiosis, dyskeratotic keratinocytes and perivascular lymphocytic infiltrate. Bazex syndrome is almost always associated with malignancy, particularly squamous cell carcinoma of the oropharynx, larynx, oesophagus and lung.23,24 In 60% of cases, Bazex syndrome is diagnosed approximately 1 year before the malignancy and it usually resolves after successful radiation therapy of the neoplasm. Leser-Trélat sign The sign of Leser-Trélat refers to a sudden increase in size and numbers of seborrhoeic keratoses in association with an internal malignancy, such as gastrointestinal adenocarcinomas (one-third of cases) or lymphoproliferative disorders (one-fifth of cases).25 Acceptance of this condition as a paraneoplastic dermatosis is somewhat controversial, because seborrhoeic keratoses are extremely common in the elderly population. Some authors consider the sign of Leser-Trélat as an early stage of malignant acanthosis nigricans.
Figure 1 Superficial perivascular tight lymphocytic infiltrate and mild papillary dermal oedema in a patient with migrating bands of erythema with ‘wood-grain’ appearance. In this clinical context, the histological features are diagnostic of erythema gyratum repens, a highly specific paraneoplastic syndrome.
Florid cutaneous papillomatosis It is characterized by rapid onset of numerous lesions clinically and histologically resembling viral warts. However, human papilloma virus has not been identified in these lesions. It appears to be an obligatory paraneoplastic syndrome since it has been linked to cancer development in all reported cases.26 The most common associated tumour is gastric carcinoma and it usually portends a poor prognosis.
layer. Later in the process appear the characteristic dyskeratosis and necrosis of superficial epidermal layers with occasional cleftlike detachment from basal layer. Because of the clinical and histological similarities of this lesion with zinc deficiencies or other nutritional dermatoses, this lesion is frequently misdiagnosed. Resection of the tumour frequently results in rapid involution of the eruption. Dermatomyositis Dermatomyositis is an inflammatory proximal myopathy with associated photodistributed violaceous erythroderma involving the scalp and peri-ocular area. Other manifestations include nailfold telangiectases, Raynaud phenomenon and Gottron papules (flat-topped papules over the knuckles).31 Histologically, the hallmark of this disorder is the interface vacuolar alteration with epidermal atrophy, dermal mucin and perivascular lymphoid infiltrate, thus similar to the findings in lupus erythematosus. The reported frequency of dermatomyositis with underlying malignancy is approximately 25% (according to most reports).32 Female patients with dermatomyositis have an increased risk of developing ovarian carcinoma; the rates of association increase with age.
Erythema gyratum repens This is a rare disorder, considered to be highly specific as a paraneoplastic syndrome. It is characterized by the presence of migrating bands of erythema with collarets of scales and a polycyclic appearance resembling ‘wood-grain pattern’. The erythematous edge of the lesion advances by approximately 1 cm/ day. It usually starts on the trunk or extremities, before covering the entire body.27,28 The histology reveals mild spongiosis with focal parakeratosis and a tight lymphohistiocytic perivascular infiltrate with mild oedema of papillary dermis (Figure 1). Direct immunofluorescence often reveals granular deposits of IgG and/ or C3 along the basement membrane zone. The most commonly associated lesion is lung carcinoma followed by oesophageal and breast carcinoma. Rarely, erythema gyratum repens may be associated with tuberculosis, Raynaud phenomenon or CREST syndrome.29 However, it usually precedes tumours and its presence should prompt a routine malignancy screen and possibly a bronchoscopy in at-risk individuals.
Paraneoplastic pemphigus This blistering disorder is associated almost exclusively with B-cell lymphoproliferative disorders, mainly non-Hodgkin lymphoma, chronic lymphocytic leukaemia and Castleman disease.7,33 Patients present with pruritic polymorphous eruption on the trunk with erythematous lesions and bulla formation, as well as with mucosal involvement (oral, genital mucosa, conjunctiva). The histological picture is an overlap of pemphigus vulgaris and erythema multiforme: suprabasilar acantholysis with interface dermatitis with necrotic keratinocytes (Figure 2). By means of immunofluorescence, IgG and C3 are seen as intercellular epidermal deposits in a linear fashion along the dermo-epidermal
Necrolytic migratory erythema This generalized eruption is the cutaneous manifestation of glucagonoma syndrome, related to increased glucagon levels produced by α-cell pancreatic tumours.30 There are irregular erythematous patches with formation of superficial blisters and shallow erosions with an annular configuration. It typically affects face, groin and perigenital area. Histologically the initial biopsies show mild acanthosis, spongiosis, parakeratosis and loss of granular
DIAGNOSTIC HISTOPATHOLOGY 15:4
205
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Figure 2 Suprabasilar acantholysis similar to pemphigus vulgaris and associated interface dermatitis with scattered necrotic keratinocytes (arrow) represent the histological features of paraneoplastic pemphigus.
Figure 3 Necrobiotic xanthogranuloma: areas of necrobiosis and granulomas composed of histiocytes, foam cells and multinucleated giant cells; cholesterol clefts are also seen.
junction. A positive test for IgG autoantibodies by indirect immunofluorescence on rodent bladder may confirm the diagnosis. Circulating antibodies to desmosomal proteins, including desmoplakin I and desmoglein I, have been identified in patients with paraneoplastic pemphigus, although it is suspected that there is a wider spectrum of target antigens.34 Paraneoplastic pemphigus is refractory to treatment and it usually does not follow a parallel course with the underlying malignancy.
neutrophilic infiltrate. Sweet syndrome is characterized by fever, neutrophilia and erythematous tender plaques and nodules, usually on the extremities. Histologically, besides the neutrophilic infiltrate (which can be minimal in neutropenic patients), there are also papillary dermal oedema and minimal epidermal changes. Although vasculopathic changes are frequent, frank vasculitis is very rare. Overall, approximately 20% of patients with Sweet syndrome have an associated cancer.38 Pyoderma gangrenosum typically starts as a sterile pustule that rapidly develops into a painful ulcer with undermined violaceous border. The lesions of pyoderma gangrenosum usually involve the lower extremity. When these lesions are associated with malignancy, they may present as haemorrhagic bullae and have a more rapid course. Fewer than 10% of pyoderma gangrenosum cases are associated with malignancies.37
Necrobiotic xanthogranuloma This eruption is characterized by multiple yellow plaques and subcutaneous nodules, often with a peri-orbital distribution but also occurring on the trunk, head and neck, and extremities. Histological examination reveals areas of necrobiosis and granulomas composed of histiocytes, foam cells and multinucleated giant cells, sometimes with cholesterol clefts (Figure 3). Necrobiotic xanthogranuloma is associated with haematological, lymphoproliferative disorders and monoclonal gammopathies.35 In 80% of patients, protein electrophoresis is abnormal, usually revealing an IgG-kappa paraprotein. Haematological malignancies may occur years after the appearance of necrobiotic xanthogranuloma.
Other paraneoplastic syndromes Generalized pruritus is a common sign in oncological patients: polycythemia rubra vera, lymphoma, Hodgkin disease, carcinoid tumours and gastrointestinal tumours.12 Rarely, localized pruritus may be associated with an underlying tumour and may signal a poor prognosis, such as in the case of onset of nasal pruritus in association with a brain tumour.39 Pruritus associated with malignancies has been observed to diminish or disappear after eradication of the tumour but it may reappear when the disease recurs. Patients with underlying malignancies may also have localized or generalized hyperpigmentation (such as in melanoma, busulfan therapy, etc) or erythroderma (e.g. Sézary syndrome).13 Erythromelalgia is a rare disorder characterized by bouts of burning pain, redness and warmth of extremities.40 It occurs concomitantly with Raynaud syndrome and can be associated in adults with lymphoproliferative disorders (in up to 40% of cases). Carcinoid tumours are associated in their great majority with episodes of flushing (usually on the face and trunk) that may be accompanied by facial oedema. Other signs include multiple episodes of flushing, telangiectases and chronic facial plethora. Less
Chronic erythema nodosum This manifests as painful subcutaneous nodules and plaques on the pretibial region. It is the prototype of septal panniculitis. In 50% of cases it is associated with infections (Streptococcus, leprosy, tuberculosis), drugs (sulphonamides, oral contraceptives), autoimmune disorders (especially sarcoidosis) and neoplastic processes (non-Hodgkin lymphoma, carcinoma of pancreas, colon and cervix).36 Neutrophilic dermatoses Both Sweet syndrome and pyoderma gangrenosum have been described in oncological patients, especially those with haematological malignancies such as acute myelogenous leukaemia.37 They are both characterized by a dense, predominantly dermal,
DIAGNOSTIC HISTOPATHOLOGY 15:4
206
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Superficial candidiasis in oncological patients is similar to that in immunocompetent patients. However, oral candidiasis (thrush) may lead to oesophageal candidiasis and prophylaxis (fluconazole, nistatin, etc) may be used in the immunosuppressed patients.44–46 Aspergillus sp infections occur by haematogenous spread or direct inoculation of skin following local trauma (injection therapy site, burns, eschars).46,48–50 In hospitals, these fungi may contaminate the air conditioning vents and central heating plants. Despite the wide distribution of the fungus, infections usually occur in immunosuppressed individuals, such as patients receiving corticosteroid therapy.48–51 In immunosuppressed patients the cutaneous lesions often ulcerate and develop a black crust. In cases of haematogenous spread, fungal hyphae may be identified within the lumen of thrombosed dermal blood vessels. The fungus is recognized by its uniform septate branching and radiating hyphae of equal thickness (dichotomus) and at 45° angles (Figure 4a). The hyphae are approximately 4 μm in diameter and the microconidia 3 μm. Aspergillus sp infections are indistinguishable from infections with Pseudallescheria boydii, which also encountered in immunosuppressed patients, especially following solid organ transplantation. Fusarium sp infections have a high incidence especially in neutropenic patients with haematological malignancies.45,46,48,52 The disseminated untreated infections with Fusarium have up to 80% mortality and they may be resistant to traditional antifungal treatments. Therefore, early diagnosis and recognition of these particular infections have a great impact on patients’ morbidity and mortality. Intravascular involvement is also seen. Histologically, unlike the Aspergillus sp, they present as hyaline, branching septate hyphae measuring 3–8 μm in width and branching irregularly from acute angles up to 90° (Figure 4b).48,52 This feature, along with the presence of relatively large macroconidia (up to 70 μm), may help in the differential diagnosis from Aspergillus sp. However, it is important to mention that in patients who underwent antifungal treatment before the biopsy was performed, the morphological characteristics of the fungal elements might change; therefore, the distinction may ultimately depend on tissue cultures. Zygomyces sp (e.g. Mucor, Rhizopus, Absidia) infections: some of the fungi of these species are aerobic, saprophytes, present worldwide; nevertheless the infections are uncommon and they usually develop in immunosuppressed patients (including oncological patients) and those with diabetic ketoacidosis.46,48,53,54 These fungal infections can involve the nasal sinuses and have cerebral extension, involving lung, gastrointestinal tract and skin, or can be disseminated (by haematogenous spread). The skin lesions develop as small erythematous macules that enlarge and eventually ulcerate with a black eschar formation; they can also resemble a vasculitic process or ecthyma gangrenosum. Isolated cutaneous infections with Zygomyces sp have a good prognosis with adequate treatment, while the mortality rate of disseminated and rhinocerebral involvement is very high (78–100%, according to various studies).46,48,53,54 The fungal hyphae of these species, particularly for Mucor, are broad (10–20 μm diameter), non-septate and branch irregularly at 90° (Figure 4c). They are usually easy to distinguish from the narrower, septate and dichotomus branches at 45° of Aspergillus
frequent are abdominal pain, diarrhoea, vomiting, rectal bleeding, bronchospasm and hypotension.41 Cutaneous granulomas may be a non-specific sign of an underlying systemic lymphoma. Their histological patterns are variegate and include sarcoid-type granuloma, palisaded and necrobiotic granuloma of granuloma annulare type and tuberculoid granuloma. In patients who present with non-infectious, granulomatous skin reactions in the absence of another sound explanation, the possibility of a systemic lymphoma should be considered.42 Several paraneoplastic syndromes affect the vascular system either by destruction of vascular walls (vasculitis), associated thrombocytopenia or hypercoagulable status of these patients (intravascular coagulopathy, migratory thrombophlebitis – Trousseau syndrome).8,43 Purpura is a common finding in patients with underlying malignancy.
Infections in immunocompromised oncological patients A large number of opportunistic organisms (fungal, bacterial, viral, protozoal or rickettsial) may produce infections in immunosuppressed oncological patients.44–48 They may represent de novo infections, reactivations of latent infections or, in patients who have undergone organ transplantation, the infectious organism may be carried by the transplanted organ. It is also important to remember that immunosuppressed patients may often lack fever and have false-negative results of serological tests for various infectious diseases, due to their immune dysfunction. For instance, false-negative test results for antibodies against Epstein–Barr, hepatitis B, human immunodeficiency viruses and syphilis may mislead the clinician. Moreover, in the biopsy specimens, an immunocompromised patient might not be able to mount a significant inflammatory response against the infectious organism so the diagnosis can be overlooked.5 In these instances, the need for tissue cultures cannot be over emphasized. Moreover, the tissue cultures represent one of the most reliable ways to classify the infectious agent. At our institution, to try to detect the most frequent infectious lesions in suspicious biopsies from oncological/immunosuppressed patients, we use a panel of special stains (Gram, Grocott methenamine silver and Fite).
Fungal infections Oncological patients who pose the highest risk for developing fungal infections are those with severe neutropenia (absolute neutrophil count of <500/ml that lasts for over 1 week), especially in leukaemia and lymphoma patients following high-dose chemotherapy or bone marrow transplantation.44–46 Cutaneous fungal infections in oncological patients may be superficial (dermatophytes, Candida species) or opportunistic disseminated primary or secondary skin infections.46 The outcome of deep or disseminated fungal infections is potentially fatal due to extensive visceral involvement, if not promptly recognized and treated. Dermatophyte infections (Microsporum, Epidermophyton and Trichophyton species) have similar presentation in cancer patients as in the general population: superficial infections of stratum corneum, nails and hair. Tinea pedis and onychomycosis are the most frequent; Majocchi granulomas are often seen.44,46
DIAGNOSTIC HISTOPATHOLOGY 15:4
207
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
a Aspergillus sp fungal hyphae within the lumen of thrombosed dermal blood vessel and interstitium. The fungus is recognized by its uniform septate branching and radiating hyphae of equal thickness, at 45° angles. b Fusarium presents as irregularly branching septate hyphae, from acute angles up to 90° (long arrow) and large macroconidia (short arrow). c The fungal hyphae Zygomyces sp, particularly for Mucor, are broad (10–20 μm diameter), non-septate and branching at 90°. d Cryptococcus presents as variably-sized spherical, budding yeasts with a mucoid capsule within a mucinous dermal background. Figure 4
sp. Angioinvasion with vasculitis, thrombosis, haemorrhage and infarction are also seen.48
Viral infections Herpes simplex (types 1 and 2) and varicella zoster viruses (HSV, VZV) are characterized by their ability to establish latency and reactivate at a later date. In immunosuppressed patients with cell-mediated immune deficiencies, these viruses lead to recurrent infections, particularly mucocutaneous lesions involving the oropharynx or genital regions.57 The infections may become widely disseminated and complicated with pneumonia, meningitis, encephalitis and purpura fulminans, sometimes resulting in death. Disseminated cutaneous lesions most often present as vesicles, pustules, haemorrhagic bullae, ulcers and black eschars, although occasionally the patients develop verrucous, hyperkeratotic lesions.44,48,57 Histologically the infections with these two viruses are almost undistinguishable, although it has been suggested that VZV infections are associated with a more profound inflammation and they can manifest with dermal vasculitis and dermal haemorrhage, usually in the absence of associated epidermal involvement.48 Both HSV and VZV usually present the characteristic multinucleated giant cells with inclusions bodies within intra-epidermal blisters (Figure 5). Immunosuppressed patients with VZV infections may have a protracted
Cryptococcosis: disseminated cryptococcosis is more common in acquired immune deficiency syndrome (AIDS) and renal transplant patients but may also occur in oncological patients, especially those with haematological malignancies.55 The skin lesions may be subcutaneous nodules, ulcerated plaques or molluscum contagiosum-like umbilicated papules.44,48 Histologically, as a clue, within a mucinous dermal background or a granulomatous reaction, there are widely spaced, variably sized (4–20 μm diameter), spherical, budding yeasts with a mucoid capsule that is better visualized by mucicarmine, PAS or Alcian Blue stains (Figure 4d).48 The presence of the capsule differentiates Cryptococcus from blastomycosis (another infection that may affect immunosuppressed patients): the latter lacks a capsule and has a monomorphous appearance. Alternariosis: Alternaria alternata is a pigmented fungus (hyphae and 5–20 μm rounded bodies) often affecting immunosuppressed hosts and presenting as cutaneous ulcers, verrucous lesions, erythematous papules and nodules.48,56
DIAGNOSTIC HISTOPATHOLOGY 15:4
208
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Bacterial infections In general, bacterial organisms producing infections in immunocompromised oncological patients are similar to those encountered in the general population. However, due to the immune dysfunctions of these patients, the infections may go unrecognized; in many instances a biopsy specimen may reveal a relatively unimpressive inflammatory infiltrate and the morphologist might fail to consider an infectious process.5 One of the histological clues to an infectious process in an immunocompromised patient is the presence of dermal haemorrhage, even in the absence of a significant inflammatory infiltrate. Such a finding should prompt the examination of special studies (Gram, GMS, PAS, AFB, Fite or Giemsa). Bacterial infections in immunocompromised patients may develop into extremely severe forms: cellulitis, necrotizing fasciitis and septicaemia. Ecthyma gangrenosum, a complication of Pseudomonas aeruginosa or other Gram-negative bacterial septicaemias, occurs with a higher frequency in immunodeficient patients, particularly those with neutropenia, and has been rarely reported in the absence of neutropenia or septicaemia.44,61 Lesions begin as painless erythematous macules that become indurated, pustular and eventually gangrenous with black eschar and surrounded by erythematous halo.48 The histology of ecthyma gangrenosum is striking and characteristic. Besides the epidermal necrosis, dermal haemorrhage and infarction due to ischaemia, there is a blue−grey perivascular cuffing involving particularly venular media and adventitia of dermal vessels (Figure 6). These are Gram-negative bacilli, most commonly Pseudomonas aeruginosa.48,61 Staphylococcal scalded skin syndrome, produced by group II staphylococci phage type 71, has been very rarely reported in adults, with the exception of immunocompromised patients.
Figure 5 Herpes simplex virus infection showing multinucleated giant cells with inclusions bodies within an intra-epidermal blister.
clinical course in which biopsies may reveal a lichenoid inflammatory reaction pattern with minimal viral inclusions.44,48,57 Cytomegalovirus (CMV) infection may be a feature of immunosuppression and may manifest as a disseminated disease.58 In these patients it is uncertain whether CMV infection represents an acquired phenomenon or reactivation of a latent infection. The histological hallmark is the presence of large, purple-staining intranuclear inclusions surrounded by a clear halo. These inclusions have been described within the enlarged dermal endothelial cells, sometimes accompanied by leucocytoclastic vasculitis, but can also be present within fibroblasts, macrophages and cells of eccrine ducts. Epstein-Barr virus (EBV) can cause a variety of infectious and diseases but of a particular importance is the development of lymphoproliferative disorders. This entity is a well-known complication of organ transplantation, but it has been also described in patients receiving methotrexate or other immunosuppressive agents, and seems to be similar to those triggered by EBV in transplant patients receiving cyclosporine.59,60
Mycobacterial infections Infections with Mycobacterium tuberculosis as well as with atypical mycobacterial organisms may occur in oncological immunosuppressed patients, sometimes with unusual patterns.44,48 In
Human herpes viruses (HHV): exanthem subitum (caused by infections with HHV-6) is a benign disease of infancy that has been recently described in patients with acute leukaemia.48 One of the forms of Kaposi sarcoma arises in immunocompromised patients, such as those post-transplant or having received immunosuppressive treatments (including corticosteroids). HHV8 genomic sequences have been identified by polymerase chain reaction in more than 90% of all types of Kaposi sarcoma lesions (including epidemic and endemic forms), suggesting a causative role for this DNA virus. Typical histological findings include proliferation of spindle cells, prominent slit-like vascular spaces and extravasated red blood cells. Human papilloma viruses (HPV): patients with deficiency in cell-mediated immunity are particularly susceptible to the development of warts, which do not tend to involute spontaneously and can be a particularly refractory therapeutic problem.
DIAGNOSTIC HISTOPATHOLOGY 15:4
Figure 6 Characteristic blue-grey perivascular cuffing of Gram-negative bacilli, involving media and adventitia of dermal vessels in ecthyma gangrenosum.
209
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
comparison with immunocompetent patients, the mycobacterial infections of immunocompromised patients are usually more extensive, can develop panniculitis, have less granulomatous reaction and more neutrophilic infiltrate, and disseminate more frequently. Protozoal infections These infections are more common in immunocompromised patients, such as oncological and transplant patients, than in the general population. Leishmania, a trypanosomal infection transmitted by a sand fly (Phlebotomus), can produce cutaneous lesions. Visceral leishmaniasis and, to a lesser extent, cutaneous leishmaniasis are increasingly recognized as opportunistic infections in immunocompromised patients.62 Cutaneous leishmaniasis occurs commonly on the face, hands and arms, and presents usually as ulcerated nodules. Histologically, there is pseudo-epitheliomatous hyperplasia overlying dermal micro-abscesses with histiocytes that contain intracellular amastigotes. The amastigotes are usually distributed at the periphery of the cell (arranged as a wreath), in contrast with blastomycosis in which similarly sized organisms are randomly distributed within the macrophages’ cytoplasm. Giemsa stain highlights these intracellular organisms. In immunocompromised/anergic patients the number of amastigotes is larger, there are fewer associated inflammatory cells and there is no evident granulomatous response.48,62
Figure 7 Radiation dermatitis changes: dermal fibrosis, stellate, atypical fibroblasts and hyalinized blood vessels.
hyalinized blood vessels) (Figure 7). Eosinophilic, polymorphic and pruritic eruption of radiotherapy (EPPER) is a complication of radiotherapy for cancer, especially breast, with a unique clinical−pathological profile, spongiosis and extensive underlying eosinophilic infiltrate.63 These lesions occur usually during radiation and before this entity was described, were diagnosed as erythema multiforme or bullous pemphigoid following radiotherapy. Several types of cutaneous vascular proliferations have been described in areas of irradiated skin, including both benign lesions, such as lymphangiomatous papules, atypical vascular lesions or benign lymphangioendothelioma, and malignant neoplasms such as angiosarcomas.64
Protothecosis P. wickerhamii is an achloric alga, originating from contaminated water and soil, that is inoculated into skin by minor trauma.48 In immunosuppressed patients the condition manifests as papular or eczematoid dermatitis with extensive scaling or may resemble pyoderma gangrenosum. Histologically, there is dermal necrosis surrounded by granulation tissue and few multinucleated giant cells. The algae are relatively large spherical bodies that have thick walls and characteristic internal septae.
Conclusion Correct and early recognition of cutaneous manifestations in oncological patients provides an important insight into the underlying malignant process, possible complications (iatrogenic or not) and prognosis. Increased clinician awareness and education regarding the association between the above mentioned lesions and internal malignancy will facilitate screening, early diagnosis or treatment. We would also like to emphasize the pivotal role of the pathologist in recognizing these entities, and timely and effective communication with the clinician of the pathology results for these patients. ◆
Other cutaneous manifestations of malignancy Non-specific cutaneous signs and lesions can be also encountered in oncological patients. They may include palor (related to anaemia), cyanosis (e.g. secondary to polycythemia) or plethora (such as in chronic carcinoid syndrome). The most common cutaneous lesions in oncological patients are probably drug related. These patients frequently take multiple medications thus complicating the clinical picture and resulting in overlapping histological features. The presence of eosinophils in a skin biopsy can be a useful clue to a drug eruption, but as a note of caution, their absence does not necessarily rule out this possibility; thus a high index of suspicion is needed in order to diagnose such reaction. Special attention should be paid to drugrelated reactions such as erythema multiforme, toxic epidermal necrolysis or Steven–Johnson syndrome that are related to high morbidity and increased mortality. Their common histological finding is the presence of epidermal necrotic keratinocytes. Other cutaneous lesions in oncological patients may be related to therapy, such as radiotherapy. The radiation dermatitis changes can be acute (histologically characterized by necrotic keratinocytes, dermal vascular thrombosis and haemorrhage) or chronic (dermal fibrosis, stellate, atypical fibroblasts and
DIAGNOSTIC HISTOPATHOLOGY 15:4
References 1 Curth HO. Skin lesions and internal carcinoma. In: Andrade R, Gumport SL, Popkin GL, Rees TD, eds. Cancer of the skin: biologydiagnosis-management. Philadelphia: WB Saunders, 1976; p. 1308–41. 2 McLean DI. Cutaneous paraneoplastic syndromes. Arch Dermatol 1986; 122: 765–7. 3 Brenner S, Tamir E, Maharshak N, Shapira J. Cutaneous manifestations of internal malignancies. Clin Dermatol 2001; 19: 290–7.
210
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
30 Wynick D, Hammond PJ, Bloom SR. The glucagonoma syndrome. Clin Dermatol 1993; 11: 93–7. 31 Sigurgeirsson B, Lindelof B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis. N Engl J Med 1992; 326: 363–7. 32 Zantos D, Zhang Y, Felson D. The overall and temporal relationship association of cancer with polymyositis and dermatomyositis. J Rheumatol 1994; 21: 1855–9. 33 Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol 1997; 12: 77–96. 34 Kimyai-Asadi A, Jih MH. Paraneoplastic pemphigus. Int J Dermatol 2001; 40: 367–72. 35 Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. J Am Acad Dermatol 1980; 3: 257–70. 36 Bohn S, Buchner S, Itin P. Erythema nodosum: 112 cases: epidemiology, clinical aspects and histopathology. Schweiz Med Wochenschr 1997; 127: 1168–76. 37 Caughman W, Stern R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders. Atypical forms of pyoderma gangrenosum and Sweet’s syndrome associated with myeloproliferative disorders. J Am Acad Dermatol 1983; 9: 751–8. 38 Fett DL, Gibson LE, Su WPD. Sweet’s syndrome: systemic signs and symptoms and associated disorders. Mayo Clin Proc 1995; 70: 234–40. 39 Andreev VC, Petkov I. Skin manifestations associated with tumors of the brain. Br J Dermatol 1975; 92: 675–8. 40 Kurzrock R, Cohen PR. Erythromelalgia and myeloproliferative disorders. Arch Intern Med 1989; 149: 105–9. 41 Wilkin JK. Flushing reactions: consequences and mechanisms. Ann Intern Med 1981; 95: 468–76. 42 Rongioletti F, Cerroni L, Massone C, Basso M, Ciambellotti A, Rebora A. Different histologic patterns of granulomas in systemic lymphoma. J Am Acad Dermatol 2004; 51: 600–5. 43 Pinzon R, Drewinko JM, Trujillo V. Pancreatic carcinoma and Trousseau’s syndrome: experience at a large cancer center. J Clin Oncol 1986; 4: 509–14. 44 Grossman ME. Cutaneous manifestations of infections in immunocompromised host, Baltimore: Williams and Wilkins, 1995 62–7. 45 Brown AE. Overview of fungal infections in cancer patients. Semin Oncol 1990; 17: 2–5. 46 Mays SR, Bogle MA, Bodey GP. Cutaneous fungal infections in the oncology patient. Am J Clin Dermatol 2006; 7: 31–43. 47 Tan HH, Goh CL. Viral infections affecting the skin in organ transplant recipients: epidemiology and current management strategies. Am J Clin Dermatol 2006; 7: 13–29. 48 Infectious diseases of the skin. In: Grayson W, Calonje E, McKee PH, eds. Pathology of the skin with clinical correlations, vol. I. St Louis: Elsevier Mosby, 2005; p. 837–992. 49 D’Antonio D, Pagano L, Gimernia C. Cutaneous asspergilosis in patients with hematological malignancies. Eur J Clin Microbiol Infect Dis 2000; 19: 362–5. 50 Khardori N, Hayat S, Rolston K. Cutaneous rhisopus and aspergillus infections in five patients with cancer. Arch Dermatol 1989; 125: 952–6. 51 Meyer RD. Cutaneous and mucosal manifestations of deep mycotic infections. Acta Derm Venerol 1986; 121: 57–72. 52 Watts JC, Chandler FW. Fusariosis. In: Connor DH, Chandler FW, Schwarts DA, eds. Pathology of infectious diseases, vol. I. Stamford: Appleton and Lange, 1997; p. 999–1001.
4 Sabir S, James WD, Schuchter LM. Cutaneous manifestations of cancer. Curr Opin Oncol 1999; 11: 139–44. 5 Rapini RP. Practical evaluation of skin lesions in immunosuppressed patients. Cutis 1988; 42: 125–8. 6 Abeloff MD. Paraneoplastic syndromes: a window on the biology of cancer. N Engl J Med 1987; 317: 1598–600. 7 Cohen PR, Kurzrock R. Mucocutaneous paraneoplastic syndromes. Semin Oncol 1994; 24: 334–59. 8 Kurzrock R, Cohen PR. Cutaneous paraneoplastic syndromes in solid tumors. Am J Med 1995; 99: 662–71. 9 Hall TC. Paraneoplastic syndromes: mechanisms. Semin Oncol 1997; 24: 269–76. 10 Moore RL, Devere TS. Epidermal manifestations of internal malignancy. Dermatol Clin 2008; 26: 17–29. 11 Kleyn EC, Lai-Cheong JE, Bell HK. Cutaneous manifestations of internal malignancy: diagnosis and management. Am J Clin Dermatol 2006; 7: 71–84. 12 Pipkin CA, Lio PA. Cutaneous manifestations of internal malignancies: an overview. Dermatol Clin 2008; 26: 1–15. 13 Chung VQ, Moschella SL, Zembiwicz A, Liu V. Clinical and pathologic findings of paraneoplastic dermatoses. J Am Acad Dermatol 2006; 54: 745–62. 14 Thomas I, Schwartz RA. Cutaneous paraneoplastic syndromes: uncommon presentations. Clin Dermatol 2005; 23: 593–600. 15 Schwartz R. Acanthosis nigricans. J Am Acad Dermatol 1994; 31: 1–19. 16 Stuart CA, Driscoll MS, Lundquist KF, Gilkison CR, Shaheb S, Smith MM. Acanthosis nigricans. J Basic Clin Physiol Pharmacol 1998; 9: 407–18. 17 Schwartz RA, Williams ML. Acquired ichthyosis: a marker for internal disease. Am Fam Physician 1984; 29: 181–4. 18 Rizos E, Milionis HJ, Pavlidis N, Elisaf MS. Acquired icthyosis: a paraneoplastic skin manifestation of Hodgkin’s disease. Lancet Oncol 2003; 3: 727–35. 19 Farina MC, Tarin N, Grilli R. Acquired hypertrichosis lanuginosa: case report and review of the literature. J Surg Oncol 1998; 68: 199–203. 20 Hegedus SI, Schorr WF. Acquired hypertrichosis lanuginosa and malignancy. A clinical review and histopathologic evaluation with special attention to the “mantle” hair of Pinkus. Arch Dermatol 1972; 106: 84–8. 21 Requena L, Aguilar A, Renedo G. Tripe palms: a cutaneous marker of internal malignancy. J Dermatol 1995; 22: 492–5. 22 Bazex A, Griffiths A. Acrokeratosis paraneoplastica — a new cutaneous marker of malignancy. Br J Dermatol 1980; 103: 301–6. 23 Richard M, Giroux J. Acrokeratosis paraneoplastica (Bazex’ syndrome). J Am Acad Dermatol 1987; 16: 178–83. 24 Bolognia JL, Brewer YP, Cooper DL. Bazex syndrome (acrokeratosis paraneoplastica). An analytic review. Medicine 1991; 70: 269–80. 25 Schwartz RA. Sign of Leser-Trelat. J Am Acad Dermatol 1996; 35: 88–92. 26 Schwartz RA. Florid cutaneous papillomatosis. Clin Dermatol 1993; 11: 89–91. 27 Kurzrock R, Cohen PR. Erythema gyratum repens. JAMA 1995; 273: 594. 28 Boyd AS, Neldner KH, Menter A. Erythema gyratum repens: a paraneoplastic eruption. J Am Acad Dermatol 1992; 26: 757–62. 29 Langolis JC, Shaw JM, Odland GF. Erythema gyratum repens unassociated with internal malignancy. J Am Acad Dermatol 1985; 12: 911–3.
DIAGNOSTIC HISTOPATHOLOGY 15:4
211
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
53 Adam RD, Hunter G, DiTomaso J. Mucormycosis: emerging prominence of cutaneous infections. Clin Infect Dis 1994; 19: 67–76. 54 Sugar AM. Mucormycosis. Clin Infect Dis 1992; 14: 126–9. 55 Evenga F, Paricio JF, Merino FJ. Primary cutaneous cryptococcosis in a immunocompromised host: case review and report of the literature. Dermatology 2002; 204: 145–9. 56 Pederson NB, Mardh PA, Halberg T. Cutaneous alternariosis. Br J Dermatol 1976; 94: 201–9. 57 McSorley J, Shapiro L, Browenstein MH. Herpes simplex and varicella zoster: comparative histopathology of 77 cases. Int J Dermatol 1974; 13: 69–75. 58 Drago F, Aragone MG, Lugani C. Cytomegalovirus in normal and immunocompromised individuals. A review. Dermatology 2000; 200: 189–95. 59 Ellman MH, Hurwitz H, Thomas C, Kozloff M. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. J Rheumatol 1991; 18: 1741–3. 60 Chai C, White WL, Shea CR, Prieto VG. Epstein Barr virus-associated lymphoproliferative-disorders primarily involving the skin. J Cutan Pathol 1999; 26: 242–7. 61 Greene SL, Su WPD, Muller SA. Ecthyma gangrenosum: report of clinical, histopathological and bacteriological aspects of eight cases. J Am Acad Dermatol 1984; 11: 781–7. 62 Choi CM, Lerner EA. Leishmaniasis: recognition and management with a focus on immunocompromised patient. Am J Clin Dermatol 2002; 3: 91–105. 63 Rueda RA, Valencia IC, Covelli C. Eosinophilic, polymorphic and pruritic eruption associated with radiotherapy. Arch Dermatol 1999; 135: 804–10. 64 Requena L, Kutzner H, Mentzel T, Durán R, Rodríguez-Peralto HL. Benign vascular proliferations in irradiated skin. Am J Surg Pathol 2002; 26: 328–37.
DIAGNOSTIC HISTOPATHOLOGY 15:4
Practice points • Banal-appearing skin lesions in immunosuppressed patients, such as oncological patients, may represent an unusual infection, a marker of tumour progression or recurrence or a drug-related reactive process • Paraneoplastic syndromes herald a new or a recurrent internal neoplasm and their early recognition is essential. The list of paraneoplastic syndromes is extensive, but the ones with the strongest correlation with malignancies are: Bazex syndrome, tripe palms, florid cutaneous papillomatosis, necrolytic migratory erythema, erythema gyratum repens and paraneoplastic pemphigus • The presence of dermal haemorrhage or thrombosis in a biopsy of an immunosuppressed patient has to raise the suspicion of infection; these patients might not be able to mount a significant inflammatory response against the infectious organism and the diagnosis can be overlooked • It is recommended to use a panel of special stains such as Gram, Grocott methenamine silver and Fite, when an infection is suspected • Immunosuppressed patients may often lack fever and have false-negative results of serological tests for various infectious diseases, due to their immune dysfunction • Based on their morphological features, different species of fungi can be identified on histology. Their histology may change if the patient has received antifungal treatment prior to the biopsy. Therefore, tissue cultures may be necessary to reliably classify the infectious agent
212
Published by Elsevier Ltd.
Histopathology of inflammatory skin disease in oncological patients
such as steroids or chemotherapy) and general cutaneous manifestations of malignancy. In addition to these lesions, cutaneous metastases or direct cutaneous extension of internal tumours can be also seen in oncological patients, but they will not represent the subject of our overview.
Doina Ivan
Paraneoplastic syndromes By definition, paraneoplastic dermatoses represent a heterogeneous group of non-inherited skin conditions that arise in association with a distant malignancy.1 They reflect the remote effects of cancer rather than being caused by tumour growth or invasion. Generally, the clinical onset and course of cutaneous disorders precede or have a parallel evolution with internal neoplasm.2,6–8 The skin disorder may also herald a new or a recurrent neoplasm; therefore, recognition of these conditions may facilitate early detection of cancer, while the failure to recognize them may have significant adverse consequences. Pathogenesis of paraneoplastic syndromes is not completely understood, but considering the diverse nature of paraneoplastic mucocutaneous lesions, it is unlikely to have a uniform aetiological basis.9 It has been postulated that there is an association between these disorders and a variety of immune and cytokinemediated aberrations, as well as the possibility of a tumourinduced host immunological response.2,3,9 The list of paraneoplastic syndromes is extensive (Table 1). For this review we have selected to discuss in more detail the dermatoses that have a stronger casual relationship with the underlying malignancies and are specific enough on clinical and histological grounds for practical dermatological and dermatopathological recognition.10–14
Victor G Prieto
Abstract The spectrum of cutaneous lesions in oncological patients includes entities encountered in the general population, lesions associated with underlying malignant processes (such as paraneoplastic syndromes) and conditions related to the immunosuppressed status of these patients or their antineoplastic treatment. The paraneoplastic syndromes represent a group of skin conditions that may precede or coexist with the diagnosis of malignancy and may also signal tumour recurrences. In general, there is a high prevalence of immunosuppression in oncological patients, related to the alteration of humoral and cellular immunity or their immunosuppressive therapy. Thus, these patients are especially susceptible to certain infections associated with high morbidity and mortality. Correct and early recognition of the cutaneous manifestations in oncological patients provides an important insight into underlying malignant process, possible complications (iatrogenic or not) and prognosis. In this review we offer a practical overview of inflammatory or neoplastic conditions associated with internal malignancies and cutaneous infectious in oncological patients.
Keywords inflammatory skin diseases; infections; oncological patients Acanthosis nigricans Acanthosis nigricans, a common marker for benign conditions such obesity and hyperinsulinism/insulin resistance, is characterized by hyperpigmented, velvety or verrucous patches on intertriginous areas.15 Histologically the lesions are characterized by hyperkeratosis, papillomatosis and acanthosis. The characteristic hyperpigmentation of these lesions is mainly due to hyperkeratosis rather than to increase of melanocytes or melanin production. Sudden onset during adulthood with rapid progression and extensive involvement (including hands, feet, mucosal membranes) may signal an underlying malignancy.16 Malignant acanthosis nigricans is most commonly associated with adenocarcinomas, 70–90% of which have gastrointestinal origin, predominantly gastric. Other primary tumour sites include uterus, lung, ovary and liver. Approximately 20% of acanthosis nigricans with sudden onset precede the diagnosis of internal malignancy and its course correlates closely with that of the tumour.15,16
Introduction The association of evident or occult internal malignancies with various cutaneous lesions has been known for a long time.1–4 Early recognition of these cutaneous manifestations is of a paramount importance, especially considering that they may precede the diagnosis of malignancy, signal a severe immunosuppressed status and purport a great impact in overall morbidity, prognosis and mortality of these patients. Banal-appearing skin lesions in immunosuppressed patients, such as oncological patients, may represent an unusual infection, a marker of tumour progression or recurrence or a drug-related reactive process.5 For practical purposes, the cutaneous lesions in oncological patients can be categorized into paraneoplastic dermatoses, skin lesions related to the immunosuppressed status of these patients (disease-related or secondary to immunosuppressive therapy
Acquired ichthyosis It occurs in adulthood and resembles clinically the autosomal dominant ichthyosis, being characterized by diffuse rhomboidal scales on lower legs (with pretibial accentuation), trunk (especially back) and arms. Histologically there is hyperkeratosis with orthokeratosis and acanthosis, with reduction or loss of granular layer.17 A number of lymphoproliferative disorders are associated with acquired ichthyosis, especially Hodgkin lymphoma (in 70–80% of cases) but also in other lymphomas, leukaemias,
Doina Ivan MD is Dermatopathologist, Assistant Professor of Pathology and Dermatology at the Departments of Pathology and Dermatology, UT-MD Anderson Cancer Center, Houston, Texas, USA. Victor G Prieto MD PhD is Chief of Dermatopathology at the Departments of Pathology and Dermatology, UT-MD Anderson Cancer Center, Houston, Texas, USA.
DIAGNOSTIC HISTOPATHOLOGY 15:4
203
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Paraneoplastic syndromes
Most common associated malignancies
Most common associated malignancies Acanthosis nigricans Acquired ichthyosis Erythroderma
Hypertrichosis lanuginosa acquisita Erythromelalgia Pityriasis rotunda Melanosis Pruritus
Flushing Acquired tylosis (nonepidermolytic palmoplantar keratoderma) Acrokeratosis paraneoplastica (Bazex syndrome) Tripe palms
Scleromyxedema Scleroedema Subacute cutaneous lupus erythematosus Paraneoplastic pemphigus
Adenocarcinomas with gastrointestinal origin Hodgkin lymphoma Cutaneous T-cell lymphoma (Sézary), Hodgkin and nonHodgkin lymphoma Colorectal, lung and breast carcinoma Myeloproliferative disorders Hepatocellular and gastric carcinoma Melanoma, post-busulfan therapy Hodgkin disease, lymphomas, carcinoid, gastrointestinal tumours, insulinoma Carcinoid, medullary carcinoma of thyroid, leukaemia Oesophageal squamous cell carcinoma
Non-Hodgkin lymphoma, chronic lymphocytic leukaemia, Castleman disease Porphyria cutanea tarda Hepatocellular carcinoma (most frequent), lung and colon cancers, lymphoma Necrobiotic xanthogranuloma Haematological and lymphoproliferative malignancies Multicentric reticulohistiocytosis Haematological malignancies, breast, ovarian, carcinomas (no predominant malignancy) Chronic erythema nodosum Non-Hodgkin lymphoma, ovarian carcinoma Subacute pancreatic necrosis Pancreatic cancer Palmar fasciitis Ovarian cancer, lung carcinomas Table 1
Squamous cell carcinoma of aerodigestive tract Lung carcinoma, gastric carcinoma Florid cutaneous papillomatosis Gastric cancer Leser-Trélat sign
Amyloidosis Xanthomas Digital clubbing Hypertrophic osteoarthropathy Erythema gyratum repens
Necrolytic migratory erythema Vasculitis Pyoderma gangrenosum Sweet syndrome
Raynaud phenomenon Trousseau syndrome Dermatomyositis
DIAGNOSTIC HISTOPATHOLOGY 15:4
Plasma cell dyscrasia Lymphoma, multiple myeloma Lung, breast cancers
multiple myeloma and a few visceral tumours. Interestingly, this condition usually occurs after the diagnosis of underlying malignancy and parallels its course.18
Adenocarcinomas with gastrointestinal origin, lymphoproliferative disorders Multiple myeloma, thyroid or multiple endocrine neoplasia Multiple myeloma Lung carcinoma, mesothelioma Lung cancer Lung (most frequent), oesophageal and breast carcinomas Pancreatic alpha-cell tumour (glucagonoma) Haematological malignancies Acute myelogenous leukaemia, multiple myeloma Acute myelogenous leukaemia, other haematological malignancies Testicular cancer, genitourinary or gastrointestinal carcinomas Pancreatic cancer, lung or gastric carcinomas Ovarian cancer (most frequent), lung, gastrointestinal, breast carcinomas
Hypertrichosis lanuginosa acquisita It represents the sudden and progressive development of fine lanugo hair in an adult. It has a strong female predominance and the soft, non-pigmented hair initially covers the face and ears, and extends caudally covering almost the entire body, sparing the palms, soles and genitalia.19 Histologically, the lanugo hairs are often found implanted in a parallel position to epidermis and are surrounded by clusters of mantle epithelium containing immature sebocytes.20 Although rare, the presence of hypertrichosis lanuginosa correlates strongly with malignancies. In men, the most common associated tumour is lung carcinoma followed by colonic tumours, while in women colorectal cancer is the most frequent association, followed by lung and breast cancers. It usually appears late in the course of the malignancy, when the tumour has already become metastatic. Tripe palms These are rugose, velvety palms with exaggeration of dermatoglyphics that can be associated with acanthosis nigricans in the majority of cases.21 The histopathological features include hyperkeratosis, papillomatosis, acanthosis and sometimes mucin deposition. Its occurrence has a very strong correlation with underlying malignancies such as lung or gastric carcinomas. When both tripe palms and acanthosis nigricans are seen, the most common associated cancer is gastric carcinoma. In 60% of cases, tripe palms are present before or at the same time as cancer diagnosis. 204
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Acrokeratosis paraneoplastica (Bazex syndrome) This is characterized by psoriasiform lesions on acral areas, ears or nose that can be hyperpigmented and associated with nail dystrophy.22 Histologically there are hyperkeratosis, parakeratosis and acanthosis with focal spongiosis, dyskeratotic keratinocytes and perivascular lymphocytic infiltrate. Bazex syndrome is almost always associated with malignancy, particularly squamous cell carcinoma of the oropharynx, larynx, oesophagus and lung.23,24 In 60% of cases, Bazex syndrome is diagnosed approximately 1 year before the malignancy and it usually resolves after successful radiation therapy of the neoplasm. Leser-Trélat sign The sign of Leser-Trélat refers to a sudden increase in size and numbers of seborrhoeic keratoses in association with an internal malignancy, such as gastrointestinal adenocarcinomas (one-third of cases) or lymphoproliferative disorders (one-fifth of cases).25 Acceptance of this condition as a paraneoplastic dermatosis is somewhat controversial, because seborrhoeic keratoses are extremely common in the elderly population. Some authors consider the sign of Leser-Trélat as an early stage of malignant acanthosis nigricans.
Figure 1 Superficial perivascular tight lymphocytic infiltrate and mild papillary dermal oedema in a patient with migrating bands of erythema with ‘wood-grain’ appearance. In this clinical context, the histological features are diagnostic of erythema gyratum repens, a highly specific paraneoplastic syndrome.
Florid cutaneous papillomatosis It is characterized by rapid onset of numerous lesions clinically and histologically resembling viral warts. However, human papilloma virus has not been identified in these lesions. It appears to be an obligatory paraneoplastic syndrome since it has been linked to cancer development in all reported cases.26 The most common associated tumour is gastric carcinoma and it usually portends a poor prognosis.
layer. Later in the process appear the characteristic dyskeratosis and necrosis of superficial epidermal layers with occasional cleftlike detachment from basal layer. Because of the clinical and histological similarities of this lesion with zinc deficiencies or other nutritional dermatoses, this lesion is frequently misdiagnosed. Resection of the tumour frequently results in rapid involution of the eruption. Dermatomyositis Dermatomyositis is an inflammatory proximal myopathy with associated photodistributed violaceous erythroderma involving the scalp and peri-ocular area. Other manifestations include nailfold telangiectases, Raynaud phenomenon and Gottron papules (flat-topped papules over the knuckles).31 Histologically, the hallmark of this disorder is the interface vacuolar alteration with epidermal atrophy, dermal mucin and perivascular lymphoid infiltrate, thus similar to the findings in lupus erythematosus. The reported frequency of dermatomyositis with underlying malignancy is approximately 25% (according to most reports).32 Female patients with dermatomyositis have an increased risk of developing ovarian carcinoma; the rates of association increase with age.
Erythema gyratum repens This is a rare disorder, considered to be highly specific as a paraneoplastic syndrome. It is characterized by the presence of migrating bands of erythema with collarets of scales and a polycyclic appearance resembling ‘wood-grain pattern’. The erythematous edge of the lesion advances by approximately 1 cm/ day. It usually starts on the trunk or extremities, before covering the entire body.27,28 The histology reveals mild spongiosis with focal parakeratosis and a tight lymphohistiocytic perivascular infiltrate with mild oedema of papillary dermis (Figure 1). Direct immunofluorescence often reveals granular deposits of IgG and/ or C3 along the basement membrane zone. The most commonly associated lesion is lung carcinoma followed by oesophageal and breast carcinoma. Rarely, erythema gyratum repens may be associated with tuberculosis, Raynaud phenomenon or CREST syndrome.29 However, it usually precedes tumours and its presence should prompt a routine malignancy screen and possibly a bronchoscopy in at-risk individuals.
Paraneoplastic pemphigus This blistering disorder is associated almost exclusively with B-cell lymphoproliferative disorders, mainly non-Hodgkin lymphoma, chronic lymphocytic leukaemia and Castleman disease.7,33 Patients present with pruritic polymorphous eruption on the trunk with erythematous lesions and bulla formation, as well as with mucosal involvement (oral, genital mucosa, conjunctiva). The histological picture is an overlap of pemphigus vulgaris and erythema multiforme: suprabasilar acantholysis with interface dermatitis with necrotic keratinocytes (Figure 2). By means of immunofluorescence, IgG and C3 are seen as intercellular epidermal deposits in a linear fashion along the dermo-epidermal
Necrolytic migratory erythema This generalized eruption is the cutaneous manifestation of glucagonoma syndrome, related to increased glucagon levels produced by α-cell pancreatic tumours.30 There are irregular erythematous patches with formation of superficial blisters and shallow erosions with an annular configuration. It typically affects face, groin and perigenital area. Histologically the initial biopsies show mild acanthosis, spongiosis, parakeratosis and loss of granular
DIAGNOSTIC HISTOPATHOLOGY 15:4
205
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Figure 2 Suprabasilar acantholysis similar to pemphigus vulgaris and associated interface dermatitis with scattered necrotic keratinocytes (arrow) represent the histological features of paraneoplastic pemphigus.
Figure 3 Necrobiotic xanthogranuloma: areas of necrobiosis and granulomas composed of histiocytes, foam cells and multinucleated giant cells; cholesterol clefts are also seen.
junction. A positive test for IgG autoantibodies by indirect immunofluorescence on rodent bladder may confirm the diagnosis. Circulating antibodies to desmosomal proteins, including desmoplakin I and desmoglein I, have been identified in patients with paraneoplastic pemphigus, although it is suspected that there is a wider spectrum of target antigens.34 Paraneoplastic pemphigus is refractory to treatment and it usually does not follow a parallel course with the underlying malignancy.
neutrophilic infiltrate. Sweet syndrome is characterized by fever, neutrophilia and erythematous tender plaques and nodules, usually on the extremities. Histologically, besides the neutrophilic infiltrate (which can be minimal in neutropenic patients), there are also papillary dermal oedema and minimal epidermal changes. Although vasculopathic changes are frequent, frank vasculitis is very rare. Overall, approximately 20% of patients with Sweet syndrome have an associated cancer.38 Pyoderma gangrenosum typically starts as a sterile pustule that rapidly develops into a painful ulcer with undermined violaceous border. The lesions of pyoderma gangrenosum usually involve the lower extremity. When these lesions are associated with malignancy, they may present as haemorrhagic bullae and have a more rapid course. Fewer than 10% of pyoderma gangrenosum cases are associated with malignancies.37
Necrobiotic xanthogranuloma This eruption is characterized by multiple yellow plaques and subcutaneous nodules, often with a peri-orbital distribution but also occurring on the trunk, head and neck, and extremities. Histological examination reveals areas of necrobiosis and granulomas composed of histiocytes, foam cells and multinucleated giant cells, sometimes with cholesterol clefts (Figure 3). Necrobiotic xanthogranuloma is associated with haematological, lymphoproliferative disorders and monoclonal gammopathies.35 In 80% of patients, protein electrophoresis is abnormal, usually revealing an IgG-kappa paraprotein. Haematological malignancies may occur years after the appearance of necrobiotic xanthogranuloma.
Other paraneoplastic syndromes Generalized pruritus is a common sign in oncological patients: polycythemia rubra vera, lymphoma, Hodgkin disease, carcinoid tumours and gastrointestinal tumours.12 Rarely, localized pruritus may be associated with an underlying tumour and may signal a poor prognosis, such as in the case of onset of nasal pruritus in association with a brain tumour.39 Pruritus associated with malignancies has been observed to diminish or disappear after eradication of the tumour but it may reappear when the disease recurs. Patients with underlying malignancies may also have localized or generalized hyperpigmentation (such as in melanoma, busulfan therapy, etc) or erythroderma (e.g. Sézary syndrome).13 Erythromelalgia is a rare disorder characterized by bouts of burning pain, redness and warmth of extremities.40 It occurs concomitantly with Raynaud syndrome and can be associated in adults with lymphoproliferative disorders (in up to 40% of cases). Carcinoid tumours are associated in their great majority with episodes of flushing (usually on the face and trunk) that may be accompanied by facial oedema. Other signs include multiple episodes of flushing, telangiectases and chronic facial plethora. Less
Chronic erythema nodosum This manifests as painful subcutaneous nodules and plaques on the pretibial region. It is the prototype of septal panniculitis. In 50% of cases it is associated with infections (Streptococcus, leprosy, tuberculosis), drugs (sulphonamides, oral contraceptives), autoimmune disorders (especially sarcoidosis) and neoplastic processes (non-Hodgkin lymphoma, carcinoma of pancreas, colon and cervix).36 Neutrophilic dermatoses Both Sweet syndrome and pyoderma gangrenosum have been described in oncological patients, especially those with haematological malignancies such as acute myelogenous leukaemia.37 They are both characterized by a dense, predominantly dermal,
DIAGNOSTIC HISTOPATHOLOGY 15:4
206
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Superficial candidiasis in oncological patients is similar to that in immunocompetent patients. However, oral candidiasis (thrush) may lead to oesophageal candidiasis and prophylaxis (fluconazole, nistatin, etc) may be used in the immunosuppressed patients.44–46 Aspergillus sp infections occur by haematogenous spread or direct inoculation of skin following local trauma (injection therapy site, burns, eschars).46,48–50 In hospitals, these fungi may contaminate the air conditioning vents and central heating plants. Despite the wide distribution of the fungus, infections usually occur in immunosuppressed individuals, such as patients receiving corticosteroid therapy.48–51 In immunosuppressed patients the cutaneous lesions often ulcerate and develop a black crust. In cases of haematogenous spread, fungal hyphae may be identified within the lumen of thrombosed dermal blood vessels. The fungus is recognized by its uniform septate branching and radiating hyphae of equal thickness (dichotomus) and at 45° angles (Figure 4a). The hyphae are approximately 4 μm in diameter and the microconidia 3 μm. Aspergillus sp infections are indistinguishable from infections with Pseudallescheria boydii, which also encountered in immunosuppressed patients, especially following solid organ transplantation. Fusarium sp infections have a high incidence especially in neutropenic patients with haematological malignancies.45,46,48,52 The disseminated untreated infections with Fusarium have up to 80% mortality and they may be resistant to traditional antifungal treatments. Therefore, early diagnosis and recognition of these particular infections have a great impact on patients’ morbidity and mortality. Intravascular involvement is also seen. Histologically, unlike the Aspergillus sp, they present as hyaline, branching septate hyphae measuring 3–8 μm in width and branching irregularly from acute angles up to 90° (Figure 4b).48,52 This feature, along with the presence of relatively large macroconidia (up to 70 μm), may help in the differential diagnosis from Aspergillus sp. However, it is important to mention that in patients who underwent antifungal treatment before the biopsy was performed, the morphological characteristics of the fungal elements might change; therefore, the distinction may ultimately depend on tissue cultures. Zygomyces sp (e.g. Mucor, Rhizopus, Absidia) infections: some of the fungi of these species are aerobic, saprophytes, present worldwide; nevertheless the infections are uncommon and they usually develop in immunosuppressed patients (including oncological patients) and those with diabetic ketoacidosis.46,48,53,54 These fungal infections can involve the nasal sinuses and have cerebral extension, involving lung, gastrointestinal tract and skin, or can be disseminated (by haematogenous spread). The skin lesions develop as small erythematous macules that enlarge and eventually ulcerate with a black eschar formation; they can also resemble a vasculitic process or ecthyma gangrenosum. Isolated cutaneous infections with Zygomyces sp have a good prognosis with adequate treatment, while the mortality rate of disseminated and rhinocerebral involvement is very high (78–100%, according to various studies).46,48,53,54 The fungal hyphae of these species, particularly for Mucor, are broad (10–20 μm diameter), non-septate and branch irregularly at 90° (Figure 4c). They are usually easy to distinguish from the narrower, septate and dichotomus branches at 45° of Aspergillus
frequent are abdominal pain, diarrhoea, vomiting, rectal bleeding, bronchospasm and hypotension.41 Cutaneous granulomas may be a non-specific sign of an underlying systemic lymphoma. Their histological patterns are variegate and include sarcoid-type granuloma, palisaded and necrobiotic granuloma of granuloma annulare type and tuberculoid granuloma. In patients who present with non-infectious, granulomatous skin reactions in the absence of another sound explanation, the possibility of a systemic lymphoma should be considered.42 Several paraneoplastic syndromes affect the vascular system either by destruction of vascular walls (vasculitis), associated thrombocytopenia or hypercoagulable status of these patients (intravascular coagulopathy, migratory thrombophlebitis – Trousseau syndrome).8,43 Purpura is a common finding in patients with underlying malignancy.
Infections in immunocompromised oncological patients A large number of opportunistic organisms (fungal, bacterial, viral, protozoal or rickettsial) may produce infections in immunosuppressed oncological patients.44–48 They may represent de novo infections, reactivations of latent infections or, in patients who have undergone organ transplantation, the infectious organism may be carried by the transplanted organ. It is also important to remember that immunosuppressed patients may often lack fever and have false-negative results of serological tests for various infectious diseases, due to their immune dysfunction. For instance, false-negative test results for antibodies against Epstein–Barr, hepatitis B, human immunodeficiency viruses and syphilis may mislead the clinician. Moreover, in the biopsy specimens, an immunocompromised patient might not be able to mount a significant inflammatory response against the infectious organism so the diagnosis can be overlooked.5 In these instances, the need for tissue cultures cannot be over emphasized. Moreover, the tissue cultures represent one of the most reliable ways to classify the infectious agent. At our institution, to try to detect the most frequent infectious lesions in suspicious biopsies from oncological/immunosuppressed patients, we use a panel of special stains (Gram, Grocott methenamine silver and Fite).
Fungal infections Oncological patients who pose the highest risk for developing fungal infections are those with severe neutropenia (absolute neutrophil count of <500/ml that lasts for over 1 week), especially in leukaemia and lymphoma patients following high-dose chemotherapy or bone marrow transplantation.44–46 Cutaneous fungal infections in oncological patients may be superficial (dermatophytes, Candida species) or opportunistic disseminated primary or secondary skin infections.46 The outcome of deep or disseminated fungal infections is potentially fatal due to extensive visceral involvement, if not promptly recognized and treated. Dermatophyte infections (Microsporum, Epidermophyton and Trichophyton species) have similar presentation in cancer patients as in the general population: superficial infections of stratum corneum, nails and hair. Tinea pedis and onychomycosis are the most frequent; Majocchi granulomas are often seen.44,46
DIAGNOSTIC HISTOPATHOLOGY 15:4
207
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
a Aspergillus sp fungal hyphae within the lumen of thrombosed dermal blood vessel and interstitium. The fungus is recognized by its uniform septate branching and radiating hyphae of equal thickness, at 45° angles. b Fusarium presents as irregularly branching septate hyphae, from acute angles up to 90° (long arrow) and large macroconidia (short arrow). c The fungal hyphae Zygomyces sp, particularly for Mucor, are broad (10–20 μm diameter), non-septate and branching at 90°. d Cryptococcus presents as variably-sized spherical, budding yeasts with a mucoid capsule within a mucinous dermal background. Figure 4
sp. Angioinvasion with vasculitis, thrombosis, haemorrhage and infarction are also seen.48
Viral infections Herpes simplex (types 1 and 2) and varicella zoster viruses (HSV, VZV) are characterized by their ability to establish latency and reactivate at a later date. In immunosuppressed patients with cell-mediated immune deficiencies, these viruses lead to recurrent infections, particularly mucocutaneous lesions involving the oropharynx or genital regions.57 The infections may become widely disseminated and complicated with pneumonia, meningitis, encephalitis and purpura fulminans, sometimes resulting in death. Disseminated cutaneous lesions most often present as vesicles, pustules, haemorrhagic bullae, ulcers and black eschars, although occasionally the patients develop verrucous, hyperkeratotic lesions.44,48,57 Histologically the infections with these two viruses are almost undistinguishable, although it has been suggested that VZV infections are associated with a more profound inflammation and they can manifest with dermal vasculitis and dermal haemorrhage, usually in the absence of associated epidermal involvement.48 Both HSV and VZV usually present the characteristic multinucleated giant cells with inclusions bodies within intra-epidermal blisters (Figure 5). Immunosuppressed patients with VZV infections may have a protracted
Cryptococcosis: disseminated cryptococcosis is more common in acquired immune deficiency syndrome (AIDS) and renal transplant patients but may also occur in oncological patients, especially those with haematological malignancies.55 The skin lesions may be subcutaneous nodules, ulcerated plaques or molluscum contagiosum-like umbilicated papules.44,48 Histologically, as a clue, within a mucinous dermal background or a granulomatous reaction, there are widely spaced, variably sized (4–20 μm diameter), spherical, budding yeasts with a mucoid capsule that is better visualized by mucicarmine, PAS or Alcian Blue stains (Figure 4d).48 The presence of the capsule differentiates Cryptococcus from blastomycosis (another infection that may affect immunosuppressed patients): the latter lacks a capsule and has a monomorphous appearance. Alternariosis: Alternaria alternata is a pigmented fungus (hyphae and 5–20 μm rounded bodies) often affecting immunosuppressed hosts and presenting as cutaneous ulcers, verrucous lesions, erythematous papules and nodules.48,56
DIAGNOSTIC HISTOPATHOLOGY 15:4
208
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
Bacterial infections In general, bacterial organisms producing infections in immunocompromised oncological patients are similar to those encountered in the general population. However, due to the immune dysfunctions of these patients, the infections may go unrecognized; in many instances a biopsy specimen may reveal a relatively unimpressive inflammatory infiltrate and the morphologist might fail to consider an infectious process.5 One of the histological clues to an infectious process in an immunocompromised patient is the presence of dermal haemorrhage, even in the absence of a significant inflammatory infiltrate. Such a finding should prompt the examination of special studies (Gram, GMS, PAS, AFB, Fite or Giemsa). Bacterial infections in immunocompromised patients may develop into extremely severe forms: cellulitis, necrotizing fasciitis and septicaemia. Ecthyma gangrenosum, a complication of Pseudomonas aeruginosa or other Gram-negative bacterial septicaemias, occurs with a higher frequency in immunodeficient patients, particularly those with neutropenia, and has been rarely reported in the absence of neutropenia or septicaemia.44,61 Lesions begin as painless erythematous macules that become indurated, pustular and eventually gangrenous with black eschar and surrounded by erythematous halo.48 The histology of ecthyma gangrenosum is striking and characteristic. Besides the epidermal necrosis, dermal haemorrhage and infarction due to ischaemia, there is a blue−grey perivascular cuffing involving particularly venular media and adventitia of dermal vessels (Figure 6). These are Gram-negative bacilli, most commonly Pseudomonas aeruginosa.48,61 Staphylococcal scalded skin syndrome, produced by group II staphylococci phage type 71, has been very rarely reported in adults, with the exception of immunocompromised patients.
Figure 5 Herpes simplex virus infection showing multinucleated giant cells with inclusions bodies within an intra-epidermal blister.
clinical course in which biopsies may reveal a lichenoid inflammatory reaction pattern with minimal viral inclusions.44,48,57 Cytomegalovirus (CMV) infection may be a feature of immunosuppression and may manifest as a disseminated disease.58 In these patients it is uncertain whether CMV infection represents an acquired phenomenon or reactivation of a latent infection. The histological hallmark is the presence of large, purple-staining intranuclear inclusions surrounded by a clear halo. These inclusions have been described within the enlarged dermal endothelial cells, sometimes accompanied by leucocytoclastic vasculitis, but can also be present within fibroblasts, macrophages and cells of eccrine ducts. Epstein-Barr virus (EBV) can cause a variety of infectious and diseases but of a particular importance is the development of lymphoproliferative disorders. This entity is a well-known complication of organ transplantation, but it has been also described in patients receiving methotrexate or other immunosuppressive agents, and seems to be similar to those triggered by EBV in transplant patients receiving cyclosporine.59,60
Mycobacterial infections Infections with Mycobacterium tuberculosis as well as with atypical mycobacterial organisms may occur in oncological immunosuppressed patients, sometimes with unusual patterns.44,48 In
Human herpes viruses (HHV): exanthem subitum (caused by infections with HHV-6) is a benign disease of infancy that has been recently described in patients with acute leukaemia.48 One of the forms of Kaposi sarcoma arises in immunocompromised patients, such as those post-transplant or having received immunosuppressive treatments (including corticosteroids). HHV8 genomic sequences have been identified by polymerase chain reaction in more than 90% of all types of Kaposi sarcoma lesions (including epidemic and endemic forms), suggesting a causative role for this DNA virus. Typical histological findings include proliferation of spindle cells, prominent slit-like vascular spaces and extravasated red blood cells. Human papilloma viruses (HPV): patients with deficiency in cell-mediated immunity are particularly susceptible to the development of warts, which do not tend to involute spontaneously and can be a particularly refractory therapeutic problem.
DIAGNOSTIC HISTOPATHOLOGY 15:4
Figure 6 Characteristic blue-grey perivascular cuffing of Gram-negative bacilli, involving media and adventitia of dermal vessels in ecthyma gangrenosum.
209
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
comparison with immunocompetent patients, the mycobacterial infections of immunocompromised patients are usually more extensive, can develop panniculitis, have less granulomatous reaction and more neutrophilic infiltrate, and disseminate more frequently. Protozoal infections These infections are more common in immunocompromised patients, such as oncological and transplant patients, than in the general population. Leishmania, a trypanosomal infection transmitted by a sand fly (Phlebotomus), can produce cutaneous lesions. Visceral leishmaniasis and, to a lesser extent, cutaneous leishmaniasis are increasingly recognized as opportunistic infections in immunocompromised patients.62 Cutaneous leishmaniasis occurs commonly on the face, hands and arms, and presents usually as ulcerated nodules. Histologically, there is pseudo-epitheliomatous hyperplasia overlying dermal micro-abscesses with histiocytes that contain intracellular amastigotes. The amastigotes are usually distributed at the periphery of the cell (arranged as a wreath), in contrast with blastomycosis in which similarly sized organisms are randomly distributed within the macrophages’ cytoplasm. Giemsa stain highlights these intracellular organisms. In immunocompromised/anergic patients the number of amastigotes is larger, there are fewer associated inflammatory cells and there is no evident granulomatous response.48,62
Figure 7 Radiation dermatitis changes: dermal fibrosis, stellate, atypical fibroblasts and hyalinized blood vessels.
hyalinized blood vessels) (Figure 7). Eosinophilic, polymorphic and pruritic eruption of radiotherapy (EPPER) is a complication of radiotherapy for cancer, especially breast, with a unique clinical−pathological profile, spongiosis and extensive underlying eosinophilic infiltrate.63 These lesions occur usually during radiation and before this entity was described, were diagnosed as erythema multiforme or bullous pemphigoid following radiotherapy. Several types of cutaneous vascular proliferations have been described in areas of irradiated skin, including both benign lesions, such as lymphangiomatous papules, atypical vascular lesions or benign lymphangioendothelioma, and malignant neoplasms such as angiosarcomas.64
Protothecosis P. wickerhamii is an achloric alga, originating from contaminated water and soil, that is inoculated into skin by minor trauma.48 In immunosuppressed patients the condition manifests as papular or eczematoid dermatitis with extensive scaling or may resemble pyoderma gangrenosum. Histologically, there is dermal necrosis surrounded by granulation tissue and few multinucleated giant cells. The algae are relatively large spherical bodies that have thick walls and characteristic internal septae.
Conclusion Correct and early recognition of cutaneous manifestations in oncological patients provides an important insight into the underlying malignant process, possible complications (iatrogenic or not) and prognosis. Increased clinician awareness and education regarding the association between the above mentioned lesions and internal malignancy will facilitate screening, early diagnosis or treatment. We would also like to emphasize the pivotal role of the pathologist in recognizing these entities, and timely and effective communication with the clinician of the pathology results for these patients. ◆
Other cutaneous manifestations of malignancy Non-specific cutaneous signs and lesions can be also encountered in oncological patients. They may include palor (related to anaemia), cyanosis (e.g. secondary to polycythemia) or plethora (such as in chronic carcinoid syndrome). The most common cutaneous lesions in oncological patients are probably drug related. These patients frequently take multiple medications thus complicating the clinical picture and resulting in overlapping histological features. The presence of eosinophils in a skin biopsy can be a useful clue to a drug eruption, but as a note of caution, their absence does not necessarily rule out this possibility; thus a high index of suspicion is needed in order to diagnose such reaction. Special attention should be paid to drugrelated reactions such as erythema multiforme, toxic epidermal necrolysis or Steven–Johnson syndrome that are related to high morbidity and increased mortality. Their common histological finding is the presence of epidermal necrotic keratinocytes. Other cutaneous lesions in oncological patients may be related to therapy, such as radiotherapy. The radiation dermatitis changes can be acute (histologically characterized by necrotic keratinocytes, dermal vascular thrombosis and haemorrhage) or chronic (dermal fibrosis, stellate, atypical fibroblasts and
DIAGNOSTIC HISTOPATHOLOGY 15:4
References 1 Curth HO. Skin lesions and internal carcinoma. In: Andrade R, Gumport SL, Popkin GL, Rees TD, eds. Cancer of the skin: biologydiagnosis-management. Philadelphia: WB Saunders, 1976; p. 1308–41. 2 McLean DI. Cutaneous paraneoplastic syndromes. Arch Dermatol 1986; 122: 765–7. 3 Brenner S, Tamir E, Maharshak N, Shapira J. Cutaneous manifestations of internal malignancies. Clin Dermatol 2001; 19: 290–7.
210
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
30 Wynick D, Hammond PJ, Bloom SR. The glucagonoma syndrome. Clin Dermatol 1993; 11: 93–7. 31 Sigurgeirsson B, Lindelof B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis. N Engl J Med 1992; 326: 363–7. 32 Zantos D, Zhang Y, Felson D. The overall and temporal relationship association of cancer with polymyositis and dermatomyositis. J Rheumatol 1994; 21: 1855–9. 33 Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol 1997; 12: 77–96. 34 Kimyai-Asadi A, Jih MH. Paraneoplastic pemphigus. Int J Dermatol 2001; 40: 367–72. 35 Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. J Am Acad Dermatol 1980; 3: 257–70. 36 Bohn S, Buchner S, Itin P. Erythema nodosum: 112 cases: epidemiology, clinical aspects and histopathology. Schweiz Med Wochenschr 1997; 127: 1168–76. 37 Caughman W, Stern R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders. Atypical forms of pyoderma gangrenosum and Sweet’s syndrome associated with myeloproliferative disorders. J Am Acad Dermatol 1983; 9: 751–8. 38 Fett DL, Gibson LE, Su WPD. Sweet’s syndrome: systemic signs and symptoms and associated disorders. Mayo Clin Proc 1995; 70: 234–40. 39 Andreev VC, Petkov I. Skin manifestations associated with tumors of the brain. Br J Dermatol 1975; 92: 675–8. 40 Kurzrock R, Cohen PR. Erythromelalgia and myeloproliferative disorders. Arch Intern Med 1989; 149: 105–9. 41 Wilkin JK. Flushing reactions: consequences and mechanisms. Ann Intern Med 1981; 95: 468–76. 42 Rongioletti F, Cerroni L, Massone C, Basso M, Ciambellotti A, Rebora A. Different histologic patterns of granulomas in systemic lymphoma. J Am Acad Dermatol 2004; 51: 600–5. 43 Pinzon R, Drewinko JM, Trujillo V. Pancreatic carcinoma and Trousseau’s syndrome: experience at a large cancer center. J Clin Oncol 1986; 4: 509–14. 44 Grossman ME. Cutaneous manifestations of infections in immunocompromised host, Baltimore: Williams and Wilkins, 1995 62–7. 45 Brown AE. Overview of fungal infections in cancer patients. Semin Oncol 1990; 17: 2–5. 46 Mays SR, Bogle MA, Bodey GP. Cutaneous fungal infections in the oncology patient. Am J Clin Dermatol 2006; 7: 31–43. 47 Tan HH, Goh CL. Viral infections affecting the skin in organ transplant recipients: epidemiology and current management strategies. Am J Clin Dermatol 2006; 7: 13–29. 48 Infectious diseases of the skin. In: Grayson W, Calonje E, McKee PH, eds. Pathology of the skin with clinical correlations, vol. I. St Louis: Elsevier Mosby, 2005; p. 837–992. 49 D’Antonio D, Pagano L, Gimernia C. Cutaneous asspergilosis in patients with hematological malignancies. Eur J Clin Microbiol Infect Dis 2000; 19: 362–5. 50 Khardori N, Hayat S, Rolston K. Cutaneous rhisopus and aspergillus infections in five patients with cancer. Arch Dermatol 1989; 125: 952–6. 51 Meyer RD. Cutaneous and mucosal manifestations of deep mycotic infections. Acta Derm Venerol 1986; 121: 57–72. 52 Watts JC, Chandler FW. Fusariosis. In: Connor DH, Chandler FW, Schwarts DA, eds. Pathology of infectious diseases, vol. I. Stamford: Appleton and Lange, 1997; p. 999–1001.
4 Sabir S, James WD, Schuchter LM. Cutaneous manifestations of cancer. Curr Opin Oncol 1999; 11: 139–44. 5 Rapini RP. Practical evaluation of skin lesions in immunosuppressed patients. Cutis 1988; 42: 125–8. 6 Abeloff MD. Paraneoplastic syndromes: a window on the biology of cancer. N Engl J Med 1987; 317: 1598–600. 7 Cohen PR, Kurzrock R. Mucocutaneous paraneoplastic syndromes. Semin Oncol 1994; 24: 334–59. 8 Kurzrock R, Cohen PR. Cutaneous paraneoplastic syndromes in solid tumors. Am J Med 1995; 99: 662–71. 9 Hall TC. Paraneoplastic syndromes: mechanisms. Semin Oncol 1997; 24: 269–76. 10 Moore RL, Devere TS. Epidermal manifestations of internal malignancy. Dermatol Clin 2008; 26: 17–29. 11 Kleyn EC, Lai-Cheong JE, Bell HK. Cutaneous manifestations of internal malignancy: diagnosis and management. Am J Clin Dermatol 2006; 7: 71–84. 12 Pipkin CA, Lio PA. Cutaneous manifestations of internal malignancies: an overview. Dermatol Clin 2008; 26: 1–15. 13 Chung VQ, Moschella SL, Zembiwicz A, Liu V. Clinical and pathologic findings of paraneoplastic dermatoses. J Am Acad Dermatol 2006; 54: 745–62. 14 Thomas I, Schwartz RA. Cutaneous paraneoplastic syndromes: uncommon presentations. Clin Dermatol 2005; 23: 593–600. 15 Schwartz R. Acanthosis nigricans. J Am Acad Dermatol 1994; 31: 1–19. 16 Stuart CA, Driscoll MS, Lundquist KF, Gilkison CR, Shaheb S, Smith MM. Acanthosis nigricans. J Basic Clin Physiol Pharmacol 1998; 9: 407–18. 17 Schwartz RA, Williams ML. Acquired ichthyosis: a marker for internal disease. Am Fam Physician 1984; 29: 181–4. 18 Rizos E, Milionis HJ, Pavlidis N, Elisaf MS. Acquired icthyosis: a paraneoplastic skin manifestation of Hodgkin’s disease. Lancet Oncol 2003; 3: 727–35. 19 Farina MC, Tarin N, Grilli R. Acquired hypertrichosis lanuginosa: case report and review of the literature. J Surg Oncol 1998; 68: 199–203. 20 Hegedus SI, Schorr WF. Acquired hypertrichosis lanuginosa and malignancy. A clinical review and histopathologic evaluation with special attention to the “mantle” hair of Pinkus. Arch Dermatol 1972; 106: 84–8. 21 Requena L, Aguilar A, Renedo G. Tripe palms: a cutaneous marker of internal malignancy. J Dermatol 1995; 22: 492–5. 22 Bazex A, Griffiths A. Acrokeratosis paraneoplastica — a new cutaneous marker of malignancy. Br J Dermatol 1980; 103: 301–6. 23 Richard M, Giroux J. Acrokeratosis paraneoplastica (Bazex’ syndrome). J Am Acad Dermatol 1987; 16: 178–83. 24 Bolognia JL, Brewer YP, Cooper DL. Bazex syndrome (acrokeratosis paraneoplastica). An analytic review. Medicine 1991; 70: 269–80. 25 Schwartz RA. Sign of Leser-Trelat. J Am Acad Dermatol 1996; 35: 88–92. 26 Schwartz RA. Florid cutaneous papillomatosis. Clin Dermatol 1993; 11: 89–91. 27 Kurzrock R, Cohen PR. Erythema gyratum repens. JAMA 1995; 273: 594. 28 Boyd AS, Neldner KH, Menter A. Erythema gyratum repens: a paraneoplastic eruption. J Am Acad Dermatol 1992; 26: 757–62. 29 Langolis JC, Shaw JM, Odland GF. Erythema gyratum repens unassociated with internal malignancy. J Am Acad Dermatol 1985; 12: 911–3.
DIAGNOSTIC HISTOPATHOLOGY 15:4
211
Published by Elsevier Ltd.
MINI-Symposium: inflammatory skin pathology
53 Adam RD, Hunter G, DiTomaso J. Mucormycosis: emerging prominence of cutaneous infections. Clin Infect Dis 1994; 19: 67–76. 54 Sugar AM. Mucormycosis. Clin Infect Dis 1992; 14: 126–9. 55 Evenga F, Paricio JF, Merino FJ. Primary cutaneous cryptococcosis in a immunocompromised host: case review and report of the literature. Dermatology 2002; 204: 145–9. 56 Pederson NB, Mardh PA, Halberg T. Cutaneous alternariosis. Br J Dermatol 1976; 94: 201–9. 57 McSorley J, Shapiro L, Browenstein MH. Herpes simplex and varicella zoster: comparative histopathology of 77 cases. Int J Dermatol 1974; 13: 69–75. 58 Drago F, Aragone MG, Lugani C. Cytomegalovirus in normal and immunocompromised individuals. A review. Dermatology 2000; 200: 189–95. 59 Ellman MH, Hurwitz H, Thomas C, Kozloff M. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. J Rheumatol 1991; 18: 1741–3. 60 Chai C, White WL, Shea CR, Prieto VG. Epstein Barr virus-associated lymphoproliferative-disorders primarily involving the skin. J Cutan Pathol 1999; 26: 242–7. 61 Greene SL, Su WPD, Muller SA. Ecthyma gangrenosum: report of clinical, histopathological and bacteriological aspects of eight cases. J Am Acad Dermatol 1984; 11: 781–7. 62 Choi CM, Lerner EA. Leishmaniasis: recognition and management with a focus on immunocompromised patient. Am J Clin Dermatol 2002; 3: 91–105. 63 Rueda RA, Valencia IC, Covelli C. Eosinophilic, polymorphic and pruritic eruption associated with radiotherapy. Arch Dermatol 1999; 135: 804–10. 64 Requena L, Kutzner H, Mentzel T, Durán R, Rodríguez-Peralto HL. Benign vascular proliferations in irradiated skin. Am J Surg Pathol 2002; 26: 328–37.
DIAGNOSTIC HISTOPATHOLOGY 15:4
Practice points • Banal-appearing skin lesions in immunosuppressed patients, such as oncological patients, may represent an unusual infection, a marker of tumour progression or recurrence or a drug-related reactive process • Paraneoplastic syndromes herald a new or a recurrent internal neoplasm and their early recognition is essential. The list of paraneoplastic syndromes is extensive, but the ones with the strongest correlation with malignancies are: Bazex syndrome, tripe palms, florid cutaneous papillomatosis, necrolytic migratory erythema, erythema gyratum repens and paraneoplastic pemphigus • The presence of dermal haemorrhage or thrombosis in a biopsy of an immunosuppressed patient has to raise the suspicion of infection; these patients might not be able to mount a significant inflammatory response against the infectious organism and the diagnosis can be overlooked • It is recommended to use a panel of special stains such as Gram, Grocott methenamine silver and Fite, when an infection is suspected • Immunosuppressed patients may often lack fever and have false-negative results of serological tests for various infectious diseases, due to their immune dysfunction • Based on their morphological features, different species of fungi can be identified on histology. Their histology may change if the patient has received antifungal treatment prior to the biopsy. Therefore, tissue cultures may be necessary to reliably classify the infectious agent
212
Published by Elsevier Ltd.