53: Paraneoplastic Pemphigus

Question 1

What is the incidence of Paraneoplastic Pemphigus (PNP) compared to pemphigus vulgaris or foliaceus?

Answer 1

The incidence of PNP is unknown, but it is less common than pemphigus vulgaris or foliaceus.

Question 2

What are the associated neoplasms with Paraneoplastic Pemphigus and their respective percentages?

Answer 2

The associated neoplasms with PNP and their percentages are:

Neoplasm Type | Percentage |
|—————|————|
| NHL | 4% |
| CLL | 19% |
| Castleman disease | 16% |
| Thymoma | 8% |
| Sarcomas | 7% |
| Waldenström macroglobulinemia | 4% |
| Poorly differentiated neoplasms | 2% |

Question 3

What is the most constant clinical feature of Paraneoplastic Pemphigus?

Answer 3

The most constant clinical feature of Paraneoplastic Pemphigus is the presence of intractable stomatitis, which is the earliest presenting sign and persists throughout the course of the disease, being extremely resistant to therapy.

Question 4

How do the lesions in Paraneoplastic Pemphigus differ from those in pemphigus vulgaris?

Answer 4

The lesions in Paraneoplastic Pemphigus differ from those in pemphigus vulgaris in that they show more necrosis and lichenoid change.

Question 5

What is the role of IL-6 in the context of Castleman tumors and Paraneoplastic Pemphigus?

Answer 5

IL-6 is known to promote B-cell differentiation and drive Ig production. Dysregulated IL-6 production has been implicated in certain autoimmune diseases, and patients with Castleman tumors associated with PNP have high serum levels of IL-6.

Question 6

What are the characteristics of the autoantibodies found in patients with Paraneoplastic Pemphigus?

Answer 6

Almost all patients with Paraneoplastic Pemphigus have autoantibodies against desmogleins, which can be demonstrated by enzyme-linked immunosorbent assay (ELISA). These autoantibodies bind to the middle portion of desmoglein 3, specifically extracellular domains 2 and 3, unlike pemphigus vulgaris patients who bind to extracellular domain 1.

Question 7

What is the clinical significance of necrosis and lichenoid changes in PNP stomatitis?

Answer 7

Necrosis and lichenoid changes in PNP stomatitis are distinguishing features that differentiate it from pemphigus vulgaris.

Question 8

What is the role of Castleman tumors in the pathogenesis of PNP?

Answer 8

Castleman tumors are associated with high serum IL-6 levels, which drive autoimmunity. Symptoms are reversed by tumor excision or anti-IL-6 receptor monoclonal antibodies.

Question 9

What is the clinical significance of refractory stomatitis in PNP?

Answer 9

Refractory stomatitis is a hallmark of PNP, persisting throughout the disease course and being resistant to therapy.

Question 10

A patient presents with intractable stomatitis and a history of Castleman disease. What is the likely underlying mechanism driving the autoimmunity in this case?

Answer 10

Castleman tumors secrete massive amounts of IL-6, which promotes B-cell differentiation and drives Ig production. Dysregulated IL-6 production has been implicated in autoimmune diseases.

Question 11

What is the significance of autoantibodies against desmogleins in PNP?

Answer 11

Almost all patients with PNP have autoantibodies against desmogleins, which bind to the middle portion of desmoglein 3 (extracellular domains 2 and 3). This is distinct from pemphigus vulgaris, where autoantibodies bind to extracellular domain 1.

Question 12

What is the role of IL-6 in the pathogenesis of PNP?

Answer 12

IL-6 promotes B-cell differentiation and drives Ig production. Dysregulated IL-6 production by tumor cells has been implicated in the development of autoimmunity in PNP.

Question 13

What is the role of anti-IL-6 receptor monoclonal antibodies in Castleman disease associated with PNP?

Answer 13

Anti-IL-6 receptor monoclonal antibodies effectively reverse systemic manifestations of Castleman disease by normalizing serum IL-6 levels.

Question 14

What is the most constant clinical feature of PNP?

Answer 14

The most constant clinical feature of PNP is intractable stomatitis, which is the earliest presenting sign and persists throughout the disease course.

Question 15

What is the significance of HLA-class II DRB03 and HLA-class I Cw14 genes in PNP?

Answer 15

There is a significant predominance of HLA-class II DRB03 and HLA-class I Cw14 genes in PNP, suggesting a genetic predisposition.

Question 16

What is the clinical relevance of squamous metaplasia of the lungs in PNP?

Answer 16

Squamous metaplasia of the lungs is likely the cause of fatal bronchiolitis obliterans involvement in PNP.

Question 17

What is the significance of IL-6 in the context of Castleman disease and its relationship with autoimmune diseases?

Answer 17

IL-6 is known to promote B-cell differentiation and drive Ig production. Dysregulated IL-6 production has been implicated in autoimmune diseases. In Castleman disease, tumor cells secrete massive amounts of IL-6, which correlates with other autoimmune phenomena such as myasthenia gravis and autoimmune cytopenias.

Question 18

How do the cutaneous lesions of Paraneoplastic Pemphigus differ from those seen in pemphigus vulgaris?

Answer 18

The cutaneous lesions of Paraneoplastic Pemphigus (PNP) differ from those in pemphigus vulgaris in that they show more necrosis and lichenoid change.

Question 19

What are the associated neoplasms with Paraneoplastic Pemphigus and their respective incidences?

Answer 19

The associated neoplasms with Paraneoplastic Pemphigus (PNP) and their incidences are as follows:

Neoplasm Type | Incidence |
|—————|———–|
| NHL | 4% |
| CLL | 19% |
| Castleman disease | 16% |
| Thymoma | 8% |
| Sarcomas | 7% |
| Waldenström macroglobulinemia | 4% |
| Poorly differentiated neoplasms | 2% |

Question 20

What role do autoantibodies play in Paraneoplastic Pemphigus and how do they differ from those in pemphigus vulgaris?

Answer 20

In Paraneoplastic Pemphigus (PNP), almost all patients have autoantibodies against desmogleins, which can be detected by enzyme-linked immunosorbent assay (ELISA). The pathogenic autoantibodies in PNP bind to the middle portion of desmoglein 3 (extracellular domains 2 and 3), whereas in pemphigus vulgaris, the autoantibodies bind to extracellular domain 1.

Question 21

What are the characteristic clinical features of paraneoplastic pemphigus (PNP)?

Answer 21

• Initial episodes of blistering affecting the upper trunk, head, neck, and proximal extremities.
• Confluent erosive lesions resembling TEN on the upper chest and back.
• Cutaneous lichenoid eruptions are common and may be the only signs of the disease.
• In chronic forms, lichenoid eruptions may predominate over blistering.
• Presence of both blisters and lichenoid lesions helps distinguish PNP from pemphigus vulgaris.

Question 22

What laboratory tests are key in diagnosing paraneoplastic pemphigus (PNP)?

Answer 22

• Identification of polyclonal IgG autoantibodies against plakin proteins, particularly desmogleins 1 and 3.
• The most characteristic autoantibodies are against envoplakin and periplakin.
• Testing for IgG autoantibodies by indirect immunofluorescence with rodent urinary bladder epithelium can indicate the presence of plakin autoantibodies.

Question 23

What are the related clinical findings associated with paraneoplastic pemphigus (PNP)?

Answer 23

• PNP is the only form of pemphigus that involves non-stratified squamous epithelium.
• 30% to 40% of cases develop pulmonary injury, often with a fatal outcome.
• Early symptoms include progressive dyspnea with initially absent findings on chest radiography.

Question 24

How does the histopathology of paraneoplastic pemphigus (PNP) differ from that of pemphigus vulgaris?

Answer 24

• Lesions in PNP can be clinically very polymorphous, showing substantial variability in histologic findings.
• Findings resulting from cell-mediated cytotoxicity are frequently observed in PNP.

Question 25

What is the role of immunoblotting in PNP diagnosis?

Answer 25

Immunoblotting is used to detect autoantibodies against plakin proteins and α2-macroglobulin-like-1, providing high specificity and sensitivity for PNP diagnosis.

Question 26

What is the clinical relevance of acral and paronychial lesions in PNP?

Answer 26

The presence of acral and paronychial lesions in PNP helps distinguish it from pemphigus vulgaris, where such lesions are uncommon.

Question 27

What is the significance of rodent urinary bladder immunofluorescence in PNP diagnosis?

Answer 27

Rodent urinary bladder immunofluorescence is used to detect IgG autoantibodies, which are indicative of plakin autoantibodies in PNP.

Question 28

How can you differentiate between erythema multiforme and paraneoplastic pemphigus (PNP) based on clinical progression?

Answer 28

Erythema multiforme and TEN are self-limited events that evolve and resolve over several weeks, whereas PNP is relentlessly progressive and evolves continuously over months.

Question 29

A patient with PNP has pulmonary symptoms but no findings on chest radiography. What is the likely progression of their condition?

Answer 29

The earliest symptoms are progressive dyspnea, which evolves into inflammation of the large airways.

Question 30

What laboratory test can be used to screen for PNP autoantibodies?

Answer 30

Testing for IgG autoantibodies by indirect immunofluorescence reactive with rodent urinary bladder epithelium is a key screening method.

Question 31

What distinguishes the lichenoid variant of PNP from other forms?

Answer 31

The lichenoid variant of PNP does not have demonstrable circulating autoantibodies, predominantly features lichenoid skin and mucosal lesions, and frequently develops bronchiolitis obliterans.

Question 32

What is the significance of plakin autoantibodies in PNP?

Answer 32

Plakin autoantibodies are the most characteristic surrogate markers for PNP.

Question 33

What distinguishes PNP from pemphigus vulgaris in terms of cutaneous lesions?

Answer 33

PNP lesions often involve both blisters and lichenoid changes affecting the palms, soles, and paronychial tissues, which are uncommon in pemphigus vulgaris.

Question 34

What is the clinical significance of bronchiolitis obliterans in PNP?

Answer 34

Bronchiolitis obliterans is a terminal complication in PNP, often associated with progressive dyspnea and fatal pulmonary injury.

Question 35

What is the significance of autoantibodies against α2-macroglobulin-like-1 in PNP?

Answer 35

Autoantibodies against α2-macroglobulin-like-1, a 170-kDa protein, are identified in the sera of 70% of PNP patients and serve as a diagnostic marker.

Question 36

What distinguishes the lichenoid eruptions in PNP from other lichenoid diseases?

Answer 36

Lichenoid eruptions in PNP often coexist with blisters and affect the palms, soles, and paronychial tissues, which is uncommon in other lichenoid diseases.

Question 37

What are the distinguishing features of paraneoplastic pemphigus (PNP) compared to pemphigus vulgaris?

Answer 37

PNP is characterized by: - Presence of both blisters and lichenoid lesions affecting palms and soles. - Acral and paronychial lesions are uncommon in PNP. - Cutaneous lichenoid eruptions may be the only signs of the disease.

Question 38

What is the significance of autoantibodies against plakin proteins in the diagnosis of paraneoplastic pemphigus?

Answer 38

The presence of polyclonal IgG autoantibodies against plakin proteins is a key finding in PNP diagnosis.

Question 39

How does the histopathology of paraneoplastic pemphigus differ from that of pemphigus vulgaris and foliaceus?

Answer 39

Histopathology of PNP is distinctive due to: 1. Clinical polymorphism of lesions with substantial variability in histologic findings. 2. Frequent observations of findings resulting from cell-mediated cytotoxicity.

Question 40

What are the common respiratory complications associated with paraneoplastic pemphigus?

Answer 40

Common respiratory complications in PNP include: - Development of pulmonary injury in 30% to 40% of cases, often with fatal outcomes. - Initial symptoms of progressive dyspnea, which may occur without findings on chest radiography.

Question 41

What histological features are expected in noninflammatory cutaneous blisters associated with suprabasilar acantholysis?

Answer 41

In noninflammatory cutaneous blisters, suprabasilar acantholysis is expected to be more prominent than the interface/lichenoid change.

Question 42

What are the common histopathological changes observed in patients with PNP?

Answer 42

Common histopathological changes include: 1. Individual keratinocyte necrosis with lymphocytic infiltration into the epidermis. 2. Vacuolar interface change with sparse lymphocytic infiltrate of the basilar epithelium.

Question 43

What is the significance of IgG autoantibodies in the context of PNP?

Answer 43

The presence of IgG autoantibodies bound to the cell surface of affected epithelium is a key indicator of the autoimmune nature of PNP.

Question 44

What histopathological finding is characteristic of PNP?

Answer 44

A thick lichenoid band along the dermal-epidermal junction similar to that seen in lichen planus.

Question 45

What is the significance of IgG autoantibodies in the context of PNP?

Answer 45

The presence of IgG autoantibodies bound to the cell surface of affected epithelium is a key indicator of the autoimmune nature of PNP, as demonstrated by direct immunofluorescence.

Question 46

What screening methods are effective for detecting occult malignancies in patients with PNP?

Answer 46

Effective screening methods include computer-aided tomography (CT) or MRI of the body from the neck to the base of the bladder, and positron emission tomography/CT using fluorodeoxyglucose for identifying occult lymphoma.

Question 47

What are the treatment options for patients with PNP and associated malignancies?

Answer 47

Treatment options include combined use of prednisone and rituximab, oral corticosteroids in doses of 0.5 to 1.0 mg/kg for partial improvement, and combination treatment directed at both humoral and cell-mediated autoimmunity, including daclizumab or basiliximab.

Question 48

What is the prognosis for patients with PNP who develop respiratory complications?

Answer 48

The development of shortness of breath with obstructive disease progressing to bronchiolitis obliterans is a terminal complication in most cases, leading to respiratory failure.

Question 49

Is there any known prevention strategy for PNP in patients with lymphoid malignancy?

Answer 49

There is no known intervention that may prevent the development of PNP in a patient with a known lymphoid malignancy.

Question 50

What is the role of histopathology in differentiating PNP from pemphigus vulgaris?

Answer 50

Histopathology in PNP shows lichenoid mucositis with individual cell necrosis and suprabasilar acantholysis, which are distinct from pemphigus vulgaris.

Question 51

What is the significance of polymorphous histologic findings in PNP?

Answer 51

Polymorphous histologic findings reflect the variability in clinical presentation and the underlying antitumor immune response.

Question 52

What is the significance of direct immunofluorescence in PNP?

Answer 52

Direct immunofluorescence shows evidence of IgG autoantibodies bound to the cell surface of affected epithelium, aiding in PNP diagnosis.

Question 53

What is the role of fluorodeoxyglucose PET/CT in PNP?

Answer 53

Fluorodeoxyglucose PET/CT is a specific imaging technique for identifying occult lymphomas in PNP patients.

Question 54

What is the role of combined prednisone and rituximab therapy in PNP?

Answer 54

Combined prednisone and rituximab therapy targets both humoral and cell-mediated autoimmunity, providing partial improvement in PNP.

Question 55

What is the significance of necrosis in PNP histopathology?

Answer 55

Necrosis in PNP histopathology is indicative of cell-mediated cytotoxicity, a distinguishing feature from other pemphigus variants.

Question 56

What histopathological findings are characteristic of PNP lesions with a mixed clinical pattern?

Answer 56

Lesions with a mixed clinical pattern show mixed histologic features of concomitant suprabasilar acantholysis and interface/lichenoid dermatitis.

Question 57

What is the clinical course of pulmonary injury in PNP?

Answer 57

Pulmonary injury in PNP progresses from inflammation of large airways to bronchiolitis obliterans, often leading to terminal respiratory failure.

Question 58

What is the most effective imaging technique for identifying an occult lymphoma in PNP patients?

Answer 58

Positron emission tomography/CT using fluorodeoxyglucose is a more specific technique for identifying an occult lymphoma.

Question 59

What is the prognosis for PNP patients who develop shortness of breath and hypoxia?

Answer 59

The development of shortness of breath and hypoxia is an ominous prognostic sign, often indicating terminal complications such as bronchiolitis obliterans or respiratory failure.

Question 60

What is the typical treatment approach for benign tumors associated with PNP?

Answer 60

Benign or encapsulated tumors such as Castleman tumors or thymoma should be surgically removed, with continued immunosuppression required for 1-2 years post-surgery.

Question 61

What is the histopathological hallmark of PNP in perilesional epithelium?

Answer 61

A lichenoid mucositis with variable degrees of individual cell necrosis and suprabasilar acantholysis is observed in perilesional epithelium.

Question 62

What is the typical response of PNP cutaneous lesions to treatment?

Answer 62

Cutaneous lesions in PNP respond quickly to therapy, but stomatitis is generally refractory to treatment.

Question 63

What is the role of prednisone and rituximab in PNP treatment?

Answer 63

Prednisone and rituximab are commonly used in combination to treat PNP, with prednisone providing partial improvement and rituximab targeting B-cell-mediated autoimmunity.

Question 64

What is the histopathological variability in PNP attributed to?

Answer 64

The histopathological variability in PNP is attributed to its presumed antitumor immune response, leading to diverse clinical and histologic patterns.

Question 65

What is the role of daclizumab or basiliximab in PNP treatment?

Answer 65

Daclizumab or basiliximab are used in combination therapy to target cell-mediated autoimmunity in PNP.

Question 66

What are the potential clinical implications of developing shortness of breath in patients with obstructive disease progressing to bronchiolitis obliterans?

Answer 66

The development of shortness of breath with obstructive disease progressing to bronchiolitis obliterans is a terminal complication in most cases, indicating a poor prognosis and potential respiratory failure.

Question 67

What is the significance of finding IgG autoantibodies in the context of immunopathology related to PNP?

Answer 67

The presence of IgG autoantibodies bound to the cell surface of affected epithelium by direct immunofluorescence indicates an autoimmune response that may require repeated biopsies and careful investigation of the adnexal structures.

Question 68

What is the recommended screening method for detecting occult malignancies in patients developing PNP?

Answer 68

The most effective and efficient method for screening for occult malignancies in patients developing PNP is either computer-aided tomography or MRI of the body from the neck to the base of the bladder.

Question 69

What treatment options are available for patients with autoimmune disease associated with malignancies?

Answer 69

Treatment options typically include prednisone and rituximab for immunosuppression, oral corticosteroids in doses of 0.5 to 1.0 mg/kg for partial improvement, and combination treatment with daclizumab or basiliximab targeting both humoral and cell-mediated autoimmunity.

Question 70

What is the initial clinical evaluation step for a patient suspected of having paraneoplastic pemphigus?

Answer 70

The initial clinical evaluation involves assessing for painful stomatitis. If absent, the diagnosis is excluded. If present, it indicates diffuse epithelial necrosis of the tongue and vermilion of the lips.

Question 71

What laboratory evaluations are performed in the diagnosis of paraneoplastic pemphigus?

Answer 71

Laboratory evaluations include biopsy for histology, direct immunofluorescence, indirect immunofluorescence, immunochemical testing, and special testing for known tumors or neoplasms.

Question 72

What are the first-line treatments for paraneoplastic pemphigus?

Answer 72

First-line treatments include prednisone (0.5-1.0 mg/kg), rituximab (375 mg/m² IV weekly x 4 wk), daclizumab (2 mg/kg IV weekly x 4 wk), and basiliximab (20 mg IV on day 0 and day 4).

Question 73

What is the differential diagnosis for paraneoplastic pemphigus?

Answer 73

The differential diagnosis includes oral lesions such as pemphigus vulgaris, Stevens-Johnson syndrome, and cutaneous lesions like erythema multiforme and drug eruption.

Question 74

What are the key steps in the clinical evaluation of a patient suspected to have paraneoplastic pemphigus?

Answer 74

1. Assess for painful stomatitis: If absent, diagnosis is excluded. If present, look for diffuse epithelial necrosis of the tongue and vermilion of lips. 2. Evaluate skin lesions for blisters and erosions resembling erythema multiforme or toxic epidermal necrolysis. 3. Conduct a biopsy for histology to confirm findings.

Question 75

What laboratory evaluations are essential in diagnosing paraneoplastic pemphigus?

Answer 75

Essential evaluations include direct immunofluorescence to detect antibodies at the basement membrane, indirect immunofluorescence to assess cell-surface binding, and immunochemical testing to identify antibodies against desmogleins and other proteins.

Question 76

What are the treatment options for a patient diagnosed with paraneoplastic pemphigus?

Answer 76

Treatment options include prednisone (0.5-1.0 mg/kg), rituximab (375 mg/m² IV weekly x 4 wk), daclizumab (2 mg/kg IV weekly x 4 wk), basiliximab (20 mg IV on day 0 and day 4), and other immunosuppressive therapies.

Question 77

What special evaluations should be conducted to rule out associated neoplasms in patients with paraneoplastic pemphigus?

Answer 77

Evaluations include imaging of chest, abdomen, and pelvis to identify common tumors, assessing for any known preexisting neoplasms, and considering excision if a tumor is found.