Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
9
Pathology Associates Of Lexington, P.A.
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Pathology of Dermatitides, especially Emergency or Challenging
Dermatology Diagnoses
Table of page contents:
  • Introduction & links
  • Clinical signs & symptoms DDX patterns (such as spider-bite-like dermonecrotic lesions). Lesion physical description definitions, HERE.
  • Emergency infectious situations NF/NSTI, SSTI, etc.
  • Histological DDX groupings [listing starts HERE].
    1. vasculitis DDX [HERE]...and lower leg stasis dermopathies [HERE].
    2. infarcts, pupura, eschars/ulcers [HERE].
    3. r/o urticaria [HERE].
    4. spongiosis (hallmark of eczema when not a specific clinical entity), [HERE]
    5. pregnancy dermatoses [HERE]
    6. blistering disorders
      [clinical blistering DDX outline HERE]
      & [histological blistering entities, HERE]
      & [DIF DDX notes, HERE] and [anti-skin antibodies, HERE]
      .
    7. pustulosis [HERE], AGEP emergency.
    8. interface action, as in EM/SJS/TEN [HERE]...SJS/TEN emergency.
    9. dermal polys [HERE]; eos. [HERE].
    10. thickening [HERE].
    11. Panniculitis, HERE.
  • psychodermatology (stress & psychiatric): This is an extremely "touchy" area (doctors and the medical system just can't "win" here). Some consider stress to trigger or be a component of acne, urticaria, eczema, vitiligo, acute telogen effluvium, factitial panniculitis, trichotillomania, some lesions of lichen simplex chronicus, and even blisters. It can go more extreme and go into the category of factitious (self-inflicted) dermatitis artifacta [pathomimia] (to include odd abscesses, scars, granulomas, and pigmentation). There are delusional entities to be aware of such as sensations of bugs, etc., crawling (Morgellon's Disease...see a dramatic case on the edge of suicide on season #1, episode 8 of the Diagnose Me TV program which, in the end, was diagnosed as dental-filling-associated Morgellon's-like syndrome due to chronic mercury toxicity, neuro-cutaneous syndrome [NCS]...a toxicity induced dysesthesia...from which the patient was cured). So, great care must be taken that one NOT count a patient condition as delusional when it might be atoxicity induced dysesthesia. Psychodermatology can include Munchausen syndrome aspects or even Munshausen by Proxy syndrome. Be alert (1) when evidence does not add up, (2) when all lesions are in reach of the hand of the patient's "handedness" [a right handed patient has no lesions where the dominant hand cannot reach], (3) when the lesions are in very odd linear patterns such as cross-secting linear lines, and when/if (4) the patient acts oddly. See reference #55, below. As with the case above, it is tragic when someone is diagnsosed as having a psychosomatic illness when there actually is an organic cause! Many such situations are finally, accurately diagnosed through the efforts of patient's or their friends or family via the internet search features.
  • Imunofluorescent (DIF) patterns DDX
  • Disease entities DDX
  • Loma Linda 600+ enties dermpath web site, HERE.
  • Pathology Outlines, non-tumor skin entities, HERE.

Since 1987, we have been fortunate to have the expertise at our private LML histology lab to back up our doctors (our hospital now running the 2nd busiest hospital ER in South Carolina) with very rapid emergency diagnoses using frozen section, same-day direct immunofluorescence, routine next-day histology, and next-day IHC stains. The emergency situations tend to revolve around infectious vs. non-infectious and steroid vs. non-steroid therapy, and diffuse, "bad" erythema of non-vesiculating type vs. pre-vesiculating (or already vesiculating/bullous) situations. Here is a growing collection of some examples of our DIF cases...most workups routine & non-emergent.

A decent thumb-nail dermatology resource...family practice, An online Czech DIF dermatology atlas ...this atlas covers many other things than just DIF. The Electronic Textbook of Dermatology has lots of details on some blistering dermatoses, etc. Dermis.net is another on-line site. Dr. Mihm's is another. The late Dr. Ackerman's subscription site is packed with info and presents very frequent e-mailed case discussions. For skin conditions of all types (with ability to study as a patient or a physician), check out this New Zealand website (DermNet NZ).

Even if done just minutes prior to biopsy, biopsy preplanning is crucial to the success of emergency diagnosis. A slightly thick shave biopsy about 1.0 cm. in greatest diameter is mandatory, if possible. It is always an advantage to include the advancing edge of a lesion (junction between normal and lesional skin) if skin is less than generally affected...as long as the biopsy is marked or oriented in such a way that the pathologist can correctly embed it to demonstrate this junction. If there are lesions of a spectrum of ages, it can be very helpful to evaluate biopsies from both a fresh and a middle-aged lesion. A punch biopsy within the interior of the lesion is also additionally helpful, especially if the lesional skin seems deeply involved (indurated). A shave of any vesiculating condition can also be placed in Michelle's type DIF transport fluid, to be held for DIF studies if truly needed (reflex work up); a  companion serum sample may allow demonstration of various anti-skin auto-antibodies, if need be, as well as serological testing for any associated or provocative auto-immune disease. 

Lab tests: We offer many skin-related lab tests locally (at LML). We can "conduit" samples to other labs. Some specialty dermatology-tests labs for info: U. of Rochester Med. Ctr. dermatology lab

NOTE: With the below listings as a starter, one is encouraged to seek up-to-date information on a particular DDX entity through such as the PubMed medical search engine of the USA National Library of Medicine (and/or your local text and other resources) or Google's Scholar engine. Also, by using the search-for-images feature of the Google search engine, you might find good photos.

OVERALL INFLAMMATORY ALERT! AND, always keep in mind that many dermatoses (example, Sweet's) are (1) entirely idiopathic while lesions very similar are (2) associated with pregnancy, (3) are parainflamatory, (4) are paraneoplastic, or (5) are associated with medications or suppliments, other internalized substances. While the clinical & histological picture is often classical (typical), an unsettling percentage of cases are atypical. Example: Sweet's lesions typically have copious neutrophils at the dermoepidermal junction. Atypical lesions may have (1) atypically lesser quantities in the typical location (S15-1062) or (2) typical deposits of neutrophils in atypical locations. Thus, it is optimal when the biopsying clinician is in communication with the interpreting pathologist when any case is less than straight forward.

Clinical Differential Diagnosis Groups:

  • dermonecrotic skins lesions:
    1. spider bites
    2. bacterial infections: staph (including MRSA) & strep most common; these can lead to cellulitis and severe local pain very concerning for necrotizing fasciitis.
    3. viral infection: herpes simplex (HSV) or zoster (HZV).
    4. fungal infection: sporotrichosis.
    5. focal vasculitis or vascular microembolus
    6. primary dermatological conditions: such as TEN, S-J, EM, pyoderma gangrenosum, lymphomatoid papulosis.
    7. miscellaneous: poison ivy/oak dermatitis; chemical burn; bed sore; localized drug reaction; diabetic ulcer; factitious/psychogenic dermatitis; pilonidal sinus.
    8. bites from blood sucking bugs (mosquitoes, etc.) & these can get infected by bacteria.
  • abnormal palm & sole colors (without keratosis):
    1. too pale...white: anemia.
    2. too red: cirrhosis or other hyperproteinemic, hyperviscous situation.
    3. yellow: jaundice/icterus & carotenemia (excess colored vegetables & fruits) will also make sclerae yellow; hypothyroidism; chronic liver disease; chronic renal disease; and situations of excessive end products of glycation (diabetes mellitus).
  • abnormal palm & sole thickening [TABLE]...and hand dermatitis:23
    Inflammatory processes may involve the back surfaces or palm surfaces of the hands. Given the thickened skin surface of the hands and the frequent exposure of the hands to irritants and potentially exacerbating factors, hand dermatitis can be difficult to treat.

    Hand dermatitis can range from an acute, extremely pruritic or painful eruption, characterized by deep-seated vesicles (dyshidrotic eczema, pompholyx), to a chronically rough, hyperkeratotic hand dermatitis. For therapeutic purposes, hand dermatitis can be classified into (1) blistery vesiculobullous types (acute and chronic) and (2) rough hyperkeratotic hand dermatitis (no vesicles in any phase of the eruption). Both types may also be marked by edema, fissures, nummular plaques, and erosions. Persons who are predisposed with atopic dermatitis are at particular risk to develop hand dermatitis. The therapeutic strategy is to eliminate any external cause and to control the cutaneous inflammation. Management is typically through topically applied medications. For severe cases, systemic immunosuppression may be necessary.

    All patients with hand dermatitis, independent of the clinical type, have reduced tolerance to irritants. The most common irritants are soap and water. Hand protection for all manual tasks, wet or dry, prevents exacerbations. Especially important is the use of vinyl gloves when doing any wet work. Moisturizing the hands regularly is critical in controlling most cases of hand dermatitis. Nightly application of a heavy moisturizer is strongly recommended.

    There is an important differential diagnosis list of other things like "hand dermatitis", including: atopic dermatitis involving the hand, tinea (superficial dermatophyte fungus infection), allergic contact dermatitis, psoriasis, lichen planus, scabies, herpes simplex, pityriasis rubra pilaris, and cutaneous lymphoma.

  • hypo & hyperpigmentation lesions & syndromes HERE. An ill-defined, light brown patch is most in keeping with postinflammatory hyperpigmentation. Also search-term this current page as well as this one, HERE.
  • dermatomal dermatoses:
    1. herpes zoster (VZV): usually vesicular & see viropathic epidermal change.
    2. recall reaction, viral: mostly reported in VZV cases but not a viral recurrence; maybe triggered as a pruritic reaction with mixed interstitial & perivascular lymphs & eosinophiles. Different from post-radiation therapy, field-limited, chemo-induced radiation-recall dermatitis (RRD).
    3. factitial dermatosis.
    4. atypical contact dermatitis.
    5. dermatomal pigmentary dermatosis (a dyschromatosis ?).
  • stubborn, usually hyperkeratotic & cracking, hand/palm & foot/sole dermatosis or dermatitis (DDX here) [S07-3257, foot; L07-2586 wrist].
  • opportunistic skin portal of entry infections:
    1. Aspergillus
    2. Fusarium filamentous mold: mostly from environment where is ubiquitous & often starts in crack or ulcer between toes, or maybe central venous catheter site (or sino-pulmonary tree) & dissemination reflected in skin as papulo-pustules. Most often in aggressive chemo cases with prolonged neutropenia.
  • biopsy sent to rule out "rash", "eczema", or dermatitis: At its broadest, eczema is a synonym for dermatitis. "Eczema" cases are...as of the time of biopsy...a wastebasket of drematidities, almost always red and probably at least histologically "wet" (spongiotic) , which do not show readily recognizable clinical patterns and features that are typical of a particular & specific dermatitis or dermatological differential diagnosis group...usually somewhat chronic.  Eczema is essentially always a spongiotic papular or papulovesicular disease 1, 11.  It mostly includes contact, perioral (face), atopic, prurigo, LSC, dyshydrotic, and exfoliative (erythema, swelling, diffuse and copious scaling).  So, except for the pattern of "dermal contact sensitivity reaction" (maybe slight acanthosis and parakeratosis of epidermis over fairly heavy & tight perivascular cuffing by lymphs & a few plasmas and eos...Pinkus p. 11611), lack of spongiosis rules out "eczema" (& with the exception of atopic dermatitis and lichen simplex chronicus 22). Dr. Ackerman dispises the term eczema & urges that doctors refine a patient's disorder down to a particular & specific dermatitis 22
    1. biopsy looks normal: look carefully for anything suggestive of angiomatous, lymphangiomatous, or angiosarcomatous clues; think also of early morphea.
    2. breast rash or erythema: be always on the alert for "inflammatory breast cancer", radiation recall dermatitis (field localized), and radiation-associated lymphangiosarcoma.
    3. problematic (eczematous) dermatitides which are spongiotic: (remember that there are those due to cuses from within [endogenous] and those from external triggers [exogenous])
      • allergic contact dermatitis: may see eosinophiles & may see intraepidermal "Langerhans cell microgranulomata"; contact can be superimposed on chronic dermatidites, say, psoriasis [S09-10070].
      • nummular (discoid) dermatitis.
      • "id" reactions: at a distance from a genesis lesion of dermatophytosis (& other agents) or contact dermatitis lesion or autosensitiazion (id reaction; auto-eczematization [S09-1103]). HERE.
      • dyshidrotic dermatitis & asteatotic.
      • erythema annulare centrifugum (EAC).
      • pityriasis rosea (PR): [S-07-3347]...tiny foci of spongiosis/spongiotic vesiculation in a clinically "dry29" eruption...early; more spongiosis & hyperplasia & parakeratosis later [S07-11834] & then the findings wane34.
      • guttate parapsoriasis.
      • acral papular eruption of childhood.
      • seborrheic dermatitis.
      • lichen striatus: a clustering linear or multilinear array of of closely-set, smooth or scaly papules in array along the lines of Blaschko, and that usually resolves in months...histopath is early spongiotic but can later be lichenoid & later patchy granulomatous23.
      • miliaria rubra.
      • irritant contact dermatitis.
      • photoallergic dermatitis.
      • vesicular dermatophytosis.
    4. problematic (eczematous) dermatitides which are minimally or not spongiotic:
      • atopic dermatitis.
      • lichen simplex chronicus.
      • dermal contact sensitivity reaction with "coat-sleeved" perivascular dermatitis (see above).
  • pruritic lesions: when chronically pruritic lesions are finally biopsied, all that one may see are the histomorphological consequences of chronic, vigorous scratching & rubbing (lichenification). These are (1) compact, volar-like orthokeratosis with hypergranulosis, (2) vertical streaks of papillary dermal collagen, (3) acanthosis, and (4) stellate fibroblast nuclei in dermis. If that reactive lesion is a plaque, it is "lichen simplex chronicus" and if a rash of papules, "prurigo nodularis" (or "prurigo papularis" [S07-9672]), and if an isolated papule, it is a "picker's nodule". "Prurigo" is the noun condition for the adjective, "pruritic". The above stellate fibroblasts are also seen in radiation dermatitis, below.
    1. nipple, breast: be alert for Paget's disease, almost all of which cases have an underlying breast cancer.
    2. cutaneous lymphoma40: look for MF-type changes.
    3. dermatitis herpetiformis (DH): intensely pruritic & bilaterally symetrical & extemities & buttocks; polys at tips of dermal papillae & DIF may show IgA at papillae tips.
    4. urticaria ("hives" or "whelps"): Why would someone biopsy urticaria? It is usually because the urticaria is stubbornly persisting (chronic is greater than 6 weeks), has become petechial or hemorrhagic, developes blisters, or become palpable beyound just "whelps". Mast cell degranulation causes dermal edema; angioedema is when edema extends susbcutaneously; sparse polys in early lesion. Acute urticaria can be triggered in association with stress of another illness or situation. Usually an "allergic" reaction; can be autoimmune related (more often have urticarial vasculitis), neoplasia related (paraneoplastic), infection related, etc. If also, in addition to itching, it burns, stings, or has petechial or ecchymotic bleeding, it could be urticarial vasculitis (more associated with autoimmune or paraneoplastic) vs. "prolonged urticaria" (e. g. "neutrophilic urticaria"). So, if prolonged lesions without bleeding = concern for early, no-hemorrhage-yet urticarial vasculitis or neutrophilic urticaria. "Palpable purpura" (leukocytoclastic vasculitis...LCV...purpura), nodular vasculitis, urticarial vasculitis and allergic vasculitis are used somewhat synonymously as applied to skin. And, our DX of urticarial vasculitis triggers a fairly extensive vasculitis lab workup for other causes (excellent review, HERE). Finally, bites can urticate prominantly and may be biopsied to have some assurance that the histology is only compatible with urticated bites.
      • Papular urticaria: this pruritic outbreak (usually childhood) is associated with insect bites from such as fleas & mosquitoes & likely some id-like papules beyond just flea-bite histology. Has eosinophiles as an allergic reaction.
      • urticarial vasculitis (clinical: see peteciae, purpura, and/or siderotic hyperpigmentation in lesions)(histology is LCV):
        • hypocomplementemic (congenital or acquired) tend systemic sxs (this group more likely autoimmune related).
        • normocomplementemic (congenital or acquired) urticarial vasculitis
      • late-phase (eosinophilic) urticaria33: non-LCV, non-fibrinonecrotic vasculitis (vasculocentric eos) in greater-than-24hour urticarial lesions.
      • late-phase (polys & eos) urticaria: non-LCV, non-fibrinonecrotic vasculitis (vasculocentric polys & eos) in greater-than-24-hour urticarial lesions [S08-14586]. It could be "neutrophilic urticaria" resistant to anti-histamine TX in idiopathic fashion [PD11-2551] or be associated with crypyrin-associated periodic syndromes (CAPS) such as familial cold urticaria, Muckle-Wells syndrome, and neonatal-onset multi-system inflammatory disorder (NOMID)43, 44.
      • Neutrophilic urticaria: rich in perivascular polys = "Urticaria with a predominantly neutrophilic infiltrate can be resistant to treatment with anti- histamines. Neutrophilic urticaria comprises approximately 10% of chronic urticaria cases. A diagnosis of neutrophilic urticaria allows the clinician to treat with agents such as dapsone or colchicine which target neutrophils. Biopsy is recommended for chronic urticaria that is not responding to conventional treatment."

        "Neutrophilic urticaria is also encountered is the cryopyrin-associated periodic syndromes (CAPS) which includes clinical presentations ranging from familial cold urticaria, Muckle-Wells syndrome and neonatal-onset multi-system inflammatory disorder (NOMID). CAPS is due to loss of function mutations in cryopyrin, a negative regulator of the inflammasome (important in innate immunity), resulting in overproduction of IL-1ß. In addition to urticarial papules, patients may experience fevers, flu-like symptoms and arthralgias. Recently, prominent peri-eccrine neutrophilic inflammation has been reported in the urticarial papules in a patient with NOMID and it remains to be determined if this is a distinct feature of CAPS. Treatment of CAPS with Anakinra, an antagonist of the IL-1 receptor, has resulted in marked clinical improvement in patients with CAPS."

        "Schnitzler’s syndrome describes the constellation of chronic urticarial rash, monoclonal IgM gammopathy in combination with bone pain, arthralgias, lymphadenopathy or leukocytosis. The urticarial lesions in this condition also demonstrate a neutrophil-rich infiltrate. Recently, evidence suggests that this condition is due to secondary dysregulation of the inflammasome, and treatment with Anakinra is also effective. Differential diagnosis: urticarial vasculitis. Levels or additional biopsies may reveal leukocytoclastic vasculitis.48"

      • chronic urticaria (lasts longer than 6 weeks), HERE:
        • physical:
          1. dermatographism
          2. cholinergic
          3. pressure
        • medicational:
        • chronic autoimmune: anti-thyroid antibodies, ANA, rheumatoid-associated.
        • idiopathic: everything without an identifiable cause.
      • mast-cell proliferative disease: HERE.
    5. Nodular lesions:
      • Erythema elevatum diutinum (EED): a rare chronic form of fibrosing vasculitis. Erythema elevatum diutinum (EED) is a rare chronic form of fibrosing vasculitis.
        1. Firm, red to brown or violaceous nodular lesions developing over joints of the elbows, knees, hands, and feet, often in a symmetric pattern, is the hallmark cutaneous lesion.
        2. EED has been associated with HIV/AIDS, hematologic disorders (IgA monoclonal gammopathy, multiple myeloma), celiac disease, Wegener’s granulomatosis, connective tissue disorders (especially systemic lupus erythematosus), and recurrent streptococcal infections.
        3. Dapsone is (2014) the first-line therapy for EED.
    6. papulosquamous dermatoses: 25% of pityriasis rosea (PR) cases can be severely pruritic; lichen planus (LP) can be pruritic; pityriasis rubra pilaris (PRP) may be very pruritic at first.
    7. transient acantholytic dermatosis (Grover's disease) = lymphs & eos.; Grovers disease with lots of eosinophiles may be maddeningly pruritic 22 [S10-445]. Don't confuse with acantholytic dyskeratosis which, as with acantholytic change, can be seen in an actinic keratosis (AK/PMK).
    8. Darier's disease: is acantholytic and tends to be purely so. Don't confuse with acantholytic dyskeratosis which, as with acantholytic change, can be seen in an actinic keratosis (AK/PMK).
    9. "endogenous eczema".
    10. scabies (pediculosis): highly infectious when crusted & heavy burden of mites (Norwegian) & can rarely produce clonal-like lymphoid lesions with epidermotropism.
    11. drug eruptions.
    12. pruritic papular eruption (PPE) of AIDS.
    13. eosinophilic pustular dermatitis of AIDS.
    14. atypical bullous pemphigoid.
    15. linear IgA dermatosis.
    16. pemphigus herpetiformis: acantholytic w/ intra-epi. polys or eos. (see below).
    17. lichen planopilaris: papulosquamous (thickening & scaley), folliculocentric, dead keratinocytes.
    18. Pityrosporum folliculitis (is caused by Malassezia furfur/P. ovalae).
    19. mast cell lesions.
    20. prurigo pigmentosa: lichenoid lesions that come & go and leave postinflammatory pigment.
    21. papular dermatitis/subacute prurigo/"itchy red bump disease" (look for a mite of cheyletiellosis...mite being in keratin layer...in case it really is a mite case).
    22. pruritic dermatoses of pregnancy.
    23. pruriginous (purpuric) angiodermatitis.
    24. fiberglass dermatitis.
    25. dermal hypersensitivity reaction (JAAD Dec 2002 47:898-907).
    26. "recall dermatitis": post-zoster dermatomal rash with eosinophiles & lymphocytes [S11-1672], see above.
  • papules/nodules/plaques:
    1. foliculitides, including Majocchi granuloma (MG)...granulomatous folliculitis due to fungus, bacteria, maybe anything that causes perifollicular extrusion of follicular contents
    2. urticarial...see pruritic lesions, above...lesions change size in hours...almost always coming & going in less than 24 hours.
    3. papulosquamous dermatoses, including LP
    4. picker's nodule: (localized LSC, lichen simplex chronicus, see above) with nondysplastic , very hypergranular squamous epithelium beneath a very compact (as in acral palmar or plantar skin) orthokeratotic cornified layer (indicative of external pressure, rubbing, picking) [S09-641].
    5. neoplasms & nevi: don't miss mycosis fungoides or myeloid sarcoma36.
    6. dyskeratoses:
    7. granulomata [S07-8662]: GA, rheumatoid, infectious, sarcoid, granuloma multiforme (annular eruption upper body in older adults central Africa).
    8. perforating (epidermal elimination disorders) dermatoses: inherited or acquired: perf. GA, perf. collagenosis, perf. elastosis, perf. folliculitis, Kyrle disease [S-07-594], perforating PXE, etc)
    9. organisms: luetic; viral (MC & VV).
    10. benign vascular lesions: pyogenic granuloma; stasis lesions such as "acral angiodermatitis" [S06-3532].
    11. granuloma annulare:
    12. sarcoid: non-necrotizing granulomatous reaction & without associated polys and with all tests negative for organisms.
    13. erythema nodosum: this is a nodular eruption (usually anterior lower legs) that can be idiopathic or associated with medications, autoimmune, inflammatory, or neoplastic background diseases. It involves the skin (dermatitis) and underlying fat (as a septal panniculitis). Dermis has a nonspecific perivascular infiltrate; underlying fat has septal polys & lymphocytes.
    14. eruptive xanthomas: yellowish & may reflect hyperlipidosis [L07-1462].
    15. pseudoxanthoma elasticum (PXE): usually as symmetrical asymptomatic yellowish papules of neck, antecubital & popliteal fossae; nitrate exposure (fertilizer/farmers) or medication (penicillamine) or genetic (genetic, at least, implies system-wide defective elastic tissue with potential for vascular problems. The skin elastosis oddly favors deeper (reticular) dermis.
    16. post-zoster eosinophilic dermatosis: rare dermatomal papules in site of previous VZV rash [S11-1672].
  • lichenification: this is when a lesion enhances or exaggerates normal skin markings [histology HERE ].
  • photodermatitide (light) eruptions:
    1. normal sunburn: the expected burn based on light exposure and duration.
    2. solar urticaria
    3. phototoxic:
      • exaggerated "sunburn" due to an ingested or endogenous (PCT) phototoxic photosensitizer; not immunologically mediated; papules1 to vesicles; clues are necrotic and balooned keratinocytes which attract polys (irritant contact "burns" and produces same picture).
      • topical (photocontact) phototoxic photosensitizer:
    4. photoallergic reaction:appears more as rash than sunburn; almost always14 histology of superficial & deep perivascular (whereas an allergic eruption is just superficial).
    5. polymorphous light eruption (PMLE): itchy papules & plaques in some...not all...sun-exposed skin. Papillary dermal edema and often heavy superficial & deep perivascular infiltrate more polymorphous than lupus (not just lymphs [PD13-2541]). Earliets is negative epidermis with predominant perivascular lymphs; early adds on spongiosis; and if is a deep-predominant perivascular lesion, might not have papillary dermal edema1.
    6. hydroa aestivale (nonscarring) and hydroa vacciniforme (scarring) = chronically recurrent varioliform (smallpox-like) vesiculations that are not associated with any pophyrin abnormality, usually begin in childhood, and begin as intraepidermal spots of balooning keratocytes which undergo reticular degeneration and a vesicle & roof necrosis23 [S-06-14352].
  • morbilliform(measles like) eruption:
    1. measles-like, symmetrical (trunk and prox. extremities), red, macular (can be faintly papular, too), and usually 2-10 mm lesions, some confluent
    2. entities causing:
      • Kawasaki disease
      • measles
      • 46% of drug reactions are this pattern
      • is one of the 4 viral exanthem patterns
  • annular (circular with clear or clearing centers...polycyclic = multiple rings & whorls) lesions:
    1. tinea corporis
    2. nummular eczema
    3. urticaria
    4. erythema multiforme (EM)
    5. erythema chrinicum migrans
    6. granuloma annulare (GA)
    7. neonatal lupus
    8. syphilis (secondary)
    9. necrobiosis lipoidicum
    10. sarcoidosis
    11. knuckle pads
    12. erythema annulare centrifugum (EAC)
    13. linear IgA disease
    14. annular lichen planus
    15. papular HIV
    16. eruptive xanthomas
    17. lipoid proteinosis
    18. erythema nodosum
  • annular, polycyclic lesions:
    1. subcorneal pustular dermatosis
    2. subacute cutaneous lupus
  • serpiginous (have snake-like linear, branched, and curving elements) lesions
  • Reticulated (lacey) pattern dermopathy:
    1. erythema ab igne: heat &/or infra-red injury to skin which may be acute to subacute or, more commonly, chronic. The more acute may have striking endothelial atypia concerning for angiosarcoma but without freely anastamosing channels and with some lumenal rims of fibrin and perivascular reactive stromal cells [S08-1660
    2. livedo reticularis (LR) = violaceus, reticular, blotchy, or mottled vascular color of skin31: it is due to increased visibility of the cutaneous venous plexus either due to venodilation, blood deoxygenation, primary spontaneous arteriolar vasospasm, or a physioloical response to cold exposure. If progresses to nodules or ulcers = livedo vasculitis (ischemia ...infarction). Livedo racemosa = reticular-pattern & thick...maybe more than 10mm.
      • cold exposure = "cutis marmorata".
      • primary LR.
      • secondary LR (causitive entity usually with increased venous outflow resistance):
        1. vasculitis
        2. emboli
        3. hypercoagulable state
    3. liposclerosis, early stage
  • red face20:
    1. rosacea: erythema, some scaliness, no comedones, patches of bumps & pustules (afflicts 13,000,000 Americans) (histo: hypervascular, enlarged seb. glands, seborrheic epidermal change, granulomatous); perioral dermatitis is a variant.
    2. acne: red, comedones, follicular bumps
    3. eosinophilic pustular folliculitis: pruritic
    4. seborrheic dermatitis: yellow scales; Malassezia-type yeast lipase results in increased arachidonic acid irritation.
    5. actinic keratoses:
    6. atopic dermatitis: pruritic, flexural folds, lichenified scaly areas, maybe also keratosis pilaris and/or icthyosis vulgaris associated; allergy related
    7. tinea facii: scaly annular lesions due to fungi
    8. ulerythema ophrygenes: from shortly after birth...follicular papules with erythematous haloes (keratosis pilaris atrophicansbfaciei)
    9. dermatomyositis: periorbital, confluent, macular violaceous erythema (heliotrope)
    10. lupus: histology has junctional activity & may have chronic folliculitis; acute (ACLE) has malar rash sparing nasolabial folds; subacute (SCLE) has hyperkeratotic papulosquamous annular and polycyclic interface vacuolar lesions without atrophy; chronic (CCLE) discoid lesions have tightly adherent scale, follicular plugging, & central atrophy; mixed connective tissue (MCTD) disease is like a lupus & scleroderma overlap.
    11. carcinoid syndrome: erythema only that comes and goes.
  • purpura/ecchymoses WITHOUT significant inflammatory infiltrate or vasculitis2:
    1. Coagulopathies, bleeding/clotting:
      • DIC.
      • purpura fulminans (extreme skin DIC).
      • coumarin/coumadin necrosis, details".
      • lupus anticoagulant associated necrosis.
    2. endotheliopathies, early: "early" infectious lesion...(don't forget rickettsial [typhus, spotted fevers, ehrlichiae])...from endothelialitis [LMC-04-9462] to vasculitis with thrombi.
      • TTP (proceeding from hemolytic uremic syndrome...HUS; >90% cases from E. coli O157:H7):
        1. E. coli induced
        2. in severe pneumococcal infections (HUS) [Infect. Med. 18(5):251-258,2001]
      • pruriginous (scratching and rubbing by itching) purpuric angiodermatitis.
      • monoclonal cryglobulinemic necrosis
      • bite envenomation (snake or insect/spider)
      • dramatically acute stasis dermatitis [LMC-04-7886]
      • at least think of necrotizing fasciitis
      • PNH
      • scurvy (clinical photo41): perifollicular bleed with perifollicular hyperkeratosis & possibly note "corkscrew-shaped" follicular plug, follicles tending to produce corkscrew hairs41.
    3. drug eruptions
  • petechiae, purpura/ecchymoses with inflammatory infiltrate and/or vasculitis:
    1. an acute phase of stasis dermatitis [S-01-8706].
    2. vasculitides: palpable purpura (leukocytoclastic?), nodular vasculitis, urticarial vasculitis and allergic vasculitis are used somewhat synonymously as applied to skin.
    3. presentation of thrombocytopenia (ITP, TTP, acute leukemia).
    4. HSP.
    5. older (within days/week) lesion may only have the RBCs, some residua of inflammatory cells, and some beginning hemosiderin macrophages [LMC-01-8237].
    6. at least think of necrotizing fasciitis (NF), necrotizing soft tissue infection (NSTI) HERE.
    7. infectious...(don't forget rickettsial [typhus, spotted fevers, ehrlichiae])...from endothelialitis to vasculitis viral (hepatitis B or C, IRV [interferon resistant viruses like HIV], cytomegalo virus, Epstein Barr Virus [LMC-04-9462], Parvo B19 ) to septic vasculitis with thrombi.
    8. NOTE: it is the pathologist's job to search for & "rule out" (as much as we can) any of the above causes AND remember that there are "bland causes" such as antiplatelet meds (such as Plavix...LMC-05-6867]), thrombocytopenia, & factors decreasing endothelial integrity.
  • vegetative (warty) plaque: sharp-margined hyperplastic, granulomatous, granulation tissue looking, growth-like, maybe even verrucoid plaque:
    1. pemphigus vegetans: [S-04-6880]; has intraepidermal abscesses.
    2. pyodermatitis pyostomatosis vegetans.
    3. verruciform sarcoidosis.
    4. chronic post-puncture or other etiology fungal plaque.
    5. mycobacterial skin lesion.
    6. cutaneous neoplasia.
  • pustulosis: (see histological group below)
    1. acute generalized exanthematous pustulosis (AGEP): often a drug eruption & can be fatal & even caused rarely by acetamenophen.
    2. oncology patient: EGFR inhibitor–induced acneiform eruption or papulopustular rashes (usually not danderous unless complicated with infection).
    3. impetigo or impetigenized vesicobullous process of other primary etiology (such as dyshidrotic eczema (pompholyx) [PD13-2564]).
    4. pustuar dermatophytosis (check with fungal stain).
    5. metastatic pustulosis (from Staph., candida, etc.): tend to be dermal [L-06-8613].
    6. peri-orbital fungal pustular folliculitis HERE.
    7. see histological DDX groups, below (intraepidermal/peri-epidermal neutrophiles).
    8. pustular psoriasis, HERE...should see Kogoj pustular origins in biopsy.
    9. SAPHO syndrome (synovitis, acne, pustulosis [usually palmar plantar], hyperostosis, & osteitis).
    10. these can be assoc. with enteropathic (IBD) CRMO (nonbacterial osteitis [NBO]).
    11. pustules can be seen with fire ant bites, H-S purpura [S07-11104], & some disseminated infections, as above.
  • vesico-bullous conditions & desquamative oral situation (chart below): Our pathology report indicating some of the below categories might bring certain entities to the dermatologist's mind to add into his/her clinical DDX in the absence of final, complete, and specific pathology DDX diagnosis resolution.
    1. cell-poor subepidermal bullae:
      • EBA: a few scattered epidermal cell necroses2.
      • PCT: actinic elastosis & stiff papillae with d-PAS positive superficial dermal vessels [S-02-9369; S-05-10872])2; small vessel amyloid can mimic on H&E. Can be reflection of hepatitis C (HCV)...about 50% of PCT cases are HCV...or other liver disease or HCC. Both familial, gene-mutation associated & secondary PCT cause these vascular changes. Type I has uroporphyrinogen decarboxylase deficiency (decreased UROD), with types II & III having normal levels (wiki-info HERE).
      • bullous pemphigoid, cell-poor (dermal edema & some scattered eosinophiles)2
      • suction/friction blister (factitial?), fluid with or without RBCs.
      • vesicular or bullous stasis dermatitis (stasis vessels may be strongly positive for fibrinogen [L07-3526, S10-11273]).
    2. Full-thickness epidermal necrosis:
      • TEN2
      • thermal burn2 (heat or cold, accidental or factitious [LMC-01-7581])
      • hypoxia2
      • fixed drug reaction2
      • grade IV GVH2
      • vascular-related necrosis over cellulitis: phlegmasia [swollen & inflammed] cerulea dolens [painful] (PCD) or plegmasia alba [pale...white; "milk leg"] dolens; both related to "venous gangrene" with large or small vein thrombosis...phlebitis-related or not...which is thought to stimulate arterial vasospsm which leads to gangrene [L07-10666].
    3. Subcorneal &/or subgranular cleavage2:(only clue may be absence of cornified...maybe even granular...layer in the biopsy22)
      • pemphigus foliaceous (eosinophiles & typical DIF pattern; trunk & extremities)
      • SSSS (generalized)
      • sometimes over cellulitis or deep subcutaneous suppuration as in necrotizing fasciitis [L07-5525].
      • subcorneal pustular dermatosis (SPD)
      • pemphigus erythematosus (eosinophiles & typical DIF pattern; affects face and V-area of neck/chest)
      • bullous impetigo (bacteria [strep. or staph.] and polys).
    4. Cleavage, degeneration in a parakeratotic surface: necrolytic migratory erythema (assoc. with functioning neuroendocrine tumor of pancrease).
    5. scalded skin (widespread flaccid bullae):
      • TEN
      • SSSS
      • bullous impetigo
      • thermal burns
    6. basement membrane zone (BMZ) immunodeposits:
      • granular:
        1. lupus
        2. PNP
      • linear or homogeneous:
        1. pemphigoid
        2. PNP
    7. intercellular peri-keratinocytic immunodeposits:
      • pemphigus, all varieties
      • IgA vesicopustular dermatosis (IAVPD)
    8. epidermal nuclear fluorescence:
      • lupus, rarely
      • MCTD, typically
      • Sjogren's syndrome
  • skin scarring, thickening, stiffening, "brawny edema" & "woody induration"; hard or poorly flexible skin, whether localized or more diffuse 22:
    1. scleroderma, systemic (multisystem disease & poor prognosis & differentiated from "localized" by absence of sclerodactyly, Raynaud's phenomenon, and nailfold capillary changes39).
    2. scleroderma, localized (good prognosis)(morphea): rare (less than 2.7/100,00039); may take trichrome stain to appreciate the fibrosis.
      • presclerotic: possibly vague superficial & deep lymphomononuclear (maybe a few plasma cells, too) involving small nerves, eccrine units, hair follicles [S11-965].
      • sclerotic :
        1. morphea (localized firm lesions). (early DFSP and a BCC type can be morpheaform)
        2. en coup de sabre (large sword-like lesions).
        3. lichen sclerosus et atrophicus and guttate morphea (foci of papillary dermal sclerosis).
    3. tryptophane myalgia syndrome.
    4. fasciitis with eosinophilia (eosinophilic fasciitis).
    5. nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy): is assoc. with renal disease & most visible as papules & plaques of skin with mid-dermal increase in interstitial spindle cells (CD34+ cells & CD68+ cells).
    6. plaques of PCT.
    7. late lesions of GVH.
    8. radiation recall dermatitis (RRD), late: varying from superficial dermal sclerosis to that plus subdermal liposclerosis, the clinical tip off is the lesion being within radiation port fields, and the histologic tip off is presence of atypical, stellate fibroblasts within the entire zone (they can be seen very deep)[S10-6884; L10-8107]. When it seems more clinically inflamed & eczematous, it may be the entity "radiation recall eruption" (or radiation enhancement eruption) dermatitis associated with chemotherapy & happening in prior port fields [S10-6884]42. When the stellate fibroblasts are seen in a skin biopsy WITHOUT rubbing-induced, LSC-type epidermal change, think radiation recall dermatitis [L10-8107].
    9. liposclerosis or lipodermosclerosis: of chronic venous insufficiency (CVI), usually of lower legs & could reflect local thrombosis in a patient with thrombophilia ().
    10. fibrotic dermis: end-stage of a number of lesions.
    11. scarring or sclerosis due to trauma: and this can be due to factitious [S07-14886] (dermatitis artefacta, neurotic excoriations, Munchausen's syndrome, and malingering34) or even such as in the functional area of delusional parasitosis Eckbom syndrome (as it applys to skin = Morgellon's Disease or syndrome (delusional parasitosis [S-01-11211 & FA-05-151]).
    12. woody edema: the skin and/or subcutaneous tissue of fibrosing chronic "woody induration" lymphedema (scleredema...scleromyxoedema [SMX]) from either "localized idiopathic scleredema" (if no obstructive lesion found [B07-247]), congenital deficiency of lymphatics (if severe enough it shows up at a young age &, if less severe, it appears with weight gain...weight loss before permanent tissue changes can reverse the swelling...at an older age &, if only one lower leg, can mimmic the swollen leg of thrombosis), or secondary local lymphatic obstuction (as dependant from a lower extremity ulcer [L07-6036] or surgical or trauma site [L08-12928], or from acute and chronic venous insufficiency...CVI) or regional due to parasites or transcutaneous entry of silica or other soil irritants into lymphatics (podoconiosis). When an extremity is deformed enough, it is called elephantiasis...with rough skin surface & hyperkeratotic, hyperplastic change being hypostatic, venostatic, or lymphostatic cutaneous verrucosis (or chronic epidermal verrucosis or [L09-3784; L10-6069]);even in a single chronically nearly-autoamputated toe [L08-13296]); dermal & subdermal stiffening being scleredema; & when clearly has also stiffened subcutaneus very deeply = lipodermatosclerosis...liposclerosis if only subcutaneous or deep tissues affected. When hypostasis is so chronically severe that it becomes erosive & ulcerating & disabling, we have even seen bilateral above-knee amputations [L10-6069] wherein the choice of diagnostic dermatopathology terminology becomes bewildering.
  • erythroderma (ED)[widespread...e.g. 90%...red skin exfoliating]: most cases are exacerbations of a current skin disease & only 1-6% of ED cases turn out to be MF/T-cell neoplasia.
    1. medication reaction: ACE inhibitors, dilantin [LMC-05-8525].
    2. mycosis fungoides (l'homme rouge refers to ED that is secondary to cutaneous T-cell lymphoma).
    3. malignant: as a reflection of internal malignancies.
    4. idiopathic erythroderma: elevated serum IgE levels, dermatopathic lymphadenopathy, & marked palmar plantar keratoderma.
    5. atopic dermatitis.
    6. seborrheic dermatitis.
    7. staphylococcal scalded skin syndrome.
    8. rare instances of pemphigus foliaceus.
    9. hereditary ichthyosis.
    10. contact dermatitis.
    11. psoriasis (usually no islands of spared skin when ED)[L07-1996].
    12. pityriasis rubra pilaris (PRP): resembles psoriasis clinically and histologically (but no loss of granular layer & no suprapapillary thinning & no clusters of polys) but when as ED, tends to have some islands of skin sparing. HERE.
    13. GVH may present with widespread macular erythema.
  • Koebner's phenomenon: situation of skin trauma inducing a dermatosis lesion (also so-called "isomorphic phenomenon") at the trauma site (seen in 33% of psoriasis; also LS & A, eczema, lichen planus, and vitiligo) usually within 10-14 days (but between 3 days and 2 years after the trauma)27 [S-06-6799].
  • Bites or sores: if worried about a spider bite, also think of a MRSA lesion of skin.

Histological Differential Diagnosis Groups:

  • superficial perivascular dermatidities devoid of epidermal involvement:
    1. incipiently early stage of pityriasis lichenoides acuta (eruptive lesions of Mucha-Habermann disease...PLEVA)22: lymphocytes around at least the venules of superficial plexus & along the interface along with vacuolar alteration plus necrotic keratinocytes plus parakeratosis. Specificity added if affects deeply also & the infiltrate is wedged shaped, & there are some balooned keratinocytes & there are some polys in the parakeratosis.
    2. incipient stage of erythema multiforme22: lymphocytes around at least the venules of superficial plexus & along the interface along with vacuolar alteration plus necrotic keratinocytes & negative for parakeratosis.
    3. incipient stage of psoriasis22: superficial perivascular mostly lymphocytic infiltrate, dilated tortuous dermal papillary capillaries & mounds of parakeratosis housing polys.
    4. "dermal contact": superficial coatsleeve perivascular lymphocytosis11.
  • satellite-cell necrosis (dead, necrotic keratocyte surrounded by mononuclears):
    1. TEN.
    2. acute GVH.
  • necrotic keratinocytes: these apoptotic cells will often be associated with pre-necrotic balooned keratinocytes & the necrotic ones tend to attract polys. Seen in EM, PLEVA, fixed drug, irritant, and phototoxic dermatitis1; and in lichen planopilaris15, GVH, and in perioral dermatitis [or was the case lupus?...S-04-1328021]. PLEVA may cause a sharply discrete small lesion (hardly ever larger than a low power microscopic field) of epidermal necrosis with adjacent epidermis nearly completely lacking in reactive change [S06-15582].
    1. epidermal reticular or vesicular degeneration of keratocytes:
      • viral exanthem (cell contents seem lost)
      • acute eczematous dermatitis (nuclei or partial cell contents noted)
      • epidermolytic hyperkeratosis
    2. epidermal spongiotic vesicular degeneration:
      • clue to insect bite is multiloculated vesicle whose locules decrease in size away from lesion center22.
    3. epidermal acantholytic vesicular degeneration:
      • acantholysis is a hallmark of pemphigus (but biopsies of very early pemphigus lesions may show only what appears to be spongiosis with polys & eos.).
  • intraepidermal/peri-epidermal neutrophiles:
    1. intraepidermal polys:
      • dermatophytosis or superficial bacteriosis
      • intra-epidermal neutrophilic dermatosis (IEN)
      • toxic shock syndrome
      • superficial pyoderma with intra-epidermal polys/pustules
    2. pustules...pustulosis: some more DDX HERE.
      • subcorneal pustular dermatosis (SPD).
      • bites...especially fire ant bites.
      • halogenoderma: (especially bromides) lesions usually of lower extremities and have pseudocarcinomatous downward epidermal growth containing pustules5.
      • infected eczematous dishydrosis.
      • pustular psoriasis5: a key diagnostic finding is polys layered (dried Kogoj's pustule-like perimeter...see DDX) between keratocytes at perimeter of pustule [L07-2586]23; the following 3 are the same with different presentations...
        1. pustular psoriasis of Zumbusch: when outbreak is in a background of clinical psoriasis.
        2. impetigo herpetiformis: hypocalcemia setting...an uncommon pustular dermatosis that typically occurs during pregnancy (or after loss of parathyroids) with sudden onset of severely pruritic erythema and pustules that, within days to weeks, become erythematosquamous plaques bordered by tiny pustules  scattered on  trunk and extremities (pustules may be spongiotic).
        3. acrodermatitis continua of Hallopeau: affecting only hands & feet (dermatitis repens a broader synonym) & like a mix of acral psoriasis and pyoderma.
        4. see pustulosis palmaris et plantaris, just below.
        5. see SAPHO via above.(or HERE)
      • acute generalized exanthemous pustulosis (AGEP): often a drug eruption; predilection for distal extremities; may have leukocytoclastic vasculitis.
      • subcorneal pustulosis like drug eruption: [S-02-10387...subsequently found to have drug-induced hepatitis with skin & liver clearing on stopping the drug; L07-2485].
      • pustulosis palmaris et plantaris: may not be a variant of psoriasis though some call it a variant of pustular psoriasis; is a deep epidermal unilocular pustule [S07-3373] & underlying dermis with chronic infiltrate & a few polys5.
      • IgG pemphigus herpetiformis, see below.
      • IgA vesicopustular dermatosis (IAVPD) (or "intra-epidermal IgA pustulosis", "IgA pemphigus", "intraepidermal neutrophilic IgA dermatosis", "IgA herpetiform pemphigus", "subcorneal pustular dermatosis with IgA deposition") : 
        1. intra-epidermal neutrophilic (IEN) dermatosis type: polys accumulate in papillae, then into epidermis, then form intra-epidermal pustules [S-01-10098].
        2. subcorneal pustular dermatosis (SPD) type: superficial epidermal pustule formation and pemphigus-like DIF.
    3. spongiform pustules (spongiosis-derived vesiculation):
      • pustular psoriasis (acrodermatitis continua; impetigo herpetiformis...see above, "pustules")...spongiform pustule of Kogoj (superficial keratinocytes get severely edematous and polys get into them and yet the cell walls form a mesh that breaks down as too many polys accumulate)5. Psoriasis HERE.
      • pustular contact dermatotis.
      • AGEP = Acute Generalized Exanthematous Pustulosis (AGEP) is a drug-induced dermatosis characterized by an acute episode of sterile pustules over erythematous-edematous skin.
      • Reiter's disease: pustules of glands penis, palms, soles & histology psoriatic5.
      • rheumatoid neutrophilic dermatitis (RND): severe RA cases, extensor surface papules, plaques, (rarely) vesicles and dermal polys without vasculitis and poly micro-abscesses of papillae.
      • vesicopustular eruption of ulcerative colitis: intraepidermal & subcorneal pustular foci and a linear BMZ IgG.
      • very superficial dermatophytosis.
      • subcorneal pustular dermatosis.
      • palmoplantar pustulosis.
      • eczematous dermatitis with impetiginization.
      • id reaction: autoeczematization or autosensitization is about complicating lesions at a distance from a primary inciting lesion, HERE.
      • dermatitis herpetiformis occasionally has spongiform pustules.
      • IgA pemphigus
      • herpetiform pemphigus
      • infantile acral putulosis
      • secondarily infected pemphigus foliaceous.
  • peri-epidermal/papillary dermal polys:
    1. dermatitis herpetiformis (DH): polys at papillary tips and DIF may be positive for IgA at same location (it may take serial stepcut sections to demonstrate...we have found the H&E polys focally & DIF negative).
    2. Sweet's syndrome of febrile neutrophilic dermatosis (be it classical [CSS]...idiopathic; parainflammatory; pregnancy associated; malignancy associated [MASS] paraneoplastic; or drug induced [DISS])57; the pathognomic histopathologic characteristic is the presence of dense infiltrate mainly comprised of mature neutrophils located primarily in the upper and mid dermis; see below.
    3. acute lupus.
    4. intra-epidermal neutrophilic dermatosis type of IAVPD.
    5. ? [S-02-8081 8y/o.
    6. deeper polys = see LCV & cellulitis HERE.
  • Intraepidermal lymphocytes:
    1. exocytosis: allergic contact, eczema [S09-3887] vs.PLC, lichenoid interface, etc.
      • without epidermal "reaction":
        1. PLC (guttate parapsoriasis): 3 features11...
          • lesion almost never larger than a 4x low power wide field.
          • thin parakeratotic scale is flat & adherred & without slits or almost all lifted off.
          • epidermis is otherwise "passive" as it suffers invasion of lymphocytes
      • with epidermal "reaction":
        1. eczema: usually spongiotic & with or without exocytosis.
        2. allergic contact:
          • dermal contact: normal epidermis over dermis with coat-sleeve, compacted perivascular lymphocytes of superficial vessels.
          • usual contact: spongiosis plus exocytosis plus superficial perivascular lymphocytosis.
    2. epidermotropism: mycosis fungoides (MF); Pautrier's non-spongiotic "microabscesses"; lymphs along the basal layer; lymphs with clear perinuclear halo, grooved convoluted nuclei. Lymphs & nuclei bigger than nuclei of dermal lymphs22.
  • spongiotic epidermis:
    1. nonspecific spongiosis:
    2. pregnancy prurigo: biopsy has nonspecific low-grade spongiosis, usually in 3rd trimester; pruritic dermatoses of pregnancy.
    3. miliarial spongiosis: "heat rash"...blocked sweat outlets
      • milaria crystallina (stratum corneum)...essentially asymptomatic
      • milaria rubra
      • milaria profunda (DEJ focus/emphasis)
    4. follicular, infundibular spongiosis:
      • atopic dermatitis (the follicular lesions)
      • infundibulofolliculitis
      • eosinophilic folliculitis (Ofuji's disease)
    5. neutrophilic (polys) spongiosis:
      • pustular psoriasis
      • other causes of spongioform pustules, above
    6. eosinophilic spongiosis:
      • allergic contact: look for dyskeratotic cells & absence of pigment incontinence
      • herpes gestationis (pemphigoid gestationis): papillary dermal eos early & vacuolar basal cells followed by subepidermal vesicle which has lots of eos.; pruritic dermatoses of pregnancy.
      • drug reaction: more likely mixed cellularity
      • arthropod bite: epidermis-to-dermis wedged-shaped lesion
      • atopic dermatitis
      • id reaction: autoeczematization or autosensitization may include tiny foci of lichenoid inflammation [S09-1103] & is about complicating lesions at a distance from a primary inciting lesion such as dermatophytosis (and ticks, bacteria, mycobacteria, m. contagiosum, scabies, etc.), contact dermatitis lesion[S09-1103], stasis dermatitis [S11-3852], and possibly other primary lesions.
      • early bullous pemphigoid (BP): intensely pruritic subepidermal cleft & dermal eos plus polys
      • early pemphigus vulgaris: look for acantholysis...especially perifollicular
      • pemphigus vegetans: epidermal thickening plus eosinophil and/or neutrophil abcesses
      • scabes
      • early incontinentia pigmenti (pigmentosus): eos plus dyskeratotic cells 7 then pigment incontinence
      • early PUPPP: pruritic dermatoses of pregnancy.
      • eosinophilic folliculitis (Ofuji's disease)
      • eosinophilic, polymorphic, and pruritic erruption
  • Interface dermatitis, basal-layer vacuolar dominant24:
    1. lymphocytes nearly monopolize:
      • with vacuolar basal cell ballooning and necrotic keratocytes with some entities:
        1. (EM) erythema multiforme: cornified layer usually normal.
        2. various lupus types and mixed connective tissue disease (& may have in vivo DIF ANA positivity with IgG...see DIF below).
        3. Disseminated idiopathic or actinic porokeratosis has [a] vacuolar interface action at the periphery along with light superficial dermal lymphocytes where one might see the cornoid lamella and [b] central atrophy with slight orthokeratotic hyperkeratosis23.
        4. Mucha-Habermann disease: parakeratosis often.
        5. graft vs. host (GVH) lesion.
        6. paraneoplastic pemphigus.
        7. HSV infection.
        8. as a morphologic effect when nitrogen mustard placed on MF lesion.
      • no ballooning of keratocytes:
        1. discoid lupus.
        2. dermatomyositis (unless maybe an overlap dermatitis [S13-568]).
        3. drug eruption, one type.
        4. LS&A (superficial morphea):look for superficial dermal sclerosis.
        5. postinflammatory pigment alteration (NOS etiology of the inflammation).
    2. mixed lymphocytes plus polys and eosinophiles:
      • fixed drug eruption.
    3. a few eos & a little spongiosis:
  • Interface dermatitis, dermo-epidermal junction, lichenoid inflammatory cell blurring dominant24:
    1. lymphocytes predominate:
      • lichen planus: compact orthokeratosis over the lines of wedged hypergranuloisis with apoptotic basal keratocytes and Civatte bodies...and can have a sort of pseudoepitheliomatous hypertrophic "look" [S07-3105]; no parakeratosis unless new erruptive lesion [S-06-13280]; beware of LP-like keratoses, both actinic & non-actinic; beware of drug-induced LP-like eruption if see eosinophils & plasma cells...or deeper dermal extension of infiltrate from interface with or without co-expression of the eos and plasma cells 21. Can be pruritic. Wickham's stria, striae, are naked-eye-visible net-like white inter-papular (LP is coalesced papules) lines on skin lesions, oral lips, & buccal mucosal lesions and are thin ridges of compact orthokeratosis above zones of wedged hypergranulosis23, 25...nearly specific for LP type of reaction, whether idiopathic or drug or photo induced (can see a microscopic "picture" of it...pseudo-Wickham's dyskeratosis...in a lichenoid actinic keratosis [S08-16022]). May be the deciding clue or only clue in bullous LP (too acute to have the BMZ lichenoid stuff), standard polygonal papules, persistently rubbed plaques (hypertrophic LP), follicular lesions (lichen planopilaris), & resolved macules (atrophic LP) & the hypergranular foci may be seen in intradermal follicles (acrotrichia) & eccrine ducts (acrosyringia)23. DIF can be helpful [S10-11310].
      • lichenoid drug eruption: tends to extend deeper; ACE inhibitors cause.
      • lichenoid photodermatitis.
      • DLE.
      • Mucha-Haberman disease.
      • lichen striatus.
      • GVH reaction/eruption of lymphocyte recovery...late lesions LP-like.
      • lichenoid purpura of Gougerot & Blum (lichen aureus) = longstanding lesions may have wiry collagen22 (and so may other longstanding lichenified lesions22), wiry collagen tending to be a clue to MF, otherwise. Dr. Ackerman has noted that the finding of “wiry collagen” can be a tip off to cases that need follow-up as possible MF (CTCL) [S10-11507...S14-449; S13-2154; S13-3075; S14-53]. But, it may be seen in other instances such as a chronic eczematous lesion of the breast nipple [S09-14044] or chronic allergic contact dermatitis lesions or chronic atopic dermatitis [S09-9799].
      • LP-like keratosis.
      • Gottron's lesions of dermatomyositis: the pathognomonic eruptions of dermatomyositis are Gottrons papules which occur over bony prominences of the hands and elbows, and the violaceous heliotrope eruption on the eyelids23. Gottron's papules = hyperkeratosis & LP-like interface change & clustered, numerous cytoid bodies of papillary dermis by DIF [S09-2138].
      • disseminated superficial porokeratosis (idiopathic or actinic), early: these herald lesions (and some non-herald actinic keratosis lesions [S08-16022]) have the porokeratotic "cornoid lamella" of a narrow parakeratotic keratosis ridge over a matching, degranulated underlying zone in a hypergranulated epidermal garnular zone; they may be found in cases which are clinically dermatomyositis but without muscle symptoms, possibly as an overlap dermatiditie [S13-568].
      • MF, plague: wiry collagen (papillary dermal thickening by wiry collagen... wiry bundles of haphazard collagen within a lichenoid infiltrate22) in mycosis fungoides usually22; may have melanophages &, when unilesional [S-06-10521], may be treatable with EBT superficial radiation. Other "wiry collagen" causes HERE.
    2. lymphocytes & abnormal lymphs plus polys & eos: lymphomatoid papulosis.
    3. lymphocytes & histiocytes:
      • lichen nitidus: usually a rash of asymptomatic small bland papules raising the junction (classical histology with cross-section in center of papule is "claw clutching a ball"). Usually in children. Unlikely to see biopsy unless papules tend in linear or generalized pattern, or with keratodermic, petechial, vesicular-hemorrhagic features. Case example/photo here.
      • lichen striatus.
      • sarcoidosis.
    4. Langerhan's cells predominate: Letterer-Siwe disease.
  • Dermal deposits & pigments:
    1. calcium deposits: "calcinosis cutis"
      • dystrophic: seen in cysts and in connective tissue injured as sequel to connective tissue disease, etc.
      • metastatic: seen in cases with hypercalcemia and or hyperphosphatemia...as nodules and sometimes causing vascular lesions that induce thrombosis (calcphylaxis).
      • idiopathic:
        1. "calcinosis universalis": nodules remindful of metastatic calcinosis.
        2. "idiopathic calcinosis": solitary calculus like nodule.
        3. "localized idiopathic dermal calcinosis": a nodule & can be oral.
        4. "tumoral calcinosis": skin deposits and over prominences [S07-9926].
        5. "scrotal calcinosis": is now believed to be a dystropic lesion related to cystic skin adnexal obstruction.
    2. inapparent eosinophilic bodies by H&E: macular amyloidosis; actinic bodies.
    3. easily apparent eosinophilic bodies by H&E: Civatte bodies of lichen planus.
    4. grey, often thickly fibrillar: actinic elastosis.
    5. rounded brownish grey bodies: acquired localized ochronosis (ALO) [S07-3037].
    6. patchy yellow or brown collagen discoloration: leprosy drug, cofazimine (also used in SLE, pyoderma gangrenosum, & Melkersson-Rosenthal syndrome23).
    7. brown pigment macrophages:
      • melanophages: finely granular & iron-stain negative. Indicates epidermal basal cell pigment incontinence & likelhood of an interface dermatitic etiology.
      • siderophages: more coarsely granular & a little golden brown by H&E & iron stain positive. May be throughout dermis [FA13-129]. Implies recurrent hemorrhage from venous hypertension (stasis) or vessel injury: pigmented purpuric dermatoses (Schamberg disease or dermatosis when affects lower extremities [ie, progressive pigmentary dermatosis, to include "itching purpura" & eczematid like purpura of Doucas and Kapetanakis], purpura annularis telangiectodes [Majocchi disease], lichen aureus [localized pigment lesions], and the pigmented purpuric lichenoid dermatosis of Gougerot and Blum). The common stasis dermatitis siderotic dermatosis [S10-13180, FA13-129] is Schamberg [DDX HERE]...check photo.
  • Superficial dermal eosinophiles (nearly normal epidermis):
    1. urticarial drug eruption (tends to have some admixed polys8).
    2. urticarial pemphigoid (tend to have a little eosinophile exocytosis and focal pre-subepidermal-cleavage vacuolar interface change). Such early change may preceed the disease progression to full-blown vesicular pemphigoid & patients may have thought they had bites37.
    3. allergic contact (almost always spongiotic).
    4. insect bite (fully-expressed have wedged-shaped profile, tending deeper).
    5. itchy red bump disease: edematous papules which may seem DH-like8.
    6. papular urticaria.
    7. scabies.
    8. creeping eruption (larva migrans).
  • Nodules and plaques rich in eosinophiles:
    1. bite reaction.
    2. lymphocytoma cutis of Lyme disease [S-06-12219], and see below.
  • Nodules and plaques rich in lymphocytes and or plasma cells: lymphocytoma cutis which are mostly idiopathic but may be a reaction to tattoo dye, jewelry (especially gold), bites, medications, folliculitis, vaccinations, acupuncture, or infection (molluscum contagiosum & Lyme disease Borrelia burgdorferi)15. Maybe also luetic or actinic when heavily plasma cells.
  • Intraepidermal eosinophiles:
    1. eosinophile dominant pemphigus herpetiformis, see below
  • Eosinophile spongiform "pustules" vs. microabscesses:
    1. pemphigus vegetans, Hallopeau type: eos. microabscesses [S-03-14127] &/or neutrophil microabscesses; Neumann type has intraepidermal vesicles and flaccid bullae and suprabasalar acantholysis & erosions, but not eos. microabscesses. (DIF positive in both; lesions typically intertrigenous and/or oral...nearly 100% have oral involvement, including the "cerebriform tongue").
    2. allergic contact (also increased lymphs and Langerhans cells).
    3. itchy red bump disease.
    4. insect bite.
    5. incontinentia pigmenti.
    6. urticarial pemphigoid (rare).
    7. dermatitis herpetiformis (mixed, polys>eos).
  • small vessel thrombi:
    1. bland fibrin thrombi: in lumens but not venule walls = DIC, TTP; coumarin necrosis [S07-9798].
    2. insect bite associated: clearly within a wedge-shaped bite reaction.
    3. fibrin in venule lumens and venule walls: livedo vasculitis or vasculopathy.
  • vasculitis histology DDX groups:[various entities HERE]
    1. Livido, livedoid, atrophie blanche23: these are physical diagnosis terms with vasculopathy implications
      • physiologic livido reticularis: a response to coldness & more common in women & children & consisting of complete rings of non-fixed skin vsacular color change..
      • secondary livido reticularis (cutis marmorata): if the rings are essentiallyb complete, it is livido reticularis; livido racemosa when broken or incomplete rings (this is not physiologic). It is livedoid vasculopathy when there is some frank, associated purpura, necrosis and/or punched-out ulcerations occur within the livedo pattern and can be primary or secondary & is due to lumen occlusion.
    2. leukocytoclastic vasculitis (LCV): polys with "nuclear dust" involving dermis & small dermal vessels, one variant being urticarial vasculitis (venulitis & vasculitic component may be very subtle amidst copious polys of what almost looks like dermal suppuration...urticarial here). DDX = serious acute cellulitis is unlikely to be biopsied and can have deceptively scant dermal polys.
    3. lymphocytic vasculitis26: (be sure to not confuse with lymphocytic perivasculitis)
      • venular with ordinary, typical lymphocytic vasculitis:
        1. without promininent extravascular pathology:
          • one type of drug eruption [S07-1562]. It may be hard to seperate this from the tight, coat-sleeve perivascular lymphocytosis of erythema annulare centrifugum (EAC) or from "dermal contact sensitivity".

          • perniosis
          • rickettsial lesion
          • allograft rejection
          • idiopathic
          • livedo vasculopathy, sometimes; usually/often thrombi.
          • Behqet's disease
          • collagen vascular disease
          • resolving leukocytoclastic vasculitis
        2. with interface dermatitis:
          • perniosis
          • perniosis-like LE
          • Behqet's disease
          • herpetic dermatitis
          • PL et VA
        3. with balooning degeneration: hydroa vacciniforme
        4. with psoriasiform epidermal hyperplasia, spongiosis, or focal epidermal necrosis:
          1. sting or bite reactions
          2. scabietic nodules
        5. with extravascular necrosis:
          1. papulonecrotic tuberculid
          2. rickettsial lesion
        6. with panniculitis:
          1. lupus panniculitis
          2. perniosis
          3. pyoderma gangrenosum (uncommonly)...steroid responsive
      • venular with lymphocytic vasculitis by atypical lymphocytes:
        1. lymphomatoid papulosis
        2. mycosis fungoides (rarely)
    4. mural fibrin or fibrinoid necrosis:
    5. thrombotic:
    6. embolic:
  • Granulomatous (HERE): if granulomatous lesions are in a skin lesion associated with central depigmentation & central hypesthesia & granulomas track cutaneous nerve twigs, think tuberculoid or dimorphic leprosy [S08-16360] (very hard to DX because our AFB stain requires an organism concentration at least as high as about 107 bacilli per gram of tissue; serum antigen tests are said to be available; a serological test, IgM PGL-1, is said in late 2008 to hold promise; DNA by PCR is available35)!!
  • Panniculitis:
    1. pattern:
      • septal: erythema nodosum or subacute nodular migratory panniculitis (scleroderma).
      • lobular and/or mixed septal plus lobular:
        1. vasculitis and connective tissue diseases: lupus vs. e. induratum vs. etc.
        2. metabolic: alpha-1 AT deficiency vs. altered fat melting point vs. pancreatic
        3. traumatic type
        4. infectious associated
        5. malignancy associated
        6. lipodystrophy
    2. malignant associated, implied:
      • atypical lymphocytic lobular panniculitis (ALLP)[L08-12332].
    1. nonmalignant associated implications:
      • neutrophilic47:
        1. lobular:
          1. no vascular damage:
            1. with enzymatic fat necrosis = pancreatic panniculitis
            2. floating fat; splaying of polys in reticular dermis = alpha-1 AT deficient panniculitis
            3. foreign bodies, blood, pseudocyst = factitial panniculitis
            4. leukocytoclasis = subcutaneous Sweet syndrome of febrile neutrophilic dermatosis (be it idiopathic, drug induced, or paraneoplastic)57.
          2. vascular damage present:
            1. no basophilic necrosis or granulomata; Hx of RA = neutrophilic panniculitis of RA.
            2. has basophilic necrosis and/or granulomata:
              1. (+) cultures or special stains/studies = infective panniculitis
              2. (-) cultures or special stains/studies:
                1. but, (+) PPD = erythema induratum
                2. (-) PPD:
                  1. has distant infection: = panniculitis bacterid
                  2. history RA = RA associated panniculitis
        2. septal :
          1. no vascular damage:
            1. has Meischer radial granuloma = early erythema nodosum
            2. no Meischer:
              1. no pancreatic disease = subcutaneous Sweet syndrome
              2. has pancreatic disease = early pancreatic panniculitis
          2. vascular damage = early erythema nodosum (rare)
        3. mixed:
          1. no vascular damage = subcutaneous Sweet syndrome
          2. vascular damage = see above, same as lobular with vascular damage.
      • eosinophilic:
      • lymphocytic:

Direct Immunofluorescent (DIF contribution to diagnosis) patterns28:
(older lesions can lose immunodeposits and be "false negative"; specimen selection = see biopsy site and immuno-dynamics notes)

Click ***HERE*** For Blistering Emergencies Table

This use of cutaneous microscopic histomorpholgical immuno-techniques searches for the presence of auto-antibodies, whether compliment-fixed or not (immune-comlexed), lodged at various sites in the patient's own skin. Sometimes & in some situations, immune complexes generated elsewhere get caught in the epidermal BMZ. The reagents are antibodies against IgG, IgA, IgM, C3, and fibrinogen. Various of these components can degrade rapidly in-vivo and ex-vivo (the transport medium attempts to retard degradation).

  • epidermal keratocyte speckled nuclear positivity6: when seen, especially if the in vivo ANA is IgG specific & with or without BMZ granular positivity for C3, it may indicate MCTD or lupus (or some other connective tissue disease) [S07-1538; L11-11282].
  • pericellular epithelial (chickenwire)18 :
    1. various types of pemphigus.
    2. burn cases.
    3. SLE.
    4. overlap with pemphigoid.
    5. rheumatoid arthritis.
    6. some other skin diseases.
  • around intra-epidermal clusters of polys: IgG, IgA, & C3 in this pattern may indicate psoriasis (is a psoriatic pattern) [S-07-302].
  • keratinocyte cytoplasm: (tend to see in diseases causing apoptotic or necrotic keratocytes...EM/TEN & maybe fixed drug).
    1. predominately basal cells: TEN-type pattern [S-06-12011, S-07-1189].
    2. other epidermal distributions: if marked by just one DIF agent, think of some medication effect; and if multi-agent positive, think of the EM-SJS-TEN spectrum.
  • basement membrane zone (BMZ):
    1. linear: (implies antibody attacking a BMZ component).
      • bullous pemphigoid: target of disease antibody BP180 & BP230 [LMC-04-5899 IFA & DIF neg.].
      • linear IgA dermatosis (atypical DH).
      • some cases of herpes gestationes.
      • EBA: antibody target is collagen IV on dermal side of BMZ.
      • bullous SLE, some cases.
    2. granular: (implies immune-complex deposition in BMZ)
      • lupus most likely when at least IgG & C3 strongly positive.
      • positive lupus band test: deposits of IgG, IgM, IgA or all three strongly in nonlesional, non-facial, sunprotected skin is highly suggestive of SLE.
      • actinic IgM only, especially if not all that strong, can be just an artifact of actinic exposure or can be seen as a nonspecific finding in biopsies of many other disorders.
      • can't r/o some subtle, background, underlying connective tissue disease.
    3. combinations:
      • pericellular plus BMZ: 
        1. paraneoplastic pemphigus (especially in Waldenström's, non-Hodgkin lymphoma, and CLL)18.
        2. herpes gestationes.
        3. pemphigus-BP overlap.
      • linear BMZ and sweat gland BMZ:
        1. cicatricial pemphigoid, skin Bx [S-04-14973].
        2. PCT, see below...can be vascular, too.
      • BMZ plus vascular (except for lupus, the BMZ deposits tend to be weak and focal):
        1. PCT (vascular deposits tend much heavier than BMZ & greater in superficial vessels)...mainly IgG, C3, and fibrin.
        2. lupus (BMZ staining tends to be much more prominent than vascular).
        3. acute & chronic GVH lesions ...mainly IgM, C3, and fibrin.
        4. rheumatoid arthritis...mainly IgM, C3, and fibrin.
        5. allergic vasculitis...mainly IgM, C3, and fibrin.
        6. urticarial vasculitis (leukocytoclastic)...mainly IgM, C3, and fibrin.
        7. granuloma annulare...mainly IgM, C3, and fibrin.
        8. necrobiosis lipoidica diabeticorum...mainly IgM, C3, and fibrin.
        9. fresh lesions of pityriasis lichenoides...mainly IgM, C3, and fibrin.
        10. cutaneous sarcoidosis...mainly IgM, C3, and fibrin.
        11. erythema multiforme...mainly IgM, C3, and fibrin.
        12. arthritis-dermatitis syndrome assoc. with intestinal bypass surgery...mainly IgM, C3, and fibrin.
        13. skin trauma (appearing 1-10 days later)...diffuse granular mainly IgM, C3, and fibrin.
        14. sun-exposed areas in healthy individuals...mainly IgM, C3, and fibrin.
    4. globular BMZ and superficial dermal:
      • in small numbers: found in plain actinic skin as well as apparently incidentally in many dermatoses.
      • in myriad numbers: lichen planus [S08-16663]; Gottron's lesions of dermatomyositis.
    5. shaggy BMZ positivity: especially fibrinogen can be heavy &, though concentrated at the BMZ, it trails into the underlying lichenoid cellularity [S10-11310]. this is seen in LP, licehnoid drug erruption, and lichenoid photodermatitis.
  • dermal collagen:
    1. actinic elastosis autofluorescence.
    2. IgM: macroglobulinemia cutis [S10-4995].
    3. any single agent: possible anti-collagen antibody deposits as with RA.
  • dermal vessels, mural positivity:
    1. vasculitis...& deposits may "be there" before any good H&E changes; H-S purpura primarily IgA & C3 [S07-11104]; vessels around lesions of Berger's may be IgA & C3 positive28.
    2. PCT: IgG, C3, fibrin...and see positivity site combinations, above.
    3. nonspecific "inflammatory" positivity.
    4. may see DIF deposits in vessels in: pyoderma gangrenosum (steroid responsive), angioimmunoblastic lymphadenopathy, angiolymphoid hyperplasia with eosinophilia, Well's syndrome (recurrent granulomatous dermatitis with eosinophilia), diabetes mellitis associated with bullous eruptions, and lepromatous Lucio's phenomenon28.
    5. Stasis dermatitis: fibrinogen +.
  • dermal vessel endothelial cells: fibrinogen only pos [S09-1981].

IFA-type global anti-skin antibodies (ASA) on human skin or monkey esophagus substrate30:
In addition to using "test-tube tests" for highly specific auto-antibodies to precise antigenic components of skin, one can use global IFA tests with endpoint reaction visible using the fluorescent microscope within human skin or classical monkey esophagus substrate. This test looks for a different line of immunological evidence: does the patient have any detectible level of circulating autoantibodies targeting against any components of their epidermal membrane (epithelial plus BMZ components)? See ARUP serology, HERE; and ARUP DDX chart, HERE.

  • anti-epidermal antibodies28 and associated intraepidermal cleaveage plane:
    1. pemphigus-type auto-antibodies to inter-epithelial adhesion components.
    2. PV-like & seen in some cases of bullous pemphigoid.
    3. PV-like & seen in some cases of cicatricial pemphigoid.
    4. PV-like & due to blood group antibody reactions.
    5. PV-like & due to thermal burns.
    6. PV-like & assoc. w/ TEN.
    7. PV-like & assoc. w/ T. rubrum infection.
    8. PV-like & assoc. w/ certain bullous drug eruptions.
    9. PV-like & assoc. w/ Darier's disease.
    10. PV-like & assoc. w/ bullous mycosis fungoides.
    11. PV-like & assoc. w/ bullous impetigo.
    12. PV-like in an abdominal pain work up for celiac serology & also had antibody to endothelium (AECA) [CP09-9].
  • anti-nuclear antibodies28: in a nonspecific, global fashion, this IFA test using HEp-2 substrate may pick up any of a variety of circulating ANAs...a number of which do not show up in commercial-lab style test-tube IFA ANA tests.
  • anti-basement-membrane-zone (anti-BMZ) antibodies28 and associated subepidermal blister cleaveage plane:
    1. bullous pemphigoid-type BMZ antibodies...BP180 & BP230...(70% of BP cases & IgG & likely high titer & antigen high in lamina lucida).
    2. cicatricial pemphigoid (likely low titer & high in lamina lucida).
    3. herpes gestationis (C3 and/or IgG...likely low titer & lamina lucida).
    4. EBA-type BMZ antibodies(likely low titer & lamina densa or just deep to it); split skin IFA labels dermal aspect; anticollagen sero-positivity.
    5. lupus-type BMZ antibodies as in bullous eruption of SLE (BESLE) (likely low titer & lamina densa or just deep to it); split skin IFA labels dermal; anticollagen VII seropositivity & may have some BP180 positivity but not BP230.
    6. DH-type BMZ antibodies (IgA)
  • epidermal cytoplasmic antibodies28:
    1. against all epidermal layers: assoc. w/ nonbullous dermatoses; often in patients w/ neoplasms.
    2. against upper & middle layers: assoc. w/ bullous dermatoses; often in patients w/ neoplasms.
    3. against basal-only layer: assoc. w/ medications, pemphigus, pemphigoid.
  • DISEASE ENTITIES:

  • Stasis dermatitis (dermopathy, dermatosis), typical & complicated:
    1. simple & typical: papillary dermis papillae broadened due to non-delicately over-expressed & a little thickened vessels and maybe some associated nonspecific chronic inflammation plus some melanophages and maybe even some siderophages & maybe a little epidermal hyperplasia, acanthosis & hyperkeratosis.
    2. with petechial hemorrhages: biopsies may be on an inpatient & with concern for septic or other vasculitis...hemorrhage plus typical changes. This can lead to prominent accumulations of siderophages, especially including deeper dermis [S10-13180].
    3. pseudo-Kaposi sarcomatous "acral angiodermatitis" [S06-3532; S09-2297]: vascular proliferative component is prominent enough to give pause to consider KS.
    4. dramatically acute stasis dermatitis [LMC-04-7886] or acute phase on chronic [S01-8706, L08-10663].
    5. vesicular or bullous stasis dermatitis (stasis vessels may be strongly positive for fibrinogen [L07-3526]).
    6. stasis change plus scleredematous dermal scarring: stasis plus chronic venous and/or lymphatic insufficiency ("woody").
    7. stasis PLUS any of the other (above) complicating coagulopathies , endotheliopathies, and drug eruptions.
  • Vesicular (blistering...bullous...Dermatitis or Dermatosis Outline, HISTOLOGY: It is greatly helpful to (1) shave remove an early, mature blister into 10% NBF formalin for routine H&E and special stains such as d-PAS, (2) punch biopsy surrounding skin no further than 1.5 cm from blister into holding fluid for special DIF studies, and (3) draw a pre-steroid-therapy blood sample for serum antibodies workup & split skin IFA (Euroimmune's ANA patterns DDX chart; ARUP's ANA results DDX chart, HERE; and ARUP's skin autoantibodies results chart, HERE and HERE). In general most drug eruptions50 have a combination of several Ackerman DDX patterns. Drug-induced dermatoses look like the specific dermatosis (for example: drug-induced linear IgA, pemphuigus, and lupus. With the initial H&E slides of the blister, there should also be a d-PAS stain to help discern whether subepidermal cleaveage is just above, within, or just below the basement membrane zone (BMZ)--
    1. Intraepidermal:
      • spongiosis:
      • balooning:
      • acantholysis:
      • cleaving:
        1. mid-upper spinous/granular:
          • friction blister: lighter friction cleaves here & can be factitial (bullous dermatitis artifacta [bullous pathomimia]).
          • Epidermolysis bullosa (EB), Weber-Cockayne type: localized & onset as child or later and seems related to strenuous physical activity.
        2. suprabasalar: EB simplex, onset very early in life; cleaves within the basal cell layer & not beneath it1.
    2. Subepidermal49, : the d-PAS stain marks lamina densa & can really help in discerning the cleaveage line; the BMZ can be split (1) through the lamina lucida (beneath basal cells) with BP antigen superficial & laminin less superficial, (2) through the lamina densa (mid-BMZ) made of type IV collagen, and (3) the deeper sub-lamina dense zone made up of anchoring fibrils mixing through EBA antigen & endomysial proteins. Most subepidermal drug eruptions have evidence of interface vacuolar change with keratinocyte necrosis there & no eos. at bulla edge (but some have linear IgA chnages or intense papillary edema leading to the blister)50. I will place an asterisk (*) by those which are caused by autoimmune antibodies.
      • no or scant inflammatory cells: [see HERE, too]
        1. epidermolysis bullosa, junctional: onset at birth and seems by electron microscopy to cleave in the lamina lucida1.
        2. epidermolysis bullosa, dystrophic (both dominant & recessive types): infancy & early childhood for dominant & at birth for recessive.
        3. epidermolysis bullosa acquisita (EBA), noninflammatory type*, & dermolytic (dystrophic) EB all onset very early in life]: Clin = adult onset & tends skin above joints & trauma realted 1 & can affect mucosa; H&E = paucicellular; electron microscopy shows cleaveage below lamina densa1; d-PAS stain shows split in BMZ with positivity in roof51; DIF = linear continuous BMZ+; serology = collagen VII antibodies present; with split skin IFA tests, marking is dermal.
        4. Hypoxemia followed by pressure on the skin site:
        5. Severe erythema multiforme (EM) (spectrum EM, SJS, TEN, adult): Clin = rare; H&E = ; DIF = ; serology = ;
        6. Bullous pemphigoid (BP), cell poor*: H&E = cleaveage with scant infl. cells & cleavage does not extend into hair follicles1; DIF = linear continuous BMZ+; serology = 80% pos. for BP230 (BPag 1) and/or BP180 (BPag2); with split skin IFA tests, marking is epidermal or combined epidermal and dermal.
        7. BP and pemphigus overlap: see DIF, above, about both perikeratinocytic and BMZ marking.
        8. Porphyria (PCT; varigate; erythropoietic; drug induced and dialysis induced; hepatoerythropoietic): Clin = documentable porphyrin metabolism erroes; the histology tends to preserve the dermal papillae projecting upward into the bulla.
        9. Pseudoporphyria: H&E is like real porphyria and some cases have irregular, linear pink intraepidermal [d-PAS positive] "caterpillar bodies" (as does PCT and maybe other porphyrias53); but there are no errors in metabolism.
        10. Suction or friction blister: fluid might have some RBCs...likely fibrin/protein-poor fluid
        11. Bullous amyloidosis: H&E check dermis carefully for any pink, smooth amyloid deposits & may use special amyloid stains to r/o or rule in.
        12. Factitial blisters: Bullous dermatitis artifacta due to thermo- (such as hot spoon) or cryo- injury (deoderant spray) cleaves here & can be factitial (bullous dermatitis artifacta [bullous pathomimia]) as with spray deoderant55. Clin = factitial lesions tend to be odd; H&E = subepidermal blister with roof epidermis necrotic55 and superficial dermal homogenization with cautery artifact type epidermal cell change (such as elongated nuclei)57; DIF = essentially negative.
        13. Blister over a scar: Clin = blister is over a known scar; H&E confirms underlying scar and absence of other specific alternative diagnostic etiology.
        14. Vesicular or bullous stasis dermatitis: stasis vascular change & siderotic macrophages; DIF = vasc. fibrinogen+; and absence of other specific alternative diagnostic etiology [L07-3526; S10-11272].
      • lymphocytes:
        1. EM: Clin = tends bilateral target lesions of palms & soles & mucosa & a single blister lesion at a time would be very rare; H&E = entirely normal cornified layer1 & intraepidermal blisters due to spongiosis & balooning and get subepidermal via the vascular reaction superficial vessels and papillary edema & there tend scant eos & see necrotic keratinocytes & roof tends to necrotic; DIF = ; serology =
        2. Paraneoplastic pemphigus)*: Clin = ; H&E = ; DIF = ; serology =
        3. LS&A:
        4. superficial morphea:
        5. lichen planus, bullous:
      • eosinophiles:
        1. bullous pemphigoid (BP)*: Clin = intensely pruritic; H&E = ; DIF = ; serology =
        2. pemphigoid (herpes) gestationis (HG)*: Clin = ; H&E = ; DIF = ; serology =
        3. acquired EBA (one type)*: Clin = ; H&E = ; DIF = linear continuous BMZ+; serology =
        4. bug...arthropod...bite: H&E = a real bug "bite" makes a wedge-shaped inflammatory reaction directly beneath the blister with apex pointing deeply (most vesicular bug bites are intra-epidermal).
      • neutrophiles:
        1. Dermatitis herpetiformis (DH)*: Clin = ; H&E = polys accum at papillary derma tips; DIF = >95% have granular and/or fibrillar IgA in perilesional dermal papillae; serology = 70-80% have IgA endomysial by IFA & IgA tTG by ELISA.
        2. Linear IgA*: Clin = ; H&E = ; DIF = ; serology =
        3. DH-like drug eruption:
        4. EBA, inlammatory type*: Clin = tends above joints; H&E = neuts early & along with vacuolar change along BMZ & then add eos.; DIF = same as noninflammatory type, above; DIF = linear continuous BMZ+; serology =
        5. Sweet's syndrome: febrile neutrophilic dermatosis, sometimes with with bulla secondary to massive papillary edema (S15-1062 r/o), be it idiopathic, drug induced, or paraneoplastic57. Always look carefully into the background of any infiltrate of polys for any mononuclear cells which might be a tip off to acute leukemia infiltrate.
        6. Lupus erythematosus (LE), bullous: Clin = ; H&E no good vacuolar basal change & subepidermal cleavage with papillary dermal miroc abscesses & d-PAS positivity in roof; DIF = linear &/or dense granular IgG, IgM, and often IgA; serology = ANA pos with ds-DNA pos. & with antibodies to type IV collagen.
        7. pyoderma gangrenosum:
        8. cellulitis: Clin = the blister FOLLOWS onset of skin inflammation.
        9. BP*: Clin = ; H&E = ; DIF = ; serology =
        10. HG (one type)*:Clin = ; H&E = ; DIF = linear continuous BMZ+; serology =
      • mixed eos & neuts:
        1. DH*: Clin = ; H&E = ; DIF = ; serology =
        2. Linear IgA*: Clin = ; H&E = ; DIF = ; serology =
        3. DH-like drug eruption:
        4. Cicatricial pemphigoid: Clin = mucous membranes, mostly; H&E = mixed & also lymphocytes...plasma cells & fibrosis later; importantly, early cleaveage in skin includes hair follicles; DIF = linear IgG & others; serology = rarely positive; immunoEM deposits in laminae lucida (& densa) & target is extracellular (maybe anchoring fibrils).
        5. BP*: Clin = ; H&E = ; DIF = linear continuous BMZ+; serology =
        6. HG*: Clin = ; H&E = ; DIF = linear continuous BMZ+; serology =
        7. epidermolysis bullosa acquisita (EBA), inflammatory type*: H&E = neuts early & along with vacuolar change along BMZ & then add eos.; DIF = same as noninflammatory type, above.
        8. Bullous arthropod bite reaction (BABR)52: Clin = tend to be groups & not flaccid & sometimes published reports when happens in setting of occult leukemia, lymphoma, or HIV positivity; H&E = often show some septation or multiloculation & lots eos & polys; DIF = nonspecific or negative.
      • urticaria pigmentosa: lots of mast cells.
    3. Mixed Intra- and Subepidermal:
      • severely spongiotic with rupture:
      • above PLUS lots pap. dermal edema
      • mixed severe spong. & balooning w/ rupture
      • severely balooned w/ rupture
  • Subcorneal pustular dermatosis (SPD):
    1. strictly subcorneal separation with accumulation of polys
    2. DIF may show IgA intercellular and subcorneal linear deposition4 [see IAVPD]
    3. does not have immunoreactant deposits1.
  • Pemphigus foliaceous (p. f.):
    1. subcorneal/intraepidermal acantholytic blister (only clue may be absence of cornified...maybe even granular...layer in the biopsy22)
    2. fluorescent (DIF) positive, pericellular, intragranular IgG
    3. can be pustular and DIF IgA neg.  
    4. serology: patient may carry antibodies (anti-desmoglein 1) to "p. f. antigen"...desmoglein 117,18
  • Pemphigus, superficial IgA type (IgA p. f.): (only clue may be absence of cornified...maybe even granular...layer in the biopsy22)
    1. can be rich in epidermal polys (see IAVPD, below)
    2. IgA deposits in upper epidermis and antigen target is
      desmocolin 118.
  • Brazilian endemic pemphigus foliaceous (fogo selvagem...Portuguese for "wild fire"...burning sensation): just like p. f. ; (only clue may be absence of cornified...maybe even granular...layer in the biopsy22)
  • SSSS (staph. scalded-skin syndrome...Ritter's disease): (only clue may be absence of cornified...maybe even granular...layer in the biopsy22)
    1. subcorneal/intraepidermal acantholytic blister...no organisms seen (due to exotoxin, exfoliatin)2
    2. therefore, a clinically very thin bulla, separating in granular layer
    3. presents as fever and a diffuse erythema; adults with renal failure or immunosupressed
    4. organisms in some noncutaneous location
    5. fluorescent (DIF) negative
  • Bullous impetigo:
    1. subcorneal/intraepidermal non-acantholytic blister...organisms seen
    2. fluorescent (DIF) negative14
  • Acute generalized pustulosis: predilection for distal extremities; has leukocytoclastic vasculitis
  • Intercellular IgA vesicopustular dermatosis (IAVPD)
    ("intra-epidermal IgA pustulosis") (IgA pemphigus13, 14):
    1. SPD (subcorneal pustular dermatosis) type:
      • H&E like SPD
      • serology: serum may contain desmocollin-1 antibody (maybe also desmocollin-2)
      • DIF: 
        1. pemphigus-like intercellular positivity for IgA
        2. may have a linear IgA subcorneal band
    2. IEN (intra-epidermal neutrophilic) dermatosis type:
      • H&E like IEN dermatosis
      • serology: serum may contain desmocollin-3 antibody
      • DIF:
        1. pemphigus-like intercellular positivity for IgA
        2. may have a linear IgA subcorneal band
  • spongiotic intra-epidermal vesiculation:
    1. sometimes seen in fully developed lesions of leukocytoclastic vasculitis1
  • Viral exanthem (such as HSV):
    1. intraepidermal acantholysis and superficial perivascular & nonadnexal dermal infiltrate; HSV may necrose & have acute dirty infiltrate
    2. rarely see individual dead keratinocytes2
    3. viropathic change: inclusions, ballooning & reticular degeneration, multinucleation
    4. infiltrate usually more mononuclear
    5. basal layer vacuolar degen. often seen2
    6. fluorescent (DIF) negative (unless is causing EM/SJS)
    7. while usually has a mononuclear dermal infiltrate, HSV can give a dirty, acute, necrotizing infiltrate
  • pemphigus herpetiformis14, 15:
    1. intraepidermal acantholysis
    2. with DIF deposition of IgG pericellular (anti-desmoglein)
    3. with polys in epidermis (neutrophile dominant variant)
    4. with eosinophiles in epidermis (eosinophile dominant variant)
    5. grouped vesicles on erythematous base clinically simulating DH
  • Pemphigus erythematosus (Senear-Usher syndrome)6:
    1. intraepidermal acantholysis
    2. fluorescent (DIF) positive, pericellular & granular BM IgG & C3 (BM pos. most likely in sun-exposed skin)
    3. as if an overlap of pemphigus and SLE
  • Herpes (pemphigoid) gestationis16:
    1. rare pregnancy-induced (25% immediately post-partum) rash of pruritic herpetiform blisters15
    2. can recur with menses, when go back to BCPs, or with next pregnancy15
    3. DIF granular BM IgM (& others) to BPAG215; 100% have C318; and pericellular IgG in epidermis; granular IgA and C3 at papilla tips only in inactive lesions18; often have anti-endomysial and/or anti-reticulin antibodies
    4. serum IFA: IgG15 anti-BMZ "HG factor" antibodies in 90%
  • Paraneoplastic pemphigus (PNP)1:
    1. clinical: painful oral, skin, scarring conjunctival17
    2. intraepidermal/suprabasal focal acantholysis, patchy, focal, slight, clefts/bullae
    3. scattered individual necrotic keratinocytes
    4. histopath. typically an interface dermatitis (slightly lichenoid lymphocytes at D-E junction)
    5. therefore can vesiculate at D-E junct. due to vacuolar process or intraepidermal due to acantholysis
    6. an immunobullous disorder: DIF pericellular (and BM...maybe adnexal) IgG & C3 fluorescent positivity17 [S-01-11869?]
    7. an associated neoplasm not always found [S-02-8851?]; usually lymphoma17
    8. circulating autoantibodies:  may be manageable with apheresis17...anti-desmoplakin I and II and other keratinocyte proteins18
    9. patients have a circulating serum IFA auto-antibody against rat bladder epithelium10 in 90-100%16; monkey esophagus or rat bladder, but, some false pos.17
    10. expensive, difficult, rarely available definitive serological test is immunoprecipitation (ag-ab complexes) electrophoresis17
  • Pemphigus vulgaris:
    1. a PEMPHIGUS diagnosis implies heavy duty prednisone and methotrexate type treatment
    2. IFA serology: patient may carry autoantibodies (anti-desmoglein 3) to inter-epidermal "p. v. antigen" (desmoglein 3)17,18
    3. suprabasal acantholysis, neg. for "dry" cleft11
    4. pericellular positivity 100% C3 & 80% IgG
    5. may see DIF positivity in nonlesional but C3 only where acantholysis
  • Pemphigus vegetans:
    1. like a longstanding p. v. & thickens to contain WBC intraepidermal microabscesses.
    2. acantholytic suprabasalar "dry" cleft11
    3. intertrigenous zones and face & present as heaped-up crusts
    4. histo & DIF like p. v. [S-04-6880]
  • Pemphigus, benign familial chronic, Hailey-Hailey's:
    1. suprabasal acantholysis, negative for "dry" cleft11
    2. little or no dermal inflammatory cells11
  • Darier's disease:
    1. acantholytic suprabasalar "dry" cleft11
    2. no lake or bulla11
    3. has dyskeratosis11
    4. little or no dermal inflammatory cells11
  • Pemphigoid, bullous:
    1. subepidermal blister with eosinophiles
    2. cell-poor subepidermal blister if cell-poor variant
    3. mild dermal infiltrate is usual; some cases almost no dermal cells; may see dermis, vesicle, and epidermis rich in eosinophiles [S-03-4826]
    4. serum IFA: 60-70% have anti-BMZ antibodies16 to such antigens as BP230 and BP18018; HG also may have anti-BP18018
    5. linear BM positive DIF/DFA, IgG & C3 (on epidermal side of NaCl-split skin prep10)
  • Pemphigoid, cicatricial (benign mucosal pemphigoid)6:
    1. most of the biopsies we evaluate for this scarring disorder are conjunctival biopsies from ophthalmologists (a few oral biopsies from oral surgeons).
    2. caution: if oral biopsy background is heavy with periodontal inflammation, DIF will be the only way (may also need anti-skin antibodies) to get the correct diagnosis [S-01--6796].
    3. only 30% have skin lesions; nearly always have oral lesions7
       & these may only show a few eosinophiles.
    4. occular differential includes such as glaucoma-drop induced sclerosis and chronic urticarial conjunctivitis sclerosis.
    5. oral clinical differential diagnosis category is PNP (above) vs. "desquamative gingivitis" (which almost generically includes cicatricial pemphigoid and erosive lichen planus...and any other vesico-bullous disorder affecting mucous membranes)7.
    6. 80% are DIF pos. for linear BM IgG & C316.
    7. serum IFA anti-BMZ antibodies in 20-40% of cases (ordered as "serum anti-skin antibodies").
    8. lamina lucida cleavage (for subepi. bulla).
    9. lesional skin biopsies may show linear DIF of sweat glands.
    10. BUT, there is a skin-only variant of head & neck blistering without mucosal lesions (Brunsting-Perry disease).
    11. cases: S-01-6796; S-01-6236/6982 had neg. anti-skin abs.; S07-6591.
  • Porphyria (especially PCT): 
    1. subepidermal vesicle; PCT may reflect HCV.
    2. actinic elastosis & stiff papillae with d-PAS positive superficial dermal vessels [S-02-9369]2
  • Lichen planus:
    1. lichenoid interface chronic infiltrate [more HERE]...except in bullous LP.
    2. DIF pos. for globular dermal IgM and C3
  • Dermatomyositis:
    1. periorbital, malar, neck and chest erythema (photo distribution) which gets dusky with time due to pigment incontinence; may have pathognomonic Gottron's papules along finger edges; telangiectasias of nail-fold cuticle; many cases malignancy-associated, especially if =>50 y/o
    2. key diff. Dx.: SLE
    3. extreme muscular weakness (such as shoulder girdle)
    4. high elevations of serum aldolase and total CPK
    5. often ANA pos. and 10% are the specific ENA pos., Jo1; but if histology is "right", muscle enzymes clearly elevated, and anti-DNA negative...differential diagnosis is 98% solved.
    6. H&E: epidermal atrophy, interface vacuolar degeneration and colloid balls [LMC-01-5811] which may be DIF pos. for IgA, IgM, or C3; & some BM thickening
  • Dermatitis herpetiformis (Duhring's disease)6:
    1. ***intensely pruritic
    2. polys and eos at tips dermal papillae
    3. DIF focal, finely granular IgA in papillary tips...sometimes BMZ
    4. 10-15% have DIF linear BMZ IgA
    5. serum IFA neg. except IgA anti-BMZ in the IgA variant16
    6. [see pemphigus herpetiformis, above]
  • Chronic bullous dermatosis/disease of childhood16:
    1. lower abdomen, anogenital, perineal lesions15
    2. DIF linear IgA at BM
    3. serum IFA IgA anti-BMZ antibodies in 60%
  • Linear IgA dermatosis/disease (LAD)6:
    1. thin, linear BM IgA & sometimes C3 (on epidermal/dermal side of NaCl-split skin prep10)
    2. drug-induced linear IgA can be as bad as TEN (Dermatology 202(2):138-139, 2001)
  • Anoxic & hypoxic epidermal detachment:
    1. full-thickness epidermal necrosis & underlying sweat gland & maybe even sebaceous necrosis. Lesser degrees of hypoxia give lesser injury.
  • Subepidermal blisters, other:
    1. sometimes seen in fully developed lesions of leukocytoclastic vasculitis1
  • EM/SJS/TEN:
    1. EM (erythema multiforme)
      • non-scaling annular, erythematous lesions , sometimes targetoid1
      • subepidermal cleavage
    2. EM major (Stevens-Johnson Syndrome...SJS)
      • subepidermal cleavage
      • use steroids
      • <10% epidermal surface area detachment4
    3. SJS/TEN overlap
      • 10-30% epidermal detachment4
    4. TEN (toxic epidermal necrolysis...Lyell's syndrome)
      • most suggest avoid steroid therapy5
      • symptomatic (skin pain, burning) widespread blotchy erythema
      • with positive Nikolsky sign (epidermis slips when thumb pressure applied)
      • with >30% epidermal surface area detachment4
      • cell-poor dermal infiltrate
    5. re: viral and EM/SJS:
      • a pox-like vesicular eruption with vesicle umbilication is a varicelliform viral eruption until proven otherwise
  • Graft vs host disease (GVH)25: (we like biopsy samples for H&E and DIF studies.
    1. Acute GVHD2:
      • typical reaction is sparsely cellular interface dermatitis (and some cases subepidermal bullae) and satellite-cell necrosis2.
      • epidermal and adnexal duct focal cell necrosis2.
      • usually associated with chemotherapy which often induces an epidermal maturation disarray.
      • interface lymphocytic exocytosis, maybe.
      • apoptotic keratocytes may be DIF positive & could have some BMZ DIF positivity.
      • clinically as generalized macular erythematous eruption of trunk, extremities, palms & soles; may hit GI tract & liver2.
    2. Subacute GVH: some of acute findings and many melanophages & maybe begin hint of LP-like but not yet the more impressive LP-like or scleroderma-like features [L07-1538].
    3. Chronic or late GVH: chronic lesions lichenoid like LP (interface lichenoid and hyperkeratosis & hypergranulosis) & late lseions add on scleroderma-like fibrosis.
  • Undeclared lupus-suspicious, can't r/o lupus:
    1. interface dermatitis, NOS.
    2. "interface dermatitis with ANA positivity without serological specificity" [S-05-8362].
  • SLE (bullous or not):
    1. more dense interface & periadnexal infiltrate.
    2. superficial & deep perivascular dermatitis.
    3. positive ANA serology, especially if anti-DNA is also positive.
    4. granular (can be homogeneous or linear) IgG, IgM and C3 DIF deposits beneath the BM are most common pattern in lesions (also can be in lesions of MCTD, GVH, EED, FDE, vasculitis and other rheumatic); nonlesional skin having positivity (DLE does not) is the "lupus band test" (many other rheumatic-type diseases have a pos. band test)9.
    5. bullous SLE can have a leukocytoclastic component, too2.
  • DLE:
    1. follicular plugging, epidermal atrophy, chronic folliculitis.
    2. ANA serology usually negative.
  • SCLE:
    1. first known as ANA-negative lupus
    2. widespread, usually photosensitive annular-polycyclic, sometimes papulosquamous (keratotic) skin lesions
    3. don't get CNS or renal components
    4. >60% have modern (HEp-2) pos. ANAs
    5. most with photosens. component are SS-A (anti-Ro) positive
    6. DIF: only 50% of lesional and 30% nonlesional skin
    7. anti-ds-dna present in low titer in 30%
  • Mixed connective tissue disease (MCTD):
  • Rheumatoid arthritis:
  • Sweet's syndrome: febrile neutrophilic dermatosis is a reactive phenomenon and should be considered to be a cutaneous marker for significant underlying (50% of cases) systemic disease12, or drug induced or paraneoplastic57.
  • PL et VA:
    1. acute lymphocytic vasculitis2.
  • Fixed drug eruption (FDE):
    1. usually only one (or a few) patches or plaques as lesions, coming back again and again (fixed) at same location
    2. papillary dermal melanophages
    3. vacuolar basal cell interface change and can cleave at this zone
    4. DIF negative
    5. may see full-thickness epidermal necrosis
  • Bullous drug eruption3:
    1. cell-poor dermal infiltrate
  • EBA (epidermolysis bullosa acquisita) (a type of pemphigoid?):
    1. cell-poor subepidermal blister; almost no dermal infiltrate3
    2. linear IgG (and C36) in BM (on dermal side of NaCl-split [toad18] skin prep10) beneath BM/lamina densa6
    3. serum IFA: anti-BMZ "EBA antigen" antibodies16 (anti-collagen IV)18
  • Porphyria:
    1. cell-poor subepidermal blister and essentially no dermal infiltrate
    2. stiffened dermal papillae protrude upward; may reflect HCV.
  • Leukocytoclastic vasculitis (LCV) (papular petechial/purpura...old terminology, allergic cutaneous vasculitis3):
    1. most commonly presents as "palpable purpura"...purpuric papules
    2. (1)polys in vessel wall, with poly "clasis" (nuclear dust); (2)perivascular polys
    3. (3)fibrinous degeneration and/or fibrin in vessel walls...must have all 3 & can be very focal and very subtle2 (may need lots of step-cuts)
    4. usually superficial plexus @ junct. pap. and retic. dermis.
    5. urticarial vasculitis is one variant.
    6. in drug induced LCV [LMC-02-2703], any lumenal fibrin is slight and not much RBC extrav.2
    7. late stages can produce ischemic epidermal necrosis and subepidermal bullae
    8. a few days to a week after petechial showers, the pigmented skin may only show some residual polys, the RBCs, and some early hemosiderin macrophages [LMC-01-8237]
  • Septic petechial/purpuric...DIC2:
    1. fairly marked platelet, fibrin ("soft" look whereas "cryo" emboli have a "hard" semi-refractile "look"), and poly thrombi in small superficial capillaries and venules as dominant (DIC) component
    2. polys dermal & perivascular infiltrate
    3. can fairly frequently have a leukocytoclastic component
    4. usually lots of RBC extravasation
    5. usually involves superficial & deep plexus
    6. common acute agents:
      • meningococci: (usually from primary nasopharyngeal infection) may lead to some intraepidermal & subepidermal pustules; lung and kidney hemorrhages; Waterhouse-Freidrichsen syndrome (adrenal hemorrhage); may have some IgG, IgM, or IgA in vessel walls2
      • Staph. aureus (as with SBE) sepsis
      • group A streptococcal sepsis
      • Pseudomonas (as assoc. with ecthyma gangrenosa...looks like skin cigarette burns)
      • toxic shock syndrome has superficial perivascular and interstitial polys and minor component of  eos., sometimes poly  spongiosis; and may have scattered and clumped necrotic  keratinocytes, even to a full-thickness TEN-like picture2
      • Vibrio vulnificus
      • rickettsiae
    7. chronic agents:
      • Lucios erythema necroticans of lepromatous leprosy
      • papulonecrotic tuberculid
      • Lues maligna
  • Cryoembolism (cryoprotein, cryoglobulin) lesions:
    1. intravascular fibrin-like plugs or casts which are very eosinophilic by H&E and have a hard "look", almost semi-refractile19. May reflect HCV infection.
    2. lymphocytes & histiocytes associated
  • Rocky Mountain spotted fever (RMSF) (and other rickettsiae):
    1. lymphocytic vasculitis
    2. very acute may show septic-type superficial & deep thrombosis, even with vascular wall necrosis and hemorrhage, BUT, mostly lymphs & histiocytes2
    3. sometimes see intimal/medial intracytoplasmic coccobacillary bodies3
  • Coma-associated eccrine gland necrosis2:
    1. epidermal and adnexal focal cell necrosis of anoxic type, see above.
  • Drug hypersensitivity reaction:
    1. eosinophiles may be a tip-off.
  • Purpura fulminans (extreme cutaneous DIC manifestations)2:
    1. presents with large, suddenly developing extremity ecchymoses.
    2. platelet & fibrin thrombi.
    3. no significant inflammatory infiltrate or vasculitis.
    4. also affects internal organs.
  • Coumarin or coumadin necrosis2:
    1. begins 2-10 days after institution of coumarin...lightly hemorrhagic at first (until ischemic effect).
    2. predilection for sites with abundant fat (buttocks, flank, breast).
    3. vessels contain homogeneous eosinophilic material2.
    4. no significant inflammatory infiltrate or vasculitis.
    5. internal organs not affected.
  • calciphylaxis or calcific arteriopathy (metastatic calcification) : dermal, subcutaneous, vascular involvement of intima with lumenal thrombosis2 & sometimes with calcifying panniculopathy; precipitators include renal failure, malignancy (non-uremic), immunosuppression, steroid therapy, albumin infusion, excess intake of vit. A or D, a chronic inflamatory process, alcoholic liver disease, connective tissue disease, and trauma.
    1. secondary hyperparathyroidism of chronic renal is particularly prone to vascular
    2. secondary hyperparathyroidism of chronic renal on dialysis prone to dermal [LMC-04-5408]
    3. subcut. fat calcification in milk-alkali syndrome, uremia, renal hyperparathyroidism
    4. met. calcif. plus coumarin necrosis picture suggests an additional abnl. protein C activity
  • Cholesterol (atheroembolism) embolism2: embolic usually to subdermal or larger vessels; painful distal ulcers; may see  livedo retcularis; distal digital gangrene...early lesions neg. for vasculitis or even dermatitis & very discordant with clinical
    1. spontaneous
    2. post-trauma (including post invasive vascular studies)
    3. post thrombolytic therapy (like streptokinase)
    4. post aortic/arterial grafting
  • Pustular psoriasis:
    1. pustules generalized over entire body
    2. 50% of cases in established psoriatics; 50% are the initial psoriatic presentation
    3. spongiotic pustules (which can get secondarily infected)
    4. secondarily infected pemphigus foliaceous (acantholytic) or eczematous (spongiotic) dermatitis can simulate pustular psoriasis clinically
    5. typically lacks classical skin histopathology of psoriasis
    6. in pregnant women, carried the old term "impetigo herpetiformis"
  • Mastocytosis syndrome:
    1. diarrhea & abdominal cramps
    2. pruritis and headaches
    3. tachycardia, hypotension, syncope
    4. more than 5 mast cells around a small superficial skin venule is TMEP or a secondary reflection of some chronic urticating disease such as chronic contact dermatitis
    5. presents with numerous small pigmented skin nodules of trunk
  • Leukemia cutis:
    1. biopsied because of petechial hemorrhages, thrombocytopenic (possibly even aleukemic...an initial presentation.
  • Cutaneous pseudolymphoma & lymphoma:
    1. pseudolymphoma: HERE.
    2. lymphoma:

References:

  1. 2nd Ed. Ackerman; Histologic Diagnosis of Inflammatory Skin Disease, 1997.
  2. Oct. 1993 ASCP Workshop, Duncan & Mihm, Dermatopathology and Emergency Medicine.
  3. March 1978 IAP Workshop, Atlanta, Mark & Mihm, Skin Biopsy in Emergency Diagnosis.
  4. Fitzpatrick [dermatology text] 4th Ed, 2 vols [in LMC library]
  5. Lever [skin path. text], 794 pages, 1967.
  6. Interpretation of Immunofluorescent Patterns in Skin Diseases [text], 1984, Valenzuela, Bergfeld, & Deodhar
  7. Murphy, Dermatopathology [text], 1995.
  8. 1st  Ed. Ackerman; Histologic Diagnosis of Inflammatory Skin Disease, 1978.
  9. Clinics in Lab. Med., 3/1986, chapter on cutaneous immunofluorescence (p85-102), Gene T. Izuno, MD, Scripps Clinic
  10. Electronic Textbook of Dermatology, Blistering Diseases web site
  11. A Guide to Dermatohistopathology, Pinkus & Mehregan, 2nd Ed., 1976.
  12. Habif, TP, Clinical Dermatology, 3rd Ed., 1996 [LMC library]
  13. Weedon D, Skin Pathology [text], 1997 (BWD's office)
  14. Maize JC, 11/27/01 personal communication &/or case consults [about case of CAP &/or other cases]
  15. e-Medicine web site, dermatology
  16. ARUP lab's web site differential diagnosis chart
  17. Allen CM, Camisa C, Review: Oral Medicine, Paraneoplastic Pemphigus...a review of the literature, Oral Disease 6:208-214,  2000.
  18. Bradwell AR, et. al., Atlas of Autoantibody Patterns on Tissues, 1997.
  19. Nash JW, et. al., "The Histo....Sites", AJCP 119(1):114-122, Jan. 2003.
  20. Barthelette S, et. al., "Common Dermatological Presentations: The Red Face", Journal of Clinical Outcomes Management 11(1):36-50, 2004.
  21. comments in expert-consultant case consultations on our cases (Maize).
  22. Ackerman AB, A Philosophy of Practice of Surgical Pathology: Dermatopathology as a Model, Ardor Scribendi, Ltd., 1999, 470 pages.
  23. Ackerman AB, his Derm 101 website ( http://www.derm101.com/index.asp ).
  24. 3rd Ed. Ackerman; Histologic Diagnosis of Inflammatory Skin Disease, 2005.
  25. McKee, Calonje, & Granter, 2 vol. text, Pathology of The Skin...
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  27. Maccarelli FJ, et. al., "koebner's Phenomenon...", Postgraduate Medicine 118(6), December 2005.
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  30. Jennette JC, Immunohistology In Diagnostic Pathology, CRC Press, 1989.
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  38. see a case discussion on You Tube.
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  53. Caterpillar Bodies..., HERE.
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(posted Nov. 2001; latest addition 13 January 2017)
 
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