HistoPath Diagnosis - An Outline

HistoPath Diagnosis - An Outline

Where is the pathology – Epidermis, Dermis, Both or Fat layer

Slide looks like normal skin

Parakeratosis and acanthosis

Parakeratosis with neutrophils

Epidermal acanthosis

Epidermal atrophy

Spongiosis

Acantholysis

Basal vacuolization

Sub epidermal blister or separation

Lichenoid infiltrate

Superficial and deep perivascular infiltrate

Extravasated red cells

Dermal papillary oedema

Nodular dermal infiltrate

Diffuse dermal infiltrate – cells, substances including drugs and organisms

Panniculitis

Tumours

Epidermal cells

Dermal cells

Adnexal structures

Metastases

Diagnosis by the most obvious dermpath feature

Often when you look at a path slide an obvious histopath feature or pattern of inflammation catches your eye. It is quite useful to have a list of differential diagnoses for these features. You should still systematically examine a slide in case a less obvious feature is actually present and is of even more importance!

I also like to look at a slide and immediately state whether I think this is an Epidermal or a Dermal histological pattern. I then assign a couple of mnemonics as follows
If Epidermal then the diagnosis will be one of the Red Scaly or Skin Coloured scaly diagnoses and the mnemonic will be the PMsPET a little cat called PETAL

If dermal then the mnemonic will be CUL DVA EVIE

If pustules obvious us II  and if vesicles or blisters use ICI   (See explanation for these mnemonics below.)

So look at the slide, look for features and patterns, decide whether Epidermal or Dermal or Both, Go through the diseases in the relevant mnemonic and then look for Specific histological features, patterns or clues to decide on the likeliest diagnosis. If you need more information on a histopath feature  look in the posts opposite and for patterns see DermatopathologyMadeSimple. If you want to see clinical pictures of the skin diseases go to GlobalSkin Atlas. If you need more information on the mnemonics look at Differential Diagnosis

Try some of the test cases in the post opposite


Epidermis.
Parakeratosis
Parakeratotic column
Alternating Ortho and Parakeratosis
Hyperkeratosis
Abscent stratum corneum
Neutrophils in the stratum corneum
Collections of cells in the epidermis
Thickened epidermis
Thinned epidermis
Epidermal perforation
Epidermis with Atypical keratinocytes
Dyskeratotic cells
Pale cells in the epidermis
Epidermotropism
Pagetoid spread of cells or nests
Follicular pathology

Dermoepidermal Junction DEJ
Basal layer damage
Lichenoid infiltrate
Thickened basement membrane

Dermis 
Grenz zone
Papillary oedema
Material laid down
Black staining
Pink staining
Blue staining
Clear cells
Clear spaces between cells
Indian filing of cells between collagen
Cells with anything within them
Papillary microabscesses
Flame figures in the dermis
Busy dermis
Dermal abscesses
Giant cells
Ectopic tissue
Perivascular infiltrate
Mid dermal infiltrate
Palisading reactions
Desmoplasia
Involvement of fat

Tumours
Blue cells in dermis
Spindled cells
Granular cells
Clear cells
Balloon cells
Excess eccrine ducts
Excess Sebaceous glands
Excess vascular spaces
Keratin cysts in the dermis
Indian filing
Atypical cells with prominent nucleoli
Proliferation downwards from Epidermis
Central pore
Space with a lining
Cords and Tubules
Papillated dermal tumour
Circular dermal islands

Adapted from Dermatopathology - Diagnosis by first impression. Christine J Ko and Ronald Barr Wiley-Blackwell

The above book is an excellent introduction to Dermatopathology. In essence it allows you to get your eye in ie it teaches you to see things on a slide. I have added a list opposite of the other Visual features that they suggest you look for when examining a slide with the likely diagnoses associated with that feature. It is especially useful in the diagnosis of Tumours . I have added a Page at the top of this website with the suggestions they make for looking at a slide where a tumour is suspected.

The conventional approach to teaching the pathological diagnosis of inflammatory skin disease has been to assign the slide to a particular reaction pattern and look for the subtle features that distinguish one disease from another that conventionally are known to cause that reaction pattern. This works quite well but if you get the reaction pattern wrong you will have trouble arriving at the correct diagnosis. You can combine the first obvious feature with reaction patterns to minimise this risk.


1. Diagnosing skin diseases is not difficult. You look at a rash and decide if it is red and scaly or red and non scaly. If it is red and scaly you use the mnemonic PMs PET (PET is Psoriasis, Eczema and Tinea. This is the Prime Minister'S Pet ( I used to always think of Kevin Rudd with a Siamese cat called Petal sitting on his lap!) The first P of PM is for Pityriasis rosea or Pityriasis versicolour, Pityriasis rubra pilaris, Pityriasis lichenoides and the M is for Mycosis fungoides, a T cell lymphoma of the skin.) The S is for Solar damage and Scabies

 Now we know that his pet cat is called PETAL. This helps us to remember Psoriasis, Eczema and Tinea but also the less common red scaly diseases of A for Annular erythemas and L for Lupus erythematosus ,Lichen Planus, Light eruption and Lues (an old name for syphilis)

2. If it is red but not scaly consider Cellulitis, Urticaria, Lupus, Light eruption, Drug reaction, Viral exanthem or Annular erythema .The mnemonic is C U L at the Department of Veterans Affairs EVIE(your girlfriend Evie) (CUL DVA EVIE) where EVIE stands for Erythema multiforme, Vasculitis and Erythema nodosum and Infiltrates

3. If there are Pustules then the mnemonic is II
(aye aye) Infective( viral, bacterial, fungal) or Inflammatory eg psoriasis or a pustular drug reaction or Sweet's syndrome. Common causes include Staph folliculitis , modified fungal infection or if the vesicles are grouped herpes simplex. Pustules on the face are Acne, Rosacea, Staph folliculitis or H Simplex if grouped.

4. If there are Blisters or vesicles The mnemonic is ICI(Imperial Chemical Industries) Inflammatory including Immunological, Contact dermatitis and Infective.
Inflammatory causes can include drugs but remember Immunological causes in the elderly particularly bullous pemphigoid. Contact dermatitis usually gives smaller vesicles rather than blisters but individual vesicles can join up into blisters. If blisters are linear and itchy it is probably a Plant contact dermatitis. Infective blisters are usually bullous impetigo due to a staph infection. If in a dermatomal distribution blisters are likely to be Herpes Zoster.

5. If Skin Coloured and Scaly The mnemonic is ( I am coming Don't go away) Ichthyosis, Acanthosis nigricans, Confluent and Reticulate papillomatosis, Dariers, Grovers and Acrokeratosis verruciformis) but these are mostly uncommon conditions.

6. Skin coloured and Non scaly  No good mnemonic except ICS (Infiltrates of cells or substances)     Most cases are Infiltrates of cells or substances  eg Granuloma annulare, Sarcoidosis, Mucinosis, Scleromyxedema, Scleredema, Scleroderma,  Metastases,

TEST CASES

Try this case. Biopsy papular lesion on the face.

 

 

Dermal process Therefor CUL DVA EVIE

 

These are granulomas. See the link on this below in the DERMIS section or go to the Dermatopathology Made Simple tab above for more information on the different types of granulomatous diseases and their histopathology.

 

See the video of the analysis below. Click to view it on YouTube then click on the circular motive at the base to increase the resolution to 1080 HD and click the outside box to view full screen.

 

 

 

This is the clinical picture

 

Test 2 

 Question: Which of the following is the best diagnosis for this slide?

Answer 1:
Spitz nevus

Answer 2:
Mastocytosis

Answer 3:
Leukemia cutis

Answer 4:
Histiocytosis

Answer 5:
Dermal nevus

Answer 

EPIDERMIS

Epidermal diseases usually show psoriasiform or spongiotic reaction patterns with varying degrees of hyperkeratosis and hyperplasia or acanthosis. The archetypical examples are psoriasis and eczema but the many diseases seen with an epidermal histology reaction pattern are best remembered by the mnemonic PMs PET a small cat called PETAL

P - Pityriasis rosea, P versicolor, P rubra pilaris, P lichenoides,
M - Mycosis fungoides
s - Solar damage, Scabies

P - Psoriasis
E - Eczema
T - Tinea and other fungi
A - Annular erythema
L - Lupus erythematosus, Lues (syphilis). Lichen planus, Light exacerbated Darier's, Linear verrucous epidermal nevus, Lichen striatus,

Some interface pathology diseases can involve the epidermis sufficiently to cause epidermal changes eg Erythema multiforme  and also dermal processes which perforate will cause epidermal changes eg Perforating folliculitis in renal failure, perforating deep fungal infections and TB.

So look at a slide.

Is the pathology Epidermal or Dermal or Both. If Epidermal use the Mnemonic PMs PETAL
If dermal use the mnemonic CUL DVA EVIE (See DERMIS) link opposite.

If Both then use both mnemonics.
Look for any other epidermal or dermal features or clues and then work through the diseases in the mnemonics to see which might best fit the histology in front of you.

If you see Pustules in the epidermis the mnemonic is II

I - Infective  Viral, Bacterial, Fungal, Rickettsial, Protozoa
I Inflammatory eg Drugs, Pustular psoriasis, Rare ( Scabies, Necrolytic migratory erythema, Subcorneal pustular dermatosis, Erosive pustular dermatosis, Acrodermatitis enteropathica)

If you see Vesicles or Blisters the mnemonic is ICI

I - Infective Viral Bacterial Fungal
C - Contact Dermatitis
I - Inflammatory - Drugs, Porphyria, Insect bite, Genetic bullous diseases
I - Immunological - The immune bullous diseases

Parakeratosis

Parakeratosis

Parakeratosis refers to retained keratinocytic nuclei in the stratum corneum. It is seen in proliferating keratinocytic disorders such as psoriasis, and in keratinocytic malignancies and premalignant conditions such as Bowen's disease and Solar keratosis. The nuclei are flattened and run  parallel to the epidermal surface.
When you see it look carefully at the underlying epidermis. You may see hyperkeratosis, hypogranulosis and acanthosis.  Histological parakeratosis usually equates to surface scale so think of the mnemonic for the red scaly diseases PMs PETAL for likely diseases.

Patterns of parakeratosis can be helpful.
Confluent in Bowen's disease and Psoriasis         Virtual Slide

Alternating in Solar keratosis                              Virtual Slide

Parakeratosis in a heaped up column in the cornoid lamellae of DSAP   Virtual Slide

Checkerboard parakeratosis in PRP   Virtual Slide

Sandwich parakeratosis over orthokeratosis in Tinea        Virtual Slide

There is also the unusual axillary granular parakeratosis with granules in the stratum corneum. See Virtual Slide

View the Video of this Topic

Hyperkeratosis - Thickened stratum corneum

Hyperkeratosis or thickened stratum corneum is a feature of the palms and soles. There is no associated inflammatory changes.      Virtual Slide

Hyperkeratosis can be layered orthokeratosis or layered parakeratosis. The latter is seen in hyper proliferative conditions such as some of the red scaly diseases and solar keratoses.   Virtual Slide

Hyperkeratosis with cornoid lamellae is a feature of porokeratoses.     Virtual Slide

Hyperkeratosis with gram positive bacteria on the surface is seen in Pitted keratolysis a Corneybacterial infection.   Virtual Slide

Epidermolytic hyperkeratosis is a distinctive change in the granular layer with intracytoplasmic vacuolization of the stratum granulosum and upper stratum spinosum giving a reticulated appearance with overlying hyperkeratosis. It is seen in acrodermatitis enteropathica and other deficiency diseases such as pellagra and necrolytic migratory erythema but also in some epidermal nevi, Bullous congenital ichthyosiform erythroderma, some isolated and disseminated epidermolytic acanthomas , some warts and a variant of keratoderma.

Papillomatosis

Papillomatosis

This occurs with the surface projection of the dermal papillae high up towards the skin surface with resultant irregular undulation of the epidermal surface and often  overlying hyperkeratosis. It is commonly seen with warts, solar keratosis, epidermal nevi  Virtual Slide  and some seborrhoeic keratoses.

 It is a major feature of a verrucous carcinoma..  Virtual Slide

Other rarer disorders to consider

Acanthosis nigricans   Virtual Slide

Nevus sebaceous         Virtual Slide

Linear Verrucous Epidermal nevus

Syringocystadenoma papilliferum  Virtual Slide

Tuberculosis verrucosa cutis          Virtual Slide

Acrokeratosis verruciformis (Acral Dariers)

View the Video of this Topic

Follicular plugging

The follicular opening is plugged with excess keratin

It is seen in discoid lupus and in lichen sclerosus and also PRP as the major disorders  but also in Darier's disease, Keratosis pilaris, Lichen spinulosus and perforating folliculitis.

Discoid Lupus    Virtual Slide

Lichen Sclerosus   Virtual Slide

Pityriasis rubra pilaris   Virtual Slide

Keratosis pilaris         Virtual Slide

Perforating folliculitis    Virtual Slide

View the video of this Topic

Acantholysis

Acantholysis is a feature seen in the epidermis as an isolated feature in some skin cancers including solar ks, SCCs and even in melanoma but also in Warty dyskeratoma.  It is a major finding in Hailey Hailey disease, Darier's disease and in Pemphigus but is also seen to a lesser extent in Grover's disease. Rarely acantholysis is seen in Pityriasis rubra pilaris.

Acantholysis is most marked in Pemphigus vulgaris and in Hailey Hailey disease. The latter is a genetic disorder where the desmoglien proteins holding the keratinocytes together are mostly missing.

  Intra epidermal blistering disorders

 If acantholysis consider Pemphigus vulgaris, Darier's disease, and Hailey Hailey disease and Grovers. Herpes infections should show features of Ballooon degeneration of keratinocytes. Other Pemphigus variants include Pemphigus erythematosus, Pemphigus vegetans and Paraneoplastic Pemphigus.

 Pemphigus Vulgaris and variants

 Clinical Pemphigus vulgaris presents initially in elderly patients with oral ulceration followed by flacid blisters and crusts on the trunk and sites of frictional trauma.It can involve the mouth and oesophagus. Histology Acantholysis which is suprabasal with villus formation . Involvement of a hair follicle is virtually diagnostic of PV. Tombstone formation of basal cells adherent to the basement membrane. These dermal papillae are called villi for this reason.Eosinophilic or neutrophilic spongiosis early in the blistering process. You dont see corps ronds or grains in Pemphigus! Can biopsy virtually anywhere.

Paraneoplastic Pemphigus has intraepidermal acantholysis but also basal layer vacuolisation and necrotic keratinocytes.

  Pemphigus vegetans This curious variant of pemphigus vulgaris is seen in the flexures and scalp with marked epidermal proliferation and abscess formation looking very infected. Histologically there is marked acanthosis and even pseudoepitheliomatous hyperplasia with intra epidermal neutrophilic abscesses but eosinophils can also be seen.

. View this Virtual Slide of Pemphigus Vegetans

 DD Hailey Hailey ( widespread acantholysis), Grovers (Localised acantholysis), Dariers disease ( dyskeratotic cells, corps ronds and grains). Clinical Flexural crusts and linear erosions particularly axillae and groin and under breasts, back of the neck. Family history. Histology Very extensive acantholysis with no follicular involvement. Some mild dyskeratosis. Dilapidated brick wall. Extensive acantholysis, Rare foci of dyskeratosis, Neg immunofluorescence. 

Consider also acantholytic disorder of the genito crural area.

View this Virtual Slide of Hailey Hailey Disease DX Path on Hailey Hailey Diseases 

View the video below on Hailey Hailey disease Histology

Absent stratum granulosum

Absent Stratum Granulosum

This is seen in ichthyosis vulgaris and under a porokeratotic cornoid lamella.

View a Virtual Slide of Ichthyosis vulgaris

View a Virtual slide of DSAP

There is also hypogranulosis seen in any disorder with marked parakeratosis particularly psoriasis. It is also seen in Necrolytic migratory erythema, Acrodermatitis enteropathica and Pellagra. It is also a feature of normal mucous membranes.

Cornoid lamellae usually point inwards towards a porokeratosis. When they are vertical and multiple consider porokeratosis ptychotropica (Verrucous porokeratosis of the gluteal cleft) if multiple dark papules on the buttock of long duration.

View this reference

Neutrophils in stratum corneum

Neutrophils in the Stratum Corneum

Whenever I see this I think of Impetigo, Fungi or Pustular psoriasis and would order a PAS stain.
Munro microabscesses are collections of neutrophils in the stratum corneum.

Other causes include AGEP acute generalised pustular dermatosis, Subcorneal pustular dermatosis and sometimes also in pemphigus foliaceous.
Acropustulosis of infancy and Neonatal scabies can also show subcorneal pustules without the scabetic organism.

View this video on Sub Corneal Pustules

  View this virtual slide of pustular psoriasis

Neutrophils in the epidermis can be seen in a variety of inflammatory conditions but remember Acne and folliculitis, Gonococcemia, Necrolytic migratory erythema, Pemphigus erythematosus or foliaceous, Neonatal pustular melanosis, Scabies and Halogenodermas.


If you see Pustules in the epidermis the mnemonic is II

I - Infective  Viral, Bacterial, Fungal, Rickettsial, Protozoa
I Inflammatory eg Drugs, Pustular psoriasis, Rare ( Scabies, Necrolytic migratory erythema, Subcorneal pustular dermatosis, Neonatal pustular melanosis, Erosive pustular dermatosis, Acrodermatitis enteropathica, Halogenodermas)

Collections of cells in the epidermis

Collections of cells in the Epidermis

They can be neutrophils, eosinophils, lymphocytes, melanocytes or histiocytes plus Paget cells. They all form collections within the epidermis and clinically appear as pustules or they induce scale. So the red scaly mnemonic PMs PETAL  or the Pustule mnemonic II should pick them up.

Neutrophils in the epidermis can be seen in a variety of inflammatory conditions but remember Acne and folliculitis, Gonococcemia, Necrolytic migratory erythema, Pemphigus erythematosus or foliaceous, Neonatal pustular melanosis, Scabies and Halogenodermas. Clear cell acanthoma also has intraepidermal or subcorneal neutrophils and can look like psoriasis histologically.


If you see Pustules in the epidermis the mnemonic is II

I - Infective  Viral, Bacterial, Fungal, Rickettsial, Protozoa
I Inflammatory eg Drugs, Pustular psoriasis, Rare ( Scabies, Necrolytic migratory erythema, Subcorneal pustular dermatosis, Neonatal pustular melanosis, Erosive pustular dermatosis, Acrodermatitis enteropathica, Halogenodermas)

Eosinophils in the Epidermis

This is known as eosinophilic spongiosis  and is commonly seen in Pemphigoid and Pemphigus, Acute Contact Dermatitis, Arthropod bites, Eosinophilic pustular Folliculitis, Incontinentia pigmenti and Erythema toxicum Neonatorum
Still remember the Pustular Mnemonic II Infective and Inflammatory. Most of the eosinophilic pustules come under the inflammatory list of diseases.

Lymphocytes in the Epidermis

These can be small normal looking lymphocytes in PMLE, Acute dermatitis, Pityriasis rosea, Pityriasis lichenoides, Graft versus host disease and Erythema multiforme and collections of atypical lymphocytes (Pautrier microabscesses) in Mycosis fungoides. They tend not to form pustules but either cause keratinocyte necrosis, or spongiosis or irritate the keratinocytes causing scale so most are caught by the red scaly mnemonic PMs PETAL

Melanocytes in the Epidermis

Melanocytes in the Epidermis can be as single cells in Superficial spreading melanoma  showing Pagetoid spread or as nests as in Spitz and Reed nevi or as single cells in neonatal congenital nevi, recurrent nevi and acral nevi.

Histiocytes in the Epidermis

These are really Langerhans cells. They occur in nests and cause a red scaly rash.

Epidermal invasion by other cells

Pagetoid spread of cells or nests in the Epidermis.

Pagetoid spread is the upward movement of atypical melanocytes into the upper spinous or sub granular layers of the epidermis and is seen in melanoma. However it is also seen in the centre of Spitz nevi, in Reed or spindled cell nevi and in some acral nevi where the lesions are benign. Some nevi of special sites will also show this phenomenon. Usually though these are single cells rather than nests but Spitz nevi do have nests high up in the epidermis.

Other tumours showing Pagetoid  spread.

Paget's disease of the nipple
Extramammary Paget's
Bowen's disease
Intra epidermal sebaceous carcinoma
Intraepidermal Merkel cell carcinoma

Rarely T cell lymphoma and histiocytosis will show pale cells in the epidermis in nests

To separate out these conditions you need to undertake immunofluorescence studies with specific cell marker antibodies.

Last thing to mention is the Borst- Jadassohn phenomenon

These are usually discrete clones of pale keratinocytes in the epidermis in irritated seborrheoic keratosis. However they can be malignant keratinocytes in Bowen's disease and rarely can also be seen in hidroacanthoma simplex, a form of eccrine poroma confined to the epidermis. Guarneri bodies are eosinophilic intra keratinocyte inclusion bodies seen in pox virus infections.

Thickened epidermis (Acanthosis)

Thickened Epidermis (Acanthosis)

This usually results from keratinocyte hyperplasia and features acanthosis of the epidermis. Often there is associated hyperkeratosis.

Check it to see if there is any cytological atypia of the keratinocytes to indicate Bowen's disease. If not consider benign lesions such as seborrhoeic keratosis, clear cell acanthoma, poroma, hidradenoma 

If koilocytosis then a wart.

 Otherwise a lot of chronic diseases eg Lichen simplex and Psoriasis will show a thickened epidermis but look out for some Deep fungal infections, TB of the skin and Reactive perforating collagenosis and the much rarer halogenodermas.

Pseudoepitheliomatous Hyperplasia is a term used to describe marked acanthosis that may simulate well differentiated squamous cell carcinoma. The following conditions may show this feature but look for it in Prurigo nodularis and hypertrophic lichen planus. 

Also Halogenodermas, Deep fungal infections, Prurigo nodules, Pemphigus vegetans, Keratoacanthoma, Orf, Condyloma acuminata, Granular cell tumour, Tuberculosis verrucosa cutis, and Acanthoma fissuratum.

Reticulated Acanthosis   Confluent and reticulated papillomatosis, Acanthosis nigricans, Reticulated Seb K and Dowling Degos Disease (Reticulated pigmented dermatosis of the flexures)

Thinned epidermis (Atrophy)

Thinned Epidermis (Epidermal Atrophy)

Usually there is flattening of the epidermal ridges. This suggests epidermal destruction as occurs in erythema mutiforme , lupus erythematosus, dermatomyositis and in lichen sclerosus. Epidermal consumption can also be a feature of melanoma and lentigo maligna on the face.

The commonest cause of epidermal thinning is ageing and sun damage with significant solar elastotic changes underneath but remember the regional differences in the body with eyelid skin epidermis being particularly thin relative to other areas.

Other rarer causes Poikilodermatous dermatitis as in MF or dermatomyositis, Chronic Lichen sclerosus, Degos disease (malignant atrophic papulosis), Post radiation, Some cases of discoid lupus and the atrophic variant of lichen planus.

Spongiosis

Spongiosis is the presence of fluid between the keratinocytes in the epidermis. 

Vesicular spongiosis is seen in pompholyx, Acute dermatitis, acute contact dermatitis , pemphigus vegetans, prebullous pemphigoid and eczematous drug reactions.

Non vesicular spongiosis is a feature of subacute dermatitis, Pityriasis rosea and Gianotti Crosti

Eosinophilic spongiosis - Bullous pemphigoid, Pemphigus vulgaris, Pemphigus vegetans, Insect bites, Allergic contact dermatitis, Erythema toxicum neonatorum, Incontinentia pigmenti

Accumulation of fluid within the keratinocytes leading to "reticular degeneration" is different.

Intracellular edema without spongiosis is seen in mucosal pachyonychia congenita, Oral white sponge nevus, Leukedema of oral mucosa, Oral hairy leukoplakia and Focal epithelial hyperplasia

Thickened basement membrane

Thickened Basement Membrane

An obviously thickened basement membrane has me thinking of lupus erythematosus. You do not usually see this feature in Dermatomyositis which is a common differential diagnosis. Also lupus tends to have a greater dermal inflammatory response than dermatomyositis.

Epidermis with atypical keratinocytes

Epidermis with Atypical Keratinocytes

Be certain they are atypical keratinocytes and not melanocytes , lymphocytes or Paget cells!
If primarily in the lower two thirds of the epidermis then we call these solar keratosis. If full thickness atypia we call these scc in situ.

You may need to do immunoperoxidase studies to determine the true nature of some of these other cells.

There can be clear cell change in keratinocytes due to glycogen in the cells.

Dyskeratotic cells (Necrotic keratinocytes)

Dyskeratotic cells

What is a dyskeratotic cell down the microscope? In the epidermis it is pink because of either early or abnormal keratinisation .Ocassionally a bit of a basophilic nucleus may persist. Unfortunately a variety of other terms are used in describing these cells in different conditions.

Kamino bodies - definitely basement membrane
Civatte bodies - dyskeratotic cells in the upper dermis
Colloid bodies - interface dermatitis, may be basement membrane and immunoglobulin
Cytoid bodies - same as colloid bodies
Corps ronds  and Grains  - acantholytic dyskeratotic cells seen in Dariers and other acantholytic disorders

Apoptotic, dyskeratotic and necrotic keratinocytes can all look the same!

You come across these terms most in Darier's disease, Lichen planus, Graft versus Host disease, Warty dyskeratoma, Fixed Drug Reactions , Spitz nevi (Kamino bodies) and Incontinentia pigmenti

Dyskeratotic cells high in the epidermis are seen in adult Still's Disease in a patient who is systemically unwell.

Necrotic keratinocytes in a follicle with multinucleated keratinocytes without inclusions are seen in measles in adults.

Extensive destruction of the epidermis is a feature of EM and Stevens Johnson disease as well as Toxic epidermal necrolysis. Burns and photo burns can also cause superficial dyskeratotic cells.
Viral epidermal destruction is seen with  balloon degeneration of keratinocytes.

Pale cells in the epidermis

Pale cells in the Epidermis

For me I think of Acrodermatitis enteropathica, Necrolytic migratiory erythema, Pellagra and Epidermolytic hyperkeratosis.
Here the clear cells are usually in the upper third of the epidermis.

You can also get clear cell neoplasms where processing removes glycogen, mucin or lipid from the cells. eg Clear cell acanthoma and clear cell variants of other tumours or nevi.
Sebaceous gland tumours and metastatic renal tumours are also clear celled.

Vacuolisation of keratinocytes usually occurs because of a processing artefact but remember papilloma virus causing this (koilocytosis0 around a shrunken raisin like nucleous in the upper spinous layer.

Individual and nests of pale cells can be seen in the epidermis with the conditions causing Pagetoid spread.

Clear cells in the basal layer either as single cells or as nests may be Toker cells as seen in Clear Cell Papulosis with either white macules in the milk line in children or as flaky areas on the nipple in females where mammary Pagets comes into the DD.

Epidermal Perforations

Epidermal Perforations

There are various disorders where dermal material is extruded through the overlying epidermis. eg Pseudoxanthoma elasticum, Elastosis perforans serpiginosa and sometimes granuloma annulare.
Chronic renal disease can lead to a perforating disorder as can Kyrles disease and perforating collagenosis.

Perforating Granuloma annulare Globalskinatlas

Kyrles Disease GlobalSkinAtlas

Epidermal Vesicles

 Spongiotic  See this link

Acantholytic  See this link

Balloon Degeneration   - Herpes, Orf, 

Reticular degeneration - Hydroa vacciniforme 

Epidermotropism/Exocytosis

Epidermotropism and Exocytosis

Exocytosis refers to the migration of inflammatory cells into the epidermis whereas Epidermotropism refers to the migration of malignant cells into the epidermis.

Exocytosis occurs in inflammatory diseases such as Eczema and Psoriasis and Pityriasis lichenoides (acute and chronic) but also in Erythema multiforme and graft versus host disease with lymphocytic exocytosis. Sweet's syndrome is another condition showing exocytosis  but here the cells are neutrophils.

Epidermotropism- We particularly think of epidermotropism and T cell lymphoma with atypical lymphocytes being found in the epidermis sometimes in nests as in Pautrier microabscesses. Histiocytoses can also be seen in the epidermis and the various conditions showing Pagetoid spread may sometimes also be exhibiting epidermotropism when the cell of oprigin is not a normal inhabitant of the epidermis.

DEJ

The Dermo Epidermal Junction (DEJ) is the site of pathology of a variety of skin diseases. If they cause sufficient epidermal damage or irritation then the disorder may present as a red scaly disease such as Pityriasis lichenoides, or lupus erythematosus or Lichen planus or Polymorphous light disease so the PMs PETAL mnemonic of the red scaly diseases should be considered when thinking about differential diagnoses.

If clefting is occurring at the DEJ or intraepidermal blisters or vesicles are seen then the blistering diseases mnemonic ICI also needs to be considered.

The other diseases with DEJ damage either showing an interface or lichenoid pathology are to be found in the red non scaly mnemonic of CUL DVA EVIE particularly the L for lupus,  DV for drugs and viral or bacterial exanthems plus E for erythema multiforme.

Basal layer damage

Basal Layer Damage

Marked basal layer damage is a feature of Erythema multiforme and its variants Stevens Johnson syndrome and Toxic epidermal necrolysis. We call this interface reaction pattern. It may also be seen to a lessor degree in lupus erythematosus and lichen planus and in the PLEVA variant of Pityriasis lichenoides. There are many fewer lymphocytes at the DEJ in interface as against lichenoid reactions.
Older terms for these changes were liquifactive degeneration and hydropic degeneration.

Lichenoid reaction pattern may overlap here but usually gives less vacuolar changes at the DEJ than interface damage  and there is a denser lymphocytic infiltrate hugging the DEJ.

Pagetoid spread of cells or nests

Pagetoid spread of cells or nests in the Epidermis.

Pagetoid spread is the upward movement of atypical melanocytes into the upper spinous or sub granular layers of the epidermis and is seen in melanoma. However it is also seen in the centre of Spitz nevi, in Reed or spindled cell nevi and in some acral nevi where the lesions are benign. Some nevi of special sites will also show this phenomenon. Usually though these are single cells rather than nests but Spitz nevi do have nests high up in the epidermis.

Other tumours showing Pagetoid  spread.

Paget's disease of the nipple
Extramammary Pagets
Bowen's disease
Intra epidermal sebaceous carcinoma
Intraepidermal Merkel cell carcinoma

Rarely T cell lymphoma and histiocytosis will show pale cells in the epidermis in nests

To separate out these conditions you need to undertake immunofluorescence studies with specific cell marker antibodies.

Follicular pathology

Follicular Pathology

Big topic but put simply if a follicle ruptures you get surrounding granulomas. Collections of neutrophils suggest a bacterial folliculitis. Follicular plugging suggests lupus erythematosus or lichen sclerosus. Clear cells in the follicular epithelium suggests follicular mucinosis. Spread of melanocytes down a follicle suggests Lentigo maligna and if atypical keratinocytes then Bowen's disease is the likely diagnosis. Ocassionally unusual things such as Mollusca can be found in follicles. Follicular variants of T cell lymphoma may also be seen.
Darier's disease and Pityriasis rubra pilaris are based around follicles

Follicular derived tumours are numerous and include Trichoepithelioma, Trichilemmoma, Pilomatricoma, Proliferating Trichilemmal cyst, Fibrofolliculoma, Trichodiscoma and Trichoblastoma. Some of these tumours are associated with the Birt Hogg Dube syndrome and renal carcinomas.

DERMIS

Dermal Pathology

Generally any Red non scaly disease will have a dermal or interface pathology. There are several classically described reaction patterns including, Superficial and Deep perivascular, Granulomatous, Lichenoid, Vasculitic and Interface plus Panniculitic (fat involved).

The mnemonic to be used is CUL DVA EVIE  (See you later at the Department of Veterans Affairs Evie (where Evie is your girlfriend)

C - Cellulitis
U - Urticaria
L - Lupus erythematosus, Lues (syphilis) Light eruption, Lichen planus

D - Drugs
V - Viral or bacterial exanthema
A - Annular erythema

E - Erythema multiforme
V - Vasculitis
I - Infiltrates of cells, substances or organisms
E - Erythema nodosum and variants

Some interface pathology diseases can involve the epidermis sufficiently to cause epidermal changes eg Erythema multiforme  and also dermal processes which perforate will cause epidermal changes eg Perforating folliculitis in renal failure, perforating deep fungal infections and TB.

So look at a slide.

Is the pathology Epidermal or Dermal or Both. If Epidermal use the Mnemonic PMs PETAL
If dermal use the mnemonic CUL DVA EVIE

If Both then use both mnemonics.
Look for any other epidermal or dermal features or clues and then work through the diseases in the mnemonics to see which might best fit the histology in front of you.

If you see Pustules in the epidermis the mnemonic is II

I - Infective  Viral, Bacterial, Fungal, Rickettsial, Protozoa
I Inflammatory eg Drugs, Pustular psoriasis, Rare ( Scabies, Necrolytic migratory erythema, Subcorneal pustular dermatosis, Erosive pustular dermatosis, Acrodermatitis enteropathica)

If you see Vesicles or Blisters the mnemonic is ICI

I - Infective Viral Bacterial Fungal
C - Contact Dermatitis
I - Inflammatory - Drugs, Porphyria, Insect bite, Genetic bullous diseases
I - Immunological - The immune bullous diseases

Grenz Zone

Grenz Zones (boundary )

I always think of them as clear areas under the basement membrane but usually a Grenz Zone  represents the clear area between a florid dermal infiltrate and the basement membrane.. Consider granuloma faciale, but also B cell lymphoma and Leukaemia, Pseudolymphoma , Lepromatous leprosy and acrodermatitis chronica atrophicans.

I admit to also thinking about amyloidosis, the collagen deposition of lichen sclerosus and the space above a dermatofibroma but technically they are not true Grenz zones.

Papillary Oedema

Papillary Oedema

Marked papillary oedema is often seen in Polymorphous light eruption and Sweet's syndrome but consider also Cellulitis and Erysipelas, Urticaria, Erythema multiforme  Arthropod bites and some of the vesiculobullous diseases. Orf and Coxsackie virus infections can also cause a lot of papillary dermal oedema.

View PMLE      Virtual Slide

View Arthropod Bite

View Sweet's Syndrome

Material laid down

Material Laid Down

At scanning view you may be aware of material in the dermis. Common things include mucin, amyloid, colloid milium, gouty crystals, calcium or bone. Exogenous foregn bodies and drug deposition may also occur. The classics would be Amalgam tatoo in the mouth, Tatoo dyes in the skin, Argyria and rarely Mercury`

Hyaline material in the dermis refers to homogenous pink deposits. The can be due to amyloid, colloid milium and are seen in Lipoid proteinosis. Occassionally paraproteinaemias can give this type of deposit in the dermis as can erythropoetic protoporphyria..

Reactions to fillers have become a common reason for skin biopsies in cosmetic patients. Some permanent fillers are injected deep in the dermis. Depot steroid injections may rarely be biopsied.At low power this looks like gouty tophi.

Excess collagen is laid down in the dermis in Scleroderma/ Localised morphoea and altered collagen and elastin is seen as a prominent band of solar elastosis in damaged sun exposed skin.

Dark Pigment deposition in the skin is seen in Ochronosis, Tattoos, Heavy metals including Mercury, Silver and Gold, Haemochromatosis and Drugs particularly the antimalarials, minocycline, amiodarone and clofazimine.

You need to become familiar with the appearance of these many substances under the microscope.

Black/Brown staining

Black/Brown Staining

Dark Pigment deposition in the skin is seen in Ochronosis, Tatoos, Heavy metals including Mercury, Silver and Gold, Haemochromatosis and Drugs particularly the antimalarials, minocycline, amiodarone and clofazimine.

Brown staining is seen with Deamatiacious fungi, foreign bodies, formalin pigment, Melanin and hemosiderin, Monsel's solution, Ochronosis and Oxalosis.

Pigment incontinence in the upper dermis - Interface and lichenoid dermatoses (melanin in melanophages) Erythema dyschromicum perstans, Fixed drug, Post inflammatory especially lupus and lichen planus, Erythema ab igne and melasma, late incontinentia pigmenti, Poikilodermatous dermatitis

Pigmented purpuric dermatoses show hemosiderin in macrophages.

Ochronosis

Monsell's solution

Minocycline Pigmentation  View Slide

Pink staining

Pink material in the Dermis                     See DX Path for details of the conditions below

Pink staining

Hyaline material in the dermis refers to homogenous pink deposits. They can be due to amyloid, colloid milium and are seen in Lipoid proteinosis. Occassionally paraproteinaemias can give this type of deposit in the dermis as can erythropoetic protoporphyria. Amyloidoma also a cause.The latter may occur at sites of insulin injection.

Pink deposits in the dermis can also be seen in some dermatofibromas, keloids and juvenile hyaline fibromatosis.


Amyloidosis

Lichen amyloidosis

Colloid milium

Colloid Milium

EPP

Erythropoetic protoporphyria

Flame figures of eosinophils

Well's syndrome

Fibrin

Bullous vasculitis

Gout

Gout

Lichen sclerosus

Lichen Sclerosus

Pilomatrixoma

Pilomatrixoma

Blue staining

Blue Staining

Blue material on a slide is commonly due to solar elastosis, mucin or calcium. Some bacteria and fungii may also look blue as may deposits of foreign material. If there is extensive leukocytoclasis in vasculitis the debris in the dermis can certainly look blue! Rarely a fixation artefact with hematoxylin in the dermis can look blue.

Lots of Blue cells in the dermis are seen in Spiradenoma, Cylindroma, Merkel cell carcinoma, BCC, Trichoblastoma and Lymphomas particularly B cell.

Clear cells

Clear Cells

First of all there are lots of Clear cell tumours and Clear cell variants of many tumours. The cells are clear because they contain glycogen, mucin or lipid that has been removed during the fixation process.

Important Clear cells are those invading the Epidermis and showing Pagetoid spread. The diagnoses here include melanoma, Pagets or Extramammary Pagets, SCC and Merkel cell variants.

Clear cells in the basal layer either as single cells or as nests may be Toker cells as seen in Clear Cell Papulosis with either white macules in the milk line in children or as flaky areas on the nipple in females where mammary Pagets comes into the DD.

Clear spaces between cells

Clear spaces between cells

These are sometimes known as clefts. They are a useful diagnostic feature with BCCs versus Trichoepitheliomas but can also be seen in melanomas and beneath the basement membrane in Lichen Planus where they are known as Max Joseph spaces.
Clefts are commonly seen in pink gouty tophi and Cholesterol deposits.Prominent clefts around cell nests in Spitz nevi can be helpful in diagnosis.
Needle shaped clefts are a prominent feature of Subcutameous fat necrosis and sclerema neonatorum in the subcutaneous fat.

Indian filing of cells between collagen

Indian filing of cells between collagen

This feature can be seen in iterstitial granuloma annulare but also in cellulitis (neutrophils) , Morphoeic BCCs, Desmoplastic trichoepitheliomas, Microcystic adnexal carcinoma, Metastatic Breast carcinoma and in some Desmoplastic melanomas and Metastatic Blue nevus like melanoma.

It can also be a feature of early Kaposi's sarcoma. Special immunoperoxidase stains may be necessary to work out the type of cell and the correct diagnosis.

Cells with anything in them

Text

Papillary microabscesses

Papillary microabscesses                  See DX Path for details of the conditions below

This term usually refers to an accumulation of neutrophils in the papillary dermis in dermatitis herpetiformis.

It can also be seen in Linear IgA disease, Cicatricial pemphigoid and rarely in bullous lupus erythematosus, EBA and AGEP.

Flame figures

Eosinophils in the dermis                 See DX Path for details of the conditions below

Large numbers in the dermis suggest arthropod bite including scabies, pre bullous pemphigoid and Well's syndrome of eosinophilic cellulitis.

Some increase is also seen in drug reactions, urticaria and so called deep dermal hypersensitivity reactions. Flame figures are orange deposits of eosinophilic basic protein seen in the dermis particularly in Well's syndrome

Busy dermis

Text

Giant cells

Giant Cells                                          See DX Path for details of the conditions below

Giant cells are of two types, named giant cells such as Touton, Langhans, and those seen with multiple nuclei in certain tumours or nevi or those filled with organisms or other material.

 Touton Giant cells are seen most in Juvenile Xanthogranuloma but also in Necrobiotic xanthogranuloma. Nuclei in the Touton giant cell are arranged in a wreath like pattern.

 Langhans giant cells are seen in granulomas particularly in sarcoidosis.The nuclei are distributed throughout the cell cytoplasm.

 Foreign body giant cells are commonly seen with ruptured epidermoid cysts.

 Watch for giant cells filled with viral particles in CMV infection.

 Sometimes you have a named tumour such as Giant cell tumour of the tendon sheath.

 Osteoclastic giant cells may be seen in Pilomatricomas.

Giant cells may also be seen in some malignancies and in deep fungal infections.

Granulomas

If you look at the slide and you see in the dermis collections of epithelioid histiocytes plus or minus surrounding lymphocytes or giant cells or neutrophils in the centre of these lesions, then you have granulomas.  

Granulomas are sub-classified into about four types.  They can be tuberculoid, sarcoidal, pallisading or infectious.  Various diseases present as different types of granulomas.  The sarcoidal granuloma is sometimes called the naked granuloma because basically you just have a collection of histiocytes without any surrounding lymphocytes or neutrophils.  In a tuberculoid granuloma you will have histiocytes but you will also have some central caseous necrosis.  In the pallisading granuloma you will find that the cells are surrounding denatured collagen and it goes under the name of necrobiosis or sometimes there is mucin or foreign body material at the centre of a pallisading granuloma.  A suppurative granuloma has centrally numerous neutrophils and they are part of an infected abscess.  

The granuloma is the body's immune attempt at isolating this infective process.  The common granulomatous diseases we see will be sarcoidosis, granuloma annulare, actinic granuloma, granulomatous rosacea, necrobiosis lipoidica, tuberculosis of the skin and leprosy.  The other condition we have to watch out for is the deep fungal infection which will have an infective granuloma. 

Granulomas                                           See DX Path for details of the conditions below


If you look at the slide and you see in the dermis collections of epithelioid histiocytes plus or minus surrounding lymphocytes or giant cells or neutrophils in the centre of these lesions, then you have granulomas.  

Granulomas are sub-classified into about four types.  They can be tuberculoid, sarcoidal, pallisading or infectious.  
Various diseases present as different types of granulomas.  
The sarcoidal granuloma is sometimes called the naked granuloma because basically you just have a collection of histiocytes without any surrounding lymphocytes or neutrophils.  

In a tuberculoid granuloma you will have histiocytes but you will also have some central caseous necrosis.  In the pallisading granuloma you will find that the cells are surrounding denatured collagen and it goes under the name of necrobiosis or sometimes there is mucin or foreign body material at the centre of a pallisading granuloma.  

A suppurative granuloma has centrally numerous neutrophils and they are part of an infected abscess.  

The granuloma is the body's immune attempt at isolating this infective process.  The common granulomatous diseases we see will be sarcoidosis, granuloma annulare, actinic granuloma, granulomatous rosacea, necrobiosis lipoidica, tuberculosis of the skin and leprosy.  The other condition we have to watch out for is the deep fungal infection which will have an infective granuloma. 

GRANULOMAS IN THE DERMIS

(Use the GlobalSkinAtlas Page link at the top of this website to access Clinical Images of some of these cases.)

If you look at the slide and you see in the dermis collections of epithelioid histiocytes plus or minus surrounding lymphocytes or giant cells or neutrophils in the centre of these lesions, then you have granulomas.  

Granulomas are sub-classified into about four types.  They can be tuberculoid, sarcoidal, pallisading or infectious (Suppurative).  Various diseases present as different types of granulomas. Foreign body material can cause any type of granuloma but usually it is sarcoidal. The sarcoidal granuloma is sometimes called the naked granuloma because basically you just have a collection of histiocytes without any surrounding lymphocytes or neutrophils.  In a tuberculoid granuloma you will have histiocytes but you will also have some central caseous necrosis.  In the pallisading granuloma you will find that the cells are surrounding denatured collagen which goes under the name ofnecrobiosis or sometimes there is mucin or foreign body material at the centre of a pallisading granuloma.  A suppurative granuloma has centrally numerous neutrophils and they are part of an infected abscess.  Mind you the commonest cause of a suppurative granuloma is a ruptured follicle or cyst.

The granuloma is the body's immune attempt at isolating this infective or inflammatory process.  The common granulomatous diseases we see will be ruptured follicular cyst, sarcoidosis, granuloma annulare, actinic granuloma, necrobiosis lipoidica, tuberculosis of the skin and leprosy.  The other condition we have to watch out for is the deep fungal infection which will have an infective granuloma.  Let's look at the histopathology of each of these conditions in turn.

Granuloma Annulare  (See Clinical Images)

This shows a pallisading or interstitial pattern where you have histiocytes, lymphocytes and some mucin in between collagen fibres in the dermis and these collagen fibres are necrobiotic.  Sometimes this is described as both the interstitial and the pallisading pattern.  The infiltrating type is the interstitial one and the pallisading pattern is where you have a central core of collagen with histiocytes surrounding it.  Mucin is seen in granuloma annulare but it isn't seen in necrobiosis lipoidica, but sometimes you need a colloidal iron stain to show up the mucin.  Granulomas may also have giant cells associated with them and the ones that are classically described are the Toton giant cell where the nuclei are in a circle; the Langerhans giant cell where the nuclei are peripherally placed and in a horseshoe shaped pattern and the foreign body giant cell where there is a diffuse arrangement of the nuclei in the cell.  A deep form of granuloma annulare in which the histiocytes pallisade around fibrin rather than mucin can be indistinguishable from a rheumatoid nodule. 

It is also useful to compare and contrast granuloma annulare with necrobiosis lipoidica.  Essentially in granuloma annulare the granulomas are focal and patchy whereas necrobiosis lipoidica is diffuse and often involves the full thickness of the dermis down to and including the fat layer.  The granuloma is pallisading or interstitial in granuloma annulare but in necrobiosis lipoidica you can have a layered or sandwich granuloma.  Mucin present in granuloma annulare but not in necrobiosis lipoidica.  Plasma cells are common though in necrobiosis lipoidica but are rare in granuloma annulare and cholesterol clefts can sometimes be seen in some old lesions of necrobiosis lipoidica but not in granuloma annulare.

A variant of granuloma annulare that should be recognised is perforating GA.  Typically these lesions occur on the back of the hands or feet and the papules have a central crust or small umbilicated area where the abnormal collagenous material is being extruded through the overlying epidermis.

See this Clinical Variant in GlobalSkinAtlas

Actinic Granuloma

This was first described by an Australian, John O'Brien and it is typically seen on sun exposed areas particularly the neck.  In these lesions there is a spreading edge with loss of elastic fibres in between so that if a special stain is done for elastic fibres they won't be there.  Actinic granuloma shows a similar pallisading picture as in granuloma annulare but there is no mucin and it has this central loss of elastic tissue. Biopsies should be taken from the edge and centre of these lesions or do an ellipse across the edge from normal skin to granulomas to loss of elastic tissue.

Necrobiosis lipoidica  (See Clinical Images)

The changes in the collagen are necrobiotic changes extending quite deeply into the reticular dermis in this condition.  There is often a layered infiltrate of lymphocytes and histiocytes in between the damaged collagen.  Mucin isn't usually seen.  Plasma cells may be seen particularly in the deep dermis and the degenerate necrobiotic collagen is very prominent.  It is probably more prominent in necrobiosis lipoidica than it is in granuloma annulare.  Many patients with necrobiosis lipoidica have or will develop diabetes mellitus.  The term necrobiosis refers to alteration in the dermal connective tissue.  There is loss of cellular definition, the area stains quite palely and as we said before there is an absence of mucin. A deep incisional biopsy is best with primary closure as otherwise healing can be slow.

Necrobiotic Xanthogranuloma

Though the terminology may seem similar to necrobiosis lipoidica, the condition is potentially more serious.  Again you have broad zones of  granuloma formation, may you may also see Toton giant cells and Langerhans giant cells.  In older lesions cholesterol clefts can also be seen and there may be plasma cells and even lymphoid follicles.  Necrobiotic Xanthogranuloma typically involves the face and the periocular skin.  It may also involve the scalp.  The clinical lesions are yellowish with prominent vessels and the patients usually have an abnormal light chain gamma globulin circulating in the blood.  Usually it is an IgG kappa light chain  and they have a paraproteinaemia.  Note that giant cells are more common in Necrobiotic xanthogranuloma than in necrobiosis lipoidica.

Juvenile Xanthogranulomas  (See Clinical Images) are not commonly biopsied.  They may occur in young children as the name suggests, but xanthogranulomas can also occur at any age.  The initial lesions look red and may be confused because of their rapid growth with a Spitz naevus, but over time they become yellow or yellow/orange.  Histologically there are a lot of histiocytes in the papillary and reticular dermis and Tuton giant cells may be seen.

Sarcoidosis  (See Clinical Images)

Sarcoidal granulomas are regarded as naked granulomasin that there is just a collection of epithelioid histiocytes.  There may be a thin rim of lymphocytes but they don't disperse through the granuloma. Epithelioid means that the histiocytes look like epidermal keratinocytes.  No necrosis or necrobiosis is usually seen in these lesions.  Sarcoidosis is a great mimic clinically so it may present as a variety of skin diseases and have lung or cardiac problems, or rarely even hypercalcaemia.  Sometimes cutaneous lesions are seen in about 25% of patients who don't show any signs of systemic sarcoidosis.  It is usually seen histologically as a diagnosis of exclusion in that infectious causes should be looked at with special stains and also polarising microscopy should be used to see that thisisn't a sarcoidal reaction to a retained foreign body.  Silica material can typically cause this as can Zirconium and even mercury.  Other conditions that can show naked granulomas include Crohn's disease, the Melkersson Rosenthal syndrome with granulomatous cheilitis,  silica granulomas and granulomatous rosacea.  

These are sarcoidal reactions at the site of a graze injury. The patient may or may not have systemic sarcoidosis

Granulomatous rosacea is one of the unusual variants of rosacea.  The granulomas are typically tuberculoid rather than sarcoidal, but there is a degree of overlap.  Usually in granulomatous rosacea there are also follicular pustules and telangictasia.  The variant perioral dermatitis has a histopathology just the same as rosacea.  Another condition that is similar is acne agminata or lupus milliaris disseminatus faceii.  These lesions are firm brownish papules usually found on the forehead.  They will show a pallisading granuloma but in the centre is a large area of caseous necrosis and hence they look like TB.  However when you do special stains or PCR there is no evidence of tubuculoid organisms.  

Rarely drug reactions can cause an interstitial granulomatous pattern.  

In tuberculoid granulomas they are often fairly poorly formed granulomas.  You often get central caseous necrosis but not always.  There is usually around the granuloma a large number of lymphocytes and plasma cells.  You may occasionally get some multi-nuclear giant cells with asteroid and schaumann bodies.

Leprosy also gives a epithelioid granuloma of the tuberculoid type.  There is usually a prominent rim of lymphocytes with a bit of central ccasseation.  The granulomas are particularly localised around large named nerves and the picture differs a bit depending on the degree of immunogenicity of the patient.  If there is a fair level of immunity then tuberculoid leprosy will occur with granulomas but few organisms.  If there isn't then you will tend to have lepromatous leprosy in which there are a  multitude of organisms and the granulomas aren't as well formed.

Foreign body granulomas

These are due to material such as tattoo pigment or quartz or glass or even beryllium.  Usually this material is birofringent and polarised to light, but other foreign bodies even sea urchin spines can give a similar picture.  Non-birefringent material includes chromium seen in deodorants and some tattoo pigments, the commonest of which is red tattoo containing mercury or cinnabar.

In summary if there is a dermal granulomatous pattern look to see if it is a sarcoidal or tuberculoid or pallisading granuloma or an infective one.  Look to see if you just have epithelioid histiocytes or a type of giant cell that is there. See if there is any central caseous necrosis.  See if there are lymphocytes or plasma cells surrounding the granuloma.  Look to see if there is any altered collagen .  Ask for special stains to look for acid and alcohol fast bacilli.  The Wade Fite stain is better than the Ziel Neilsen. Always do polarising microscopy to see if there is any birefringence  indicating a foreign body.

Infective Granulomas - Deep fungal infections- Sporotrichosis

Here you may as well as seeing a granulomatous process in the dermis see pseudo epitheliomatous hyperplasia.  You get a suppurative granuloma and when special stains are done you may see the fungal spores of sporotrichosis – these are usually cigar shaped.  Chromoblastomycosis  can give a similar picture but here you may get clusters of brown spores when you use the appropriate stain which are  sometimes known as "copper pennies".  

Granulomas are sometimes seen when you have a ruptured cyst or follicle and these are generally localised around hair follicles or cystic structures. They are probably the commonest granulomas biopsied in clinical practice.

The condition interstitial granulomatous dermatitiswill histologically show pallisading and neutrophilic granulomatous dermatitis.  The lesions are often skin coloured papules with an umbilicated or crusted surface.  Patients with these lesions can often have autoimmune diseases such as rheumatoid arthritis or lupus or may even have lymphomas, so this interstitial granulomatous dermatitis is important but it can also be caused by certain drugs, particularly the calcium channel blockers, beta blockers, ACE inhibitors and even some antihistamines.  The histological picture of the interstitial granulomatous drug reaction is similar to granuloma annulare with a busy dermis.  There may be epidermotropism as well and this is what makes you think there may be an underlying lymphoma.  It can also be a lichenoid reaction with vacuolar changes as well. This is more suggestive of a drug cause. View this link for more details

The last and very rare condition to mention isgranulomatous mycosis fungoides or granulomatous slack skin disease.  Here you have a granulomatous infiltrate in the dermis which also destroys elastic fibres similar to actinic granuloma.  The diagnosis is made on the basis of the atypical lymphocytes that form these granulomas.  View this link for more details.