#dermpathJC April 2018 summary:

#dermpathJC April 2018:

Thursday, April 26th, 9pm EST

Article discussed: Melanocytes Pattern in the Normal Nail, with Special Reference to Nail Bed Melanocytes

Authors: Perrin, Christophe, MD, Michiels, Jean-F., MD, Boyer, Julien, MD, Ambrosetti, Damien, MD

American Journal of Dermatopathology, 2018;40(3):180-184.

Temporary open access available at: https://onlinelibrary.wiley.com/doi/abs/10.1111/cup.13085

Summary author: Silvija P. Gottesman, MD (@SGottesmanMD)

 

Journal Club Summary:

For this month’s journal club we focus on an excellent study that helps define normal melanocytic density in different parts of the nail (nail bed, proximal nail fold, and the nail matrix).

Pigmented nail lesions are divided in three defining categories: melanocytic activation AKA “melanotic macule of the nail unit (melanotic pigmentation of the matrix epithelium without any increase in the density of melanocytes), melanocytic proliferation (lentigo simplex & nevus of the nail matrix), and nail melanoma.

The melanocyte density is a helpful parameter in the distinction of melanotic macule & nail melanoma. Less than 30 melanocytes/mm favor a benign lesion, whereas more than 40 melanocytes/mm favors melanoma. Caveat: some nail melanomas can be low density, and we must rely on other histologic features.

Below is an image depicting a longitudinal section of the nail unit apparatus. Where DPNF is the dorsal proximal nail fold and the Eponychium is the ventral portion of the proximal nail fold. Beyond the proximal nail matrix is the distal nail matrix and then is the nail bed (not depicted in the image here).

Picture1

Density of nail epithelium melanocytes:

– Nail eponychium (ventral proximal nail fold): between 0 and 5 melanocytes per mm, restricted to the basal cell layer.

– Nail matrix: between 4 and 14 melanocytes per mm, in the basal and suprabasal layers.

– Nail bed: between 0 and 5 melanocytes per mm, also restricted to the basal layer.

Dr Gardner  (@JMGardnerMD) shared a diagnostic pearl from Dr Beth Ruben: “unlike acral nevi where pagetoid spread can be ok, pagetoid spread is a bad sign in a nail melanocytic lesion.”

HMB45 and Melan-A are more sensitive markers than tyrosinase and MITF in the detection of intraepithelial nail melanocytes. But since MITF is a nuclear marker, it may be helpful in judging the size and shape of the nuclei of nail melanocytes.

Picture2

MITF (nuclear stain) in action. Small nuclei of nail melanocytes highlighted. And positive cytoplasmic staining of mastocytes in the surrounding dermis as a positive control.

This paper analyzed nail epithelium from 5 Caucasian cadavers. My understanding is that racial differences is not due to differences in the number of melanocytes, but rather the size, distribution, and number of melanosomes (all races have SAME melanocyte density). The one exception is sun damaged skin of elderly Caucasian patients, where MORE melanocytes in sun exposed skin (solar hyperplasia) is seen as compared to darker skinned patients.

For more discussion about Nail Pathology please check out Dr Gardner’s interview with Dr Beth Ruben (@BethRubenMD), a world famous dermatopathologist and nail pathologist. YouTube link: https://youtu.be/_pwNak_CzUc

Bonus: Dr Ruben’s processing techniques for nail unit tissue: make the lab aware the specimen is delicate and may also contain hard keratin. Nair (NaOH/CaOH) solution can be used prior to processing to soften the specimen. Cedarwood oil may be helpful in processing specimens as well. Soaking the block prior to cutting the tissue after processing can minimize knife trauma. Albumin can help sections stay on the slide.

 

Looking forward to next month’s journal club,

Kind regards,

Silvija P. Gottesman, MD

 

 

 

 

#dermpathJC March 2018 summary:

#dermpathJC March 2018:

Thursday, March 22nd, 9pm EST

Article discussed: Nuclear and cytoplasmic features in the diagnosis of Clark’s nevi

Authors: Valdebran M, Bandino J, Elbendary A, Gad A, Arudra KC, Feraudy S, Elston DM.

Journal of Cutaneous Pathology, 2018;45(3):204-207.

Temporary open access available at: https://onlinelibrary.wiley.com/doi/abs/10.1111/cup.13085

Summary author: Silvija P. Gottesman, MD (@SGottesmanMD)

 

Journal Club Summary:

Study by Elston et al, looked at 100 Clark’s nevi and 84 melanomas for the presence of 14 various cytologic features. Cases from special sites, dysplastic nevi with severe atypia, and cases with inadequate material were excluded. In a way, controversy was avoided by looking at dysplastic nevi with mild and moderate atypia versus melanoma. For many pathologists, distinguishing typical non-severe Clark’s nevi from melanoma is not too difficult. Would have appreciated a discussion on really hard cases and how those compare to melanoma. But in those cases, it is probably best to proceed with molecular testing for a definitive answer.

14 different cytologic features were evaluated, definitions summarized in the table below.

Clarks1

Clark’s nevi lack mitotic figures, abnormal mitotic figures, they lack multiple nucleoli and for the most part have either absent or inconspicuous nucleolus. High nuclear to cytoplasmic ratio did not distinguish between Clark’s nevi and melanomas. Dusty cytoplasm and solid hyperchromasia is also equally seen in Clark’s nevi and melanomas.

Clarks2

When present in >20% of the melanocytes: pleomorphism with enlarged nucleus, notching and mitotic figures, peppered moth chromatin, multiple nucleoli prove helpful features in diagnosing melanomas.

Clarks3

Many pathologists make the diagnosis of Clark’s nevi based on architecture and they use the nuclear atypia for grading of the lesion.

DY74AVsVAAACMPX

DY74AVrU8AA2jKw

If too many categories are used, it makes it difficult to decide on a more standardized management. Some pathologists like two tier grading (mild and severe atypia, yet 42% of pathologists (number from a poll during this journal club) use hybrid categories for grading, such as mild to moderate and moderate to severe. There are some Clark’s nevi that have no atypia and several pathologists agree.

Screen Shot 2018-03-31 at 10.56.20 AM

An algorithm for treatment of dysplastic nevi based on cytologic atypia:

Mild atypia = observe

Mild to moderate = observe

Moderate, and “margins appear free” = observe

Moderate, and present at lateral margins = excise

Moderate to severe = excise

Severe = excise

 

It was asked during the discussion if nevi get a grade of atypia for the epidermal component and for the dermal component. A true pearl from the discussion from Dr Joseph Susa (@CutisViaLux) shared word for word “It’s one nevus. It gets one grade. It will be treated one way by the clinician. ” Thank you Dr Susa!

 

For closing thoughts, I will leave you with the “dysplastic” nevus article, a topic so neatly summarized by Dr . He too proposes a two tier grading system. Full article at http://dermpath.com/blog/counterpoint-dysplastic-nevus/

 

Join us next month to learn about nail pathology and how to distinguish normal versus abnormal number of melanocytes.

 

Kind regards,

Silvija Gottesman, MD

#dermpathJC February 2018 Summary:

#dermpathJC February 2018:

Thursday, February 22nd, 9pm EST

Article discussed: Pityriasis lichenoides-like drug reaction: A clinical histopathologic study of 10 cases

Authors: Magro C, Guo R, Nguyen G, Tsang H, Momtahen S.

Dermatology Online Journal, 2017;23(11).

Open access article, PDF available at: https://escholarship.org/uc/item/7xd8j71z

Summary author: Silvija P. Gottesman, MD (@SGottesmanMD)

 

Journal Club Summary:

Drug eruptions are seen commonly in #dermpath practice and can have different histologic patterns: dermal hypersensitivity pattern with superficial and deep perivascular and interstitial lymphoeosinophilic infiltrate, another pattern with interface dermatitis and necrotic keratinocytes, subcorneal pustulosis as in drug induced acute generalized exanthematous pustulosis etc.

Today’s journal club discussion was regarding an uncommon pattern: PLEVA-like drug eruption.

In children, pityriasis lichenoides et varioliformis acuta (PLEVA) most commonly arises secondary to an infection: Toxoplasma, viruses, S. aureus, Group A beta-hemolytic streptococci. Pediatric patients with PLEVA typically have a benign course and the lesions resolve within few months with topical steroids and phototherapy. First-line treatment for pediatric patients should include both oral erythromycin and narrowband ultraviolet B phototherapy (Geller L, Antonov NK, Lauren CT, Morel KD, Garzon MC. Pityriasis Lichenoides in Childhood: Review of Clinical Presentation and Treatment Options. Pediatr Dermatol. 2015;32(5):579-92.).

The journal club article was interesting however the major limitation that it was retrospective and drug association was made after the fact. Clinically, the lesions depicted in this paper did not look typical for PLEVA, rather more in line with Pityriasis lichenoides chronica (PLC). Clinical images of the remaining 9 cases were not shown.

Screen Shot 2018-03-14 at 9.50.35 PM

Pityriasis lichenoides-like drug reaction histology findings are identical to that of PLEVA. Most common drugs involved were antidepressants and statins. Skin lesions appeared 2 weeks to a few months after drug administration.

Screen Shot 2018-03-14 at 9.50.54 PM

Authors classify PLEVA-like drug eruption as a T-cell dyscrasia, despite no T cell gene rearrangement detected. Only 2 out of 9 cases were tested. Perhaps as more cases are reported in the future, a TCR result can be included for all to see if truly such a connection exists. A question to keep in mind: Is it clear that PLEVA has a risk of transformation to mycosis fungoides (MF)? Or is it MF all along that was not histologically diagnosable?

See you all next on 03/22/2018 at 9pm EST for another great journal club.

 

Thank you,

Silvija Gottesman, MD

#dermpathJC January 2018 Summary:

#dermpathJC January 2018:

Thursday, January 25th, 9pm EST

Article discussed: Primary Cutaneous Perivascular Epithelioid Cell Tumor (PEComa):  Five new cases and review of the literature.

Authors: Lauren N. Stuart, Russell G. Tipton, Michael R. DeWall, Douglas C. Parker, Christina D. Stelton, Annie O. Morrison, Landon W. Coleman, Scott W. Fosko, Claudia I. Vidal, Maria Yadira Hurley, Amy H. Deeken, Jerad M. Gardner

Journal of Cutaneous Pathology, 2017;44:713-721.

Open access article, PDF available at:  http://onlinelibrary.wiley.com/doi/10.1111/cup.12972/epdf

Summary author: Dr. Amy H. Deeken (@AmyHDeekenMD).

 

Journal Club Summary:

Perivascular Epithelioid Cell tumor (aka PEComa) is a rare mesenchymal clear cell neoplasm with a diverse nomenclature including: angiomyolipoma, lymphangiomyomatosis, clear cell tumor of the lung, and myomelanocytic tumor of the falciform ligament.

When these neoplasms occur primarily in the skin, they begin as a painless, irregular non-pigmented papule/nodule or plaque on the extremities (most commonly on the leg in this series).   Because these neoplasms are so uncommon, the authors include pictures of their five cases for illustrative purposes of the variety of presentations and histologic variability.

1

Photo Credit:  Dr. Wayne Breer

2

Photo Credit:  Dr. Amy Deeken

3

Photo credit:  Dr. Lauren Stuart

 

There is no accepted normal cell counterpart.  The tumor is comprised of epithelioid cells with bland nuclei, clear or granular eosinophilic cytoplasm, in a nested and trabecular pattern.  The clear cells characteristically stain positively with melanocytic and smooth muscle markers.  However, primary cutaneous location is associated with a much higher likelihood of negative smooth muscle stains (almost 50%).  When they are positive, the staining pattern is often patchy or focal with <5% of cells staining in some studies.  The most reliable positive marker was SMA (42%) followed by desmin (30%).  The other marker of interest in the discussion was CD 10.  This stained positive in all three cases in which it was tested.  This unexpected finding was discussed as it relates to the differential diagnosis which could lead to the mistaken diagnosis of metastatic renal cell carcinoma.  Other IHC results were included in this informative table which also includes the most common differential diagnoses considered in these lesions –

4

Molecular testing of PEComas arising from other locations reveal positive results for TFE3 gene fusions and TFE3 immunohistochemical staining.  However, these molecular alterations are lacking in the primary cutaneous form of the disease.  This observation in association with unconventional immunostain patterns for smooth muscle suggests the possibility of more than one subtype in the PEComa family of neoplasms.  The mTOR pathway has been suggested to be a contributing factor the development of the primary cutaneous PEComa.

This is a rare lesion, and the clinical behavior has not been entirely elucidated.  Most studies list small sample size as a limiting factor in their analysis.  Primary cutaneous PEComas have generally exhibited benign behavior, the cases included in this series are no exception.  There was discussion among the #dermpathJC participants regarding optimum surgical therapy.  The study’s principle author, Dr. Jerad Gardner, advocated for conservative excision to negative margins due to the low volume of data regarding their clinical behavior and rare case reports of metastatic lesions.

 

In short –

#DermPath JC #pearl of the evening from Dr, Joseph Susa, @CutisViaLux – “When people start bringing up metastatic balloon cell melanoma with unknown primary, it’s time to start thinking of PEComa”

 

See you all next on 02/22/2018 at 9pm EST for another great journal club.

 

Thank you,

Silvija Gottesman, MD

#dermpathJC December 2017 Summary:

#dermpathJC December 2017:

Thursday, December 28th, 9pm EST

Article discussed: Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type. Diagnostic Considerations

Authors: Alexandra Hristov.

Archives of Pathology and Laboratory Medicine, 2012; 136: 876–881.

Open access article, PDF available at: http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2012-0195-RA?code=coap-site

Summary author: Dr. Silvija P. Gottesman (@SGottesmanMD).

Journal Club Summary:

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type (PCDLBCL-LT), was recognized 20 years ago as a unique diagnostic entity, with exclusive involvement of the leg, intermediate prognosis and a diffuse dermal infiltrate of large B-cells.

PCDLBCL-LT – involves lower legs of women, F:M ratio is 2-4 : 1, median age 70s. However, 10-20% of the time, other parts of the body may be involved. Most common spread is to lymph nodes, bone marrow and the CNS. 50% survival at 5 years.

PCDLBCL-LT histology findings: grenz zone, diffuse sheets of large B-cells in the dermis, large centrocytes, centroblasts and immunoblasts. Mitotic figures are easily identified. T-cells are sparse.

Model of LC transformation

PCDLBCL-LT markers: B-cell (CD19, CD20, CD22, CD79a, PAX-5), also BCL2, IRF4/MUM1 and FOXP1. This IHC profile may also be seen in other diffuse large B-cell lymphomas that involve the skin secondarily.

Screen Shot 2017-12-28 at 7.44.38 PM

WHO notes 10% of PCDLBCL-LT do not express BCL2 or IRF/MUM1. Some classify BCL2- DLBCL of the skin as “primary cutaneous DLBCL, other.”

PCDLBCL-LT also commonly express BCL6, but typically lack CD10. IgM is another sensitive marker but may be difficult to interpret.

Primary cutaneous follicle center cell lymphoma vs EBV diffuse large B-cell lymphoma of the elderly vs Lymphomatoid granulomatosis. Figure below:

Screen Shot 2017-12-28 at 7.52.09 PM

PCDLBCL-other should be used to describe rare cases of primary cutaneous T-cell and histiocyte-rich large B-cell lymphoma, or cases of intravascular large B-cell lymphoma or plasmablastic lymphoma that are limited to the skin at presentation.

Primary cutaneous follicle center cell lymphoma (PCFCL) – most common primary cutaneous B-cell lymphoma. Affects older adults, men more common than women. Often on head/neck and trunk. Extracutaneous spread, in 10%, to lymph nodes and bone marrow. 95% survival at 5 years.

PCFCL involving the leg tends to have a worse outcome and more likely to express BCL2, MUM1, FOX-P1, and IgM.

Reactive T-cells often prominent in PCFCL and is a helpful feature in distinguishing it from PCDLBCL-LT.

Look for inside out follicles in pcFCL – Neoplastic follicle center cells surrounding small lymphocytes and abutting dermal collagen.

PCFCL – pan B-markers, BCL6, less commonly CD10. Disrupted follicular networks highlighted by CD21, CD23, or CD35. All marginal zone B cells are BCL2+ and BCL6-. Opposite is true for normal follicular B cells and those in pcFCL. If centrocyte like B cells in skin are BCL6+ and BCL2+ consider cutaneous involvement of systemic follicular lymphoma. Strong expression of CD10 and BCL2 is suggestive of cutaneous involvement of a systemic follicular lymphoma. MUM-1 usually negative in pcFCL and positive in pcDLBCL-LT.

EBV can lead to so many odd lymphoid proliferations in immunocompromised. Here are two examples below:

EBV-positive diffuse large B-cell lymphoma of the elderly – necrosis is common and a background mixed inflammatory infiltrate may be seen that includes histiocytes and plasma cells. Also BCL6+, CD30+, MUM1+ and some B-cell markers.

Lymphomatoid granulomatosis – skin involvement in 25-50% of patients, >90% will have pulmonary involvement, CNS is common too. Median survival of 2 years. It is angiocentric and angiodestructive, large EBV+ B-cells, necrosis and a mixed infiltrate. DSLpsWqUMAA8CxA

In the words of Dr Deeken: Lymphoma work-up: All of the CD’s and don’t forget the EBV 😉

#hemepath

 

See you all next on 01/25/2018 at 9pm EST for another great journal club.

 

Thank you,

Silvija Gottesman, MD

#dermpathJC November 2017 Summary:

#dermpathJC November 2017:

Thursday, November 30th, 9pm EST

Article discussed: Cutaneous Collagenous Vasculopathy: Report of Two Cases Presenting as Disseminated Telangiectasis and Review of the Literature.

Authors: Laure Bondier, Mathilde Tardieu, Perrine Leveque, Isabelle Challende, Nicole Pinel, Marie T. Leccia.

American Journal of Dermatopathology, 2017; 39: 682–688.

Free access for 4 weeks at: http://journals.lww.com/amjdermatopathology/Abstract/2017/09000/Cutaneous_Collagenous_Vasculopathy___Report_of_Two.6.aspx

Summary author: Dr. Silvija P. Gottesman (@SGottesmanMD).

Journal Club Summary:

Cutaneous collagenous vasculopathy (CCV) – an idiopathic microangiopathy, acquired telangiectasias localized mainly on the extremities. CCV can also involve the trunk, but usually spares the face. It is asymptomatic & slowly progressive.

To date, 34 cases reported since its initial description in 2000. Cases more frequently seen in women, median age 63.5, median time to patient reporting skin changes to a clinician is more than 7 years, with range from 0.4yrs to >20 yrs.

No mucosal or nail involvement. Systemic involvement was not noted in any patient. Family history is negative for telangiectasias or bleeding disorders, and no autosomal dominant pattern of inheritance was found.

cut colag vasc clin

Cutaneous collagenous vasculopathy clinical ddx. Clinically telangiectasias 2/2 liver disease, Osler-Weber-Rendu syndrome, hereditary benign telangiectasia and CREST syndrome can look similar.

Proposed etiology of endothelial injury due to comorbidities such as HTN and dyslipidemia seems reasonable.

CCV has distinct histology findings: dilated vessels in the superficial dermis with vessel walls thickened with hyaline material that stains for type IV collagen. The hyaline material is accentuated with a PAS stain.

This is similar to thickened hyaline vessels in PCT, which are also highlighted with PAS stain. But in CCV there will be no dermal fibrosis, no deep thickened vessels. Can be used to differentiate from vascular thickening in stasis dermatitis.

cut colag vasc histo

Electron Microscopy of cutaneous collagenous vasculopathy: thickened vascular walls contain collagen fibrils scattered in a fine granular material. Luse bodies (long spacing collagen) noted.

Luse body – presence of abnormal long-spaced collagen in the outer vessel walls was reported in only 9 cases of CCV. Luse bodies have low specificity and can be found in various other conditions (scleroderma, blue nevus, melanoma.). Their presence is not necessary for diagnosis.

Screen Shot 2017-11-28 at 10.30.03 PM

Interestingly, in this review 4 (11.7%) cases were treated with calcium channel blockers. The amount of effectiveness of this treatment is yet to be reported.

Thanks to all who participated! Next dermpath journal club scheduled for 12/28/2017 at 9PM EST! See you soon!

 

 

#dermpathJC September 2017 Summary:

#dermpathJC September 2017:

Thursday, September 26th, 9pm EST

Article discussed: Desmoplastic melanoma may mimic a cutaneous peripheral nerve sheath tumor: Report of 3 challenging cases.

Authors: Machado I, Llombart B, Cruz J, Traves V, Requena C, Nagore E, Parafioriti A, Monteagudo C, Llombart-Bosch A.

Journal of Cutaneous Pathology, 2017; 44: 632638.

Free access for 3 months at: http://onlinelibrary.wiley.com/doi/10.1111/cup.12949/epdf.

Summary author: Dr. Silvija P. Gottesman (@SGottesmanMD).

Journal Club Summary:

  • Desmoplastic melanoma (DM) occurs on chronically sun-damaged skin, head and neck of elderly patients. It can mimic a scar, clinically and histologically. Cutaneous malignant peripheral nerve sheath tumor (MPNST) is rare.
  • Three challenging cases of desmoplastic melanoma were presented in this manuscript, all patient’s were over 70 years old, the lesions were on chronically sun damaged skin.
    • Case 1: 90 year old male, right cheek lesion with invasion into the zygomatic muscle. Histology showed atypical spindle cell proliferation, high mitotic index Ki-67 was 70%, extensive perineural invasion, prominent solar elastosis and atypical intraepidermal melanocytic proliferation (AIMP), S100+, nestin+, CD56+, PGP9.5+ and vimentin+ ,Mel-A- and HMB45-. The AIMP was Mel-A+ and HMB45+.
    • Case 2: 72 year old woman with right medial cheek lesion with atypical biphasic spindle cell proliferation, perineural invasion, solar elastosis, lymphoid aggregates and atypical junctional melanocytic proliferation that help sway diagnosis toward melanoma. Strong and diffuse S100+.
    • Case 3: 73 year old man with a lesion on the right index finger. S100+ spindle cell tumor with several biopsies over the course of several years as they patient was initially refusing treatment. Melanocytic differentiation  was proved with immunohistochemistry: strong S100, SOX10, Melan-A, HMB45 and MITF positivity. Final diagnosis: mixed desmoplastic melanoma undergoing progression to a higher grade.
  • Epithelioid MPNST has SMARCB1/INI1 loss, while INI1 gene is retained in DM and most spindle MPNST.
  • BRAF and RAS mutations usually absent in DM. Rarely MPNST may harbor V600E mutation.
  • Clinicopathologic and genetic findings of desmoplastic melanoma, MPNST, and cutaneous clear cell sarcoma are neatly summarized below:IMG_1594
  • Excellent paper by Plaza JA et al. PubMedID: 26661921 discussed an extended panel of immunohistochemistry for desmoplastic melanoma: all cases expressed p16, WT-1, SOX-10, nestin and S100p and 95% of cases expressed p75.
  • Another excellent paper that dissects the “often muddled and conflicting ways in which neurotropism is defined” PubMedID: 26050260Neurotropic melanoma can be used to describe any type of melanoma that has perineural involvement. PNI: Increased risk of recurrence and decreased disease free survival. Remains equivocal in melanoma. Neurotrophins and their receptors (TrkA, RET, p75NGFR, NCAM) expression in tumor cells allows for proproliferative and proinvasive response to the neural microenvironment.
  • A question arose how to differentiate desmoplastic melanoma from spindle cell melanoma. An excellent figure from nature.com Modern Pathology is enclosed:

unnamed.jpg

  • Take home points:
    • Desmoplastic melanoma occurs on sun damaged skin, on the head and neck of elderly patients. Cutaneous MPNST is rare.
    • Desmoplastic melanoma has diffuse S100+ staining, whereas MPNST has patchy S100+.
    • Serial H&E sections in search of junctional component are useful in desmoplastic melanoma cases.

Thanks to all who participated! See you in October at the American Society of Dermatopathology Annual Meeting in Baltimore, MD and back to #dermpathJC on November 30th at 9PM EST!