Invisible Dermatosis, Diagnostic Discrepancy Between the General Pathologist and Dermatopathologist

Received: 18 October 2018 Revised: 22 July 2019 Accepted: 29 July 2019 DOI: 10.1111/cup.13554

ORIGINAL ARTICLE

Invisible dermatosis, diagnostic discrepancy between the general pathologist and dermatopathologist

Ahmed Alhumidi1 | Najd Alshamlan2 | Mona Alfaraidi3 | Khaled Mohajer4

1Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Abstract Arabia Background: Many clinically indicated skin biopsies show minimal histological 2Department of Pathology, King Faisal changes referred to as “invisible dermatoses.” They pose a challenge to general Specialist Hospital, Riyadh, Saudi Arabia 3Department of Pathology, King Fahad pathologists and dermatopathologists. This study determines the discrepancy Medical City, Riyadh, Saudi Arabia between the general pathologists' diagnosis and the dermatopathologist's diagnosis 4 Division of Dermatology, Department of and helps define a pathway for reaching the correct diagnosis. Dermatology, King Saud Medical City, Riyadh, Saudi Arabia Methods: In total, 81 skin cases were selected from a tertiary hospital pathology department. They were diagnosed by general pathologists as “no specific diagnosis,” Correspondence Ahmed Alhumidi, Pathology Department, King or “minimal pathologic changes.” These cases were reviewed carefully and diagnosed Saud University, King Abdullah bin Abdul Aziz by a dermatopathologist. His diagnoses were compared with the original diagnoses. Road, King Saud University District, Riyadh 12372, Saudi Arabia. Results: Out of the 81 cases, 43 cases (53%) were reported by the derm- Email: [email protected] atopathologist to have a specific diagnosis while 38 cases (46.9%) remained nonspecific. Both inflammatory and neoplastic diagnoses of potential clinical significance were made in the first group of 43 cases. The remaining 38 cases with nonspecific results were due to inadequate biopsy, inactive lesions or inadequate clinical data. Conclusion: “Invisible dermatoses” describes skin diseases with clinically evident but histologically hidden changes. They are difficult cases for general pathologists and dermatopathologists to diagnose. Hence, it is important to be aware that minor changes on a skin biopsy do not mean it is disease-free.

KEYWORDS dermatopathology, histopathology, invisible dermatoses, skin biopsy

1 | INTRODUCTION picked up by the experienced eye of a dermatopathologist.1,2In this study, we reviewed a number of skin biopsies diagnosed by general One of the most important steps in treating any skin disease is pathologists as “nonspecific dermatitis” to determine the discrepancy reaching the proper diagnosis on a skin biopsy. Without an adequate between their diagnoses and the diagnosis of a dermatopathologist. sample, it is almost never possible to reach an accurate diagnosis. How- Diagnosis of these diseases requires recognition of subtle microscopic ever, even with a skin biopsy of good quality some skin conditions are features, special stains, and careful clinicopathological correlations. difficult to interpret under a microscope due to their close resemblance to normal skin. This group of diseases with skin manifestations that are 2 | MATERIALS AND METHODS clinically evident but histologically hidden are termed “invisible dermatoses.” General pathologists tend to label skin biopsies of this group as Eighty-one skin biopsies were selected from the archives of the nonspecific dermatoses, overlooking the subtle changes that may be pathology department in a tertiary hospital. These cases were

J Cutan Pathol. 2019;1–8. wileyonlinelibrary.com/journal/cup 1 2 ALHUMIDI ET AL.

FIGURE 1 A, A case of Becker's melanosis shows subtle changes on low power (H&E, original magnification ×40). B, On high power, the rete ridges are elongated and shows plate-like structure (H&E, original magnification ×200)

diagnosed over the past 15 years by general pathologists as “no specific (46.9%) remained nonspecific. Both inflammatory and neoplastic diag- diagnosis,”“no significant pathology changes,” or “minimal pathologic noses of potential clinical significance were made in the first group of changes.” The general pathologists' experiences range from five to 43 cases. Of these 43 cases, the final dermatopathologist's diagnoses 20 years. The slides were retrospectively and blindly examined and were were Becker's melanosis (n:7) (Figure 1), spongiotic dermatitis (n:7), reviewed by a dermatopathologist who had not seen the cases before. pityriasis alba (n:6), pigmented purpuric dermatosis (n:5), mucinosis This dermatopathologist had performed his training in a reputable center (n:4) (Figure 2), pityriasis versicolor (n:3) (Figure 3), acute generalized in the United States, followed by 5 years of experience in the field of exanthematous pustulosis (AGEP) (n:2), mycosis fungoides (n:2) dermatopathology. The original diagnosis was compared with that of the (Figure 4), urticaria (n:2), macular amyloidosis (n:2) (Figures 5 and 6), dermatopathologist. Special stains were performed in some cases as vitiligo (n:2) (Figure 7), and telangiectasia macularis eruptiva perstans requested by the dermatopathologist. The special stains that were (TMEP) (n:1) (Figure 8); Figure 9 and Table 1. requested included the following: Perl's stain on five cases, PAS stain on Thirty-eight cases (46.9%) were reported as nonspecific. Of those, three cases, Alcian Blue on four cases, and Giemsa stain on one case. 15 (39.47%) cases were reported as inadequate specimens. The lack of Immunohistochemistry for cytokeratin five of six was performed on two adequacy was either due to fragmentation or crushing artifact of the cases and CD117 was performed on one case. Informed consent and an biopsy (n: 2) or due to superficial biopsies in cases suspected to be pan- institutional review board (IRB) approval have also been obtained. niculitis (n: 6). The seven other inadequate biopsies were alopecia cases with a superficial biopsy (n: 4) or small longitudinal biopsies (n: 3). Eleven 3 | RESULTS (29%) cases were diagnosed as nonspecific because they were inactive lesions and showed only postinflammatory hyperpigmentation. Eight cases Out of the 81 cases, 43 cases (53%) were reported by the derm- (21%) showed nonspecific epidermal ulceration only. Four cases (10%) atopathologist to have a specific diagnosis while the other 38 cases were difficult to interpret due to inadequate clinical data (Figure 10).

FIGURE 2 A, A cutaneous mucinosis reveals no significant abnormality on low power (H&E, original magnification ×40). B, On higher power, the changes in the reticular dermis are still subtle (H&E, original magnification ×200). C, Alcian blue stain exhibits increase in the dermal mucin confirming the diagnosis of cutaneous mucinosis ALHUMIDI ET AL. 3

FIGURE 3 A, Most of pitryasis versicolor cases show no inflammation (H&E, original magnification ×40). B, A careful examination of stratum corneum shows fungal hyphae and spores even without special stains (H&E, original magnification ×400)

FIGURE 4 A, A number of mycosis fungoides cases show scanty lymphocytes in epidermis that might be overlooked on low and medium power (H&E, original magnification ×100). B, Careful examination on high power reveals few to atypical lymphocytes around the basal layer of epidermis (H&E, original magnification ×400)

FIGURE 5 A, Low power of a case of macular amyloidosis shows normal skin appearance (H&E, original magnification ×40). B, High power exhibits amphophilic globules that can be overlooked by unexperienced pathologist (H&E, original magnification ×400)

4 | DISCUSSION dermatology diseases that were overlooked by the general pathologists. These conditions include the following: Invisible dermatoses are diseases that have obvious clinical lesions, Becker's melanosis usually presents clinically as pigmented pat- but subtle microscopic findings and are therefore easily overlooked by ches on the shoulder, back, or chest. Histologically, it might be easily the inexperienced pathologist. A diagnosis of no significant pathologi- missed by the pathologist in the absence of clinicopathological corre- cal changes or nonspecific findings' is usually made by the general lation. The histological features of this entity show regular elongation pathologist for these diseases.1,2 of the rete ridges with hyperpigmentation of the basal layer.4 These specimens necessitate careful slide examination starting Spongiotic dermatitis is characterized by intercellular edema from the keratin layer. 3 In this study, we noticed a group of within the epidermis (spongiosis). This pattern of injury is observed in 4 ALHUMIDI ET AL.

FIGURE 6 A, Congo red special stain is usually negative in cutaneous amyloidosis (Congo red, original magnification ×400). B, High molecular weight cytokeratin reveals positivity in the keratinocytes and underlying amyloid deposits (immunohistochemistry, original magnification, ×400)

FIGURE 7 A, A vitiligo case reveals no significant abnormality in H&E stain (H&E stain, original magnification ×40). B, Melan-A immunostain shows loss of melanocytes, confirming the diagnosis of vitiligo (immunohistochemistry, original magnification ×100)

FIGURE 8 A, Telangiectasia macularis eruptive perstans (TMEP) case show subtle changes in papillary dermis (H&E, original magnification ×100). B, Giemsa stain shows many spindle cells mastocytes (Giemsa, original magnification ×100). C, CD117 immunostain confirms the diagnosis of mastocytosis (immunohistochemistry, original magnification ×100) many dermatologic diseases, including eczema, id reaction, pityriasis that usually affects children and presents clinically as hypopigmented rosea, and many others. If spongiotic dermatitis has been previously patches. It can be confused with other disorders that cause treated or the dermatologist suspected other types of dermatoses, hypopigmentation such as hypopigmented mycosis fungoides necessi- such as lichenoid, the pathologist may diagnose it as nonspecific tating skin biopsy. Pathologically, it usually reveals minimal spongiosis changes. Pityriasis alba is a type of eczematous/spongiotic dermatitis with dermal melanophages. ALHUMIDI ET AL. 5

Group 1=Specific Results (n=47, 55.3%) Gougerot and Blum. All of these clinical variants share microscopic 4.65%2.33% changes, such as extravasated red blood cells and hemosiderin-laden 4.65% 4.65% 16.28% macrophages. In Schamberg disease, there are only subtle deposits of 4.65% 4.65% 16.28% hemosiderin in scanty inflammatory infiltrate that can be easily 6.98% unnoticed by the pathologist.5

9.30% 13.95% There are some clinical conditions that exhibit an increase in the 11.63% normal dermal mucin. These diseases include generalized myxedema, Becker's Melanosis Spongiotic Dermatitis pretibial myxedema, lichen myxedematosus, or papular mucinosis, Pityriasis Alba Pigmented Purpuric Dermatoses Mucinosis Pityriasis Versicolor reticular erythematous mucinosis, self-healing juvenile cutaneous AGEP Mycosis Fungoides mucinosis, and scleroderma. On H/E staining, this increase in the der- Urticaria Macular Amyloidosis mal mucin might be missed. Alcian blue and colloidal iron stains are Vitiligo Telangiectasia Macularis Eruptiva Perstans used to highlight this material and are of great aid in diagnosing these diseases.6,7 FIGURE 9 Number of cases according to the dermatopathologist's diagnoses Pityriasis/tinea versicolor is a fungal infection that is caused by Malassezia furfur. Clinically, it presents as multiple hyperpigmented Pigmented purpuric dermatosis has four variants that have been patches primarily affecting the trunk and upper extremities. Some- described: progressive pigmentary dermatosis of Schamberg, purpura times, it mimics other inflammatory dermatoses or even mycosis annularis telangiectodes of Majocchi, eczematoid-like purpura of fungoides. Skin biopsies usually reveal very subtle dermal inflamma- Doucas and Kapentanakis, and pigmented purpuric dermatitis of tion on low power microscopic examination. On higher power

TABLE 1 Cases with specific results given by the dermatopathologist

Case Dermatopathologist's no. Demographics Clinical history General pathologist's diagnosis diagnosis 1 18-year-old female Brown patch on the lateral chest Basal layer hyperpigmentation Becker's melanosis 2 20-year-old male Brown-black patch on the back Smooth muscle hamartoma 3 23-year-old male Pigmented macule on the upper arm Postinflammatory hyperpigmentation 4 38-year-old male Irregular pigmentation on the back Postinflammatory hyperpigmentation 5 40-year-old female Pigmented lesion above the nipple Basal cell hyperpigmentation 6 43-year-old male Light brown patch on the shoulder Unremarkable skin 7 45-year-old female Brown and hairy patch on the upper back Skin with no pathological significance 8 40-year-old female Erythematous patch on the lower abdomen Parakeratosis with dermal eosinophils Spongiotic dermatitis 9 33-year-old female Well defined plaque on the right arm Postinflammatory hyperpigmentation 10 26-year-old male Scaly plaques on the back Nonspecific dermatosis 11 25-year-old female Dry scaly lesion on the face Nonspecific dermal inflammation 12 20-year-old male Brown macular ring around the neck Nonspecific changes 13 19-year-old male Macule in the groin Postinflammatory hyperpigmentation 14 17-year-old male Brown patch in the left arm extensor Parakeratosis only 15 9-year-old male Hypopigmented patch on the back Melanocytes are present. No atypical Pityriasis alba lymphocytes seen 16 14-year-old male White macules on the chest No specific skin changes 17 14-year-old female Scaly pink plaque on the cheek Postinflammatory hyperpigmentation 18 15-year-old male Poorly defined patch on the upper arm Postinflammatory hyperpigmentation 19 17-year-old male Hypopigmented patch on the right leg No atypical lymphocytes seen 20 18-year-old female Pale patches on the forearm Negative for MF 21 25-year-old female Pigmented lesions on right leg Lichenoid dermatitis Pigmented purpuric dermatosis 22 30-year-old male Speckled pepper-like discoloration on the Postinflammatory hyperpigmentation buttock 23 32-year-old male Irregular patches of brown pigmentation on No significant pathology the lower limbs 24 45-year-old male Dark brown plaques on the left lower limb No specific diagnosis (Continues) 6 ALHUMIDI ET AL.

TABLE 1 (Continued)

Case Dermatopathologist's no. Demographics Clinical history General pathologist's diagnosis diagnosis 25 50-year-old female Brown pigmented lesions on the lower Postinflammatory hyperpigmentation limbs 26 20-year-old female Skin lesions on both legs No significant pathology Mucinosis 27 30-year-old male Skin nodules on lower abdomen Dermal edema 28 41-year-old male Solitary skin colored papule on the left arm Perivascular inflammation 29 46-year-old male White papule on the back Dermal edema 30 19-year-old male White discoloration on back No significant pathology Pityriasis versicolor 31 20-year-old male Hyperpigmented macules on the chest Postinflammatory hyperpigmentation 32 20-year-old female Hypopigmented and hyperpigmented Perivascular dermatitis lesions on the back 33 34-year-old male Generalized skin lesions with recurrent Subcorneal neutrophils with spongiosis Acute generalized history of antibiotic intake exanthematous pustulosis 34 50-year-old female Multiple pustules over swollen skin Spongiotic dermatitis with neutrophilic infiltration 35 19-year-old female Hypopigmented patch on trunk and buttock Perivascular dermatitis Mycosis fungoides 36 35-year-old male Erythematous patches on the trunk Few lymphocytes in epidermis not enough to diagnose MF 37 40-year-old male Erythematous plaque on lower limbs No significant pathological changes Urticaria 38 51-year-old male Multiple papules on the abdomen No significant pathological changes 39 40-year-old female Hyperpigmented patch on the upper back Melanin incontinence Macular amyloidosis 40 62-year-old female Hyperpigmented patch on the thigh No significant pathology 41 20-year-old male Hypopigmented patch above the upper lip Postinflammatory hypopigmentation Vitiligo 42 58-year-old male Multiple hypopigmented patches on the Negative for mycosis fungoides upper arm 43 38-year-old female Hyperpigmented macule on the trunk Basal cell hyperpigmentation Telangiectasia macularis eruptiva perstans examination, careful assessment of the keratin layer exhibits fungal eosinophils in the superficial dermis. The presence of subcorneal pus- hyphae and spores that can be seen on H/E stain.8 tules may lead the pathologist to think of infectious etiologies such as Acute generalized exanthematous pustulosis (AGEP) is a type of impetigo and fungal infection. Therefore, following a broader drug reaction that manifests clinically as generalized tiny pustules. It approach is very helpful. 6 has a relatively specific histological finding in the presence of careful Mycosis fungoides is the most common cutaneous lymphoma and clinical correlation. Microscopically, it reveals multiple small sub- it clinically mimics many inflammatory dermatoses. It has an indolent corneal pustules in a single punch skin biopsy with some scattered clinical course, which may persist in its early stage for several years

Group 2, nonspecific results n=38, 44.7%

Post Inflammatory Inadequate Biopsy Ulcerated Lesions Inadequate clinical Pigmentary n =15 n = 8 data n =4 Changes, n = 11

Superficial Biopsy Small Longitudinal (suspected Superficial Biopsy Fragmented Biopsy (for Small Biopsy, n=2 panniculitis) (for alopecia), n=4 alopecia), n=3 n=6

FIGURE 10 Number of cases that were reported as non-specific ALHUMIDI ET AL. 7 without transforming to a more advanced stage. Early stages of this to biopsy when assessing an inflammatory dermatosis is extremely type of lymphoma might show minor changes histologically, such as important. In most cases, microscopic examination of a fully devel- scanty lymphocytes in papillary dermis and overlying epidermis with oped lesion will provide more information than examination of an minimal or even no cytological atypia. Its diagnosis requires a careful evolving or resolving lesion. However, a biopsy of an early lesion is correlation between clinical and pathological findings and sometimes required for ulcerated, vesicobullous and pustular lesions. Two speci- warrants multiple tissue biopsies before confirming or excluding the mens are preferred for alopecia cases, a transverse section and the diagnosis. usual vertical section. Deep biopsies reaching the subcutis are Urticaria is characterized clinically by the presence of transient required for diagnosing panniculitis and medium-sized vasculitis.6 and recurrent wheals that are often pruritic. The dermatologist usually does not need to perform a biopsy in classical lesions. However, 5 | CONCLUSION chronic forms must be differentiated from urticarial vasculitis by a tissue biopsy. In chronic urticaria, interstitial mixed-cell infiltrate with Invisible dermatoses present a diagnostic challenge to both pathologists variable numbers of eosinophils and neutrophils are present. This infil- and dermatologists. Thus, keeping this entity in mind is very helpful trate most commonly spares the epidermis and can be overlooked by when dealing with these nearly normal skin conditions. It is important pathologists by low or medium power microscopic examination.9 for a pathologist to understand that subtle and unclear changes on a Primary cutaneous amyloidosis is characterized by superficial amy- skin biopsy do not necessarily mean it is disease free. For that reason, loid deposits at the dermal-epidermal junction. Microscopically, the requesting special stains on such cases may contribute to the specificity amount of amyloid deposit is usually scanty and is difficult to diagnose of the histopathological diagnosis. It is also crucial for the dermatologist under the microscope. Congo red stain, which is used to detect sys- to realize the importance of adequate biopsies in guiding the diagnosis temic amyloidosis, is usually negative in cutaneous forms. However, of such conditions. Raising this awareness along with proper clinico- high molecular weight cytokeratin immunostaining is the gold stan- pathological correlation is fundamental to achieving a precise diagnosis. dard method to detect this type of amyloidosis.10 Vitiligo is an acquired loss of melanin pigment and melanocytes. It usually needs a clinical suspicion in addition to a skin biopsy for defi- ACKNOWLEDGEMENTS nite diagnosis. In few cases, especially in its early stage, it may overlap The article has not been submitted elsewhere. The manuscript has with early hypopigmented mycosis fungoides. Therefore, microscopic been read and approved by all authors. examination will confirm the diagnosis of either one. On H/E stained slides, the findings of vitiligo are similar to normal skin apart from subtle epidermal hypopigmentation. An expert dermatopathologist can CONFLICT OF INTEREST confirm the absence of melanocytes in the epidermis even without No conflict of interest. special stains or immunostains. Melan-A immunohistochemistry can be used to confirm the loss of epidermal melanocytes. Telangiectasia macularis eruptiva perstans (TMEP) is a rare form ORCID of cutaneous mastocytosis that presents clinically as ill defined, telen- Najd Alshamlan https://orcid.org/0000-0002-3113-615X giectatic brown macules located mainly over the trunk and extremities. Microscopically, TMEP characteristically reveals scanty ovoid to spindle shaped mast cells in papillary dermis that can be ignored by REFERENCES the pathologist in the absence of clinical suspicion. Special stains such 1. Mysore V. Invisible dermatoses. Indian J Dermatol Venereol Leprol. as Giemsa and toluidine blue stains, as well as CD117 immunohisto- 2010;76(3):239-248. 11 chemistry, are useful for highlighting the mast cells. 2. Brownstein MH, Rabinowitz AD. The invisible dermatoses. J Am Acad In our study, 38 of the examined cases were still reported to have Dermatol. 1983;8(4):579-588. nonspecific findings even by the dermatopathologist. The reasons for 3. Tomasini C. Invisible dermatoses from the perspective of the dermatopathologist: new observations. G Ital Dermatol Venereol. 2017;125 this interpretation include inadequate specimens, inactive or treated (5):500-515. lesions, ulcerated lesions and inadequate clinical data. The inadequate 4. Becker SW. Concurrent melanosis and hypertrichosis in distribution specimens were due to fragmentation of the biopsy, crushing artifacts, of nevus unius lateris. Arch Dermatol Syph. 1949;60(2):155-160. and superficial biopsies in patients with panniculitis and alopecia. 5. Randall SJ, Kierland RR, Montgomery H. Pigmented purpuric erup- tions. Arch Dermatol Syphiligr. 1951;64(2):177-191. Eleven cases were diagnosed as nonspecific because they were par- 6. Elder D, Elenitsas R, Rosenbach M, Murphy G, Rubin A, Xu X. Lever's tially treated or had inactive lesions showing only postinflammatory hyper- Histopathology of the Skin. 11th ed. The Netherlands: Wolters Kluwer; pigmentation. The ideal lesion to be biopsied for these conditions should 2014: chapter 9 (582–667), chapter 17 (1044–1060). not be previously treated especially with anti-inflammatory agents.6 7. Tomasini C, Michelerio A. Invisible dermatoses: clues and pitfalls to diagnosis. Diagnostic Histopath. 2018;24(8):320-337. The dermatopathologist's ability to give an accurate diagnosis 8. Galadari I, El Komy M, Mousa A, et al. Tinea versicolor: histologic and often depends on the clinical information, differential diagnosis and ultrastructural investigation of pigmentary changes. Int J Dermatol. clinicopathologic correlation. Additionally, selecting the proper lesion 1992;31(4):253-256. 8 ALHUMIDI ET AL.

9. Huston DP, Bressler RB. Urticaria and angioedema. Med Clin North Am. 1992;76(4):805-840. How to cite this article: Alhumidi A, Alshamlan N, Alfaraidi M, 10. Fathaddin A, Alhumidi A. The utility of Congo red stain and Mohajer K. Invisible dermatosis, diagnostic discrepancy cytokeratin immunostain in the detection of primary cutaneous amyloidosis. Internet J Pathol. 2015;17(1):1-7. between the general pathologist and dermatopathologist. J 11. Tumer G, Jow T, Lambert WC. Telangiectasia macularis eruptiva Cutan Pathol. 2019;1–8. https://doi.org/10.1111/cup.13554 perstans: report of three cases. Skinmed. 2017;15(3):171-174.